Patients initially recognized to have high-risk disease must have had no prior systemic therapy (other than topotecan/cyclophosphamide initiated on an emergent basis and within allowed timing); patients observed or treated with a single cycle of chemotherapy per a low or intermediate risk neuroblastoma regimen (e.g., as per ANBL0531, ANBL1232 or similar) for what initially appeared to be non-high risk disease but subsequently found to meet the criteria will also be eligible; patients who receive localized emergency radiation to sites of life-threatening or function-threatening disease prior to or immediately after establishment of the definitive diagnosis will be eligible
Patients with INRG stage L2 tumors without amplification of MYCN regardless of tumor histology (may meet criteria for may meet criteria for high risk classification but are not eligible for this trial)
Pathologically confirmed RCC with a component of either clear cell histology or sarcomatoid histology that has not been previously treated in the adjuvant or neoadjuvant setting and classified as being at high risk of RCC recurrence
Patients with de novo MDS who have, or have previously had, Intermediate-2 or High risk disease as determined by the International Prognostic Scoring System (IPSS). Current Intermediate-2 or High risk disease is NOT a requirement.
De novo high-risk (HR) Ph-like B-ALL for which any of following criteria are present at diagnosis:
Participants must have pathologically confirmed, newly diagnosed high-risk acute myeloid leukemia, as defined by at least one of the following criteria:\r\n* Age >= 65 years\r\n* Age >= 18 years with adverse risk karyotype, as per European Leukemia Net Guidelines\r\n* Age >= 18 years with antecedent or underlying myelodysplastic syndrome, chronic myelomonocytic leukemia (CMML) or myeloproliferative neoplasm\r\n* Age >=18 years with acute myeloid leukemia (AML) with myelodysplastic syndrome (MDS)-related changes\r\n** Note: For patients in category A, a sample to evaluate patient cytogenetics will be sent at the time of diagnosis per standard clinical care and the absence of favorable risk cytogenetics must be confirmed by day 8; if the cytogenetic analysis reveals that the patient harbors favorable risk cytogenetics, or if the cytogenetic results are not received prior to day 8, the participant will be removed from the study; patients removed due to presence of favorable cytogenetics would be considered to be inevaluable and will be replaced; in addition, patients who receive less than half of their total alisertib dose during induction would be considered to be inevaluable and will be replaced
Patients will be excluded from this study if they are found to harbor “favorable” risk cytogenetics
Subjects must not have had prior systemic therapy except for localized emergency radiation to sites of life-threatening or function-threatening disease and/or no more than 1 cycle of chemotherapy per a low or intermediate risk neuroblastoma regimen (as per P9641, A3961, ANBL0531, or similar) prior to determination of MYCN amplification status and histology.
Relevant diseases or clinical situations which may increase the patient's risk
MDS patients must have Intermediate (>3 to 4.5 points), High Risk (>4.5 - 6) or Very High Risk (>6 points) disease according to the Revised International Prognostic Scoring System 2012.
Documented diagnosis of MDS according to World Health Organization (WHO) criteria that meets International Prognostic Scoring System (IPSS) classification of low or intermediate-1 risk disease at screening as determined by microscopic and standard cytogenetic analyses of the bone marrow and peripheral complete blood count (CBC) and who are refractory to or are not amenable or eligible for approved MDS therapy. The second expansion cohort will enroll patients with low or intermediate-1 risk MDS with symptomatic anemia, who, experienced ESA treatment failure or do not qualify (serum erythropoietin level > 500 U) for ESA treatment and who have not received prior HMA and/or lenalidomide.
Patient with IPSS category of Int-2 or high-risk MDS.
Participants' disease must be defined as either high-risk or intermediate risk:\r\n* Definition of high-risk: any of the following high-risk features:\r\n** Positive margins (defined as tumor at ink)\r\n** Extracapsular extension of lymph node\r\n** Gross T4a or T4b primary tumor\r\n** Any lymph node >= 6 cm (N3)\r\n* Definition of intermediate-risk: absence of any high-risk features AND any one of the following intermediate risk features:\r\n** Close margins (defined as < 5 mm)\r\n** T3 or microscopic T4 tumor\r\n** Two or more positive lymph nodes involved with squamous cell carcinoma\r\n** Single lymph node > 3 cm and < 6 cm\r\n** Perineural invasion\r\n** Lymphovascular invasion\r\n** Level IV or level V involvement of oral cavity or oropharyngeal tumors\r\n** T2 oral cavity tumor with > 5 mm depth of invasion
Ages =< 50 years of age with hematologic diseases treatable by allogeneic HCT who through pre-existing medical conditions or prior therapy are considered to be at high risk for regimen related toxicity associated with a high dose transplant (> 40% risk of transplant-related mortality [TRM]); this criterion can include patients with a HCT-comorbidity index (CI) score of >= 1; transplants should be approved for these inclusion criteria by the principal investigators at the collaborating centers and at Fred Hutchinson Cancer Research Center (FHCRC); all children < 12 years must be discussed with the FHCRC principal investigator (PI) prior to registration
Patients with rapidly progressive intermediate or high grade NHL
Subjects who are at significant risk for general anesthesia
Dose Expansion Cohort #4 - Patients will have relapse of CD123+ \other\ hematologic malignancies not included in the cohorts above (e.g., high-risk/very high-risk MDS, MPN, CMML, CML blast crisis). Other CD123+ malignancies may be considered upon discussion with the Medical Monitor.
Rapidly progressive or highly proliferative disease (total white blood cell count of >15 × 10^9/L) or other criteria that render the subject at high risk of requiring intensive cytotoxic chemotherapy within the next 3 months.
Diagnosis of primary MDS classified as very low, low or intermediate risk with <5% blasts of >= 16 weeks duration
Patients must have high risk neuroblastoma according to COG risk classification at the time of study registration. Patients who were initially considered low or intermediate risk, but then reclassified as high risk are also eligible.
Relapsed or refractory myelodysplastic syndrome (MDS), International Prognostic Scoring System intermediate or high-risk, with no available therapies
Relapsed or refractory acute myeloid leukemia or IPSS-R intermediate/high/very high-risk MDS patients
Risk category very low, low or intermediate (Revised International Prognostic Scoring System, IPSS-R)
Group B: Subjects with relapsed or refractory AML, Subjects with relapsed or refractory high-risk MDS, defined as revised International Prognostic Scoring System (IPSS-R) intermediate or greater disease.
Myelodysplastic syndrome (MDS) with intermediate or high-risk IPSS or equivalent IPSS-R score with < 10% blasts in the bone marrow
Diagnosis of MDS (de novo or secondary) by bone marrow biopsy based on the World Health Organization (WHO) classification - Low and Intermediate-1 risk categories MDS using the IPSS (International Prognostic Scoring System)
Diagnosis of MDS by bone marrow biopsy of Intermediate-2 and High risk category MDS based on the WHO classification using the IPSS (International Prognostic Scoring System)
Presence of at least one of the features defining high risk; these include:\r\n* High risk chromosomal translocations by fluorescence in situ hybridization (FISH): t(4;14), t(14;16), t(14;20), deletion (del)(17p), del(1p), amplification 1q\r\n* Myeloma Prognostic Risk Signature (MyPRS) gene expression profiling (GEP)-70 high risk signature either from diagnosis or at time of registration for the study\r\n* Lactate dehydrogenase (LDH) > 300 U/L at diagnosis\r\n* Relapse from prior therapy within 12 months
Inclusion Criteria include:\n\n          -  Localized prostate cancer meeting the NCCN criteria of Intermediate Risk or patients\n             having only one NCCN high-risk feature\n\n               -  NCCN Intermediate Risk is defined as having at least one of the following: PSA\n                  10-20 ng/ml, Gleason score =7, T2b-T2c\n\n               -  High Risk with a single high risk feature is defined as having only one of the\n                  following: PSA>20 ng/ml, Gleason score 8-10, or T3a\n\n               -  Excluded are those in the following risk groups: Low risk; High risk with more\n                  than 1 high risk factor; Locally advanced/very high risk=T3b-T4; Metastatic: N1\n                  or M1\n\n          -  Planning to undergo standard prostate-only external beam radiation therapy\n\n          -  ECOG Performance Status 0-2\n\n        Exclusion Criteria include:\n\n          -  Liver disease, including known cirrhosis or active hepatitis\n\n          -  Patients on systemic corticosteroids (>10mg prednisone per day) or other\n             immunosuppressive drugs\n\n          -  Known HIV+ patients\n\n          -  Regional lymph node involvement or distant metastases\n\n          -  Patients planning to receive whole pelvic irradiation\n\n          -  Prior treatment for prostate cancer, except TURP or ADT. For ADT, it may only be given\n             for a maximum of 6 months\n\n          -  Patients who had or plan to have orchiectomy as the form of hormonal ablation\n\n          -  Known sensitivity or allergic reactions to acyclovir or valacyclovir
the newly diagnosed and/or previously unresected disease is judged to be at high risk for recurrence due to its size (>5 centimeters) or location at an anatomic site making it unlikely to be resected with negative margins (eg. adjacent to neurovascular structures)
High risk of systemic progression defined as:
Subject has poor-risk disease defined as International Prognostic Index (IPI) score ? 3 (high-intermediate or high-risk classification).
Understand that CC-122 could have a potential teratogenic risk.
Must meet criteria for high-risk MGUS or low-risk smoldering myeloma as described below:
Patients enrolling after only 1 failed induction attempt must meet at least one of the following additional eligibility criteria of high risk: ? 60 years of age adverse cytogenetics or molecular characteristics
Unacceptable anesthesia risk
Other disorders associated with a high risk of fistula formation including percutaneous endoscopic gastrostomy (PEG) tube placement within 3 months before the first dose of study therapy
Patients with high risk multiple myeloma in partial response (PR) or better at the time of enrollment with no prior progression and within 18 months from initiation of systemic anti-myeloma therapy, which may include single or planned tandem autologous HSCT. [High risk is defined by the presence of any one of the following: deletion of chromosome 13 by conventional cytogenetics, hypodiploidy, abnormality in chromosome 1(1q amplification or 1p deletion), t(4;14), t(14;16), t(14;20) or deletion of 17p by fluorescence in situ hybridization (FISH) or conventional karyotyping; high risk criteria based on commercially available gene expression profiling (GEP) ; and elevated beta-2 microglobulin (? 5.5 mg/L at diagnosis), detected at any time prior to enrollment]; or
DIPSS Intermediate-1, Intermediate -2, or High risk (Passamonti et al 2010)
All risk by Follicular Lymphoma International Prognostic Index (FLIPI) 0-5 factors
MDS should be classified as:\r\n* Intermediate 3+ or higher risk according to the revised international prognostic scoring system (IPSS-R)
Active connective tissue disorders, such as lupus or scleroderma that in the opinion of the treating physician may put the patient at high risk for radiation toxicity;
Must meet criteria for high risk disease\r\n* Patients with INSS stage 3 disease are eligible with the following\r\n** MYCN amplification, regardless of age or additional biologic features\r\n** Age >18 months (> 547 days) with unfavorable pathology, regardless of MYCN status
Must meet criteria for high risk disease\r\n* Patients with INSS stage 2a/2b with MYCN amplification regardless of age or additional biologic features
INCLUSION CRITERIA\n\n          1. Written informed consent obtained prior to any screening procedures and in accordance\n             with federal, local, and institutional guidelines.\n\n          2. Age ? 18 years.\n\n             Higher Risk Myelodysplastic Syndrome (Part F):\n\n          3. Documented diagnosis of MDS with 5-19% myeloblasts.\n\n          4. Patients should be intermediate-2 or high-risk MDS by International Prognostic Scoring\n             System (IPSS).\n\n          5. Patients believed to be IPSS high risk, without clearly meeting IPSS categories above\n             should be discussed with the medical monitor prior to enrolling.\n\n          6. HMA refractory patients including:\n\n               1. ? 2 cycles of azacitidine and/or decitabine or experimental agents (such as\n                  SGI-110 or ASTX727 or similar) with clear progressive disease (PD) (no count\n                  recovery with ?50% increase in bone marrow blasts)\n\n                  OR\n\n               2. ? 4 cycles of azacitidine and/or decitabine (or other hypomethylating therapy)\n                  with lack of improvement (no CR/CRi/PR/HI).\n\n          7. Patients receiving a stable dose of erythropoiesis-stimulating agent (ESA) for at\n             least 1 month at the time of study entry may continue to receive ESA.\n\n        EXCLUSION CRITERIA\n\n        Patients in All Parts of the Study:\n\n          1. Major surgery within 4 weeks before C1D1.\n\n          2. Impaired cardiac function or clinically significant cardiac diseases.\n\n          3. Uncontrolled active severe systemic infection requiring parenteral antibiotics,\n             antivirals, or antifungals within one week prior to C1D1.\n\n          4. Patients with known symptomatic brain metastasis.\n\n          5. Prior malignancies:\n\n               1. Patients in All Parts of the Study: Patients with adequately resected basal or\n                  squamous cell carcinoma of the skin, or adequately resected carcinoma in situ\n                  (i.e. cervix) may enroll irrespective of the time of diagnosis.\n\n               2. Patients with Higher Risk MDS only: Concomitant malignancies or previous\n                  malignancies with less than a 1-year disease free interval at the time of\n                  enrollment.\n\n             INDICATION-SPECIFIC EXCLUSION CRITERIA\n\n             Higher risk Myelodysplastic Syndrome (Part F):\n\n          6. IPSS low or intermediate-1 risk MDS.\n\n          7. Evidence of transformation to AML by World Health Organization (WHO) (?20% blasts in\n             bone marrow or peripheral blood).\n\n          8. Patients receiving granulocyte-colony stimulating factor (G-CSF) or granulocyte\n             macrophage-colony stimulating factor (GM-CSF) within the 3 weeks prior to C1D1.
Primary resistant/refractory disease detected at the conclusion of at least 4 cycles of aggressive multidrug induction chemotherapy on or according to a high-risk neuroblastoma protocols.
At risk of bowel perforation
General poor health, multiple co-morbidities placing the patient at risk or otherwise unsuitable for trial participation
Subject has high-risk features (e.g., based on Gleason score, PSA, clinical stage, % positive biopsies), and the treating physician feels the subject should undergo radical prostatectomy sooner than planned within the protocol
Relapsed multiple myeloma in patients that have been treated previously with autologous hematopoietic stem cell transplantation (auto-HCT), bortezomib and an imunomodulatory agent, AND with at least one of the following high-risk criteria \r\n* High-risk multiple myeloma defined by cytogenetic or fluorescence in situ hybridization (FISH) detection of any one or more of the following: \r\n** Deletion 17p \r\n** Translocation t(4;14) \r\n** Translocation t(14;16) \r\n** Translocation t(14;20)\r\n** Chromosome 1q gain \r\n** Chromosome 1p deletion\r\n** Deletion 13q by conventional karyotyping (FISH only not acceptable)\r\n** Hypodiploidy\r\n* High-risk gene expression profiling (GEP) at the time of relapse (by Signal Genetics Myeloma Prognostic Risk Signature [MyPRS] score)\r\n* Beta-2 (B2) microglobulin > 5.5 mg\r\n* Plasmablastic morphology (> 2%)\r\n* Relapsed plasma cell leukemia
high risk group MDS, according to IPSS Risk Stratification (Norway Only) Part B:
high/intermediate (int-2) risk group MDS, according to IPSS Risk Stratification (Norway Only)
NHL (Part 1 and 2): Intermediate or high risk by Ann Arbor Staging with Cotswald Modifications that meets criteria for active disease requiring therapy.
PROCUREMENT INCLUSION CRITERIA: Any patient regardless of sex with a solid tumor expressing any of the following antigens (PRAME, SSX2, MAGEA4, NY-ESO1-1 and/or survivin) with:\r\n* Active disease after first line therapy;\r\n* Refractory disease;\r\n* As adjuvant therapy for high risk disease (high risk disease is a disease that has a > 50% risk of progression within 5 years)
Any patient regardless of sex with a solid tumor expressing any of the following antigens (PRAME, SSX2, MAGEA4, NY-ESO1-1 and/or survivin) with:\r\n* Active disease after first line therapy;\r\n* Refractory disease;\r\n* As adjuvant therapy for high risk disease (high risk disease is disease that has a > 50% risk of progression within 5 years)
AD intermediate or worse in non-risk organs or AD better in risk organs after 12 weeks (Initial Course 2)
AD worse in risk organs after week 6 (after Initial Course 1), or AD worse or AD intermediate in risk organs after week 12 (after Initial Course 2).
AD worse in risk organs after week 6 (after Initial Course 1), or AD worse or AD intermediate in risk organs after week 12 (after Initial Course 2) of Stratum I OR
Low/intermediate-risk papillary urothelial carcinoma of the bladder, at initial occurrence or recurrent with > 6 months interval free of disease
Must have low, intermediate-risk or high-risk disease, defined as:\r\n* Low-risk: Embryonal, botryoid, spindle cell tumors only\r\n** Subset 1\r\n*** Stage 1, Group I, Group II\r\n*** Stage 1 Group III orbital only\r\n*** Stage 2, Group I, Group II\t\r\n** Subset 2\r\n*** Stage 1, Group III non orbit\r\n*** Stage 3, Group I, II\r\n* Intermediate-risk: Embryonal, botryoid, or spindle cell rhabdomyosarcoma (RMS)\r\n** Stage 2 or 3 and Group III\r\n** Alveolar, undifferentiated, or anaplastic RMS\r\n** Stage 1-3, group I-III\r\n* High-risk: Embryonal, botryoid, spindle cell, alveolar, undifferentiated, or anaplastic RMS with metastatic disease at diagnosis (stage 4)\r\n* Patients treated on RMS13 in the low or intermediate risk arm that experience disease progression prior to week 13 will transfer to the high risk arm and proceed with high risk chemotherapy starting at week 1 of the protocol
Patients must have International Prognostic Scoring System (IPSS) categories of low- or intermediate-1-risk disease
Patients determined to be at increased risk of arterial or venous thrombosis by the investigator
High risk for poor compliance with therapy or follow-up as assessed by investigator
One or more high risk features including: seminal vesicle invasion, extracapsular extension, positive margins, or a PSA post surgery between 0.2 and < 2.0
High risk T3 tumors that fulfill any of the following – circumferential tumor, extension into mesorectal fascia > 5 mm, prediction of positive circumferential resection margin, are also excluded.
Patients with one of the high risk myeloid diseases as outlined below. Patients must have less than 5% blasts on the last bone marrow (BM) evaluation prior to starting the conditioning regimen. Diseases included on this protocol include:\r\n* Acute myeloid leukemia (AML) in first complete remission (CR1) with intermediate or high risk features as defined below:\r\n** Cytogenetic abnormalities which are not considered “good risk” cytogenetic features (i.e t(8:21), t(15:17), inv 16 without c-kit mutations. And/or\r\n** Therapy related AML with history of antineoplastic therapy (radiation and/or chemotherapy) And/or\r\n** Normal karyotype with mutations of FLT3, RUNX1, TP53 mutation, ASXL1 or any others that are considered to be high risk\r\n* AML in >= 2nd remission\r\n* Myelodysplastic syndrome, myeloproliferative neoplasms, or MDS/myeloproliferative neoplasms (MPN) overlap syndrome with:\r\n** International prognostic scoring system risk score intermediate-2 (INT-2) or high risk at the time of transplant evaluation. And/or\r\n** Any risk category if life-threatening cytopenia exists And/or\r\n** Karyotype or genomic changes that indicate high risk for progression to acute myelogenous leukemia, including abnormalities of chromosome 7 or 3, mutations of TP53, or complex or monosomal karyotype.\r\n* Chronic myelomonocytic leukemia (CMML): CMML-1 or CMML-2.\r\n* Chronic myeloid leukemia (CML) with the following features:\r\n** Patients who have failed or are intolerant to BCR-ABL tyrosine kinase inhibitors. And/or\r\n** CML with BCR-ABL mutation consistent with poor response to tyrosine kinase inhibition (e.g T351l mutation)\r\n* Patients with severe aplastic anemia.
Has a target lesion/s in a region that previously received high dose radiation therapy (RT) (>50 Gy) demonstrating any of the following: \r\n* carotid artery encasement (> 180 degrees) \r\n* unprotected carotid artery (i.e. skin is directly over the carotid without intervening soft tissue, especially after prior neck dissection without a vascularized free flap) (a&b due to risk of carotid blow out)\r\n* skin infiltration by tumor (due to risk of fistula)\r\n* located in the larynx/hypopharynx primaries (due airway threat) treated with high dose radiation therapy (>50Gy) within 6 months or less of trial enrollment
Pathologically demonstrated BCG-unresponsive, high-risk non-muscle-invasive bladder cancer (NMIBC) defined as CIS with or without papillary component, any T1, or Ta high-grade lesions
Intermediate-2 or high-risk disease per IPSS
Subject has a history of Type 1 Diabetes (T1D) or is considered at high risk for T1D, where high risk is defined as
Eligible patients with a histopathological confirmed diagnosis of hematologic malignancy in one of the following categories:\r\n* Acute myelogenous leukemia:\r\n** Patients with de novo or secondary disease in unfavorable risk group including poor risk cytogenetics according to National Comprehensive Cancer Network (NCCN) guidelines for acute myelogenous leukemia (AML) i.e., monosomal karyotype, -5, 5q-, -7, 7q-, 11q23-non t (9;11), inv (3), t (3;3), t (6;9), t (9;22) and complex karyotypes (>= 3 unrelated abnormalities), or all patient in intermediate risk groups accept patients with FLT3-NPM1+ disease\r\n** Patients with active disease\r\n** Patients with chemosensitive active disease\r\n* Acute lymphocytic leukemia:\r\n** Patients with de novo or secondary disease according to NCCN guidelines for acute lymphocytic leukemia (ALL) hypoploidy (< 44 chromosomes); t (v;11q23): MLL rearranged; t (9;22) (q34;q11.2); complex cytogenetics (5 or more chromosomal abnormalities); high white blood cell (WBC) at diagnosis (>= 30,000 for B lineage or >= 50,000 for T lineage); iAMP21loss of 13q, and abnormal 17p\r\n** Patients with active disease\r\n** Patients with chemosensitive active disease\r\n* Myelodysplastic syndrome in high-intermediate (int-2) and high risk categories
Patients at very high risk for relapse post HCT as defined by very high disease risk index.
Myelodysplastic syndrome (MDS)/myeloproliferative disorders (MPD) other than myelofibrosis: \r\n* International prognostic scoring system (IPSS) risk score of INT-2 or high risk at the time of diagnosis.\r\n* Any IPSS risk category if life-threatening cytopenia(s) exists.\r\n* Any IPSS risk category with karyotype or genomic changes that indicate high risk for progression to acute myelogenous leukemia.\r\n* MDS/ myeloproliferative disorder overlap syndromes without myelofibrosis.\r\n* MDS/MPD patients must have less than 10% bone marrow myeloblasts and ANC > 0.2 (growth factor supported if necessary) at transplant work-up.
Participants must have pathologically confirmed primary myelofibrosis according to World Health Organization (WHO) criteria or secondary myelofibrosis as defined by the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria\r\n* Intermediate-2/ high-risk disease as per Dynamic International Prognostic Scoring System (IPSS) (DIPSS) criteria OR\r\n* Intermediate-1 risk disease with one of the following additional unfavorable features known to impact the survival adversely\r\n** Red cell transfusion dependency\r\n** Unfavorable Karyotype\r\n** Platelet count =< 100 x 10^9/L
Diagnosis of primary or secondary myelofibrosis with transplant indication by Dynamic International Prognostic Scoring System (DIPSS)-plus (> intermediate -1)
Must be considered either low-risk (T1-T2a, Gleason =< 6, prostate specific antigen [PSA] < 10 ng/mL) or favorable intermediate-risk (Gleason 3 + 4 = 7, percentage of positive biopsy cores < 50%, no more than one National Comprehensive Cancer Network [NCCN] intermediate risk factor)
Patients who require immediate cytoreduction due to high risk of tumor lysis syndrome (ie, absolute lymphocyte count greater than 100k/uL)
Confirmed diagnosis of primary myelofibrosis or post-polycythemia vera / essential thrombocythemia myelofibrosis classified as high risk, intermediate-2 risk, or intermediate 1 risk by International Prognostic Scoring System (IPSS)
Has intermediate-high risk, high risk, or M1 NED RCC as defined by the following pathological tumor-node-metastasis and Fuhrman grading status:
Intermediate-high risk RCC: pT2, Grade 4 or sarcomatoid, N0, M0; pT3, Any Grade, N0, M0
High risk RCC: pT4, Any Grade N0, M0; pT, Any stage, Any Grade, N+, M0
Patients with High-Risk Multiple Myeloma. High-risk is defined by the presence of any one of the following: deletion of chromosome 13 by conventional cytogenetics, hypodiploidy, abnormality in chromosome 1(1q amplification or 1p deletion), t(4;14), t(14;16), t(14;20) or deletion of 17p by fluorescence in situ hybridization (FISH) or conventional karyotyping; high-risk criteria based on commercially available gene expression profiling (GEP) detected at any time prior to enrollment;
Pathologically proven acute myeloid leukemia (AML) or intermediate, high-risk, or very high risk Myelodysplastic Syndrome (MDS) as defined by the World Health Organization (WHO) criteria or Revised International Prognostic Scoring System (IPSS-R) which is relapsed or refractory (R/R) to standard therapy and/or for which standard therapy is contraindicated or which has not adequately responded to standard therapy.
(Arm A only): Subjects with high-risk MDS (i.e. International Prostate Symptom Score [IPSS] intermediate-2 or high-risk; or revised [R]-IPSS high or very-high risk). Patients with intermediate-1 risk by IPSS or intermediate risk by R-IPSS with high-risk molecular features including TP53, ASXL1, EZH2, and/or RUNX1 mutations are also eligible
High-risk neuroblastoma with either primary refractory or secondary refractory osteomedullary disease (persistent neuroblastoma at osteomedullary sites after prior treatment)
Have a confirmed diagnosis of:\r\n* International Prognostic Scoring System (IPSS) intermediate-1, intermediate-2 or high-risk MDS including chronic myelomonocytic leukemia (CMML) OR\r\n* Low blast count AML with =< 30% blasts previously classified as refractory anemia with excess blasts in transformation and, who have not been previously treated with a hypomethylating agent
Any other condition that would cause a risk to the patient if he/she participated in the trial.
The patient must have a diagnosis of one of the following (one must be yes):\r\n* Bone marrow failure disorders:\r\n** Acquired bone marrow failure disorders include aplastic anemia, paroxysmal nocturnal hemoglobinuria (PNH):\r\n*** SAA must have failed at least one cycle of standard immunosuppressive therapy with calcineurin inhibitor plus anti-thymocyte globulin (ATG)\r\n*** PNH must have failed treatment or not tolerated treatment with eculizumab or progressed during or after treatment with eculizumab\r\n** Hereditary bone marrow failure disorders include Diamond-Blackfan anemia, Shwachman-Diamond syndrome, Kostmann syndrome, and congenital amegakaryocytic thrombocytopenia\r\n* Other non-malignant hematologic or immunologic disorders that require transplantation:\r\n** Quantitative or qualitative congenital platelet disorders (including but not limited to congenital amegakaryocytopenia, absent-radii syndrome, Glanzmann’s thrombasthenia)\r\n** Quantitative or qualitative congenital neutrophil disorders (including but not limited to chronic granulomatous disease, congenital neutropenia)\r\n** Congenital primary immunodeficiencies (including but not limited to severe combined immunodeficiency syndrome, Wiskott-Aldrich syndrome, CD40 ligand deficiency, T-cell deficiencies)\r\n** Hemoglobinopathies (including sickle cell disease and thalassemia)\r\n* Acute leukemias:\r\n** Acute myeloid leukemia (AML) - antecedent myelodysplastic syndrome, secondary\r\nAML, intermediate cytogenetics, high risk cytogenetic abnormalities or normal cytogenetics with high-risk\r\nmolecular mutations (including but not limiting to Flt3-ITD mutation), or other high risk features as per clinical judgment of the study principal investigator (PI) (or in the absence of the study PI, another equally qualified clinician)\r\n** Acute lymphoblastic leukemia (ALL) - B cell or T cell\r\n* Chronic myelocytic leukemia (CML):\r\n** Chronic phase (intolerant or unresponsive to imatinib and/or tyrosine kinase inhibitors)\r\n** Second chronic phase or accelerated phase who are ineligible for conventional myeloablative transplantation\r\n* Myeloproliferative and myelodysplasia syndromes:\r\n** Myelofibrosis (with/without splenectomy) with intermediate to high risk features\r\n** Advanced polycythemia vera not responding to therapy\r\n** Myelodysplastic syndrome (MDS) with an Revised International Prognostic Scoring System (IPSS-R) score of intermediate or higher\r\n** Secondary MDS with any IPSS score\r\n** Chronic myelomonocytic leukemia (CMML)\r\n* Lymphoproliferative disease:\r\n** Chronic lymphocytic leukemia (CLL), low-grade non-Hodgkin lymphoma (NHL) (recurrent or persistent) cytotoxic therapy refractory or with less than 6 months duration of complete response (CR) between courses of conventional therapy\r\n** Multiple myeloma (MM) progressive disease after auto bone marrow transplantation (BMT), tandem allo after prior auto\r\n** Waldenstrom’s macroglobulinemia (failed one standard regimen)\r\n** T or B cell lymphoma with poor risk features\r\n** Hodgkin disease:\r\n*** Received and failed frontline therapy\r\n*** Failed or not eligible for autologous transplantation
Poor psychiatric risk
Has MDS or CMML and must also have one of the following Prognostic Risk Categories, based on the Revised International Prognostic Scoring System (IPSS-R):
Very high (>6 points).
High (>4.5-6 points).
Intermediate (>3-4.5 points): a patient determined to be in the Intermediate Prognostic Risk Category is only allowable in the setting of >=5% bone marrow myeloblasts.
Confirmed diagnosis of MDS according to the French-American-British (FAB) criteria. Subjects with MDS must have intermediate, high, or very high risk IPSS-R scores and cytopenia of at least one lineage.
Ages =< 50 years of age with hematologic diseases treatable by allogeneic HCT who through pre-existing medical conditions or prior therapy are considered to be at high risk for regimen related toxicity associated with a high dose transplant (> 40% risk of transplant related mortality [TRM]); this criterion can include patients with a hematopoietic cell transplant-comorbidity index (HCT-CI) score of > 3; transplants should be approved for these inclusion criteria by the principal investigators at the collaborating centers and at Fred Hutchinson Cancer Research Center (FHCRC); all children < 12 years must be discussed with the FHCRC principal investigator (PI) prior to registration
Patients with rapidly progressive intermediate or high grade NHL
Patient must have a clinical diagnosis of low- to intermediate-risk non-muscle invasive bladder cancer according to the 2016 American Urological Association (AUA) Guidelines, except for strongly-suspected PUNLMP.
High-Risk NMIBC as classified per the 2016 AUA Guidelines
Patients vulvar HSIL that is not HPV-16+ or is associated with multiple types of high-risk HPV are not eligible
Patient must be willing to undergo two biopsies- before and on-treatment, provided the procedure is not deemed high-risk and is clinically feasible
Patients with systemic diseases which may be associated with unacceptable anesthetic/operative risk
MDS classified as intermediate 1-risk or high risk according to the international prognostic scoring system (IPSS) or revised-IPSS
Diagnosis of primary of secondary myelofibrosis with transplant indication by Dynamic International Prognostic Scoring System (DIPSS)-plus (> intermediate-1)
One of the two following populations:\r\n* High risk for recurrence of RCC after nephrectomy, in the opinion of the investigator, OR\r\n* Locally advanced, unresectable or metastatic disease, in the opinion of the investigator, and good or intermediate risk by Clinical Trial Independent Data Monitoring Committee (IDMC) Heng Criteria
High risk for post-embolization hepatic failure:\r\n* Child's C cirrhosis\r\n* > 80% liver involvement by tumor
Intermediate 1 (INT-1) or higher risk MDS defined by International Prognostic Scoring System (IPSS) criteria
Diagnosed with high risk hematologic disorders warranting stem cell transplant per institutional standard of care
If the diagnosis is MF-CP, must have Dynamic International Prognostic Scoring System (DIPSS) intermediate-2/high risk disease and either be intolerant/resistant to ruxolitinib as determined by the treating investigator or ineligible for ruxolitinib therapy as determined by the treating investigator
Patients with favorable, intermediate and poor risk categories will be eligible for the study; patients must be categorized according to favorable versus intermediate/poor risk status at registration; international Metastatic RCC Database Consortium (IMDC) must be used to determine prognostic factors
Patients must have undergone resection of the disease and demonstrate high risk pathologic features including:\r\n* T4\r\n* Node positive disease\r\n* T2/T3N0 disease with any 1 additional feature, including:\r\n** Recurrent Disease\r\n** Perineural invasion\r\n** Lymphovascular space invasion\r\n** Poorly differentiated histology\r\n** Positive Margins\r\n** Satellitosis or in-transit metastases\r\nNote: Not all patients with T2N0 cancer with one additional risk factor may be ideal candidates for this study, such as patients with only focal perineural invasion without other adverse features; clinical judgment should be used by the investigator in carefully selecting patients believed to be at significant risk of recurrence with radiation alone
Subjects with high-risk MDS (i.e. International Prognostic Scoring System [IPSS] Intermediate-2 or high-risk; or R-IPSS high or very-high risk). Patients with Intermediate-1 risk by IPSS or Intermediate risk by R-IPSS and with IDH1 or IDH2, or high-risk molecular features including TP53, ASXL1, EZH2, and/or RUNX1 mutations are also eligible
This treatment is for patients with high risk hematologic malignancies; high risk is defined as:\r\n* Any patient with a hematologic malignancy in which allogeneic HSCT is pursued with the expectation of cure; patients may have post-treatment residual disease, but the disease should be stable or minimally progressive and must be responsive to chemotherapy\r\n* Any patient with an untreated hematologic malignancy in which allogeneic HSCT is thought to be the sole or the best option for cure and in which prior treatment is unlikely to meaningfully address the disease\r\n* Patients without morphologic evidence of disease but with high risk features which would predict for relapsed despite remission at HSCT such as adverse cytogenetics, third (3rd) or greater complete response (CR), or failure to recover peripheral blood counts to normal ranges; while these patients do not have detectable disease by current methods, like all patients they have non-detectable disease which in their case is highly aggressive
Other disorders associated with a high risk of fistula formation including percutaneous endoscopic gastrostomy (PEG) tube placement within 3 months before the first dose of study therapy
Other disorders associated with a high risk of fistula formation including percutaneous endoscopic gastrostomy (PEG) tube placement
Treatment plan to receive a continuous course of IMRT delivered as single daily fractions of 2.0 to 2.1 Gy with a cumulative radiation dose between 60 Gy and 70 Gy depending on whether patients are considered post-operative high risk or unresectable/organ preservation high risk. Planned radiation treatment fields must include at least two oral sites buccal mucosa, retromolar trigone, floor of mouth, oral tongue, soft palate, hard palate) with a portion of each site receiving a minimum total of 50 Gy.
Leukemia or myelodysplastic syndrome (MDS) in aplasia; these patients may be taken to transplant if after induction therapy they remain with aplastic bone marrow and no morphological or flow-cytometry evidence of disease >= 28 days post-therapy; these high risk patients will be analyzed separately
Active connective tissue disorders, such as lupus or scleroderma, that in the opinion of the treating physician may put the patient at high risk for radiation toxicity
Patients must be diagnosed with a high-risk and/or advanced hematologic malignancy defined as one of the following
MDS with International Prognostic Scoring System (IPSS) intermediate-2 or higher, therapy-related MDS or chronic myelomonocytic leukemia (CMML)
Have very low, low or intermediate-risk disease by the Revised International Prognostic Scoring System (IPSS-R)
Subjects must have IPSS-R high or very high risk myelodysplastic syndromes (MDS) by World Health Organization (WHO) classification
Male or female subjects, age 18 to 75 years admitted to hospital with a clinical diagnosis of acute PE categorized as low risk or intermediate-risk or submassive PE and for whom catheter-based therapy is not planned;
Primary or secondary myelofibrosis intermediate or high risk by Dynamic International Prognostic Scoring System (DIPSS) in chronic or accelerated phase
Subject currently being treated with biguanides or other agents known to increase risk of lactic acidosis
Acute myeloid leukemia (AML) in CR1 with intermediate or high risk features including:\r\n* Cytogenetic abnormalities associated with myelodysplastic syndrome including abnormalities of chromosome 5 or 7\r\n* History of anti-neoplastic therapy (radiation or chemotherapy)\r\n* Extramedullary involvement\r\n* WBC count >= 100,000 cells/uL at diagnosis\r\n* Rearrangements or mutations of 11q23 (MLL)\r\n* Abnormalities of chromosome 3\r\n* TP53 mutation or loss of 17p\r\n* Complex or monosomal karyotype \r\n* Normal karyotype with mutations of FLT3, RUNX1, or ASXL1
Myelodysplastic syndrome, myeloproliferative neoplasms, or myelodysplastic syndrome/myeloproliferative neoplasms (MDS/MPN) overlap syndrome with:\r\n* International prognostic scoring system risk score of intermediate (INT)-2 or high risk at the time of transplant evaluation\r\n* Any risk category if life-threatening cytopenia exists\r\n* Karyotype or genomic changes that indicate high risk for progression to acute myelogenous leukemia, including abnormalities of chromosome 7 or 3, mutations of TP53, or complex or monosomal karyotype
Myelofibrosis with Dynamic International Prognostic Scoring System (DIPSS) scores of INT-2 or high risk or any risk category if life threatening cytopenias are present
Chronic lymphocytic leukemia with high risk disease as defined by the European Society for Blood and Marrow Transplantation (EBMT) consensus criteria
At least one lesion (metastasis or primary tumor) being considered accessible by non-high-risk collection procedures for biopsy.
Have at least 2 of the following high risk features associated with her DCIS-high grade (grade II-III), palpable mass, hormone receptor negative (less than 1%), Her2 positive, young age (less than 45 years old), and large size (greater than 5 cm)
No risk of vital organ compression.
Patients deemed to be “high risk” by pre admission testing (care process model [CPM]) or by a preoperative risk assessment by the hospitalist for perioperative complications
Subjects must have a confirmed diagnosis of active multiple myeloma according to IMWG criteria; in addition, subjects must have “high-risk” multiple myeloma according to one of the following criteria:\r\n* Any of the following high-risk cytogenetic features, documented by fluorescence in situ hybridization (FISH) or metaphase karyotyping: deletion 17p, t(4;14), t(14;16), t(14;20)\r\n* Standard-risk cytogenetics but elevated lactate dehydrogenase (LDH) and beta-2-microglobulin > 5.5 mg/L (i.e., Revised International Staging System [R-ISS] stage III)
Deemed to be not otherwise eligible for a myeloablative hematopoietic cell transplant; high risk characteristics for a myeloablative transplant include age > 60 years and a HCT comorbidity index > 3
PART 2 GROUP 1 INCLUSION CRITERIA: Subject has high-risk neuroblastoma with a protocol-defined genomic aberration that allows assignment to Group 1
PART 2 GROUP 2A INCLUSION CRITERIA: Subject has high-risk neuroblastoma with a protocol-defined genomic aberration that allows assignment to Group 2
PART 2 GROUP 3 INCLUSION CRITERIA: Subject has high-risk neuroblastoma with a protocol-defined genomic aberration that allows assignment to Group 3
Patients must have high risk or intermediate risk disease, defined below; staging evaluation should be determined by imaging studies and complete head and neck exam in accordance with the American Joint Committee on Cancer Staging Manual, 7th edition\r\n* High risk patient must meet one of the following criteria:\r\n** Surgically unresectable oral cavity; patients who are technically resectable but refuse surgery due to morbidity (eg. total glossectomy) are also eligible; medically inoperable patients are not eligible\r\n** Larynx: T4 any N; T2-3 and >= N2a\r\n** Hypopharynx: T1-2N1-3 or T3-4N0-3\r\n** Oropharynx: p16(-) AND T3-4 or >= N2a\r\n** Unknown primary: p16(-) AND >= N2a\r\n* Intermediate risk patients must meet one of the following criteria:\r\n** Oropharynx: p16(+) AND one of the following\r\n*** T3 or >= N2a AND >= 10 pack-years tobacco exposure \r\n*** T4 or N3 disease irrespective of tobacco exposure\r\n** Unknown primary: p16(+) AND one of the following:\r\n*** >= N2a AND >= 10 pack-years tobacco exposure\r\n*** N3 disease irrespective of tobacco exposure\r\nNote: for patients with oropharyngeal or unknown primary tumors, p16 status must be known, and can be performed at the local site; p16-positive disease is defined as >= 70% of tumor cells demonstrating diffuse nuclear and cytoplasmic staining by p16 immunohistochemistry (IHC); a positive test for human papilloma virus (HPV) -16 by in-situ hybridization (ISH), if this is the local site preference for assessing HPV status, may substitute for p16 IHC testing; p16 staining is not required for non-oropharyngeal sites
Has previously untreated, de novo, non-M3 acute myeloid leukemia (AML) with intermediate-risk disease (intermediate-I or intermediate-II) as defined by ELN criteria OR normal cytogenetics (after analysis of 20 or more metaphases) with mutated nucleophosmin (NPM1) without FMS-related tyrosine kinase 3-internal tandem duplication (FLT3-ITD); monoallelic CEBPA mutations are not considered favorable risk and are therefore eligible
Patients must have one of the following hematologic malignancies: acute myelogenous leukemia (AML), induction failure, high-risk for relapse first remission (with intermediate-risk or high-risk cytogenetics including complex karyotype, abnormal [abn][3q], -5/5q-, -7/7q-, abn[12p], abn[17p], myeloid/lymphoid or mixed-lineage leukemia [MLL] gene re-arrangement and t [6;9]47, fms related tyrosine kinase 3 [flt3] mutation positive and/or evidence of minimal residual disease by flow cytometry), secondary leukemia from prior chemotherapy and/or arising from myelodysplastic syndromes (MDS), any disease beyond first remission
Myelodysplastic syndrome (MDS): Primary or therapy related, including patients that will be considered for transplant; these include any of the following categories: 1) revised International Prognostic Scoring System (IPSS) intermediate and high risk groups, 2) malondialdehyde (MDA) with transfusion dependency, 3) failure to respond or progression of disease on hypomethylating agents, 4) refractory anemia with excess of blasts, 5) transformation to acute leukemia, 6) chronic myelomonocytic leukemia, 7) atypical MDS/myeloproliferative syndromes, 8) complex karyotype, abn(3g), -5/5g-, -7/7g-, abn(12p), abn(17p)
Leukemia or MDS in aplasia; these patients may be taken to transplant if after induction therapy they remain with aplastic bone marrow and no morphological or flow-cytometry evidence of disease >= 28 days post-therapy; these high risk patients will be analyzed separately
MDS patients: \r\n* Cytogenetics consistent with poor or very poor risk group by 5-risk classification;\r\n* Cytogenetics consistent with monosomal karyotype\r\n* Bone marrow blast count > 5% but less than 20% at any time during their disease course before HSCT\r\n* Peripheral blood blast =< 5% at HSCT
Patient may have been pretreated with intermediate to high dose cytarabine (more than 1000mg/m2/d over 5d) if the day of the last infusion was at least 90 days before inclusion in the study
Myelodysplasia (MDS) requiring transplant as defined as: International Prognostic Scoring System (IPSS) intermediate 2 (INT-2) or high risk; revised (R)-IPSS high or very high; World Health Organization (WHO) classification: refractory anemia with excess blasts (RAEB)-1, RAEB-2; severe cytopenias: absolute neutrophile count (ANC) < 0.8, anemia or thrombocytopenia requiring transfusion; poor or very poor risk cytogenetics based on IPSS or R-IPSS definitions; therapy-related MDS; blasts must be < 5% by bone marrow aspirate morphology
understand that the study medication may have teratogenic risk
DONOR: A comorbid condition which, in the view of the investigators, renders the subject at high risk from treatment complications
Patients must be at high risk for recurrence, which will be defined during the pre-treatment screening period as meeting one of the following criteria:\r\n* A histologically positive nodal deposit >= 0.2 mm\r\n* Histologic grade 3\r\n* Peritumoral lymphatic vessel or vascular invasion\r\n* Oncotype Dx score of 25 or greater
known and possible risk for QT prolongation
Must be considered intermediate or high risk:\r\n* Oropharynx intermediate risk patients include those who have all of the following:\r\n** Human papillomavirus (HPV)/p16 (positive [+]) disease, a significant tobacco smoking history (> 10 pack years) and N2b-N3 disease OR\r\n** HPV (negative [-]) disease, =< 10 years of smoking and large tumors (T2-T3)\r\n* Oropharynx high risk patients include those who are either:\r\n** HPV (-) with > 10 years of smoking, OR\r\n** HPV (-), =< 10 years of smoking and T4 disease\r\n* Oral cavity, larynx, hypopharynx are considered high/intermediate risk (regardless of HPV, p16 or smoking status)
Histologically confirmed non-metastatic high-risk clear cell RCC (T2a-T4NanyM0 or TanyN1M0)
Patients belonging in the National Comprehensive Cancer Network (NCCN) high recurrence risk group:\r\n* High risk:\r\n** Clinical stage T3a, or Gleason score = 8-10, or PSA > 20 ng/mL
Patient has very low risk, low risk, intermediate risk or very high risk disease as defined by the NCCN
Subjects with conditions that carry high anesthetic risk in the opinion of the treating anesthesiologist are not eligible (i.e. subjects with significant airway compression by tumor or craniofacial abnormalities).
Significant organ compromise that will increase risk of toxicity or mortality
High risk for relapse defined as: 1st CR with high risk features for relapse (including history of prior malignancy treated with chemotherapy or radiotherapy, or history of myelodysplastic syndrome, myeloproliferative disorder, chronic myelomonocytic leukemia, myelodysplastic syndrome [MDS]/myeloproliferative neoplasm [MPN] or other hematologic malignancy thought to have evolved to AML [i.e., secondary AML, (sAML)]; high risk cytogenetics at diagnosis; fms-related tyrosine kinase 3 [FLT3] mutated at diagnosis; or presence or minimal residual disease assessed by polymerase chain reaction [PCR], cytogenetics, and/or flow cytometry at time of enrollment) 2nd CR regardless of disease characteristics at the time of diagnosis
High-risk pathologic features must be present: compromised/positive surgical margins (=< 2 mm) or extra-nodal extension (patient with other high-risk features gross perinueral invasion, bone invasion, angiolyphatic invasion, or a constellation of these factors may be eligible based on case-by-case basis at discretion of principal investigator)
Any factors that increase the risk of QTc prolongation or risk of arrhythmic events, or unexplained sudden death under 40 years of age in first-degree relatives or any concomitant medication known to prolong the QT interval.
Concurrent malignancies other than BCC, other than those with negligible risk of metastases or death
BCG-unresponsive high risk non-muscle-invasive bladder cancer after treatment with adequate BCG therapy
Systemic diseases associated with unacceptable anesthesia or operative risk
It is not required that patients have the risk factors mentioned
Pathological diagnosis of adenocarcinoma of the prostate, judged to be at high risk for recurrence based on any of the following (in accordance with the International Society of Urological Pathology (ISUP) Consensus 2005: Gleason score 8-10 OR Gleason score of 4+3 AND clinical T2b-4 AND PSA >20ng/mL OR N1 disease (involvement of lymph nodes at or below the bifurcation of the common iliac arteries) defined radiologically as greater than 10mm on short axis using standard CT or MRI, or biopsy proven
Patients who due to age, pre-existing medical conditions, or, prior therapy are considered to be at high-risk for regimen-related toxicity associated with fully ablative transplant conditioning, and therefore reduced intensity conditioning is recommended
Patients must have relapsed or refractory acute leukemias or high-risk MDS for which no standard therapies are anticipated to result in a durable remission
PROCUREMENT: Diagnosis of a cancer for which the presence of a high risk HPV type has been documented in a biopsy sample (results may be pending at this time)
TREATMENT: Diagnosis of a cancer for which the presence of a high risk HPV type has been documented in a biopsy sample
For cohort 2: intermediate-2 or high risk MF patients as defined by DIPSS either not eligible for ruxolitinib or having failed under ruxolitinib
For cohort 1 only: patients with evidence of intermediate 2 or high risk disease (according to DIPSS)
Myelodysplastic syndrome\r\n* Refractory anemia with excess blasts (RAEB) I or II\r\n* High-risk International Prognostic Scoring System (IPSS)\r\n* Secondary myelodysplastic syndrome (MDS)
Recipients with myelofibrosis must have at least 2 of the following features, or be Dynamic International Prognostic Scoring System (DIPSS) intermediate-2 or high risk:\r\n* Hemoglobin < 10 g/dl, or > 10 g/dl with transfusion dependence\r\n* WBC < 4,000 or > 30,000/mm^3 or requires cytoreductive therapy to maintain WBC < 30,000/mm^3\r\n* Abnormal cytogenetics
Has one of the following diagnoses: Subjects must have refractory or relapsed AML or ALL, CML in blast phase, or high risk MDS (defined by Revised International Prognostic Scoring System [IPSS-R] score as High or Very High for inclusion in Part 1 of the study. Subjects must have refractory or relapsed AML or high-risk MDS (defined by IPSS-R score as High or Very High for inclusion in Part 2 of the study.
Risk-group classification into the D’Amico or National Comprehensive Cancer Network (NCCN) ‘high-risk’ group, as defined by the presence of any one of the following high-risk factors:\r\n* Pre-biopsy prostate-specific antigen (PSA) >= 20\r\n* Biopsy Gleason score 8-10\r\n* Clinical stage T3
PART 1: Disease criteria\r\n* Diagnosis of primary MF (PMF) as defined by the 2008 World Health Organization classification system or diagnosis of secondary MF as defined by the International Working Group (IWG) for Myeloproliferative Neoplasms Research and Treatment criteria\r\n* Patients meeting the criteria for intermediate-1, intermediate-2 or high-risk disease by the Dynamic International Prognostic Scoring System (DIPSS) or DIPSS-plus scoring system
DONOR: Male donors will be preferred to avoid reactivity against H-Y minor histocompatibility antigens and associated risk of risk of acute GvHD, especially grafts from multiparous women
Inability to hold anticoagulation for surgery due to high risk of a cerebral vascular event, myocardial event, or like risk
Patients must have undergone chemotherapy and surgery for high-risk neuroblastoma prior to enrollment on trial
Myeloid disorder (myelodysplastic syndrome [MDS] with intermediate/high risk features or refractory disease or myeloproliferative disorder; primary or secondary if high-risk features or refractory disease)
Myelodysplastic syndromes (MDS), intermediate-1 (INT-1), intermediate-2 (INT-2) or high Revised International Prognostic Scoring System (IPSS-R) score that has failed at least 1 first line therapy
Myelofibrosis (MF):\r\n* Intermediate-2 or high risk by Dynamic International Prognostic Scoring System (DIPSS)-plus OR\r\n* Monosomal karyotype OR\r\n* Presence of inv(3)/i(17q) abnormalities OR \r\n* Other unfavorable karyotype OR leukocytes >= 40 x 10^9/L AND\r\n* Circulating blasts =< 9%
Patients must have high-risk neuroblastoma with at least ONE of the following:
Primary resistant/refractory disease detected at the conclusion of at least 4 cycles of aggressive multidrug induction chemotherapy on or according to a high-risk neuroblastoma protocol (examples include Children's Oncology Group trials: A3973, ANBL0532, ANBL09P1, etc.).
Patients with a diagnosis of AML, acute biphenotypic leukemia, or high risk MDS (>= 10% blasts or International Prognostic Scoring System [IPSS] >= intermediate-2) will be eligible; patients with CML in myeloid blast phase are also eligible
High-risk NB, as defined by risk-related treatment guidelines and the International NB Staging System, i.e., stage 4 with (any age) or without (> 18 months) v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN)-amplification, or MYCN-amplified NB other than stage I
Must be diagnosed with treatment requiring PMF or post ET/PV MF with intermediate-1, intermediate -2 or high risk disease according to the International Working Group (IWG) prognostic scoring system, or if with low risk disease then with symptomatic splenomegaly that is >= 5 cm below left costal margin by physical exam
PHASE I\r\n* Primary or secondary AML according to World Health Organization (WHO) classification, with relapsed or refractory disease or newly diagnosed older subjects (greater than or equal to 65 years of age), not candidates for intensive chemotherapy\r\n* Subjects with myelodysplastic syndrome (MDS), International Prognostic Scoring System (IPSS) intermediate (Int)-2 or high risk (refractory anemia with excess blasts [RAEB]-2 only, i.e. greater than or equal to 10% blast) who are resistant or intolerant to standard treatment and are not candidates for transplantation \r\n* Subjects with acute lymphoblastic leukemia (ALL), relapsed, refractory or intolerant to standard treatment and for whom no effective treatment options are available
High risk for distal recurrence defined as any of the following conditions: A) Confirmed both monosomy 3 and 8q amplification; B) Class II tumor
Patients excluded from this protocol are those with high risk hematologic malignancies in remission (and no prior allogeneic HSCT), where allogeneic HSCT is indicated but an appropriately matched HSC source (sibling, unrelated adult or UCB) is available
Prior kyphoplasty, vertebroplasty, local radiation therapy for symptomatic bone lesions (e.g., uncontrolled pain or high risk of pathologic fracture) are permitted
Patients who have had chemotherapy for MM; exception: local radiation therapy for symptomatic bone lesions (e.g., uncontrolled pain or high risk of pathologic fracture)
Significant risk of suicide based on the investigator’s judgment
Patients with myelodysplastic syndromes (MDS): a. de novo MDS with intermediate or high-risk International Prognostic Scoring System (IPSS) scores; patients with intermediate-1 features should have failed to respond to hypomethylating agent therapy, or b. patients with treatment-related MDS
RECIPIENT: Clinical history of at least one life-threatening infection and/or MDS with International Prognostic Scoring System (IPSS) category of intermediate-1, intermediate-2, or high
National Comprehensive Cancer Network (NCCN) risk category very low, low, or intermediate risk:\r\n* Combined Gleason score =< 7\r\n* Prostate specific antigen (PSA) within three months of enrollment < 20 ng/ml\r\n* Clinical stage T1a-cN0M0 or clinical stage T2aN0M0
Acute myeloid leukemia in first remission with any of the following high risk features defined as:\r\n* Adverse cytogenetics: -5, deletion (del) 5q, -7, del7q, abnormalities involving 3q, 9q, 11q, 20q, 21q, 17, +8 or complex karyotype (> 3 abnormalities)\r\n* Preceding myelodysplastic or myeloproliferative syndrome\r\n* Presence of high risk molecular abnormalities including FLT3 mutations, DNMT3A, TET2; ras; kit\r\n* French–American–British (FAB) monosomy (M)6 or M7 classification\r\n* Treatment related acute myeloid leukemia (AML)\r\n* Residual cytogenetic or molecular abnormalities
Myelodysplastic syndromes with intermediate, high or very high risk Revised International Prognostic Scoring System (R-IPSS) score, chronic myelomonocytic leukemia (CMML) or therapy related myelodysplastic syndromes (MDS)
Unacceptable anesthesia risk
Patients with a diagnosis of primary myelofibrosis (PM), post polycythemia vera myelofibrosis (PPV MF), or post essential thrombocythemia myelofibrosis (PET MF) requiring therapy, including those previously treated and relapsed or refractory, or if newly diagnosed, with intermediate or high risk according to International Working Group (IWG-MRT) criteria
PHASE II: Diagnosis of AML in remission 1 or 2 or a diagnosis of myelodysplastic syndrome either intermediate 1 or 2, or high risk by the International Prognostic Scoring System
Patients with high risk multiple myeloma who are transplant candidates, in partial response (PR) or better; high risk will be defined as patients with any of the following:\r\n* Fluorescence in situ hybridization showing t(4:14), t(14:16)t (14:20) deletion (Del) 17/17p or gain (amp) 1q; \r\n* Deletion 13 by conventional cytogenetic analysis; \r\n* High risk signatures as determined by the GEP-70 or EMC-92 gene expression profiles;\r\n* Relapsed disease within 18 months of prior autologous stem cell transplant (ASCT)
Patients with the diagnosis of MDS (low, int-1 by International Prognostic Scoring System [IPSS], or hypocellular) who are either previously treated or untreated are eligible for this trial
Patients who are concurrently receiving or requiring any of the following agents, which may increase the risk for mithramycin related toxicities, such as hemorrhage:\r\n* Thrombolytic agents\r\n* Aspirin or salicylate-containing products, which may increase risk of hemorrhage\r\n* Dextran\r\n* Dipyridamole\r\n* Sulfinpyrazone\r\n* Valproic acid\r\n* Clopidogrel
Patients with previously untreated AML or high risk myelodysplastic syndrome (MDS) (>= 10 % blasts or International Prognostic Scoring System [IPSS] >= intermediate-2); prior therapy with hydroxyurea, hematopoietic growth factors, azacytidine, all-trans retinoic acid (ATRA), or an isolated dose of cytarabine up to 2 g is allowed; patients with history of MDS transformed to AML are eligible regardless of their prior therapy for MDS provided this will be their first induction therapy for AML
International Prognostic Scoring System (IPSS) risk categories Int-2 or High (IPSS overall score ? 1.5) and
Participant has a diagnosis other than previously untreated de novo MDS with IPSS risk categories Int-2 or High, including:
MDS with IPSS risk categories Low or Int-1 (overall IPSS score < 1.5)
MDS with at least one of the following poor-risk features: \r\n* Poor-risk cytogenetics (7/7q minus or complex cytogenetics)\r\n* International Prognostic Scoring System (IPSS) score of intermediate (INT)-2 or greater; treatment-related MDS\r\n* MDS diagnosed before age 21 years \r\n* Progression on or lack of response to standard deoxyribonucleic acid (DNA)-methyltransferase inhibitor therapy \r\n* Life-threatening cytopenias, including those generally requiring greater than weekly transfusions
Accrual to each treatment arm will include standard risk and poor risk patients, except for Regimen D; all patients on Arm D will be poor risk by virtue of risks of relapse and/or transplant related mortality
All other patients, including those with treatment related malignancies and/or those who have AML derived from MDS, will have received extensive prior chemo/radiotherapy and, therefore, will be considered to be at poor risk of conditioning and transplant related morbidities, and potentially transplant related mortality; patients with life threatening non-malignant genetic and acquired disorders will also, by virtue of their history of, optional transfusions and/or infection be considered poor risk; stopping rules for non-relapse related mortality in these heavily treated patients are, therefore, slightly less stringent than patients in the poor risk transplant groups; stopping rules for the principal endpoints of graft failure and GvHD are the same for all groups
Acute myelogenous leukemia in high risk CR1 as defined by at least one of the following: \r\n* Greater than 1 cycle of induction therapy required to achieve remission\r\n* Preceding myelodysplastic syndrome (MDS)\r\n* Presence of fms-like tyrosine kinase receptor-3 (Flt3) abnormalities\r\n* French-American-British (FAB) M6 or M7 leukemia, or\r\n* Adverse cytogenetics for overall survival such as: \r\n** Those associated with MDS\r\n** Complex karyotype (>= 3 abnormalities); or \r\n** Any of the following: inv(3) or t(3;3), t(6;9), t(6;11), + 8 [alone or with other abnormalities except for t(8;21), t(9;11), inv(16) or t(16;16)], t(11;19)(q23;p13.1)]\r\n* Other risk factors determined by the patient’s attending physician to be high risk features requiring transplantation
High-risk MDS status-post cytotoxic chemotherapy
Patients with seminomatous or nonseminomatous germ-cell tumors (GCT) in one of the following groups: A) first relapse or progression or second response with an intermediate or high risk according to the Beyer model; B) second relapse or beyond
Myelodysplastic syndrome (MDS): \r\n* Intermediate-1 International Prognostic Scoring System (IPSS) score with poor risk cytogenetics as defined by IPSS\r\n* Intermediate-2 or High International Prognostic Scoring System (IPSS) score\r\n* MDS/ myeloproliferative disorder overlap syndromes\r\n* Any score with life threatening cytopenia(s), including red cell or platelet transfusion dependence\r\n* Receipt of at least one cycle of cytotoxic chemotherapy, azacitidine or decitabine\r\n* MDS patients must have =< 5% bone marrow myeloblasts and absolute neutrophil count (ANC) >= 0.2 (growth factor supported if necessary) at transplant work-up
A histologically or pathologically confirmed diagnosis of AML based on WHO classification which is previously untreated by systemic therapy or is in first relapse after achieving a complete remission to initial induction, consolidation and/or maintenance therapy or MDS with IPSS scores of intermediate -2 or higher risk risk which has been previously treated with hypomethylating agents
Low-risk disease, defined as all MLL germline cases
High-risk disease, defined by MLL rearrangement AND meets the following criteria:
Patients with Fanconi anemia (FA) must have aplastic anemia (AA), myelodysplastic syndrome without excess blasts, or high risk genotype as defined below\r\n* Aplastic anemia is defined as having at least one of the following when not receiving growth factors or transfusions:\r\n** Platelet count < 20 x 10^9 IL\r\n** Absolute neutrophil count (ANC) < 5 x 10^8/L\r\n** Hemoglobin (Hgb) < 8 g/dL\r\n* Myelodysplastic syndrome with multilineage dysplasia with or without chromosomal anomalies\r\n* High risk genotype (e.g. IVS-4 or exon 14 FANCC mutations, or BRCA1 or 2 mutations)
Refractory leukemia or MDS; these patients may be taken to transplant in aplasia after induction or re-induction chemotherapy or radiolabeled antibody; these high risk patients will be analyzed separately (Arm 3)
Subjects at significant risk for general anesthesia
Serious uncontrolled concomitant disease that would contraindicate the use of the investigational drug used in this study or that would put the subject at high risk for treatment-related complications.
Patients with intermediate-1 or higher risk MDS who have failed therapy with a hypomethylating agent, or have failed lenalidomide therapy if harboring a 5q-chromosomal deletion.
Myeloproliferative neoplasms/myelofibrosis, either primary as a result of polycythemia vera or essential thrombocythemia, with disease risk of intermediate or high-risk according to Dynamic International Prognostic Scoring System (DIPSS) criteria; blasts must be < 10% by bone marrow aspirate morphology
Patients must have histologically documented multiple myeloma (MM)\r\n* Patients in early relapse (less than 24 months from initiation of systemic anti-myeloma therapy which may include single or planned tandem autologous transplant) after primary therapy that included and autologous HSCT; OR\r\n* Later stage; OR\r\n* High risk factors defined by the presence of any one of the following detected at any time prior to enrollment: deletion of chromosome 13 by conventional cytogenetics, hypodiploidy, abnormality in chromosome 1 (1q amplification or 1p deletion), t(4;14), t(14;16), t(14;20) or deletion of 17p by fluorescence in situ hybridization (FISH) or conventional karyotyping; high risk criteria based on commercially available gene expression profiling; OR\r\n* Extramedullary disease, plasma cell leukemia or high lactate dehydrogenase (LDH)
Patients must have histologically documented myelofibrosis (MF)\r\n* Patients with Dynamic International Prognostic Scoring System (DIPSS) plus intermediate stage 2 or higher risk MF; OR\r\n* Subset of intermediate stage 1 patients; defined by:\r\n** Poor-risk molecular profile (triple negative: JAK2, CALR, MPL); OR\r\n** Presence of any of the following mutations: ASXL1, SRSF2, EZH2, IDH1/2; OR\r\n** Severe thrombocytopenia, severe anemia, high peripheral blood blasts percentage; OR\r\n** Unfavorable cytogenetic abnormalities (rearrangements of chromosome 5 or 7 or >= 3 abnormalities
Patient has pathologic high risk factors on either the initial biopsy specimen report or follow up biopsy (if done): high histologic grade, mucinous histology, lymphatic or vascular invasion.
High or intermediate-2 risk disease, as defined per protocol
Inclusion Criteria include:\n\n          -  Histologically confirmed adenocarcinoma of the prostate\n\n          -  Patients choosing active surveillance\n\n          -  Patients meeting definition of NCCN low risk, intermediate risk OR patients having\n             only one NCCN high-risk feature\n\n               -  NCCN Low Risk is defined as having all of the following: PSA < 10 ng/ml, Gleason\n                  ? 6, T1-T2a\n\n               -  NCCN Intermediate Risk is defined as having at least one of the following and no\n                  high risk features: PSA 10-20 ng/ml, Gleason score =7, T2b-T2c\n\n               -  High Risk with a single high risk feature is defined as having only one of the\n                  following: PSA>20 ng/ml, Gleason score 8-10, or T3a\n\n               -  Excluded are those in the following risk groups: High risk with more than 1 high\n                  risk factor; Locally advanced/very high risk=T3b-T4; Metastatic: N1 or M1\n\n          -  Patients must be planning and medically able to tolerate multiple transrectal\n             ultrasound guided injections.\n\n          -  ECOG Performance status 0-2\n\n        Exclusion Criteria include:\n\n          -  Active liver disease, including known cirrhosis or active hepatitis\n\n          -  Patients on systemic corticosteroids (>10 mg prednisone per day) or other\n             immunosuppressive drugs\n\n          -  Known HIV+ patients\n\n          -  Regional lymph node involvement or distant metastases\n\n          -  Other current malignancy (except squamous or basal cell skin cancers)\n\n          -  Other serious co-morbid illness or compromised organ function that, in the opinion of\n             the investigator, would interfere with treatment or follow up\n\n          -  Prior treatment for prostate cancer except TURP. If prior TURP, patients must be\n             deemed able to receive prostate biopsy and multiple intra-prostatic injections by the\n             investigator\n\n          -  Patients taking 5-alpha-reductase inhibitors (e.g. finasteride, dutasteride)\n\n          -  Patients who had or plan to use ADT or have history of an orchiectomy.\n\n          -  Patients who are planning to undergo radical treatment for prostate cancer within 12\n             months.\n\n          -  Known sensitivity or allergic reactions to acyclovir or valacyclovir
Pathologically confirmed relapsed or refractory (primary refractory and relapsed refractory) Acute Myeloid Leukemia (AML) (defined by World Health Organization (WHO) criteria) for which no further conventional therapy is suitable for the patient, or confirmed myelodysplastic syndrome defined according to WHO classification, with an International Prognostic Scoring System (IPSS) risk category of intermediate-2 or high risk, that is relapsed, refractory or intolerant to conventional therapy within 3 weeks of registration.
Malignancies other than disease under study within 5 years prior to Day 1 of Cycle 1 except those with a negligible risk of metastasis or death
Confirmed diagnosis of refractory/relapsed AML or high-risk MDS
Patient has newly diagnosed AML and refuses or is not eligible for treatment with aggressive chemotherapy and/or SCT; OR AML and has relapsed or been refractory to prior therapy; OR High-risk MDS, defined as IPSS intermediate-2 (INT-2) or IPSS high-risk, and refuses or is not eligible for standard or aggressive chemotherapy and SCT or prior experimental therapies; OR High-risk MDS, defined as IPSS INT-2 or IPSS high risk, and has failed or been refractory to deoxyribonucleic acid (DNA) hypomethylating agents (azacitidine or decitabine), lenalidomide, standard/aggressive chemotherapy, SCT, or prior experimental therapies.
Patients must have one of the following hematologic malignancies: acute myelogenous leukemia (AML), induction failure, high-risk for relapse first remission (with intermediate-risk or high-risk cytogenetics, fms-related tyrosine kinase 3 [FLT3] mutation positive and/or evidence of minimal residual disease by flow cytometry), secondary leukemia from prior chemotherapy and/or arising from myelodysplastic syndrome, any disease beyond first remission
Any condition presenting an unacceptably high anesthetic or surgical risk
MDS and >5% blasts, or IPSS risk group intermediate-1, intermediate-2 or high risk
AML and ALL in 1st complete remission (CR) at high risk of relapse based on negative prognostic factors (for the definition of high-risk of relapse see Appendix H).
Low-intermediate risk of relapse defined as:
Must have histologically or cytologically confirmed diagnosis of MDS according to WHO classification that meets IPSS low to intermediate-1 risk criteria.
Confirmed high-risk HPV infection by a commercially available high-risk DNA assay (eg, Hybrid Capture II [Qiagen]);
Patients must have high risk neuroblastoma according to COG risk classification at the time of study registration. Patients who were initially considered low or intermediate risk, but then reclassified as high risk are also eligible.
Intermediate risk based on National Comprehensive Cancer Network (NCCN)
High risk AML (see NCCN risk criteria)
Low risk AML (see NCCN risk criteria)
Patients must have stage 3 high-risk neuroblastoma or metastatic neuroblastoma (not 4S)
All patients will undergo testing for prognostic factors according to the CLL-IPI (testing obtained ? 120 days prior to registration)\r\n* Note: Patients with CLL-IPI risk category of high risk or very high risk (total score of 4-10) will be randomized to Arms A or B\r\n* Note: Patients with CLL-IPI risk category of low risk or intermediate risk (total score of 0-3) will be registered to Arm C
For high risk and very high risk CLL-IPI (Arms A and B) only; obtained ? 30 days prior to randomization: Absolute neutrophil count (ANC) ? 1500/mm^3
For high risk and very high risk CLL-IPI (Arms A and B) only; obtained ? 30 days prior to randomization: Platelet count ? 100,000/mm^3
For high risk and very high risk CLL-IPI (Arms A and B) only; obtained ? 30 days prior to randomization: Hemoglobin ? 11.0 g/dL
For high risk and very high risk CLL-IPI (Arms A and B) only; obtained ? 30 days prior to randomization: Aspartate aminotransferase (aspartate transaminase [AST]) ? 3 x upper limit of normal (ULN)
For high risk and very high risk CLL-IPI (Arms A and B) only; obtained ? 30 days prior to randomization: Creatinine ? 1.5 X ULN
High dose TBI regimen: 18 to =< 45 years
International Prognostic Scoring System (IPSS)-revised (R) intermediate, high or very high risk disease
Histologic confirmation of one of the following:\r\n* Myelodysplastic syndrome (MDS) fulfilling all the criteria below:\r\n** International Prognostic Scoring System (IPSS) intermediate-2 or high risk MDS; or Revised International Prognostic Scoring\r\nSystem (IPSS-R) intermediate, high, or very high risk MDS \r\n** Relapsed/refractory disease\r\n** Requiring therapy based on the presence of one or more cytopenias (hemoglobin [Hb] < 10 g/dL and/or red cell transfusion dependence, platelets < 50,000/uL, or absolute neutrophil count [ANC] < 1,000/ uL) or excess blasts (>= 5% in the peripheral blood or bone marrow)\r\n* Myelodysplastic/myeloproliferative Neoplasm (MDS/MPN) as defined by the World Health Organization (WHO) criteria, including chronic myelomonocytic leukemia (CMML), atypical chronic myelogenous leukemia (CML), and MDS/MPN-unclassifiable fulfilling the criteria listed below\r\n** Relapsed/refractory disease\r\n** Requiring therapy based on the presence of one or more cytopenias (Hb < 10 g/dL and/or red cell transfusion dependence, platelets < 50,000/uL, or ANC < 1,000/ uL), excess blasts (>= 5% in the peripheral blood or bone marrow), or palpable splenomegaly or\r\n** Previously untreated subsets (e.g atypical CML, MDS/MPN unclassifiable) requiring therapy as defined above and in whom no approved therapies exist\r\n* Myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis fulfilling the criteria listed below:\r\n** Intermediate-2 or high risk disease according to the Dynamic International Prognostic Scoring System (DIPSS) classification\r\n** Refractory or intolerant to JAK inhibitor therapy, or deemed - ineligible for ruxolitinib therapy due to pre- existing cytopenias (thrombocytopenia < 50,000/uL, anemia hemoglobin < 9 g/dL or red cell transfusion dependence); requiring further therapy based on the presence of one or more cytopenias (Hb < 10 g/dL and/or red cell transfusion dependence, platelets < 50,000/uL, or ANC < 1,000/uL), excess blasts (>= 5% in the peripheral blood or bone marrow), or palpable splenomegaly
Patients at high-risk for thromboembolic disease, such as those with prior heterotopic ossification (h/o) deep venous thrombosis (DVT).
Classified as high or very high risk according to the Revised International Prognostic Scoring System (IPSS-R) risk category.
Previously treated MDS or CMML, defined as prior treatment with at least one hypomethylating agent (HMA; azacitidine and/or decitabine) for intermediate or high risk MDS or CMML whose disease progressed or relapsed as follows:
High-risk group: Oral cavity, larynx, hypopharynx, or p16-negative oropharynx cancer, stage T1-2N2a-N3 or T3-4-N0-3 based on the following diagnostic workup:
Must have had invasive urothelial cancer at high risk of recurrence originating in the bladder, ureter, or renal pelvis
Other disorders associated with a high risk of fistula formation including percutaneous endoscopic gastrostomy (PEG) tube placement within 3 months before the first dose of study therapy
Subjects at significant risk with general anesthesia
For patients with oropharyngeal cancer only: the institution will do p16 testing, and if p16 is negative, this tissue must be submitted for central review for confirmation before Step 2 registration; note: if the institution finds that the patient is p16 positive, the patient is excluded from this trial on the basis of distinct biology, prognosis, and low- or intermediate-risk rather than high-risk status
IPSS-R risk category of Intermediate, High, or Very High assessed at screening
Serious medical illness that in the judgment of the treating physician places the patient at high risk of operative mortality
Drugs which have an increased risk for QTc prolongation should be avoided
Declared high-risk for anesthesia by attending anesthesiologist, cardiologist, or other physician
Patients who are concurrently receiving or requiring any of the following agents, which may increase the risk for mithramycin related toxicities, such as hemorrhage:\r\n* Thrombolytic agents\r\n* Aspirin or salicylate-containing products, which may increase risk of hemorrhage\r\n* Dextran\r\n* Dipyridamole\r\n* Sulfinpyrazone\r\n* Valproic acid\r\n* Clopidogrel
>= 55 years of age with AML of any risk classification, or 18-54 years of age with intermediate or high risk AML as defined by National Comprehensive Cancer Network (NCCN) risk assignment
High risk disease defined by all of the following:\r\n* >= 10% bone marrow plasma cells AND\r\n* Abnormal serum free light chain (FLC) ratio (< 0.26 or > 1.65) by serum FLC assay AND\r\n* Monotypic plasma cell S-phase >= 0.3%
MDS classified as Low-risk or Int-1 risk or Int-2 risk according to International Prognostic Scoring System (IPSS) classification; in addition, patients should never have been classified as High-risk since their MDS was diagnosed.
High-risk acute myeloid leukemia in CR1 with any of the following features:\r\n* Complex karyotype (>= 3 clonal chromosomal abnormalities)\r\n* Any of the following high risk chromosomal abnormalities: \r\n** Monosomal karyotype (-5, 5q-, -7, 7q-)\r\n** t(11q23), t(9;11), inv(3), t(3;3) t(6;9) t(9;22)\r\n** Normal karyotype with FLT3-internal tandem duplication (ITD) mutation
Other disorders associated with a high risk of fistula formation including percutaneous endoscopic gastrostomy (PEG) tube placement within 3 months before the first dose of study therapy or concurrent evidence of intraluminal tumor involving the trachea and esophagus
Any co-morbid condition that is in the view of the attending physician renders the patient at high risk from treatment complications
Patients must have high-risk neuroblastoma
Myelodysplastic syndrome of all subtypes including refractory anemia (RA) or all International Prognostic Scoring Systems (IPSS) categories if severe pancytopenia, transfusion requirements not responsive to therapy, or high risk cytogenetics; blasts must be less than 5%; if >= 5% requires therapy (induction or hypomethylating agents) pre-transplant to decrease disease burden
HIGH RISK PATIENTS:
Patients must have adverse-risk AML defined as poor-risk karyotype (complex, monosomal or other known poor risk cytogenetic abnormality), poor-risk mutations/fusion genes or known history of antecedent hematologic disorder, or treatment related AML, or be >= 60 years of age
AML with favorable risk cytogenetic abnormalities including t(15;17), t(8;21) or inv(16)
Tumors must be staged T1-4, N2b-3, M0 (human papillomavirus positive [HPV]+ or HPV negative [-]); patients with HPV+ tumors should have at least one high risk feature such as T4, N3, or smoking history of > 10 pack years
Patients must have high risk or intermediate risk disease, defined below; staging evaluation should be determined by imaging studies and complete head and neck exam in accordance with the American Joint committee on Cancer Staging Manual, 7th edition\r\n* High risk patients must meet one of the following criteria: \r\n** Unresectable oral cavity\r\n** Larynx: T4 any N; T2-3 and >= N2a\r\n** Hypopharynx and p16(-) oropharynx: stage III-IVb except T1N1\r\n** p16(-) Oropharnyx: stage III-IVb except T1N1\r\n* Intermediate risk, p16(+) oropharynx patients must meet one of the following criteria:\r\n** T3 or >= N2a AND >= 10 pack-years tobacco exposure \r\n** T4 disease, irrespective of smoking status\r\n** N3 disease, irrespective of smoking status\r\n*** Note: for oropharyngeal patients, p16 status must be known, and can be performed at the local site; p16-positive disease is defined as >= 70% of tumor cells demonstrating diffuse nuclear and cytoplasmic staining by p16 immunohistochemistry (IHC); a positive test for human papilloma virus (HPV)-16 by in-situ hybridization (ISH), if this is the local site preference for assessing HPV status, may substitute for p16 IHC testing; p16 staining is not required for non-oropharyngeal sites
Patients must have high or intermediate risk disease, defined as follows:\r\n* High risk: non-oropharyngeal subsite including larynx or hypopharynx (p16 status not required) or human papilloma virus (HPV)/p16- oropharynx subsite\r\n* Intermediate risk: HPV/p16+ oropharyngeal squamous cell cancer with: >= 10 pack (pk)-year (yr) smoking history and >= N2 nodal disease, or the presence of T4 tumor or N3 nodal disease, irrespective of smoking status
High risk myelodysplastic syndrome (MDS)\r\n* Intermediate II and high risk by International Prognostic Scoring System (IPSS)\r\n* Intermediate, high, or very high by World Health Organization (WHO) classification-based Prognostic Scoring System (WPSS)\r\n* Transfusion dependent\r\n* Therapy-related MDS or MDS evolved from previous hematological disorder (excepting myelofibrosis)
High risk neuroblastoma with persistent or relapsed disease
Patients must have low- or intermediate-risk adenocarcinoma of the prostate as defined by:\r\n* Low-risk disease\r\n** Histopathology score (Gleason sum): =< 6, and T-stage (per current American Joint Committee on Cancer [AJCC] staging criteria): T1c-T2a, and prostate-specific antigen (PSA) < 10\r\n* Intermediate-risk disease as either:\r\n** Histopathology score (Gleason sum): =< 6, T-stage (per current AJCC staging criteria): T1c-T2a, and PSA: > 10 but =< 20 Or\r\n** Histopathology score (Gleason sum): 7 with =< 50% cores positive, T-stage (per current AJCC staging criteria): T1c-T2a, and PSA < 10
Risk factors for Torsades de Pointes such as hypokalemia, hypomagnesemia, cardiac failure, clinically significant/symptomatic bradycardia, or high-grade atrioventricular (AV) block
Patients must have at least one of the following indicators of poor risk disease:\r\n* >= 3 risk factors by the Follicular Lymphoma International Prognostic Index, or 2 risk factors by the Follicular Lymphoma International Prognostic Index and at least one bulky mass or lymph node > 6 cm in size \r\n* Follicular Lymphoma International Prognostic Index (FLIPI score):\r\n** Age > 60 years\r\n** Involvement of > 4 nodal sites\r\n** Stage III-IV disease\r\n** Hemoglobin < 12.0 g/dL\r\n** Lactate dehydrogenase (LDH) > upper limit of normal (ULN)\r\n*** 0-1 of the above risk factors: low risk\r\n*** 2 risk factors: intermediate risk\r\n*** >= 3 risk factors: poor risk
Patients with pre-existing medical conditions or other factors that renders them at high risk for regimen related toxicity or ineligible for a conventional myeloablative HCT
Patients must have high risk disease as defined below:\r\n* High risk PV ANY ONE of the following:\r\n** Age > 60 years\r\n** Previous documented thrombosis, erythromelalgia or migraine (severe, recurrent, requiring medications, and felt to be secondary to the myeloproliferative neoplasm [MPN]) either after diagnosis or within 10 years before diagnosis and considered to be disease related\r\n** Significant (i.e. > 5 cm below costal margin on palpation) or symptomatic (splenic infarcts or requiring analgesia)\r\n** Platelets > 1000 x 10^9/L\r\n** Diabetes or hypertension requiring pharmacological therapy for > 6 months\r\n* High risk ET ANY ONE of the following:\r\n** Age > 60 years\r\n** Platelet count > 1500 x 10^9/L\r\n** Previous documented thrombosis, erythromelalgia or migraine headaches (severe, recurrent, requiring medications, and felt to be secondary to the MPN) either after diagnosis or within 10 years before diagnosis and considered to be disease related\r\n** Previous hemorrhage related to ET\r\n** Diabetes or hypertension requiring pharmacological therapy for > 6 months
Intermediate-2/ high-risk disease as per Dynamic International Prognostic Scoring System (IPSS) (DIPSS) criteria OR intermediate-1 risk disease with one of the following additional unfavorable features known to impact the survival adversely\r\n* Red cell transfusion dependency\r\n* Unfavorable karyotype\r\n* Platelet count < 100 x 10^9/l
Patients must have high risk disease as defined below:\r\n* High risk PV ANY ONE of the following:\r\n** Age >= 60 years\r\n** Previous documented thrombosis, erythromelalgia or migraine (severe, recurrent, requiring medications, and felt to be secondary to the myeloproliferative neoplasm [MPN]) either after diagnosis or within 10 years before diagnosis and considered to be disease related\r\n** Significant splenomegaly (> 5 cm below the left costal margin) or symptomatic splenomegaly (splenic infarcts or requiring analgesia)\r\n** Platelets > 1000 x 10^9/L\r\n** Diabetes or hypertension requiring pharmacological therapy for > 6 months\r\n* High risk ET ANY ONE of the following:\r\n** Age >= 60 years\r\n** Platelet count > 1500 x 10^9/L\r\n** Previous documented thrombosis, erythromelalgia or migraine headaches (severe, recurrent, requiring medications, and felt to be secondary to the MPN) either after diagnosis or within 10 years before diagnosis and considered to be disease related\r\n** Previous hemorrhage related to ET\r\n** Diabetes or hypertension requiring pharmacological therapy for > 6 months
High-grade serous adenocarcinoma
Patients who are deemed to have high-risk or extensive metastatic, hormone sensitive prostate cancer (mHSPC) per “clinical judgment” of the treating physician are eligible for enrollment if they are unsuitable candidates for docetaxel or if they have declined docetaxel therapy
DIPSS intermediate-2 or high risk MF
Patients must have recurrent/progressive high-risk neuroblastoma, refractory high-risk neuroblastoma that had less than a partial response to standard treatment or persistent high-risk neuroblastoma that had at least a partial response to standard treatment.
Patients with standard-risk acute GVHD, according to refined Minnesota Criteria. Refined Minnesota Criteria are available at https://redcap.ahc.umn.edu/surveys/?s=bNmFhseJIf. Standard-risk acute GVHD according to the refined Minnesota Risk Criteria requires meeting one of the criteria below:
Poor medical risk
Subject has favorable risk cytogenetics as categorized by the National Comprehensive Cancer Network Guidelines Version 2, 2014 for AML.
Must have ? 1 of the following high-risk prognostic factors:
Subject has a high cardiovascular risk, including, but not limited to, recent coronary stenting or myocardial infarction in the past year.
Inclusion Criteria:\n\n        For Part 1:Patients must have one of the following diagnoses:\n\n          -  Aggressive systemic mastocytosis (ASM) as confirmed by World Heath Organization (WHO)\n             diagnostic criteria.\n\n          -  Systemic mastocytosis-associated hematologic non-mast cell disease (SM-AHNMD) as\n             confirmed by WHO diagnostic criteria, and the patient also has at least 1 C-finding\n             attributable to systemic mastocytosis (SM). The AHNMD must be myeloid, with the\n             following exceptions that are excluded: Acute myeloid leukemia (AML), Myelodysplastic\n             syndrome (MDS) that is very high- or high-risk as defined by the International\n             prognostic scoring system for myelodysplastic syndromes (IPSS-R) and Philadelphia\n             chromosome positive malignancies.\n\n          -  Mast cell leukemia (MCL) as confirmed per WHO diagnostic criteria.\n\n          -  Histologically- or cytologically- confirmed myeloid malignancy as confirmed by IWG-MRT\n             or WHO diagnostic criteria that is relapsed or refractory to standard treatments. AML,\n             MDS that is very high- or high-risk as defined by the IPSS-R, and Philadelphia\n             chromosome positive malignancies are excluded.\n\n          -  Upon discussion with the sponsor, other relapsed or refractory, potentially\n             avapritinib-responsive hematologic neoplasms (e.g., evidence of aberrant KIT or\n             platelet derived growth factor receptor (PDGFR) signaling) may be considered for\n             enrollment.\n\n        For Part 2:\n\n          -  Group 1: ASM as confirmed by WHO diagnostic criteria.\n\n          -  Group 2: SM-AHNMD as confirmed by WHO diagnostic criteria, that also has at least 1\n             C-finding attributable to SM. The AHNMD must be myeloid, with the following exceptions\n             that are excluded: AML, MDS that is very high- or high-risk as defined by the IPSS-R,\n             and Philadelphia chromosome positive malignancies.\n\n          -  Group 3: MCL as confirmed per WHO diagnostic criteria.\n\n        Eastern Cooperative Oncology Group (ECOG) performance status of 0-3.\n\n        Exclusion Criteria:\n\n          -  QT interval corrected using Fridericia's formula (QTcF) >470 milliseconds\n\n          -  Platelet count <25,000/mL\n\n          -  Absolute neutrophil count <500/mL\n\n          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) >3 x the upper\n             limit of normal (ULN); >5 × ULN if associated with clinically suspected liver\n             infiltration by mastocytosis or another disease for which the patient enrolled into\n             the study\n\n          -  Total bilirubin >1.5 × ULN; >3 × ULN if associated with liver infiltration by the\n             disease being treated or in the presence of Gilbert's Disease\n\n          -  Estimated (Cockroft-Gault formula) or measured creatinine clearance <40 mL/min\n\n          -  Brain malignancy or metastases to the brain\n\n          -  History of a seizure disorder or requirement for anti-seizure medication\n\n          -  Known risk of intracranial bleeding, such as a brain aneurysm or history of subdural\n             or subarachnoid bleeding
Has previously untreated AML and is considered to be at high risk for disease progression and/or is unlikely to derive more than transient benefit from standard therapy by having at least one of the following:
Has previously untreated AML and is considered to be at high risk for disease progression and/or is unlikely to derive more than transient benefit from standard therapy by having at least one of the following:
Refrain from sperm and blood donation for at least 90 days after the final dose of durvalumab 8. For Cohort A subject must be transplant non-eligible (TNE) and meet at least one of the following high risk factors:
Have one of the following high risk factors at the time of NDMM diagnosis;
Central confirmation of the categorization of the MDS risk classification, as per the Revised - International prognostic scoring system (IPSS-R) Intermediate risk with >10% blasts or poor or very poor cytogenetics, or IPSS-R High or Very High risk (Results of central pathology review required prior to receiving the first dose of IP). Acute myeloid leukemia (AML) Cohort:
Patient must have IPSS categories of low- or intermediate-1-risk disease; patients must have IPSS score determined by cytogenetic analysis prior to randomization; patients must have cytogenetic analysis done (to calculate IPSS); if the current bone marrow biopsy is a dry tap, patients with cytogenetic failure and < 10% marrow blasts will be eligible; subjects with cytogenetic failure must have previous cytogenetic results (fluorescence in situ hybridization [FISH] is not a substitute) within the last 6 months post last type of MDS treatment (in this case, not referring to growth factors as type of MDS treatment)
Patients aged < 50 yrs at high risk for regimen related toxicity using standard high dose regimens; factors considered high risk include pre-existing conditions such as a chronic disease affecting kidneys, liver, lungs, or heart or previous failed HCT
Subject must have untreated, histologically proven high-risk DLBCL defined by IPI 3 to 5 and/or Double-hit or higher or double protein expression
patients must have high intermediate or high risk disease
Diagnosis of acute myeloid leukemia (AML) or high or very high-risk MDS by International Prognostic Scoring System revised for whom transplant is recommended
High-risk AML for which transplant is recommend based on cytogenetic, molecular and morphologic features; patients must meet institutional standards for disease control prior to transplant
For MDS; International Prognostic Scoring System (IPSS)-revised criteria of high or very high at diagnosis
Agreement to comply with all local requirements of the lenalidomide risk minimization plan
Intermediate-1, intermediate -2, or high risk disease according to the IWG -MRT Dynamic International Prognostic Scoring System
If the patient has been diagnosed with MDS, disease of patient must be classified as Int-1, Intermediate-2 (Int-2) or High-risk, according to International Prognosis Scoring System (IPSS) classification. Note: Only Int-2 or High-risk patients will be enrolled at French site.
For the Phase II portion only, patients must have high-risk MM based on one or more of the following criteria at the time of initial diagnosis (prior to any chemotherapy):\r\n* Poor-risk genomic signature according to the University of Arkansas 70-gene model (available clinically as myeloma prognostic risk score [MyPRS] score, Signal Genetics, Inc) AND/OR\r\n* Translocation (14;16), and/or translocation (14;20), and/or deletion (17p) by fluorescence in-situ hybridization (FISH) or cytogenetics AND/OR\r\n* Primary plasma cell leukemia (defined by either >= 2,000 plasma cells/mL of peripheral blood, or 20% on a manual differential count) AND/OR\r\n* Serum lactate dehydrogenase (LDH) >= 2 x institutional upper limit of normal (IULN) AND/OR\r\n* 1q21 amplification by FISH analysis AND/OR\r\n* High risk by the SKY92 signature\r\n* All tests for establishing high risk status must be completed within 28 days prior to registration for patients with no prior therapy, or within 28 days prior to initiation of first Induction course for patients with prior therapy
Patients age >= 55 years with AML OR patients age < 55 years with AML, who also through pre-existing medical conditions or prior therapy are considered to be at high risk for serious toxicities associated with a conventional, high-dose preparative regimen
Only patients with Relapse Risk Score > 0 (“high risk”) will be enrolled during Part 1; patients with all Relapse Risk Scores will be enrolled during Part 2 (low risk group terminated August 2014)
International Prognostic Scoring System (IPSS) low risk or intermediate-1 risk MDS
Have uncontrolled metabolic disorders or other nonmalignant organ or systemic diseases or secondary effects of cancer that induce a high medical risk and/or make assessment of survival uncertain.
For MDS and CMML participants, prognostic risk category, based on the Revised International Prognostic Scoring System (IPSS R), of:
Very high (>6 points),
High (>4.5 to 6 points), or
Intermediate (>3 to 4.5 points): a participant determined to be in the Intermediate Prognostic Risk Category is only allowable in the setting of >=5% bone marrow myeloblasts.
For dose escalation part: Patients with MCL at high risk for tumor lysis syndrome
QT prolonging drugs with a known risk to induce TdP
Diagnosis of MF (either primary or post essential thrombocythemia/polycythemia vera) requiring therapy, including those previously treated and relapsed or refractory, or if newly diagnosed, with intermediate-1 or -2 or high risk according to International Prognostic Scoring System (IPSS)
Active connective tissue disorders, such as lupus or scleroderma, which in the opinion of the treating physician may put the patient at high risk for immunologic toxicity
To be considered at high risk for induction mortality patients must have 1 or 2 of the following risk factors (patients >= 60 must have at least 1 risk factor, patients < 60 must have at least 2 risk factors) present; at least one risk factor in every patient must be an AML-related factor: \r\n* AML-related factors include: \r\n** Antecedent hematologic disorder (AHD) (MDS, chronic myelomonocytic leukemia [CMML], or MPD) or history of exposure to cytotoxic chemotherapy [therapy-related (t)-AML]), or WHO-defined AML with MDS-related changes or apparent de novo AML with MDS-associated karyotype\r\n** Unfavorable cytogenetics as defined by the European Leukemia Net\r\n* Patient-related factors:\r\n** Age >= 70\r\n** ECOG performance status (PS) >= 2\r\n* Co-morbidities:\r\n** Serum creatinine > 1.3 g/dL
current or prior high-risk sexual activity,
current or prior high-risk sexual activity,
Clinically significant ECG abnormalities or any factors that increase the risk of corrected QT interval prolongation or risk of arrhythmic events
Patients with risk factors for QTc prolongation or Torsade de Pointes.
Classified as high risk OR intermediate-2 risk as defined by the International Prognostic Scoring System (IPSS) for PMF, or intermediate-1 risk (IPSS) associated with symptomatic splenomegaly, hepatomegaly, anemia (hemoglobin < 10.0 g/dL), and/or unresponsive to available therapy
Subjects who are at a risk for a thromboembolic event and are not willing to take prophylaxis for it.
Patients with previously treated low or intermediate-1 risk MDS by the International Prognostic Scoring System (IPSS) classification
Previously untreated low or intermediate-1 risk MDS patients
Patients must be intermediate or high-risk Rai stage CLL\r\n* Intermediate risk (formerly Rai stage I/II) is defined by lymphocytosis plus enlarged lymph nodes at any site, with or without hepatomegaly or splenomegaly\r\n* High risk (formerly Rai stage III/IV) is defined by lymphocytosis with or without enlarged nodes and spleen plus disease-related anemia (hemoglobin < 11 g/dL) or thrombocytopenia (platelet count < 100 x 10^9/L) that is not attributable to autoimmune hemolytic anemia or thrombocytopenia
Able to tolerate high-dose cyclophosphamide, fludarabine and high-dose IL-2
Able to tolerate high-dose cyclophosphamide, fludarabine, and high-dose IL-2
Active connective tissue disorders, such as lupus or scleroderma, that in the opinion of the treating physician may put the patient at high risk for radiation toxicity
Pathologically (histologically) proven diagnosis of prostatic adenocarcinoma, at intermediate risk for recurrence, within 180 days prior to registration as determined by having one or more of the following intermediate-risk features: \r\n* Gleason score 7\r\n* Prostate specific antigen (PSA) > 10 but =< 20\r\n* Clinical stage T2b-T2c\r\n* Patients previously diagnosed with low risk (Gleason score =< 6, clinical stage < T2a, and PSA < 10) prostate cancer undergoing active surveillance who are re-biopsied and found to have intermediate risk disease according to the protocol criteria are eligible for enrollment within 180 days of the repeat biopsy procedure
Patients with all three intermediate risk factors who also have >= 50% of the number of their biopsy cores positive for cancer are ineligible for this trial
High-risk NB as defined by risk-related treatment guidelines and the International NB Staging System i.e., stage 4 with (any age) or without (> 365 days of age) v-MYC myelocytomatosis viral related oncogene, neuroblastoma derived (avian) (MYCN) amplification, MYCN-amplified stage 3 (unresectable; any age), or MYCN-amplified stage 4S
Participant has active, high risk bleeding (such as, via gastric ulcers or gastric varices) within 14 days prior to randomization
Diagnosis of myelofibrosis (either primary or post essential thrombocythemia/polycythemia vera) requiring therapy, including those previously treated and relapsed or refractory, or if newly diagnosed, with intermediate-1 or -2 or high risk according to International Working Group (IWG) criteria
A risk of reactivation of hepatitis B or C.
Myelodysplastic Syndrome (MDS), fulfilling the following criteria: Subjects with de novo MDS who have or have previously had Intermediate-2 or High risk disease as determined by the International Prognostic Scoring System (IPSS). Current Intermediate-2 or High risk disease is not a requirement; Subjects must have < 20% bone marrow blasts, assessed within 60 days of informed consent; Subjects may have received prior therapy for the treatment of MDS prior to enrollment
International Prognostic Scoring System (IPSS) low Risk or intermediate-1 risk MDS
Eligible diagnoses:\r\n* Myelodysplastic syndrome (MDS) including chronic myelomonocytic leukemia (CMML) with at least one of the following poor-risk features:\r\n** Poor-risk cytogenetics\r\n** International Prognostic Scoring System (IPSS) score of intermediate (INT)-2 of greater\r\n** Treatment-related or secondary MDS\r\n** MDS diagnosed before age 21\r\n** Progression on or lack of response to standard deoxyribonucleic acid (DNA)-methyltransferase inhibitor therapy\r\n** Life-threatening cytopenias, including those requiring frequent transfusions\r\n* Small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL) with 17p deletion, or with progression < 6 months after second or greater treatment regimen; must have the following to be an acceptable candidate as well:\r\n** =< 20% of bone marrow cellularity involved by SLL/CLL (to lower risk of graft rejection)\r\n** No lymph nodes >= 5 cm in any dimension\r\n** No massive splenomegaly, defined as > 6 cm below the left costal margin\r\n* T-cell prolymphocytic leukemia (PLL) in partial remission (PR) or better prior to transplantation; must also have =< 20% of bone marrow cellularity involved by PLL (to lower risk of graft rejection)\r\n* Interferon- or tyrosine kinase-refractory chronic myelogenous leukemia (CML) in first chronic phase, tyrosine kinase inhibitor (TKI)-intolerant CML in first chronic phase, or CML in second or subsequent chronic phase\r\n* Philadelphia chromosome negative myeloproliferative disease (including myelofibrosis)\r\n** Intermediate-2 or high risk score by Dynamic International Prognostic Scoring System (DIPSS) plus is required for a diagnosis of myelofibrosis\r\n* Multiple myeloma or plasma cell leukemia with a PR or better to the last treatment regimen, based on the International Myeloma Working Group (IMWG) criteria\r\n* Hematologic malignancy in complete remission with minimal residual disease (MRD) non detectable OR detectable by conventional cytogenetics, fluorescence in situ hybridization (FISH), flow cytometry, or molecular testing or hematologic malignancies in partial remission
High or high-intermediate disease risk.
High risk of developing thromboembolic events, who are unwilling to take venous thromboembolism prophylaxis.
Patients must have disease that requires therapy, including intermediate-1, intermediate-2, or high-risk disease according to the International Prognostic Scoring System (IPSS) or Dynamic-IPSS
Subjects must have a target meningioma that is not amenable to surgery due to patient preference or high risk for surgical complications
Adult patients with intermediate or high-risk smoldering multiple myeloma (SMM) are eligible; patients need to have clonal bone marrow plasma cells >= 10% and/or monoclonal spike in blood of >= 3 g/dL and/or monoclonal urine component (Bence jones proteinuria) >= 500 mg/24 hours and need to meet subject inclusion criteria and exclusion criteria as per below
Patients must have histologically confirmed SMM based on the following criteria:\r\n* (A) Mayo clinic criteria (patient must have at least 2 risk factors present):\r\n** 1. Bone marrow core biopsy plasma cell involvement by cluster of differentiation (CD)138 immunohistochemistry >= 10%\r\n** 2. Monoclonal spike >= 3 g/dL\r\n** 3. Free light chain ratio in serum < 0.125 or > 8; *2 of 3 risk factors: intermediate risk for progression at a rate of 51% at 5 years, *3 of 3 risk factors: high risk for progression at a rate of 76% at 5 years\r\n* OR (B) Programa para el Tratamiento de Hemopatias Malignas (PETHEMA) criteria (patient must have at least 1 risk factor present)\r\n** 1. >= 95% abnormal plasma cells/total plasma cells in bone marrow compartment\r\n** 2. Immunoparesis *1 of 2 risk factors: intermediate risk for progression at a rate of 46% at 5 years, *2 of 2 risk factors: high risk for progression at a rate of 72% at 5 years\r\n* OR (C) Southwestern Oncology Group (SWOG) criteria (patient must have 2 risk factors present or one risk factor if this risk factor is a 70–gene signature (GEP70) score of > 37.2) \r\n** 1. Monoclonal spike >= 3 g/dL\r\n** 2. Involved free light chain >= 25 mg/dL\r\n** 3. GEP70 risk score > 37.2 *>= 2 risk factors: high risk of progression at a rate of 70% at 2 years*; we would also include patients with 1 risk factor as long as this risk factor is GEP70 risk score > 37.2 since patients with this risk factor have an intermediate risk of progression at a rate of 50% at 2 years
Patients with MDS (up to 20% blasts) of any risk; patients with lower risk MDS (low and intermediate [int]-1 by International Prognostic Scoring System [IPSS]) could have received prior non-hypomethylating agent therapy (i.e. growth factors or lenalidomide); patients with higher risk MDS (int-2 or high by IPSS) should not have received prior therapy with a hypomethylating agent
Tumors must be histologically or cytologically proven and considered low or intermediate grade; patients with high grade neuroendocrine carcinomas or small cell carcinomas are excluded from the study
Other serious non-malignancy-associated medical conditions that may be expected to limit life expectancy or significantly increase the risk of Serious Adverse Events (SAEs).
Patients underwent allo-SCT with intermediate risk and high risk AML and high risk MDS (defined by American Society for Blood and Marrow Transplantation [ASBMT] criteria), who are within 60 to 100 days after allo-SCT
Patients with high risk hematologic malignancies, including those with induction failure and in relapse
High risk ET/PV (age > 60; history of thrombosis). Previously treated with at least one other agent (hydroxyurea, interferon, anagrelide) and determined to be either intolerant/resistant
The patient is deemed by their treating physician to be at low risk of recurrence from previous malignancies.
At least one high-risk cytogenetic feature defined by the presence of 17p deletion, 11q deletion and/or p53 mutation
Any patient with any factors that increase the risk of QTc prolongation or risk of arrhythmic events or unexplained sudden death under 40 years of age in first-degree relatives or any concomitant medication known to prolong the QT interval.
Systemic diseases associated with unacceptable anesthesia or operative risk
Patients with a history of pulmonary disease or findings present on baseline high-resolution chest CT scan that, in the opinion of the treating investigator, would put the patient at risk of complications of pneumonitis will be excluded
Participants must have the following features:\r\n* Intermediate-risk disease defined as Gleason 4+3 = 7 disease OR\r\n* High-risk disease defined as Gleason 8-10 OR PSA > 20 ng/mL OR T3 disease (by prostate MRI)
Have a diagnosis of high-risk AML as established by a poor-risk karyotype, poor-risk molecular features, a therapy-related AML, age >= 60 or with antecedent hematologic disorder
Patients must not have a known diagnosis of hepatitis B or C; patients with the following risk factors must have hepatitis screening pre-treatment:\r\n* Blood transfusions prior to 1990\r\n* Current or prior intravenous (IV) drug users\r\n* Current or prior dialysis\r\n* Household contact with a hepatitis B or C patient\r\n* Current or prior high-risk sexual activity\r\n* History of jaundice
High-risk participants who have received chemopreventive drugs in the past are not allowed to enter the study
Patients with one of the following diagnoses:\r\n* Intermediate, high and very high risk (per International Prognostic Scoring System [IPSS]-revised [R]) untreated MDS or any MDS with >= 5% marrow blasts (by French American British [FAB] and World Health Organization [WHO] diagnostic criteria); NOTE: MDS/MPN overlap is allowed\r\n* CMML requiring treatment per doctor of medicine (MD) judgment\r\n* Low and very low risk MDS patients symptomatic and/or transfusion dependent, (>= 4 U red blood cells [RBC] over the preceding 12 week period) who have failed erythropoietin-stimulating agents (ESAs) or who have a low likelihood of responding to ESAs\r\n* MDS and CMML patients relapsed/refractory to hypomethylating agents as evidenced by one of the following:\r\n** Progressed at any time during treatment with hypomethylating agents\r\n** Failed to achieve a response after 6 cycles of 5-azacytidine or 4 cycles of decitabine\r\n** Progressed after treatment with hypomethylating agents had been discontinued\r\n*** NOTE: MDS/MPN overlap is allowed\r\n* Relapsed or refractory AML exposed to =< 3 prior regimens (note, induction and consolidation including stem cell transplantation count as one regimen)\r\n* For exploratory phase I LDE225 days 1-7 with azacitidine or LDE225 days 1-28 with decitabine cohorts only: untreated AML/CMML/MDS/MPN overlap or relapsed/refractory AML/CMML/MDS/MPN overlap WITHOUT prior exposure to a hypomethylating agent (HMA)\r\n* Elderly (age >= 60) untreated AML and not a candidate for induction therapy\r\n* Untreated AML < 60 year of age who are not candidates to undergo standard induction chemotherapy\r\n* Primary myelofibrosis (PMF) and post essential thrombocytopenia (ET)/polycythemia vera (PV) MF with a Dynamic International Prognostic Scoring System (DIPSS)-plus score of intermediate or high, or a > 10% blasts in the marrow and who are in need of therapy and who have failed previous treatment with a janus kinase 2 (JAK2) inhibitor and, if appropriate, have failed Interferon based treatment
IPSS low, intermediate -1, intermediate-2, or high risk MDS (including CMML) in Dose Escalation and Dose Confirmation-Randomization; only intermediate-2, or high risk MDS in Dose Confirmation-Open Label
High risk OR intermediate-2 risk as defined by Dynamic International Prognostic Scoring System (DIPSS), OR intermediate-1 risk as defined by DIPSS and associated with symptomatic splenomegaly, and/or hepatomegaly
Intermediate or high-grade: grades 2 or 3 on scale of 1-3
Subjects must have their diagnosis of high-risk AML or high-risk MDS confirmed by pathologic review of bone marrow biopsy according to World Health Organization (WHO) guidelines
We will define patients as high risk AML and thus eligible if they meet one or more of the following criteria:\r\n* Secondary AML (from underlying MDS or therapy related)\r\n* Presence of complex cytogenetic abnormalities (>= 3 cytogenetic abnormalities), all monosomies, del 5q, del 7q, inv3, t(3;3), t(6;9), t(9;22), abn 11q23 (excluding t[9;11])\r\n* Fms-related tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) mutation positive\r\n* Age >= 65 years
We will define subjects as high risk MDS and thus eligible if they have a MD Anderson Comprehensive Cancer MDS Risk Score >= 9
Other disorders associated with a high risk of fistula formation including percutaneous endoscopic gastrostomy (PEG) tube placement within 3 months before the first dose of study therapy
Patients previously diagnosed with low risk (Gleason score < 6, clinical stage < T2a, and PSA < 10) prostate cancer undergoing active surveillance who are re-biopsied and found to have intermediate risk disease according to the protocol criteria are eligible for enrollment within 180 days of the repeat biopsy procedure
Pathological diagnosis of AML (by World Health Organization [WHO] criteria) or higher risk MDS (includes intermediate [int]-2 and high risk MDS by International Prognostic Scoring System (IPSS) along with one of the following:\r\n* Patients with de novo or secondary MDS with progression/refractoriness after HMA treatment who have not transformed to AML\r\n* Patients with MDS and prior HMA treatment for MDS who transformed to AML \r\n* Patients with AML who are refractory/relapsed after HMA therapy for their AML are eligible
Advanced MDS by virtue of intermediate-2 or high-risk MDS by International Prognostic Scoring System (IPSS) score, or high or very-high risk by IPSS-revised (R)
Either: (i) high-risk disease, defined as T1 and/or high-grade and/or CIS or (ii) intermediate-risk disease, defined as Ta low-grade with at least 3 of the following 4 risk factors: multiple tumors, tumor size > 3cm, early recurrence (<1 year from previous staging procedure), or recurrence with a frequency of more than once in any 12 month period
Low risk pathologic features (by AJCC 2010 criteria)
Subjects with CLL or SLL who are BTKi intolerant and have received < 6 months of BTKi therapy or are ineligible for BTKi must have failed at least 1 (high-risk) or 2 (standard-risk) other lines of non-BTKi therapy.
Subjects who relapse within 1 year of initial treatment, excluding patients with favorable-risk status according to NCCN Guidelines (NCCN 2015). Favorable-risk cytogenetics: inv(16), t(16;16), t(8;21), t(15;17)
Patient must be stratified/classified into one of the following risk categories:\r\n* The highest risk feature assessed pathologically will determine the patient's category/treatment arm assignment\r\n** Low risk: T1-T2, N0-N1 AND clear (> 3 mm) margins, AND no ECE or PNI/LVI\r\n** High risk: any of the following features: one or more positive margin(s) with any T stage, OR “extensive” (> 1 mm) ECE, OR >= 5 metastatic lymph nodes (regardless of primary tumor margin status)\r\n* Intermediate risk: any of the following features: one or more “close” (< 3 mm) margin(s), OR “minimal” (=< 1 mm) ECE, OR N2a (1 or more lymph node > 3 cm in diameter), OR N2b (2-4 lymph nodes positive, any diameter < 6 cm), OR with perineural invasion or lymphovascular invasion\r\n** Unknown risk: patients found to have N2C or N3 disease on final pathologic analysis are at unknown risk for recurrence, but are not candidates for deintensified adjuvant therapy in this trial; these patients will be treated on Arm C\r\n** Patients not categorized into the appropriate risk category will be considered ineligible for the study
Due to risk of disease exacerbation patients with porphyria are not eligible
Low, intermediate-1, intermediate-2 or High-risk category by IPSS
Patients with VS or meningiomas deemed very high surgical risk for stroke and/or other complications by the attending surgeon, such as meningiomas with major vascular or dural sinus infiltration
Patients who are high risk for developing the following anthracycline, paclitaxel, trastuzumab or pertuzumab related toxicities including:\r\n* History of congestive heart failure, myocardial infarction or cardiomyopathy, uncontrolled hypertension despite adequate medications\r\n* Pre-existing peripheral neuropathy >= grade 3 \r\n* Prior anthracycline therapy\r\n* Known hypersensitivity to any of the study medications\r\n* Patients older than age 65 due to increased risk of cardiotoxicity
Hodgkin's disease: High risk subjects with responsive disease after first relapse.
The clinical trial will be offered to all high risk (defined below) patients with hematologic malignancies who require stem cell transplants as part of their standard of care using matched related or unrelated donors
Patients with progressive, locally recurrent, or metastatic osteosarcoma (i.e. high-risk only) with at least one indicator lesion avid on 99mTc-MDP scan will be eligible.
For subjects with metastatic RCC who have had no prior systemic treatment for RCC and are considered a poor risk according to Motzer criteria, defined by having >= 3 of the following 5 risk factors for short survival: Karnofsky performance score < 80%, lactate dehydrogenase (LDH) > 1.5 X of ULN, hemoglobin < lower limit of normal (LLN), corrected serum calcium > 10 mg/dL (2.5mM), a time from initial diagnosis of RCC to initiation of systemic therapy of < 1 year
High-risk or Intermediate-2 risk MF (as defined by the Dynamic International Prognostic Scoring System [DIPSS-plus])
Patients with peripheral blood involvement with white blood count (WBC) > 20,000 or those considered to be at high risk for tumor lysis syndrome (TLS) by high tumor burden are EXCLUDED for the Phase I component of the study
De novo or secondary International Prognostic Scoring System (IPSS) low- or intermediate-1- risk myelodysplastic syndromes (MDS), including chronic myelomonocytic leukemia (CMML)
Serious chronic or acute illness considered by the principal investigator (PI) to constitute an unwarranted high risk for investigational drug treatment
Low-dose aspirin (=< 325 mg/day) may be continued in subjects at higher risk for arterial thromboembolic disease
The patient has either refused or is not considered an appropriate immediate candidate for transplantation and is considered to be at high risk for recurrence by having at least one of the following prognostic factors:
High risk cytogenetics (-5, -7, del(5q), abnormal 3q, 11q23 translocations, complex cytogenetics) or if cytogenetics are normal the presence of a FLT3 mutation without a NPM1 mutation
At high risk for a venous thromboembolic event (VTE) and not willing to take VTE prophylaxis
Low and intermediate-risk disease as defined by MIPI score.
Patient at high risk for deep vein thrombosis not willing to take DVT prophylaxis.
Patients must have one of the following hematologic malignancies: \r\n* AML any stage and cytogenetic risk-group with the only exception being that patients with AML and favorable cytogenetics t(8;21), inv 16, or t(15;17) who achieve complete remission with one course of induction chemotherapy are not eligible; \r\n* MDS with intermediate or high risk International Prognostic Scoring System score (IPSS scores) or treatment related MDS; patients with low risk MDS are eligible if they fail to respond to hypomethylating agent therapy such as azacitidine or decitabine
Other disorders associated with a high risk of fistula formation, including percutaneous endoscopic gastrostomy (PEG) tube placement within 3 months before the first dose of study therapy or concurrent evidence of intraluminal tumor involving the trachea or esophagus
Untreated histologically confirmed acute myeloid leukemia OR advanced myelodysplastic syndrome (intermediate [INT]-2 or High risk) not previously treated with anthracycline-based chemotherapy OR a therapy-related myeloid neoplasm
Intermediate or high grade lesions: 2 or 3 on a scale of 1-3 or grades 2 to 4 on a scale of 1-4
Patients with advanced myelodysplastic syndromes (MDS), including those with International Prognostic Scoring System (IPSS) Int-2 and high-risk disease with less than 10% marrow blasts and no circulating myeloblasts after most recent therapy. Patients with acute leukemia that develops from a pre-existing MDS must meet the inclusion criteria for patients with AML detailed above.
Patient age > 50, or for patients < 50 years of age but because of pre-existing medical conditions or prior therapy are considered to be at high risk for regimen-related toxicity associated with conventional myeloablative transplants
Require treatment for MF and classified at least as intermediate risk level 1 defined by the International Working Group.
All prognostic risk groups according to the International Prostate Symptom Score (IPSS) and MD Anderson Risk Model
Ages =< 50 years of age with hematologic diseases treatable by allogeneic HCT who through pre-existing medical conditions or prior therapy are considered to be at high risk for regimen related toxicity associated with a high dose transplant (> 40% risk of transplant related mortality [TRM]); this criterion can include patients with a HCT-comorbidity index (CI) score of >= 1; transplants should be approved for these inclusion criteria by the principal investigators at the collaborating centers and at the Fred Hutchinson Cancer Research Center (FHCRC); all children < 12 years must be discussed with the FHCRC principal investigator (PI) prior to registration
Patients with rapidly progressive intermediate or high grade NHL
Patients with high risk cytogenetics at diagnosis must have achieved at least very good partial response following autologous stem cell transplantation (cohort 2):\r\n* Patients must have complex karyotype, 1q25, del17p, t4;14 and/or t14;16 by fluorescence in situ hybridization (FISH) and/or del13 by karyotyping
Patient must agree to allow 2 separate biopsies of any malignant lesion; biopsies do not need to be done if:\r\n* Tumor is not considered accessible by either the investigator or the person performing the biopsy (it is determined the risk is too high due to location near vital organs or too great of a risk of an adverse event)\r\n* Patient is on anticoagulation and it would be unsafe to temporarily hold the anticoagulation\r\n* Consent of the principal investigator (PI) not to have a biopsy done
Female subjects with histologically diagnosed relapsed high-grade serous or high-grade endometrioid ovarian cancer;
Subjects must have undergone primary gross total resection (no re-resected patients are allowed) with fulfillment of at least 1 of the following histologic criteria for high-risk disease:
Patients at high risk of residual HL post ASCT
Patients must weigh between 35-135 kg MDS low -int-1 risk as determined by IPSS score and confirmed by bone marrow examination within 6 months prior to study entry
Myelodysplastic syndromes with International Prognostic Scoring System score (IPSS score) >= 2 or myelodysplasia that has not responded to chemotherapy
Aggressive non-Hodgkin lymphomas (NHL) and other histologies such as diffuse large B cell (DLBC) NHL - a) not eligible for autologous HCT, b) not eligible for high-dose HCT, c) after failed autologous HCT, or d) be part of a tandem auto-allo approach for high risk patients
CRITERIA FOR ASSIGNMENT TO THE LOW-RISK ARM OF THE PROTOCOL:
Histologic diagnosis of nodular desmoplastic medulloblastoma (includes medulloblastoma with extensive nodularity); patients with focal areas of anaplasia or other atypical features suggesting a more aggressive phenotype in a tumor which would otherwise be considered nodular desmoplastic should be treated on the intermediate risk arm; in such unusual cases, final risk stratification will be at the discretion of the principal investigator and study pathologist
LOW RISK HIGH-GRADE GLIOMA (patients must meet all of the following criteria):
CRITERIA FOR ASSIGNMENT TO THE INTERMEDIATE-RISK ARM OF THE PROTOCOL
CRITERIA FOR ASSIGNMENT TO THE HIGH-RISK ARM OF THE PROTOCOL
Patients with extraneural metastasis are eligible for treatment on the high-risk arm
Myelodysplastic syndrome\r\n* Refractory anemia with excess blasts (RAEB) I or II\r\n* High-risk International Prognostic Scoring System (IPSS)\r\n* Secondary MDS
Patients must have one of the following hematologic malignancies: acute myelogenous leukemia (AML), induction failure, high-risk for relapse first remission (with intermediate-risk or high-risk cytogenetics, fms-related tyrosine kinase 3 [flt3] mutation positive and/or evidence of minimal residual disease by flow cytometry), secondary leukemia from prior chemotherapy and/or arising from myelodysplastic syndrome (MDS), Langerhan's cell histiocytosis, any disease beyond first remission; or
Intermediate or adverse cytogenetic risk
AML associated with favorable risk karyotypes including inv(16), t(8;21), t(16;16), or t(15;17)
Patients must have high-risk neuroblastoma according to COG risk classification at the time of study enrollment.
Patients may be eligible after only 1 previous regimen if in a high risk category
Any co-morbid disease that would increase risk of toxicity as determined by PI
Patients with severe SSc as defined by the American College of Rheumatology and at high-risk for a fatal outcome based on the following prognostic factors in groups 1-5:
Pregnancy Prevention Risk Management Plan
Understand that CC-122 could have a potential teratogenic risk.
Must meet any of these criteria for high risk disease:\r\n* Relapse or progressive disease according to uniform response criteria within 2 years after starting first-line therapy or within 2 years after autologous stem cell transplant\r\n* Failure to achieve partial response (PR) within 6 months of staring first-line therapy\r\n* Presence of high risk cytogenetic features (t[14;16], t[14;20], deletion 17p)\r\n* Chromosome 14 translocations other than to chromosome 11\r\n* Chromosome 1p deletion and 1q amplification\r\n* Myeloma Prognostic Risk Score (MyPRS) gene expression score equal or higher than 45.2\r\n* High risk 70 gene expression profile (MyPRS GEP70^TM)\r\n* Any other high risk genetic profile that is determined by future IMWG consensus or by internal myeloma panel consensus; for the latter, any additional criteria will be submitted as an addendum\r\n* Diagnosed with multiple myeloma between the ages of 18-50
The original diagnosis of AML must have been confirmed by bone marrow aspirate and/or biopsy review by a Johns Hopkins (JH) hematopathologist; patients are eligible if they have AML that is not classified as poor-risk or APL; poor-risk AML is defined as therapy-related, arising from a previous marrow disorder, or de novo AML associated with any of the following characteristics: trilineage dysplasia, fms-related tyrosine kinase 3 (FLT3)/internal tandem duplication (ITD) mutation, poor risk cytogenetics including: chromosome 3, 5, or 7 abnormalities, t(6;9), and complex karyotype
Patients with high-risk cytogenetics, t(4:14); t(14;16), t(14:20), deletion p17, gain in 1q, are eligible
Histologically confirmed intermediate- to high-risk prostate adenocarcinoma (T1c-T3b, PSA > 10, and/or Gleason score >= 7) who have a greater than 15% risk of lymph node involvement as determined by the Roach equation
Patients with a histologically confirmed diagnosis of myelodysplastic syndrome (MDS) by World Health Organization (WHO) classification, and lower-risk MDS as defined by the International Prostate Symptom Score (IPSS) classification (low or intermediate [int]-1 disease) or Revised-International Prostate Symptom Score (R-IPSS) classification (very low or low) are eligible; patients with MDS/myeloproliferative neoplasm (MPD) overlap syndromes including chronic myelomonocytic leukemia (CMML) are also eligible if they have low or int-1 disease per IPSS; patients may have received MDS-directed therapy (i.e. lenalidomide), although patients with prior exposure to hypomethylating agents (e.g. 5-azacitidine or decitabine) are not eligible
Patients with low risk myelofibrosis
Patients must have a history of de novo or therapy-related AML (defined by World Health Organization [WHO] classification of >= 20% bone marrow blasts) or high-risk MDS (defined by International Prognostic Scoring System [IPSS] or Revised International Prognostic Scoring System [IPSS-R])
High-risk (class 2) uveal melanoma as determined by gene expression profiling (GEP)
MDS or high-risk AML, morphologically confirmed and based on World Health Organization criteria), who are transplant candidates with an available human leukocyte antigen (HLA)-matched sibling or unrelated donor with at least 8/8 match\r\n* Definition of high-risk AML:\r\n** Age >= 60 years\r\n** Age < 60 years with any of the following:\r\n*** Secondary AML\r\n*** Poor risk cytogenetics, which include abnormalities of chromosome 3, 5, or 7, trisomy 8, 11q23 abnormalities, t(6;9), 20q-, and complex karyotype\r\n*** Fms-related tyrosine kinase 3 (FLT3) mutation\r\n*** Disease status >= second complete remission (CR2) at time of HCT\r\n*** Detectable disease at time of HCT
Intermediate 1, intermediate 2 or high risk MDS by IPSS
International prognostic score-revised (IPSS-R) of >3.5 (Intermediate, High or Very High)
Physical or psychiatric conditions that in the estimation of the investigator place the patient at high risk of toxicity or non-compliance
Physical or psychiatric conditions that in the estimation of the investigator place the patient at high risk of toxicity, non-compliance, or inability to complete the study requirements
Intermediate -1 or -2 or high-risk Myelofibrosis (per Passamonti et al 2010)
Pregnant women are excluded to avoid the risk of systemic intrauterine/neonatal HSV infection
History of acute or chronic pancreatitis or any risk factors that may increase the risk of pancreatitis.
Patients must have Low or Intermediate 1 stage of disease as defined by International Working Group (IWG) risk stratification of primary myelofibrosis in the dynamic international prognostic scoring system (DIPSS). In addition, they must show some active hematopoiesis with a cellularity of at least 15%, irrespective of the degree of reticulin and/or collagen fibrosis as defined by Manoharan criteria.
Patients with Intermediate 2 or High risk stage of disease as defined by International Working Group (IWG) risk stratification of primary myelofibrosis in the dynamic international prognostic scoring system (DIPSS) and/or bone marrow biopsy showing less than 15% cellularity in the presence +2 or more reticulin fibrosis (by Manoharan criteria), collagen fibrosis, or osteosclerosis.
High cardiovascular risk, including but not limited to, recent coronary stenting or myocardial infarction in the past year
Any serious medical condition considered by the investigator to constitute an unwarranted high risk for investigational treatment
Chronic or high-dose corticosteroid therapy
Other disorders associated with a high risk of fistula formation including percutaneous endoscopic gastrostomy (PEG) tube placement within 3 months before the first dose of study therapy
Understand that the (investigational Product) IP could have a potential teratogenic risk.
Intermediate or High risk, poor prognosis CLL/SLL
Since induction courses can vary at referring institutions, in cases where the drugs (or doses) are in question, 2 or more members of the study committee will decide on the adequacy of the therapy; likewise, if in cases where high risk status is in question (either based on disease type or risk classification) 2 or more members of the study committee will decide on the adequacy of the therapy
Patients at significant increased risk for general anesthesia are not eligible
High risk OR intermediate-2 risk defined by dynamic international prognostic scoring system (DIPSS) OR intermediate-1 risk defined by DIPSS and associated with symptomatic splenomegaly and/or hepatomegaly
Patients whose AML is classified as favorable according to the European LeukemiaNet (ELN) disease risk assessment.
Intermediate-2 or High-grade risk MDS (including chronic myelomonocytic leukemia (CMML))
Malignancy at high risk of treatment failure for which autologous hematopoietic stem cell transplantation is considered within standard practice\r\n* Group A: High-risk neuroblastoma \r\n* Group B: Recurrent or refractory Hodgkin lymphoma; recurrent or refractory non-Hodgkin lymphoma\r\n* Group C: High-risk, recurrent or metastatic sarcoma; recurrent or advanced stage Wilms tumor; desmoplastic small round cell tumor; metastatic or recurrent retinoblastoma, high-risk germ cell tumors, and high-risk brain tumors
Patients with isolated hepatic metastasis must satisfy a Clinical Risk Score of 3 or higher
The first 3 patients on the experimental arm will be high risk myeloma and subsequent patients will be low risk myeloma; high risk multiple myeloma patient who have: deletion (del) 17p, del 1p, T (4;14), T (14;16), plasma cell leukemia (PCL), > 1 cytogenetic abnormality, hypodeploid; patients who fail adequate initial therapy (Revlimid, Velcade, dexamethasone [RVD], thalidomide, Velcade, dexamethasone [TVD], or cyclophosphamide, bortezomib, dexamethasone [CyBorD]) and planned to receive non-chemotherapy/cytotoxic salvage regimen (except for single agent cyclophosphamide)
Patients with surgically resected metastatic disease at high risk of relapse are also eligible.
Intermediate-2/ high-risk disease as per Dynamic International Prognostic Scoring System (IPSS) (DIPSS) criteria or intermediate-1 risk disease with one of the following features within one year from screening:\r\n* Red cell transfusion dependency\r\n* Unfavorable karyotype \r\n* Platelet count < 100 x 10^9/L\r\n* Symptomatic splenomegaly\r\n* Peripheral blood (PB) blasts > 1%
Individuals with PMF, post-PV MF, or post-ET MF classified as high risk or intermediate risk as defined by the Dynamic International Prognostic Scoring System (DIPSS) for PMF or DIPSS Plus, if cytogenetics are available
Subject currently being treated with biguanides or other agents known to increase risk of lactic acidosis.
Diagnosis of MF (either primary or post essential thrombocythemia/polycythemia vera) requiring therapy, including those previously treated and relapsed or refractory, or if newly diagnosed, with intermediate-1 or -2 or high risk according to International Prognostic Scoring System (IPSS)
Patients with relapsed/refractory AML regardless of cytogenetic risk
Subjects with COPD or subjects with increased risk of respiratory depression
Classification by the International Prognostic Scoring System (IPSS) as low or intermediate-1 risk MDS according to cytogenetics, blood cytopenias and % bone marrow blasts within 28 days of the first dose of treatment in this study
Other disorders associated with a high risk of fistula formation including percutaneous endoscopic gastrostomy (PEG) tube placement within 3 months before the first dose of study therapy or concurrent evidence of intraluminal tumor involving the trachea and esophagus
Subject has concurrent, uncontrolled medical condition, laboratory abnormality, or psychiatric illness which could place him/her at unacceptable risk, including, but not limited to: Subject has been diagnosed or treated for another malignancy within 3 years of enrolment, except in situ malignancy, or low-risk prostate, skin or cervix cancer after curative therapy A co-morbid condition which, in the view of the Investigators, renders the subject at high risk from treatment complications.
Known adverse cytogenetic risk
Known favorable cytogenetic risk
Patients must have diagnostic/pre-treatment specimens obtained within 28 days prior to registration submitted for cytogenetic (and fluorescent in situ hybridization [FISH] if possible) analysis to determine risk status; high risk classification will be defined as del(5q)/-5, del(7q)/-7, abn3q26 [inv(3)/t(3;3)], 11q23 rearrangement [except t(9;11)], 17p-, t(6;9), t(9;22), complex (at least 3 unrelated abnormalities [abn]), and monosomal karyotype (either loss of two different chromosomes or loss of one chromosome along with a structural chromosome abnormality other than add, ring and mar); karyograms and cytogenetics/FISH analysis reports must be submitted for discipline review
Congenital or acquired immune deficiency at increased risk of infection.
WHO-confirmed MDS, with an International Prognostic Scoring System (IPSS) score of > 1.0 (defined as intermediate 2 or high-risk)
Documented diagnosis of myelodysplastic syndromes (MDS) or non-proliferative chronic myelomonocytic leukemia (CMML), White blood cells (WBC) ? 13,000 /mm3, World Health Organization (WHO)) that meets International Prognostic Scoring System (IPSS) criteria for low or intermediate-1 risk disease
Patients must be candidates for short or long term androgen deprivation in combination with external beam radiation therapy (RT) based on the following criteria:\r\n* Intermediate risk disease: T2b/c, or Gleason 7, or prostate-specific antigen (PSA) 10-20\r\n* High risk disease: Gleason 8-10, or PSA > 20, or T3/4
Scheduled to receive chemotherapeutic agent(s) associated with moderate, high, or very high risk of emetogenicity for no more than 5 consecutive days for a documented malignancy, or a chemotherapy regimen not previously tolerated due to vomiting
Participants with unrelated adverse events, medical illnesses, or changes in performance status that, per investigator discretion, put them at high risk for continuing participation in the clinical study
Any co-morbid condition that‚ in the view of the attending physician‚ renders the patient at high risk from treatment complications
History of significant disease that in the Investigator's opinion would put the patient at high risk on the trial
Patients must have high-risk neuroblastoma according to COG risk classification at the time of study enrollment. Patients who were initially considered low or intermediate risk, but then reclassified as high risk are also eligible.
International Prognostic Scoring System (IPSS) low- or intermediate-1-risk MDS, including chronic myelomonocytic leukemia (CMML)-1
De novo myelodysplastic syndromes (MDS): International Prognostic Scoring System intermediate-1 (IPSS-1) with poor risk cytogenetics or higher IPSS
Other disorders associated with a high risk of fistula formation including percutaneous endoscopic gastrostomy (PEG) tube placement within 3 months before the first dose of study therapy or concurrent evidence of intraluminal tumor involving the trachea and esophagus
If re-evaluation of a patient’s disease shows unfavorable risk features or intermediate risk features, the patient will be removed from the HOD08 study and consented to the HOD99 or the HOD05 study
Intermediate or high risk disease, defined as stage IB, IIIA, any IV or IA/IIA with “E” lesion(s), 3 or more nodal sites involved, or bulky mediastinal adenopathy
Malignancies other than disease under study within 5 years prior to Cycle 1, Day 1, with the exception of those with a negligible risk of metastasis or death
Intermediate risk prostate cancer patients will be eligible for this study; risk groups will be assigned as per National Comprehensive Cancer Network (NCCN) guidelines; intermediate risk patients will be defined as:\r\n* PSA 10-20 ng/ml or\r\n* Gleason score = 7 or\r\n* Clinical stage T2b/T2c
Has factors conferring high risk of relapse.
Part II: Patients with one of the following documented conditions: CML in CP that is Philadelphia chromosome (Ph)-positive (by cytogenetics) or BCR-ABL1-positive by fluorescent in situ hybridization [FISH], or PCR), as well as resistant to at least 2 FDA-approved tyrosine kinase inhibitors (TKIs); or a myeloproliferative neoplasia which includes: PMF and myelofibrosis secondary to polycythemia vera (PV) and essential thrombocythemia (ET) myelofibrosis (MF) (with intermediate-1, intermediate-2 or high risk disease according to the International Working Group [IWG] prognostic scoring system) (i.e., Non-Acute Group patients).
Serious uncontrolled concomitant disease that would contraindicate the use of any of the investigational drugs used in this study or would put the participants at high risk for treatment-related complications
Histologically/cytologically confirmed, advanced solid tumors, AML or high risk and very high risk MDS
Serious intercurrent chronic or acute illness, such as cardiac disease, hepatic disease, or other illness considered by the investigator as an unwarranted high risk for an investigational product
3. A pathologically confirmed diagnosis of AML or CMML-2 by World Health Organization (WHO) classification that is relapsed or refractory or for which no current therapies are anticipated to result in a durable remission, or MDS by WHO classification are RAEB-1 or RAEB-2 and that have failed at least three cycles of hypomethylating therapy, or primary (PMF), post-polycythemia vera (PPMF) or post-essential thrombocythemia (PTMF) MF by WHO classification, are high-risk category by the Dynamic International Prognostic Scoring System (DIPSS Plus), have ?1% circulating blasts, and have failed treatment with ruxolitinib
MDS with at least one of the following poor-risk features:\r\n* Poor-risk cytogenetics\r\n* International Prognostic Scoring System (IPSS) score of intermediate-2 (INT-2) or greater\r\n* Treatment-related or secondary MDS\r\n* MDS diagnosed before age 21 years\r\n* Progression on or lack of response to standard deoxyribonucleic acid (DNA)-methyltransferase inhibitor therapy\r\n* Life-threatening cytopenias, including those requiring frequent transfusions
Any co-morbid condition that in the judgment of the investigator renders the subject at high risk of treatment complications or reduces the possibility of assessing clinical effect.
Myelodysplastic syndrome (MDS) with International Prognostic Scoring System (IPSS) intermediate-2 or higher; or therapy-related MDS
Subject must be either (1) at high risk for candidiasis (1 month - < 2 years ONLY) or (2) have a definitive diagnosis of invasive candidiasis/candidemia (ICC) (All age groups)
Has any other clinically important abnormalities such that risk to patient of participation outweighs the potential benefit of therapy as determined by the investigator
Rhabdomyosarcoma (RMS) \r\n * RMS patients will be eligible if relapse occurs following an autologous transplant or if the patient relapses following initial treatment, but is not eligible for an autologous transplant; patients who do not achieve a CR with initial therapy will also be eligible provided they can be rendered free of bulky disease as defined above\r\n * RMS patients will be eligible in first CR or PR if they present with high-risk disease; high risk disease is defined as stage IV RMS with at least 2 other risk factors listed from the following: \r\n** Bone and/or bone marrow metastases \r\n** Age =< 1 or >= 10 years \r\n** Primary tumor site other than head/neck (except parameningeal) or genitourinary (GU) (except bladder or prostate)
High risk renal cancer per modified UISS criteria
All patients must be diagnosed with neuroblastoma, and categorized as high risk at the time of diagnosis; exception: patients who are initially diagnosed as non-high-risk neuroblastoma, but later converted (and/or relapsed) to high risk neuroblastoma are also eligible
No more than 12 months from the date of starting the first induction chemotherapy after diagnosis to the date of ASCT except for the rare occasions as noted below; for tandem ASCT patients, this will be the date of the FIRST stem cell infusion; exception: for those who are initially diagnosed as non-high risk neuroblastoma, but later converted (and/or relapsed) to high risk neuroblastoma, the 12 months restriction should start from the date of induction therapy for high risk neuroblastoma (not from the initial induction therapy for non-high risk disease), to the date of ASCT
Patients with relapsed/refractory AML regardless of cytogenetic risk
Patients whom, in the opinion of the treating urologic oncologist, should undergo cystectomy due to high-risk features
Patients must have disease that requires therapy, including intermediate-1, intermediate-2, or high-risk disease according to the International Prognostic Scoring System (IPSS) or Dynamic-IPSS
High-risk cancer planned for neoadjuvant therapy, full or partial excision of one or both neurovascular bundles
Confirmed diagnosis of:\r\n* Primary myelofibrosis (MF) or post-polycythemia vera (PV)/essential thrombocythemia (ET) MF classified as high risk, intermediate-2 risk, or intermediate-1 risk who are unresponsive or unable to receive current therapy which may or may not include ruxolitinib; OR\r\n* MPN/MDS syndrome (chronic myelomonocytic leukemia [CMML], juvenile myelomonocytic leukemia [JMML], atypical chronic myeloid leukemia [aCML], or MDS/MPN unclassifiable)
Diagnosis and staging of de novo acute GvHD of the GIT (any site except isolated “upper” GIT disease);\r\n* Patients must be classifief as \high risk\ by the combined Minnesota (MN)/Center for International Blood and Marrow Transplant (CIBMTR) grading\r\n* Biopsies should be obtained by full endoscopy including esophagogastroduodenoscopy (EGD) and flexible sigmoidoscopy or colonoscopy; however, it is not necessary to have confirmation of GvHD diagnosis before initiating IASA therapy; such is not recommended\r\n* If other diagnoses are excluded, it is not necessary to biopsy all potentially involved sites in the GIT to initiate therapy\r\n* It is possible that other diagnoses may be present as well, and this should not exclude eligibility so long as they are distinct (this statement is generic, but applies especially to various types of infective colitis; that said, concomitant anti-infective therapy must be on-going)\r\n* Although this study is designed for patient with high-risk de novo, acute GvHD of the lower gastrointestinal tract, selected patients with more advanced, even “steroid refractory” acute GvHD may be considered for this study providing they fulfill two criteria: 1) have no history of prior IASA; and 2) are personally approved by the principal investigator (PI), or in his absence, his designee
Poor surgical risk (defined as American Society of Anesthesiology Score > 3)
Patient is at high risk for bowel perforation
High-risk patients (as defined by the American College of Sports Medicine risk-stratification schema using the American College of Sports Medicine [ACSM]/American Heart Association exercise pre-participation questionnaire) who do not receive medical clearance from a physician
Any co-morbid condition which, in the view of the principal investigator, renders the patient at high risk from treatment complications
Patients with AML or high-risk MDS receiving non-intensive therapy including hypomethylating agents, single-agent chemotherapy, targeted therapy agents, single or combination non-intensive agents offered on a clinical trial, or any other chemotherapy offered for patients with AML and high-risk MDS that does not require a prolonged 4-6 week hospitalization including the following populations:\r\n* Newly diagnosed AML\r\n* Relapsed or primary refractory AML\r\n* Newly diagnosed high-risk MDS\r\n* Relapsed or primary refractory high-risk MDS
Currently reside in one of the four selected high risk neighborhoods
The participant has a 5-year breast cancer risk 1.67% or lifetime risk of 20% according to the Gail model; or has a prior diagnosis of lobular carcinoma in situ (LCIS)
On cytotoxic chemotherapy in the high/moderate/low emetogenic risk categories or oral antineoplastic agents in the high or moderate emetogenic risk categories according to the latest National Comprehensive Cancer Network (NCCN) guideline within 2 weeks of study enrollment
Patients with any co-morbid condition which renders patients at high risk of treatment complication
Additionally, patients that have a high risk of breast cancer and are pursuing prophylactic mastectomies (for example BRCA mutation carriers) will also be considered
High risk of regurgitation
Myelodysplastic syndrome (MDS) including chronic myelomonocytic leukemia (CMML) with at least one of the following poor?risk features:\r\n* Poor?risk cytogenetics\r\n* International Prognostic Scoring System (IPSS) score of intermediate (INT)?2 of greater\r\n* Treatment?related or secondary MDS\r\n* MDS diagnosed before age 21\r\n* Progression on or lack of response to standard deoxyribonucleic acid (DNA)?methyltransferase inhibitor therapy\r\n* Life?threatening cytopenias, including those requiring frequent transfusions
Philadelphia chromosome negative myeloproliferative disease (including myelofibrosis)\r\n* Intermediate-2 or high risk score by Dynamic International Prognostic Scoring System (DIPSS) Plus is required for a diagnosis of myelofibrosis
Have a history of chronic untreated trauma (unrelated to their cancer), psychiatric hospitalization or suicide attempt(s) in the past 5 years, or current moderate to high suicide risk based on our pilot study and other study experience that such patients often require more intensive resources.
High-Risk aGVHD (ARM 1)\r\n* Pediatric or adult hematopoietic cell transplant (HCT) recipients with high-risk acute GVHD, as determined by the refined Minnesota Medical (MN) acute GVHD risk score OR high risk on the basis of blood biomarkers (Ann Arbor score 3); patients in this arm must start treatment within the first 7 days after onset of high-risk aGVHD or
VTE risk score >= 1, using labs drawn within 28 days of consent
pT1 breast cancer, excised with negative margins\r\n* Low risk-pTis breast cancer, excised with negative margins\r\n* Criteria for low risk-pTis:\r\n** Screen-detected\r\n** Low to intermediate nuclear grade\r\n** =< 2.5 cm in size\r\n** Resected with negative margins at >= 3 mm
Able to complete an acceptable baseline cardiopulmonary exercise test (CPET), in the absence of high risk electrocardiogram (ECG) findings or other inappropriate response to exercise as determined by the investigator
Neurologic and/or orthopedic limitations that preclude the participation in the training program (e.g. bone metastases that may pose a high risk of pathologic fracture)
Patients considered to be high risk for surgical complications will be excluded from the research protocol
Histological diagnosis of high-grade osteosarcoma
Able to complete an acceptable baseline cardiopulmonary exercise testing (CPET), in the absence of high-risk electrocardiograph (ECG) findings or other inappropriate response to exercise as determined by the investigator
PHASE I: Women with sporadic cancers (WSC) (does not have hereditary breast/ovarian cancer syndrome [BRCA carrier, strong family history]); if there is any uncertainty, the surgeon will use the Tyrer-Cuzick (Tyrer et al., 2004) risk model to calculate risk; the Tyrer-Cuzick model calculates a personal lifetime risk of breast cancer based on multiple factors; it has become the standard model because it incorporates not only factors such as estrogen exposure and first degree relatives, but also second degree relatives and paternal lineage; a lifetime risk of 20% or greater is considered high risk and would necessitate increased screening methods to the traditional annual mammogram; for this study, anyone with a lifetime risk up to 19% on the Tyrer-Cuzick model will be considered average risk for breast cancer; anyone with a lifetime risk of 20% or greater will be excluded from participation
PHASE II: WSC (does not have hereditary breast/ovarian cancer syndrome [BRCA carrier, strong family history]); if there is any uncertainty, the surgeon will use the Tyrer-Cuzick (Tyrer et al., 2004) risk model to calculate risk; for this study, anyone with a lifetime risk up to 19% on the Tyrer-Cuzick model will be considered average risk for breast cancer; anyone with a lifetime risk of 20% or greater will be excluded from participation
Diagnosis of neuroblastoma as defined by the International Neuroblastoma Risk Group Staging System (INRGSS)
Any patient unable to complete the exercise regimen or deemed a fall risk will be excluded
Revised international prognostic scoring system (IPSS-R) intermediate, high or very high
Individuals with active uncontrolled hepatitis B or C are ineligible as they are at high risk of lethal treatment-related hepatotoxicity after HSCT
Patient condition associated with a high risk of bleeding such as recent surgery or peptic ulcer disease
AYA meets at least 1 of 3 criteria indicating potentially high palliative care or end-of-life needs:            \r\n* Any high-risk cancer (i.e., metastatic or stage IV)\r\n* Receiving moderate- to high-intensity chemotherapy during 3-5 consecutive days in an in- or out-patient setting\r\n* A diagnosis with an estimated 5-year event-free survival of < 50%
The patient must be aware of the high risk and experimental nature of the treatment and provide informed consent
Any intraoperative complications that per the investigator's judgment increase the risk to the patient.
High risk for poor compliance with radiotherapy, humidification, or follow-up as assessed by the investigator
Patients that are high risk for TLS or potential/intermediate risk for TLS as described below:\r\n* High risk: Hyperuricemia of malignancy (uric acid levels > 7.5); or diagnosis of very aggressive lymphoma/leukemia based on Revised European-American Lymphoma (REAL) classification; acute myeloid leukemia, chronic myelogenous leukemia (CML) in blast crisis; high grade myelodysplastic syndrome only if they have > 10% bone marrow blast involvement and given aggressive treatment similar to acute myeloid leukemia (AML)\r\n* Potential risk: Diagnosis of aggressive lymphoma/leukemia based on (REAL) classification; plus one or more of the following criteria: lactate dehydrogenase (LDH) >= 2 x upper limit of normal (UNL); stage III-IV disease; stage I-II disease with at least 1 lymph node/tumor > 5 cm in diameter; for patients with potential/intermediate risk for TLS-only those planned to receive alternating regimens (or non-standard regimens) in 2 cycles (example; rituximab-hyperfractionated cyclophosphamide-vincristine [vincristine sulfate]-Adriamycin [doxorubicin hydrochloride]-dexamethasone [R-Hyper-CVAD] alternating with methotrexate/arabinofuranosyl cytidine [cytarabine] [MTX/ARA-C]) will be eligible
Primary or secondary myelofibrosis intermediate or high risk by Dynamic International Prognostic Scoring System 26 (DIPSS26) in chronic or accelerated phase
All at-risk relatives of the participants found to have LS
Patients referred for lung cancer screening using a low-dose CT scan modality who are considered high risk by USPSTF guidelines.
Known to be at high risk for breast cancer due to known or suspected pathologic BRCA mutation (i.e. first-degree relative with known mutation) or prior chest radiation therapy before age 30
BMRI indication: high risk screening per American Cancer Society (ACS) guidelines
DEFINITION OF RISK COHORT FOR CONSIDERATION OF RPFNA
Have a 5 year Gail risk of >= 1.67% or 2x risk for age as given in model, or 10 year Tyrer-Cuzick risk 2x population risk as listed in model
MEDICAL ELIGIBILITY CRITERIA FOR PERTAINING TO HIGH RISK GROUPS UNDERGOING RPFNA
High risk population: African American men are at higher risk for prostate cancer compared to that of Caucasian men; this study is targeting the local community which is predominantly African American and thus considered high risk; since this study is being done in the context of a larger community outreach effort, other races and ethnicities will not be excluded, however the majority of the participants will be African American
Phase II: Participants must be asymptomatic, not at increased risk due to family history or personal high risk syndromes
Risk of cancer greater than 60% or less than 20%
Patients at high risk of colorectal cancer e.g. ulcerative colitis
Patient must be scheduled to undergo allogeneic hematopoietic stem cell transplant (HSCT) (adults or pediatric patients) or autologous HSCT (pediatric patients only) and be at high risk or very high risk of developing veno-occlusive disease (VOD).
All patients must have a pathologically confirmed diagnosis of neuroblastoma, < 30.99 years of age and classified as high risk at the time of diagnosis. Exception: patients who are initially diagnosed as non-high-risk neuroblastoma, but later converted (and/or relapsed) to high risk neuroblastoma are also eligible.
Women must be considered at high risk for breast cancer based on family history (first or second degree relative diagnosed with breast cancer under the age of 60), prior precancerous biopsy or a 5-year Gail model risk estimate of >= 1.7% or 10-year Tyrer-Cuzick risk of 2 x population risk as listed in the model
RANDOMIZED CONTROLLED TRIAL: Utilizing the breast cancer surveillance consortium risk calculator, women will have either (a) an intermediate 5-year risk (> 1.67%-2.49%) and extremely dense breasts or (b) a high 5-year risk (>= 2.50%) and either heterogeneously dense or extremely dense breasts
At high risk of developing breast cancer defined by one or more of the following: Gail model lifetime risk > 20%, a history of deleterious BRCA1/2 mutation or mantle radiation, a history of ductal cancer in situ, or a history of high risk premalignant breast lesion.
Patients with myelodysplastic syndrome (MDS) with intermediate-2 or high risk per International Prognostic Scoring System (IPSS) (or intermediate, high, very high risk by Revised International Prognostic Scoring System [IPSS-R]) or myeloproliferative neoplasm; primary or secondary if high-risk features or refractory disease
30 pack year history of smoking (i.e., the base population of high risk smokers to get screened)
Intermediate (Int)-2 or high risk myelodysplastic syndrome (MDS)
At high risk of developing breast cancer (history of ductal carcinoma in situ [DCIS], lobular carcinoma in situ [LCIS], atypical ductal hyperplasia [ADH], Gail 5 year risk > 1.66% or lifetime risk > 20%)
Enrolled on the longitudinal high risk cohort study or being seen in the Cancer Prevention Center
Is taking risk reduction therapy with tamoxifen
Able to complete an acceptable baseline cardiopulmonary exercise testing (CPET) in the absence of high risk electrocardiography (ECG) findings or other inappropriate response to exercise as determined by the investigator
Modified Gail/CARE model risk at 5 years ? 1.67%. (Note: Risk models are to be used only if there is no known previous diagnosis of resected ductal carcinoma in situ [DCIS] or LCIS and there is no known deleterious mutation in BRCA1, BRCA2, PTEN, or TP53)
MDS – low/intermediate-1 International Prognostic Scoring System (IPSS) risk category patients are eligible only if they have failed prior therapy or are transfusion-dependent
Underlying kidney disease with a high risk of disease recurrence in the transplanted kidney
Myelodysplastic syndrome (MDS): transfusion-dependent (requiring at least one transfusion per month), or intermediate or higher Revised International Prognostic Scoring System (IPSS-R) risk group
High-risk indoor tanner (defined as using an indoor tanning bed at least 10 times in the previous 12 months)
High risk medical condition (e.g. kidney disease)
Medically at risk in the judgment of the study physician
Projected probability of developing breast cancer by either the Gail model (5-year risk) or the Tyrer–Cuzick model (10-year risk) that is at least 2-fold greater than that for the population; for the Gail model any value of 5-year risk >= 1.67% satisfies the requirement
3. Subjects with breast, lung or pancreatic carcinoma who are at high risk of relapse post definitive therapy at least 4 and no more than 24 weeks from completion of definitive therapy at the time of signing informed consent as described below for each indication:
Patients who have ONLY HPV 16 OR HPV 16 AND 18 and no other High-Risk HPV by Cobas test will be included.
Myelodysplastic syndrome (MDS): transfusion-dependent, or intermediate or higher IPSS-R risk group
Subjects who are at high risk for breast cancer will be considered for participation in the study
ELIGIBILITY CRITERIA FOR HIGH RISK PATIENTS FOR THE CLINICAL TRIAL
Diagnosis: histologic verification at either the time of original diagnosis or a previous relapse of high risk neuroblastoma.
At high risk of developing colorectal cancer, based upon a history of having a colonoscopy and having any colorectal adenoma diagnosed and/or removed within the past 3 years
Diagnosis: histologic verification at either the time of original diagnosis or a previous relapse of high risk neuroblastoma.
Patients must have high risk non-muscle invasive urothelial bladder carcinoma (Tis, Ta high grade [HG], or T1) that is pathologically confirmed by the Memorial Sloan Kettering Department of Pathology or a documented history of TaHG or T1 non-muscle invasive urothelial bladder tumors
Currently being treated with or having been treated in the last 12 months with any investigational drug for high risk superficial bladder cancer
Subject considered by the Investigator to be high-risk for breast conservation surgery and/or intra-operative radiation therapy
Is receiving chemotherapeutic agent(s) associated with moderate or high risk of emetogenicity, or a chemotherapy regimen not previously tolerated due to vomiting
Has Suicidal Risk Assessment (SRA) scores >= 6
Intermediate to high-risk disease, defined as one of the following factors: PSA > 10, T2b or greater, or a Gleason score of 7 or greater
Intermediate to high-risk disease (as determined by elevated prostate specific antigen [PSA] [PSA > 10], tumor [T]-stage [T2b or greater], Gleason score [Gleason score > 6] or other risk factors)
High risk benign lesions as the primary pathology diagnosis
Intermediate to high-risk disease (as determined by elevated PSA [PSA > 10], T-stage [T2b or greater], Gleason score [Gleason score > 6] or other risk factors)
Patient is at low risk for metastasis with Gleason score at diagnosis < 8.
High-risk or very-high risk prostate cancer eligible for standard of care surgery\r\n* At least clinical T3a disease, and/or Gleason >= 8, and/or PSA > 20, as per clinical assessment and routine guidelines
Intermediate to high-risk disease (as determined by elevated PSA [PSA > 10], T-stage [T2b or greater], Gleason score [Gleason score > 6] or other risk factors)
Patients who are on anticoagulants or high dose aspirin therapy that cannot be safely stopped for greater than 10 days prior to treatment should be excluded to limit increased risk for urinary obstruction
Intermediate to high-risk disease (as determined by elevated prostate-specific antigen [PSA] [PSA > 10], T-stage [T2b or greater], Gleason score [Gleason score > 6] or other risk factors)
Patients with low-risk, intermediate-risk and high-risk tumors according to National Comprehensive Cancer Network (NCCN) guidelines (2.2014) will be included
Must have previously untreated (with definitive therapy) prostate cancer with intermediate or high risk features defined as:\r\n* Intermediate risk:\r\n** Prostate specific antigen (PSA) level is between 10 and 20 ng/ml or\r\n** Gleason score is 7 or\r\n** Stage T2b or T2c\r\n* High risk:\r\n** Gleason 8 and higher OR\r\n** PSA > 20 at the time of diagnosis OR\r\n** Seminal vesicle involvement OR\r\n** Possible (on magnetic resonance [MRI]) extra-capsular extension (T3 disease)
Participants at higher risk due to age, frailty, or the emergent nature of their condition
GROUPS 1, 2, AND 3: Group 1: participants identified as being high-risk for familial or hereditary pancreatic cancer, and must conform to one or more of the following requirements:\r\n* Have a strong family history of pancreatic cancer; this is defined as pancreatic cancer occurring in one first- degree relative and two other relatives, or two first- degree relatives; or, \r\n* Have a known high-risk genetic syndrome (e.g., BRCA 1&2, STK11, CDNK2A, PRSS1, and MSH 2&6)
Any disease risk classification, as assessed by the Dynamic International Prognostic Scoring System (dIPSS)
Intermediate or high risk prostate cancer (clinical tumor stage T2b or higher, Gleason 7 or higher, or PSA greater than 10); previously obtained MR imaging may be used for clinical T staging (extracapsular extension, seminal vesicle invasion)
HIGH-RISK POPULATION:
National Comprehensive Cancer Network (NCCN) high risk disease (cT3 or Gleason score 8-10 or prostate specific antigen [PSA] > 20)
Adult males with unfavorable intermediate- to high-risk localized disease identified as one of the following three categories for unfavorable intermediate-high risk factors, but must have visible disease on baseline MRI of the following:\r\n* Clinical or radiographic T2b-T4 primary tumor\r\n* Gleason score 7-10 in any core\r\n* PSA >= 10 prior to initiation of therapy
Relapsed/Refractory Cohorts: Pathologically confirmed relapsed or refractory (primary refractory and/or relapsed refractory) AML or confirmed intermediate, high, or very high risk MDS that is relapsed, refractory or intolerant to conventional therapy
Treatment-naïve/ Unfit Cohorts: Previously untreated patients with histological confirmation of AML who are ineligible for treatment with a standard cytarabine and anthracycline induction regimen; or previously untreated patients with intermediate, high, or very high risk MDS. Prior and concurrent therapy with hydroxyurea, oral etoposide, erythroid and/or myeloid growth factors is allowed.
Revised International Prognostic Scoring System (IPSS-R) criteria for intermediate, high-risk or very high-risk
For International Prognostic Staging System (IPSS) high-risk or intermediate-2 MDS, participants must be intolerant of hypomethylating agents or not have responded to 4 treatment cycles of decitabine or 6 treatment cycles of azacitidine, or must have progressed at any point after initiation of a hypomethylating agent.
For IPSS intermediate-1 or low-risk MDS, participants must be transfusion dependent for red blood cells or platelets (as determined by instructional practices or local standard of care). Participants who are red blood cell transfusion dependent must also have failed erythropoiesis stimulating agents (primary resistance or relapse after a response) or have serum erythropoietin (EPO) levels > 500 U/L.
Extensive prior surgery/radiation present that would render the biopsy highly complex and the risk of intraoperative injury high
Patients at risk for fall or who have had recent fractures
High risk medical condition (e.g. kidney disease, uncontrolled diabetes, etc.)
Any co morbid condition that‚ in the view of the attending physician‚ renders the patient at high risk from ketorolac treatment complications
At risk for cancer-related infertility, as assessed by their clinician(s), including the oncofertility specialist
“High risk” patients
The patient must be at low- or low-intermediate risk for disease recurrence and progression according to the EAU guidelines
During clinician’s pre-surgical evaluation, presents with high risk for non-therapeutic resection related to cancer diagnosis (PCS study)
Has a metastatic neuroendocrine histology with MSKCC pathology confirmation as moderately or poorly differentiated or intermediate or high grade
Men or women, 18 years of age or older, with a confirmed diagnosis of international prognostic scoring system (IPSS) intermediate-1, intermediate-2 or high-risk MDS including Chronic Myelomonocytic Leukemia (CMML) or AML.
In the Dose Expansion Segment, hypomethylating agent (HMA) treatment-naïve MDS subjects (including CMML), and intermediate-2 or high-risk MDS subjects (including CMML) relapsed or refractory to prior HMA treatment are allowed, and treatment-naïve AML subjects who are at least 65 years of age will be allowed if they also have at least one of the following criteria
In the Dose Expansion Segment, which includes the 10-day regimen, subjects who have received 2 complete full dose cycles or more of a hypomethylating agent (HMA) decitabine or azacitidine (except for intermediate-2 or high-risk MDS subjects (including CMML) relapsed or refractory to prior HMA treatment).
Medical conditions such as ischemic heart or lung disease that may be considered an unacceptable risk.
Unable to provide informed consent or high risk that patient may not comply with\n             protocol requirements (i.e. due to health and/or participation in other research\n             studies).
Lactose-intolerance or are unwilling/unable to consume the protocol-specified standardized high-fat, high-calorie breakfast.
Prostate adenocarcinoma with High Risk (HR) and Unfavorable Intermediate Risk (UIR) for recurrence classification as determined by one of the following combinations: o High risk (HR): subjects with one or more of the following risk factors:
N0 o Unfavorable Intermediate Risk (UIR): subjects with no HR features but with one or more of the following adverse risk factors:
Greater than 50% of biopsy cores positive and at least one other risk factor: Gleason score (GS) 7 and/or PSA 10-20 and/or T2b/c
Declared high-risk for anesthesia by attending anesthesiologist, cardiologist, or other physician
Patients at risk for GI perforation.