Refractory anemia with excess blasts (RAEB-1)
Refractory anemia with excess blasts (RAEB-2)
Patients must have fewer than 20% marrow blasts within 60 days of consent.
REGISTRATION STEP 2-RANDOMIZATION: Patients must have morphologically confirmed, previously untreated acute myeloid leukemia (AML) or MDS with excess blasts-2 (MDS-EB-2)\r\n* Patients with acute promyelocytic leukemia (APL), biphenotypic leukemia, blastic transformation of chronic myelogenous leukemia (CML or BCR/ABL), are not eligible\r\n* Patients must have disease present in the blood or bone marrow; patients with only extramedullary disease in the absence of bone marrow or blood involvement are not eligible\r\n* All tests for establishing baseline disease status eligibility must be based on blood and/or bone marrow examination performed within 42 days prior to randomization (registration Step 2)
Cytogenetic analysis must be performed from diagnostic bone marrow (preferred) or if adequate number of circulating blasts from peripheral blood; FISH testing for common B-lineage ALL abnormalities including t(9;22) (BCR/ABL1), t(12;21) (ETS-variant gene 6 [ETV6]/runt-related transcription factor 1 [RUNX1]), t(1;19) (pre-B-cell leukemia homeobox 1 [PBX1]/transcription factor 3 [TCF3]), +4,+10,+17, (centromeric [Cen]4/Cen10/Cen17), t(11q23;var), (myeloid/lymphoid or mixed lineage leukemia [MLL]), deletion (del)(9p) (cyclin-dependent kinase inhibitor 2A [CDKN2A]/Cen9), and t(14;var) (immunoglobulin heavy chain [IGH] is encouraged); if there are few or no circulating blasts and an adequate marrow sample cannot be obtained for cytogenetic analysis, the patient may still enroll on the trial
Patient has one of the following: \r\n* Patients has previously untreated de novo AML and meets the criteria for AML with >= 20% bone marrow blasts as set out in the World Health Organization (WHO) Myeloid Neoplasm classification\r\n** Attempts to obtain bone marrow either by aspirate or biopsy must be made unless clinically prohibitive; in cases where it is clinically prohibitive, peripheral blood with an excess of 20% blasts and in which adequate flow cytometric and cytogenetics/FISH testing is feasible can be substituted for the marrow exam at diagnosis\r\n* Patients has cytopenias and/or bone marrow blasts but does not meet the criteria for the diagnosis of AML (WHO Myeloid Neoplasm classification) because of < 20% marrow blasts and meets the criteria for a diagnosis of myelodysplastic syndrome (MDS)\r\n* Patients has a history of transient myeloproliferative disorder (which may or may not have required chemotherapy intervention), who:\r\n* Are > 8 weeks since resolution of transient myeloproliferative disease (TMD) with >= 5% blasts, OR\r\n* Patients who have an increasing blast count (>= 5%) in serial bone marrow aspirates performed at least 4 weeks apart
In the event that the patient’s bone marrow blast count is >= 50% blasts, patients may be registered but should receive steroids for 3-5 days in order to reduce tumor burden prior to blinatumomab administration, as follows\r\n* Prephase treatment with dexamethasone (10-20 mg/m^2) for 3-5 days is required for patients with bone marrow blasts >= 50%, peripheral blood blasts 15,000/uL or higher, or elevated lactate dehydrogenase (LDH) suggesting rapidly progressive disease per investigator opinion\r\n** Pre-treatment should conclude at least 24 hours prior to the first dose of blinatumomab (although additional dexamethasone is automatically given as a pre-med prior to the first dose); at the time of first infusion of blinatumomab, the absolute peripheral blast count should be < 25,000/uL\r\n** Note: For the purposes of the study, day 1 of the cycle will be the first day of blinatumomab administration
Patients with MDS must have experienced treatment failure with at least one cycle of hypomethylating therapy or induction therapy and have ? 10% bone marrow blasts
Patients must have evidence of acute leukemia in their peripheral blood or bone marrow; patients must have >= 5% blasts in the peripheral blood or bone marrow within 14 days prior to registration; at least >= 20% of those blasts must be CD22-positive (surface) based on local immunophenotyping and histopathology
Acute myeloid leukemia (AML), myelodysplastic syndrome (MDS)-refractory anemia with excess blasts (RAEB) (including chronic myelomonocytic leukemia [CMML] with excess blasts and MDS/myeloproliferative neoplasm [MPN] overlap syndrome) not in remission (defined as >= 5% blast in bone marrow or peripheral blood) prior to leukemia cell harvest; patients may receive additional cytoreductive therapy after leukemia cell harvest and before admission for transplant, , at the discretion of the treating physician; for patients with MDS-EB1 (< 10%blasts) or CMML-1, it is recommended that they proceed directly to transplant after the harvest if donor is available; if there is an extended delay, interval therapy with HMA is allowed\r\n* Patients may or may not have active disease at the time of transplant conditioning, but for reduced intensity conditioning (RIC) candidates, it is strongly recommended that disease is cytoreduced such that the pre-transplant admission marrow shows:\r\n** < 30% blasts in a normocellular marrow (>= 50% cellularity), or\r\n** < 50% blasts in a hypocellular marrow (< 50% cellularity)
Acute myeloid leukemia (AML): must have < 5% marrow blasts at the time of transplant
Acute lymphocytic leukemia (ALL): must have < 5% marrow blasts at the time of transplant
Chronic myeloid leukemia (CML): patients in chronic phase 1 (CP1) must have failed or be intolerant of tyrosine kinase inhibitors (TKIs); patients beyond CP1 will be accepted if they have < 5% marrow blasts at time of transplant
Myelodysplasia (MDS)/myeloproliferative syndrome (MPS): patients must have < 5% marrow blasts at time of transplant
Presence of circulating leukemic blasts (in the peripheral blood) detected by standard pathology for patients with AML, ALL or CML
Presence of >= 5% circulating leukemic blasts (in the peripheral blood) detected by standard pathology for patients with MDS/MPS
ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C): Relapsed or refractory B-cell or T-cell ALL after multi-agent chemotherapy (>= 5% marrow lymphoblasts, assessed by morphology and flow cytometry; flow cytometry will be used to confirm immunophenotype and percentage of blasts will be assessed by morphology)
ELIGIBILITY CRITERIA - PHASE II (ARM D): Relapsed or refractory B-cell or T-cell ALL after multi-agent chemotherapy (>= 5% marrow lymphoblasts, assessed by morphology and flow cytometry; flow cytometry will be used to confirm immunophenotype and percentage of blasts will be assessed by morphology)
Men or women ?18 years who are candidates to receive IV decitabine, ie, subjects with MDS previously treated or untreated with de novo or secondary MDS, including all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia [CMML]), and subjects with MDS International Prognostic Scoring System (IPSS) int-1, -2, or high-risk MDS.
Diagnosis of acute myeloid leukemia (i.e. >= 20% peripheral or marrow blasts)
Inclusion Criteria:\n\n          -  ? 18 years of age at the time of signing informed consent\n\n          -  Diagnosis of AML according to the World Health Organization (WHO) 2008 criteria\n\n          -  Relapsed or refractory disease meeting the following criteria: (a) Primary refractory,\n             ie, refractory to induction with a standard anthracycline-based regimen or a\n             hypomethylating agent (e.g. decitabine or azacitidine) for patients ineligible for\n             anthracycline-based therapy; (b) First relapse after a first complete remission (CR)\n             lasting less than 12 months; or (c) Second or later relapse. Relapse is defined as the\n             reappearance of leukemic blasts in the peripheral blood or ? 5% leukemic blasts in the\n             bone marrow after prior achievement of a CR or CRi.\n\n          -  Blasts at least 5% in bone marrow\n\n          -  Peripheral white blood cell (WBC) count: no upper limit at Screening, but must be < 10\n             x 109/L on Day 1 prior to treatment; patients with excessive blasts may be treated\n             with hydroxyurea to bring counts down.\n\n          -  Chemistry laboratory parameters within the following range:\n\n               1. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ? 2x the\n                  upper limit of normal (ULN)\n\n               2. Total bilirubin ? 1.5x the ULN; patients with Gilbert's syndrome can enroll if\n                  conjugated bilirubin is within normal limits.\n\n               3. Creatinine clearance > 50 mL/min (measured or calculated by Cockcroft-Gault\n                  method)\n\n          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients with\n             ECOG score of 2 may be included, after discussion with the Sponsor Medical Monitor, if\n             score is influenced by symptoms attributable to underlying AML disease.\n\n          -  Able to read, understand and provide written informed consent\n\n        Exclusion Criteria:\n\n        Patients who meet any of the following criteria will be excluded from the study.\n\n          -  History of, or known, central nervous system (CNS) disease involvement, or prior\n             history of National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events\n             (CTCAE) Grade ? 3 drug-related CNS toxicity\n\n          -  Prior allogeneic transplant is excluded during Dose Escalation Stage;\n\n          -  Prior solid organ transplantation\n\n          -  Treatment with anti-thymocyte globulin (ATG) within 14 days prior to start date\n\n          -  Treatment with any local or systemic antineoplastic therapy or radiation within 14\n             days prior to the initiation of AMV564 administration (hydroxyurea is exempted if used\n             to reduce total WBC counts)\n\n          -  Clinically significant cardiac disease,\n\n          -  Pulmonary, renal, hepatic, gastrointestinal, neurological or psychiatric disease that\n             would limit compliance with study requirements\n\n          -  Evidence of active, uncontrolled, viral, bacterial, or systemic fungal infection.\n             Prophylactic therapy according to institutional protocols is acceptable.\n\n          -  Known positive test result for human immunodeficiency virus (HIV) or acquired immune\n             deficiency syndrome (AIDS)\n\n          -  Active hepatitis C virus (HCV) or hepatitis B virus (HBV).\n\n          -  Second primary malignancy that has not been in remission for greater than 3 years.\n             Exceptions that do not require a 3-year remission include: non-melanoma skin cancer;\n             cervical carcinoma in situ on biopsy or squamous intraepithelial lesion on\n             Papanicolaou (PAP) smear; localized prostate cancer (Gleason score < 6); or resected\n             melanoma in situ.\n\n          -  Any serious underlying medical or psychiatric condition (e.g. alcohol or drug abuse),\n             dementia or altered mental status or any issue that would impair the ability of the\n             patient to understand informed consent or that in the opinion of the investigator\n             would contraindicate the patient's participation in the study or confound the results\n             of the study.\n\n          -  Ability to become pregnant. However, female patients who have a negative serum or\n             urine pregnancy test before enrollment and agree to use two highly effective forms of\n             contraception (oral, injected or implanted hormonal contraception and condom;\n             intrauterine device and condom; diaphragm with spermicidal gel and condom) during the\n             trial and for 90 days afterward (90 days after the end of AMV564 treatment) are\n             considered eligible.\n\n          -  Male patients with partners of childbearing potential.\n\n          -  Pregnant or breastfeeding women
Hyperleukocytosis with ? 30,000 leukemic blasts/µL blood (hydroxyurea permitted up to 24 hours prior to beginning study drugs)
Known prior progression to acute myeloid leukemia (AML), defined by at least 20% blasts in the blood or bone marrow.
Acute Myeloid Leukemia (AML) or Acute Lymphoblastic Leukemia (ALL) in first or second remission. Remission is defined as the absence of blasts in the peripheral circulation at the time of enrollment, < 5% blasts in the bone marrow and absence of extramedullary disease including CNS involvement.
Chronic Myelogenous Leukemia (CML) in first or subsequent chronic phase failing to respond (or intolerant) to at least two different tyrosine kinase inhibitors. CML in accelerated or blast phase (CML-AP/BP) are eligible without requirement to fail tyrosine kinase inhibitor therapy, but must be in remission at time of enrollment. Remission is defined as the absence of blasts in the peripheral circulation at the time of enrollment, < 5% blasts in the bone marrow and absence of extramedullary disease including CNS involvement.
Chronic Myelomonocytic Leukemia (CMML) with < 10% blasts in the bone marrow
Have an established, pathologically confirmed diagnoses of AML by World Health Organization (WHO) criteria with ?20% bone marrow blasts based on histology or flow cytometry
Participants must have pathologically confirmed relapsed or refractory acute myeloid leukemia following International Working Group (IWG) criteria\r\n* For subjects with relapsed AML: evidence of >= 5% blasts in the bone marrow or >= 5% blasts in peripheral blood or the development of extramedullary disease who relapse after:\r\n** Allogeneic hematopoietic stem cell transplant, or\r\n** A minimum of one cycle of standard cytotoxic chemotherapy or two cycles of any hypomethylating agent-based therapy\r\n* For subjects with refractory AML: a minimum of 2 prior induction regimens (example: patients who receive 7+3 followed by 5+2 would count as one induction regimen) or a minimum of two cycles of any hypomethylating agent-based therapy
RAEB-1 per World Health Organization (WHO) MDS criteria (5% to <10% BM blasts)
RAEB-2 per WHO MDS criteria (10% to <20% BM blasts)
RAEB-t per French-American-British (FAB) classification (20% to 30% BM blasts)
Pathologically confirmed myelodysplastic syndrome (MDS) diagnosis (regardless of initial International Prognostic Scoring System [IPSS] risk category) or oligoblastic acute myeloid leukemia (AML) with 21-30% bone marrow (BM) blasts in whom DNMTi have failed; patients who have developed AML after DNMTi therapy can be enrolled as long as they have initiated DNMTi therapy while they were in the MDS or oligoblastic AML (20-30% BM blasts) phase and the study chair agrees; failure of DNMTis is defined as: failure to achieve a complete response (CR), partial response (PR) or hematologic improvement (HI) after at least 4 cycles of DNMTi or progressed after such therapy
Patients with a diagnosis of acute myeloid leukemia (AML) not transformed from MDS or transformed from MDS with > 30% blasts in bone marrow or white blood cells (WBC) > 25 x 10^3/L
Known prior progression to acute myeloid leukemia (AML) defined by at least 20% blasts in the blood or bone marrow.
Participants must have at least 1 of the following: 1 site of measurable disease greater than (>) 1 centimeter (cm) in the longest diameter and >1 cm in the shortest diameter by radiological imaging; bone marrow involvement; cerebrospinal fluid with blasts present
MDS - Marrow blasts must be > 5% and disease failed at least 1 prior hypomethylating agent
More than 5% blasts in bone marrow
Patients will be eligible to receive donor-derived multiTAA-specific T cells following any type of allogeneic HSCT as\r\n* Adjuvant therapy for AML/MDS (Group A); or\r\n* Treatment for refractory/relapsed or minimal residual AML/MDS disease (Group B)\r\n** Residual disease at the time of transplant or post transplant relapse is defined as polymerase chain reaction (PCR) positivity, specific cytogenetic abnormalities, an abnormal population on flow cytometry or increased blasts on bone marrow biopsy, in the peripheral blood, or any other extramedullary sites\r\n* Minimal residual disease (MRD) will be defined as detection in blood, bone marrow, or other tissues any of the following:\r\n** Any leukemia specific marker such as t(8;21); inv 16; t (15;17), t(9;22) or t(4;11) documented in the patient’s leukemia cells pre-transplant on a post-transplant evaluation\r\n** Expression of a leukemia associated antigen known to be a marker for residual disease like WT1\r\n** A leukemia-specific phenotype (e.g. expression of markers including CD13 and/or CD33 and/or CD117 and/or human leukocyte antigen–antigen D related positive [HLA-DR+]) post-transplant at a level of ? 0.01%\r\n** Mixed donor chimerism (> 20%)
Residual disease at the time of transplant or post-transplant relapse is defined as polymerase chain reaction (PCR) positivity, specific cytogenetic abnormalities, an abnormal population on flow cytometry, or increased blasts on bone marrow biopsy or in the peripheral blood; minimal residual disease (MRD) will be defined as detection in blood or marrow of any of the following:\r\n* Any leukemia-specific marker (such as t(12;21); t(9;22) or t(4;11)) documented in the patient’s leukemia cells pre-transplant on a post-transplant evaluation\r\n* A leukemia-specific phenotype (e.g. expression of markers including CD10 and/or CD19 or CD3 and/or CD4 or CD8) post-transplant at a level of ? 0.01%\r\n* Mixed donor chimerism (> 20%)
High-risk MDS/CMML (defined as ? 10% peripheral blood or marrow blasts and/or IPSS score ? 1.5) and relapsed or refractory to prior therapy
Residual disease at the time of transplant (bulky or minimal) or post transplant relapse as evidenced by polymerase chain reaction (PCR) positivity, specific cytogenetic abnormalities, an abnormal population on flow cytometry or increased blasts on bone marrow biopsy or in the peripheral blood; minimal residual disease (MRD) will be defined as detection in blood or marrow of any of the following:\r\n* Any leukemia specific marker (such as t(9:22) or t(4:11)) documented in the patient’s leukemia cells pre transplant on a post transplant evaluation\r\n* An immune globulin rearrangement known to be a disease marker for this patient post transplant\r\n* A leukemia specific phenotype post transplant at a level of ? 0.01%\r\n* Mixed donor chimerism (any level)
PHASE I: If relapse/refractory status with no prior history of allogeneic HCT (one of the following)\r\n* 2nd or greater marrow relapse, with or without extramedullary disease\r\n* 1st marrow relapse at end of 1st month of re-induction with marrow having\r\n* >= 0.01% blast by morphology and/or MPF, with or without extramedullary disease\r\n* Primary refractory as defined as having M2 or M3 marrow after 2 or more separate induction regimens\r\n* Subject has indication for HCT but has been deemed ineligible
In morphologic remission (< 5% marrow blasts) based on bone marrow (BM) biopsy performed +/- 5 days of day 28 post-transplantation
Patients must have IPSS score determined by cytogenetic analysis prior to randomization; patients with cytogenetic failure and =< 10% marrow blasts will be eligible
Participants with leukemia must meet one of the following:\r\n* In first hematologic relapse, OR\r\n* Refractory to one or two courses of frontline induction therapy (>= 5% blasts in the bone marrow or peripheral blood confirmed by flow cytometric analysis)\r\n* Note: participants aged 1 to 5 years with induction failure and favorable cytogenetics (i.e., hyperdiploid or human ets variant 6 [ETV6]-runt-related transcription factor 1 [RUNX1]) will not be eligible for this protocol; other patients younger than 6 years will be eligible
Participant with lymphoma must meet one of the following:\r\n* In first relapse, OR\r\n* Refractory to one or two courses of frontline induction therapy with measurable disease\r\n* Relapse in ALL is defined as the reappearance (in a patient who has previously achieved remission) of leukemic blasts in the bone marrow or peripheral blood\r\n** Should flow cytometric analyses suggest relapse (by the reappearance of a similar immunophenotype to the original leukemia) in the presence of < 5% blasts morphologically, a repeat bone marrow test is recommended to confirm relapse\r\n** Molecular or genetic relapse is characterized by the reappearance of a cytogenetic or molecular abnormality\r\n** Early relapse is defined as relapse on therapy or < 6 months after completion of frontline therapy; late relapse is defined as relapse occurring >= 6 months after completion of frontline therapy
Very high risk pediatric/young adult patients with acute myeloid leukemia (AML): Patients =< 25 years, however, are eligible with (M2 marrow) with =< 25% blasts in marrow after having failed one or more cycles of chemotherapy; this group of patients will be analyzed separately
Myelodysplasia (MDS) International Prognostic Scoring System (IPSS) intermediate (Int)-2 or high risk (i.e., refractory anemia with excess blasts [RAEB], RAEB in transformation [RAEBt]) or refractory anemia with severe pancytopenia or high risk cytogenetics; blasts must be < 10% by a representative bone marrow aspirate morphology
Fewer than 20% blasts in the bone marrow or peripheral blood
Participants must have a diagnosis of acute lymphoblastic leukemia and disease meets at least one of the following criteria:\r\n* Relapsed or refractory to chemotherapy as defined by ? 5% leukemic blasts in the bone marrow\r\n* Relapsed after hematopoietic stem cell transplantation (HSCT)
Relapsed/refractory AML. Treatment-naive patients who are not eligible for standard induction chemotherapy may also be eligible after discussion with the PI if in the best interest of the patient. Patients with high-risk myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN) (defined as >= 10% bone marrow blasts) may also be eligible after discussion with the PI.
Had accelerated phase or leukemic transformation (>= 10% blasts in peripheral blood [PB] or bone marrow [BM] any time prior to HCT)
Patients can be in chronic phase (CP) with bone marrow (BM) blast count =< 10% or after progression to acute myeloid leukemia (AML) and achieved =< 5% BM blasts (morphologic complete remission [CR] prior to transplant);
> 10% bone marrow blasts at transplant if no history of AML and > 5% if had previous progression to AML;
Patients with high-risk MDS, and chronic myelomonocytic leukemia (CMML) with bone marrow blasts between 10% and 20%, relapsed or refractory to prior hypomethylating agent (HMA) therapy, defined as prior receipt of 4 cycles of HMA therapy with failure to attain a response, or relapse after prior response to HMA therapy
Peripheral blood blasts ? 10%
Prior chemotherapy for AML. Hydroxyurea is allowed for the control of peripheral leukemic blasts in subjects with leukocytosis
Morphological disease in the bone marrow (? 5% blasts)
Bone marrow blasts of at least 10%
Subjects with a histologically confirmed diagnosis of MDS, including both MDS and refractory anemia with excess blasts in transformation (RAEB-T) (acute myeloid leukemia [AML] with 20-30% blasts and multilineage dysplasia by French-American-British [FAB] criteria) by World Health Organization (WHO), and chronic myelomonocytic leukemia (CMML) are eligible
Patient must be diagnosed with acute leukemia in morphologic complete remission (CR1 or CR2) or with MDS with no circulating blasts and with less than 5% blasts in the bone marrow
If relapse/refractory status with no prior history of allogeneic HCT (one of the following)\r\n* 2nd or greater marrow relapse, with or without extramedullary disease\r\n* 1st marrow relapse at end of 1st month of re-induction with marrow having >= 0.01% blast by morphology and/or MPF\r\n* Primary refractory as defined as having > 5% blasts by multi-parameter flow or polymerase chain reaction (PCR) after 2 or more separate induction regimens\r\n* Subject has indication for HCT but has been deemed ineligible, inclusive of persistent MRD prior to HCT
Patients must have relapsed (first or greater relapse) or refractory T-cell acute lymphoblastic leukemia (T-ALL) with: \r\n* Relapsed T-ALL with an M2 (blasts >= 5 to =< 25%) or M3 (> 25% blasts) marrow with or without an extramedullary site of relapse; including central nervous system (CNS) 2 OR\r\n* Refractory disease after induction failure of newly diagnosed patients OR no more than two more cycles of therapy OR\r\n* Refractory disease with no more than one prior salvage attempt following the current relapse
Patients who are currently undergoing or who previously underwent allogeneic HCT for \r\n* Acute myeloid leukemia (AML) of any subtype and any of the following:\r\n** With relapse or refractory disease (>= 5% marrow blasts by morphology, or circulating blasts, chloroma or granulocytic sarcoma) at the time of the pre-HCT work-up\r\n** With minimal/measurable residual disease (MRD: defined as detectable disease by morphology, flow cytometry, molecular or cytogenetic testing but < 5% marrow blasts by morphology, no circulating blasts) at the time of the pre-HCT work-up\r\n** With marrow aplasia or marked hypoplasia (bone marrow cellularity =< 10%) following chemotherapy for prior refractory AML at the time of the pre-HCT work-up\r\n** With relapse or refractory disease (>= 5% marrow blasts by morphology, or circulating blasts) at any time after HCT\r\n** With MRD at any time after HCT\r\n* Acute lymphoid leukemia (ALL) of any subtype and any of the following:\r\n** With relapse or refractory disease (>= 5% marrow blasts, or circulating blasts) at the time of the pre-HCT work-up\r\n** With MRD at the time of the pre-HCT work-up\r\n** With marrow aplasia or marked hypoplasia (bone marrow cellularity =< 10%) following chemotherapy for prior refractory ALL at the time of the pre-HCT work-up\r\n** With relapse or refractory disease (>= 5% marrow blasts, or circulating blasts) at any time after HCT\r\n** With MRD at any time after HCT\r\n* Biphenotypic/undifferentiated/any other type of acute leukemia and any of the following:\r\n** With relapse or refractory disease (defined as detectable disease by morphology, flow cytometry, molecular or cytogenetic testing but < 5% marrow blasts by morphology, no circulating blasts) at the time of the pre-HCT work-up\r\n** With MRD at the time of the pre-HCT work-up\r\n** With marrow aplasia or marked hypoplasia (bone marrow cellularity =< 10%) following chemotherapy for prior refractory acute leukemia at the time of the pre-HCT work-up\r\n** With relapse or refractory disease (>= 5% marrow blasts, or circulating blasts) at any time after HCT\r\n** With MRD at any time after HCT \r\n* Chronic myeloid leukemia with a history of blast crisis and \r\n** With relapse or refractory disease (>= 5% marrow blasts, or circulating blasts) at any time after HCT\r\n** With persistent rising minimal residual disease (defined as detectable disease by morphology, flow cytometry, molecular or cytogenetic testing but < 5% marrow blasts by morphology, no circulating blasts on >= 2 of two consecutive tests), refractory or ineligible for treatment with tyrosine kinase inhibitors at any time after HCT
Patients with newly diagnosed AML based on the World Health Organization classification who have persistent leukemia after a course or more of treatment with induction chemotherapy (the diagnosis of persistent disease, which is defined as > 10% blasts by evaluation of bone marrow biopsy or bone marrow aspirate)
Confirmation of ‘measurable disease’ by blast % will be defined as a marrow blast percentage of > 5% by morphologic assessment on bone marrow examination; this criteria does not apply to myeloid sarcoma which must also show measurable lesion by computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET)/CT or photograph (i.e. Leukemia cutis); if marrow blasts of =< 5% blasts are enumerated the patient may be eligible only if there is clear (probable or definite) flow cytometric, cytogenetic or molecular aberrations (e.g. FLT3-ITD, NPM1, etc.) documenting relapse of the leukemia associated clone defined prior to HCT
Inability to tolerate intensive chemotherapy (e.g., patients with AML with 20%-30% blasts and TRM ?4).
Acute myeloid leukemia (AML) – must have < 5% marrow blasts at the time of transplant
Acute lymphocytic leukemia (ALL) – must have < 5% marrow blasts at the time of transplant
Chronic myeloid leukemia (CML) – patients in CP1 must have failed or be intolerant of tyrosine kinase inhibitors (TKIs); patients beyond CP1 will be accepted if they have < 5% marrow blasts at time of transplant
Myelodysplasia (MDS)/myeloproliferative syndrome (MPS)/chronic myelomonocytic leukemia (CMML) – patients must have < 5% marrow blasts at time of transplant
Presence of circulating blasts (in the blood) detected by standard pathology for patients with AML, ALL or CML
Presence of >= 5% circulating leukemic blasts (in the blood) detected by standard pathology for patients with MDS/MPS/CMML
If relapse/refractory status with no prior history of allogeneic HCT (one of the following)\r\n* 2nd or greater marrow relapse, with or without extramedullary disease\r\n* 1st marrow relapse at end of 1st month of re-induction with marrow having >= 0.01% blast by morphology and/or MPF\r\n* Primary refractory as defined as having > 5% blasts by multi-parameter flow after 2 or more separate induction regimens\r\n* Subject has indication for HCT but has been deemed ineligible, inclusive of persistent MRD
Patients can be in chronic phase (CP) with bone marrow (BM) blast count =< 10% or after progression to acute myeloid leukemia (AML) and achieved =< 5% BM blasts (morphologic complete remission [CR] prior to transplant)
> 10% bone marrow blasts at transplant if no history of AML and > 5% if had previous progression to AML (in a bone marrow biopsy 4 weeks prior to start of conditioning on study)
Diagnosis of B- or T-ALL or LLy by immunophenotyping:\r\n* LLy participants must have < 25% tumor cells in bone marrow and peripheral blood by morphology and flow cytometry; if any of these show >= 25% blasts, patient will be considered to have leukemia
Must have a diagnosis of chronic phase (CP) (defined as peripheral blood and bone marrow < 10% blasts) primary myelofibrosis (PMF) or post essential thrombocythemia (post-ET) or polycythemia vera (post-PV) myelofibrosis by World Health Organization (WHO) criteria OR a diagnosis of a myeloproliferative neoplasm in accelerated/blast phase (MPN-AP/BP) defined as either a peripheral blood or bone marrow with >= 10% blasts
TP53 mutant relapsed/refractory AML following 7+3 (or similar cytarabine containing induction chemotherapy for AML) disease detected by one of the following methods:\r\n* Bone marrow blasts > 5%, or\r\n* Hematologics flow cytometry assay (threshold > 0.5%) (alternative equivalent assay may be substituted), or\r\n* Persistent cytogenetic abnormality (e.g. del5, del17p, etc) by fluorescence in situ hybridization (FISH) or conventional karyotyping, or\r\n* Persistent TP53 mutation (at least 5 variant reads with at least 50x coverage)
Patients with > 10% blasts on a day +14 bone marrow biopsy following 7+3 may either be enrolled or may be treated with a course of standard re-induction (e.g. 5+2 or similar) and then re-evaluated for response; eligible patients will meet any of the above criteria on a subsequent biopsy
Use of hydroxyurea is permitted to control blasts until day -3
Subjects with a histologically confirmed diagnosis of MDS, including both MDS and refractory anemia with excess blasts (RAEB)-T (acute myeloid leukemia [AML] with 20-30% blasts and multilineage dysplasia by French-American-British [FAB] criteria) by World Health Organization (WHO) and chronic myelomonocytic leukemia (CMML) are eligible
Patients must have a confirmed diagnosis of either:\r\n* Acute lymphoblastic leukemia\r\n* Lymphoblastic lymphoma with detectable abnormal blasts in the bone marrow
AML ONLY: AML with > 30% circulating blasts and > 50% bone marrow blasts
Refractory acute leukemia (> 5% blasts) or progressive disease
Acute leukemias: Must be in remission by morphology (< 5% blasts); NOTE: cytogenetic relapse or persistent disease without morphologic relapse is acceptable; also a small percentage of blasts that is equivocal between marrow regeneration versus (vs.) early relapse are acceptable provided there are no associated cytogenetic markers consistent with relapse
Myelodysplastic syndrome: any subtype including refractory anemia (RA) if severe pancytopenia or complex cytogenetics; blasts must be less than 5%. If 5% or more requires chemotherapy for cytoreduction to =< 5% prior to transplantation
> 65 years not previously treated for AML and who are not candidates for intensive chemotherapy nor candidates for established alternative chemotherapy Or Patients with cytologically confirmed and documented MDS), in relapse or refractory after previous treatment line including at least one hypomethylating agent and have ?10% bone marrow blasts;
No blasts or promyelocytes in peripheral blood
Patients with AML must have less than 10% bone marrow blasts and < 100/mcL absolute peripheral blood blast count
For subjects with ALL or AML, presence of >5% blasts in the bone marrow (based on a bone marrow aspirate/biopsy sample with ?200 nucleated cells and the presence of bone marrow spicules) and/or >1 x 109/L blasts in the peripheral blood (with the restriction that peripheral blast count in subjects with AML must be <50 x 109/L prior to the start of study therapy).
AML according to world health organization (WHO) criteria (i.e. bone marrow blasts >20%)
Blasts in Peripheral Blood or Bone Marrow ?15% (either myeloid or lymphoid blasts)
Promyelocytes and Blasts in Peripheral Blood or Bone Marrow ?30%
Cytogenetic clonal evolution Blast phase is defined as ?30% blasts in peripheral blood or bone marrow, or presence of extramedullary disease, except for liver or spleen.
Relapsed ALL, biphenotypic/bilineal leukemia, or acute myeloid leukemia (AML) with =< 10% blasts in the bone marrow prior to transplantation
Relapsed ALL defined as > 5% malignant blasts in bone marrow or peripheral blood
Diagnosis of relapsed or refractory AML, ALL, acute biphenotypic leukemia (assigned to the appropriate group by the treating physician and pathology/cytogenetics), advanced MDS defined as ?10% bone marrow blasts, advanced MPN, MDS/MPN overlap syndrome with ?10% bone marrow blasts, or advanced CML after failure of at least 3 TKIs
Diagnosis of relapsed or refractory AML, ALL, acute biphenotypic leukemia (assigned to the appropriate group by the treating physician and pathology/cytogenetics), advanced MDS defined as ?10% bone marrow blasts, advanced MPN, MDS/MPN overlap syndrome with ?10% bone marrow blasts, or advanced CML after failure of at least 3 TKIs
Isolated extramedullary leukemia without also meeting bone marrow criteria for acute leukemia (ie, ?20% blasts in bone marrow aspirate)
Response to therapy and completion of at least one cycle of consolidation therapy, and with disease status meeting one of the following criterion\r\n* Minimal residual disease, as defined by detectable disease by flow cytometry but with marrow that is at least 10% cellular with < 5% blasts on morphologic review\r\n* CRi/CRp, as defined by absence of detectable disease by flow cytometry, and marrow that is at least 10% cellular with < 5% blasts on morphologic review, but with neutrophil count < 1000/ul and/or platelet count <100,000/ul. As previously stated, a platelet threshold of < 80,000/ul will be used to define CRp in pediatric patients, as per consensus pediatric response criteria\r\n* Elevated expression above of WT1 in bone marrow or peripheral blood; (increased expression of WT1 will be determined if the number of copies of WT1 divided by the number of copies of ABL x 10^4 is > 250 for bone marrow, or > 50 for peripheral blood)
Relapsed or refractory high-grade myeloid neoplasms, defined as having a blast count of >= 10% blasts at initial diagnosis; examples include excess blasts (EB)-2, with >= 10% blasts at initial diagnosis, acute myeloid leukemia (AML) or chronic myelomonocytic leukemia (CMML-2); standard definitions of relapse will apply (i.e., characterized by >= 5% abnormal blasts as assessed by multiparameter flow cytometry or morphologic examination; peripheral blood blasts; or extramedullary granulocytic sarcoma, per European LeukemiaNet [ELN] 2017 guidelines); bone marrow aspirate/biopsy will be accepted if performed outside University of Washington/Fred Hutchinson Cancer Research Center (UW/FHCRC); determination of disease status should occur within 30 days of signing informed consent\r\n* R/R high-grade myeloid neoplasm following intensive induction chemotherapy; relapsed high-grade myeloid neoplasm: patients will be classified as relapsed if they have >= 5% blasts after being in a complete remission (CR) following treatment for high-grade myeloid neoplasm; refractory high-grade myeloid neoplasm: patients may be classified as refractory if they have received at least one prior cycle of induction chemotherapy, whether with cladribine cytarabine mitoxantrone (GCLAM) or another regimen\r\n** Patients may have received up to two courses of intensive induction chemotherapy during initial treatment prior to enrollment on this protocol; for example, patients who have received two courses of granulocyte colony stimulating factor (G-CSF) GCLAM (or similar) chemotherapy, with most recent high-dose cytarabine-containing chemotherapy > 6 months ago and CR lasting > 6 months, will be eligible for this protocol; regimens “similar to GCLAM” would include cytarabine at doses of 1g/m^2 for at least 5 doses; examples of regimens “similar to GCLAM” would be GCLA, fludarabine cytarabine granulocyte (FLAG), and FLAG-idarubicin (ida); however, patients who received more than two courses of GCLAM (or similar) chemotherapy, or patients who received two courses of GCLAM and had CR lasting < 6 months, would not be eligible\r\n* R/R high-grade myeloid neoplasm following less intensive induction chemotherapy. Patients who have received at least three cycles of treatment with a hypomethylating agent (HMA; such as azacitidine or decitabine) and still have >= 10% blasts will be eligible for the study (they will be considered refractory); similarly, patients who have received three or more cycles of HMA therapy who have had a response (e.g., achieving CR with < 5% blasts), but who then progress using standard definitions of relapse, will also be eligible (they will be considered relapsed)
Pathologically confirmed disease as follows:\r\n* AML patients who either have: \r\n** Relapsed or refractory disease after receiving one or more courses of induction chemotherapy, hypomethylating agent therapy, or bone marrow transplant or \r\n** De novo AML but not deemed to be a candidate for conventional therapy based on age, co-morbidities, or patient preference\r\n* MDS, chronic myelomonocytic leukemia (CMML), or MDS/myeloproliferative neoplasm (MPN) with high risk features as defined below who have relapsed after initial response or are refractory (failure to achieve a complete response [CR], partial response [PR], or hematologic improvement [HI]) after receiving at least 4 cycles of hypomethylating agents 5-azacitidine or decitabine +/- other therapies +/- bone marrow transplant OR with de novo MDS but have refused to receive hypomethylating therapy: \r\n** Intermediate (INT)-2 or high International Prognostic Scoring System (IPSS) score OR high or very high Revised International Prognostic Scoring System (IPSS-R) or\r\n** Secondary MDS (defined as MDS developing in a patient with an antecedent hematologic disorder or any patient with prior chemotherapy or radiation exposure) or\r\n** INT-1 IPSS or intermediate R-IPSS MDS with excess blasts (>= 5% blasts in bone marrow [BM]) or transfusion-dependency or\r\n** MDS progressing to oligoblastic AML with 21-30% BM blasts or\r\n** CMML or MDS/MPN with >= 5% marrow blasts, transfusion-dependency, abnormal karyotype, or proliferative features (white blood cell count >= 13,000/uL, splenomegaly on physical examination, or extramedullary disease)
Inclusion Criteria:\n\n          -  Acute leukemia: Patients with refractory or relapsed AML, other than acute\n             promyelocytic leukemia (APL).\n\n          -  Patients with a monosomal or complex karyotype may enroll at the time of day 14 biopsy\n             after induction chemotherapy, if residual disease is identified.\n\n          -  Patients must express HLA-A2.01 and myeloid blasts must express PRAME.\n\n          -  Absolute lymphocyte count (ALC) > 300/mm^3 or cluster of differentiation (CD)3+ >150\n             cells/ mm^3.\n\n          -  Patients who have relapsed and are greater than 100 days after a stem cell transplant\n             are eligible unless they have active GVHD requiring systemic immunosuppressive\n             therapy, defined as a need for > 10 mg prednisone or equivalent/day and active use of\n             a calcineurin inhibitor.\n\n          -  Relapsed or refractory AML or MDS.\n\n               -  AML patients must have > 5% bone marrow blasts at study entry, without\n                  alternative causality (e.g. bone marrow regeneration).\n\n                  a. Relapsed or refractory AML according to the Modified International Working\n                  Group Criteria for AML.\n\n                    1. Relapsed: Bone marrow blasts ?5 percent; or reappearance of blasts in the\n                       blood\n\n                    2. Refractory: Failure to achieve complete remission (CR) or complete remission\n                       with incomplete blood count recovery (CRi) after induction chemotherapy\n\n               -  MDS patients:\n\n                    1. High Grade MDS (RAEB-2) with 10-19% blasts, not responding to\n                       hypomethylation therapy or\n\n                    2. RAEB-1 or RAEB-2 MDS recurrence after initial response.\n\n          -  Age ? 18 years.\n\n          -  Life expectancy of at least 2 months.\n\n          -  Karnofsky performance status: > 60%.\n\n          -  Informed consent has been obtained\n\n          -  Patients who have come off previous cancer therapy for at least 14 days for prior\n             cytotoxic agents, and prior to D0, except when hydroxyurea is given only when needed\n             to control hyperleukocytosis. Persistent clinically significant toxicities from prior\n             chemotherapy must not be greater than Grade 1 (CTCAE 4.03) at the time of enrollment.\n             Salvage/lymphodepleting chemotherapeutic agents may be given up to 3 days prior to T\n             cell reinfusion if necessary to control rapidly growing disease.\n\n          -  Able to meet local institutional criteria for T cell apheresis collection.\n\n          -  Renal function:\n\n               1. All patients must have a calculated creatinine clearance > 40 mL/min according to\n                  Cockcroft-Gault Equation.\n\n               2. Routine urinalysis must show no clinically significant abnormalities.\n\n          -  Subject has adequate organ function as measured by:\n\n             i. Adequate LFTs: Total bilirubin ? 3.0 x the institutional upper normal limits (ULN)\n             with direct bilirubin < 1.6 x ULN.\n\n        ii. Alanine transaminase (ALT)/aspartate transaminase (AST) and Alkaline Phosphatase ? 5 x\n        ULN.\n\n        iii. Cardiac: left ventricular ejection fraction at rest must be ? 40%.\n\n        iv. Pulmonary: forced expiratory volume (FEV) 1, forced vital capacity (FVC), carbon\n        monoxide diffusing capacity (DLCO) ? 50% predicted (corrected for hemoglobin).\n\n          -  Acceptable coagulation status:\n\n               -  International normalized Ratio (INR)/ Prothrombin Time (PT) ? 1.5 times ULN.\n\n               -  Partial thromboplastin time (PTT) < 1.5 times ULN.\n\n          -  For fertile men and women, agreement to use effective contraceptive methods during the\n             study and for 3 months after administration of BPX-701.\n\n        Exclusion Criteria:\n\n        Patients who have any of the following are not eligible for enrollment (initiation of\n        BPX-701 infusion) in this study:\n\n          -  Inadequate lymphocyte count for collection.\n\n          -  Bovine product allergy.\n\n          -  History of prior malignancy other than: i) those associated with the current disease,\n             ii) previously treated with a curative intent therapy less than 1 year ago and except\n             superficial skin cancers.\n\n          -  Participation in any investigational drug study < 28 days prior to D0 (BPX-701\n             infusion).\n\n          -  Uncontrolled leptomeningeal leukemic disease.\n\n          -  Uncontrolled disseminated intravascular coagulation.\n\n          -  Other serious illness or medical conditions, which in the investigator's opinion could\n             hamper patient's understanding of the study, compliance to study treatment, and/or\n             safety or interpretation of study results. These conditions include (but are not\n             restricted to):\n\n               1. Congestive heart failure or angina pectoris (New York Heart Association Class III\n                  or IV) except when it is medically controlled. Uncontrolled hypertension or\n                  malignant arrhythmias.\n\n               2. Presence of significant neurologic or psychiatric disorders impairing the ability\n                  to obtain consent.\n\n               3. Uncontrolled bacterial, viral or fungal infection.\n\n               4. Known HIV, hepatitis B virus (HBV), hepatitis C virus (HCV) positivity or subject\n                  not meeting the selection criteria as defined for the Foundation for the\n                  Accreditation of Cell Therapy (FACT) and American Association of Blood Banks\n                  (AABB).\n\n          -  Unwillingness or inability to comply with procedures required in this protocol.
Acute leukemias: Must be in remission by morphology (< 5% blasts); Note cytogenetic relapse or persistent disease without morphologic relapse is acceptable; also a small percentage of blasts that is equivocal between marrow regeneration vs. early relapse are acceptable provided there are no associated cytogenetic markers consistent with relapse
Myelodysplastic syndrome: International Prognostic Scoring System (IPSS) interleukin-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 neutrophil 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; if >= 5% blasts, patient requires chemotherapy for cytoreduction to < 5% blasts prior to transplantation
ALL patients who have relapsed or have residual disease following treatment with curative intent; ALL patients must have ROR1 expressed on > 90% of the leukemia blasts to be eligible
Very high risk pediatric patients with AML: Patients < 21 years, however, are eligible with (M2 marrow) with < 25% blasts in marrow after having failed one or more cycles of chemotherapy
Blasts in peripheral blood < 20,000 (treatment with hydroxyurea is permitted up to 24 hrs prior to LY251092 administration to achieve blast counts < 20,000 prior to enrollment)
Subjects must have evaluable disease defined as > 5% blasts on marrow aspirate or biopsy, extramedullary disease (central nervous system [CNS] involvement is prohibited), or at least 20% blasts in the peripheral blood within 4 weeks prior to enrollment; Note: subjects with second or subsequent relapse are considered to have evaluable disease even without having > 5% marrow blasts if they are found to have persistent/recurrent disease-associated molecular or cytogenetic abnormalities at any time since their last cycle of intensive chemotherapy
Patients treated on this study will have:\r\n* Acute myeloid leukemia in morphologic complete remission (CR) not requiring treatment for their disease for 4 weeks\r\n* A history of acute myeloid leukemia (AML) with < 10% residual blasts (use highest count on staging studies) after induction therapy and persisting with < 10% blasts for at least 8 weeks without reinduction and at the time of HSCT\r\n* Refractory anemia (RA) or refractory anemia with ring sideroblasts (RARS) or isolated 5q- \r\n* Refractory anemia with excess blasts (RAEB)-1, refractory cytopenia with multilineage dysplasia (RCMD)+/-ringed sideroblasts (RS), or myelodysplastic syndrome (MDS) not otherwise specified (NOS) with stable disease for at least 3 months\r\n* RAEB-2 must demonstrate chemo-responsiveness; chemo-responsiveness is defined as a persistent blast percentage decrease by at least 5 percentage points to therapy and there must be =< 10% blasts (use highest count on staging studies) after treatment and at the time of transplant\r\n* Hodgkin or Indolent non-Hodgkin’s lymphoma \r\n* Myeloma with < 5% plasma cells in the marrow\r\n* Myeloproliferative disorders (excludes chronic myelomonocytic leukemia [CMML])\r\n* Aplastic anemia\r\n* A hematological or oncological disease (not listed) in which allogeneic HSCT is thought to be beneficial, and the disease is chemoresponsive \r\n* Patients without clear manifestation of their disease status in terms of stage and/or responsiveness should be discussed with the principal investigator (PI) and enrollment analysis should be documented in the study records
Expectation that we can obtain about 10 million blasts from blood and/or marrow (e.g., circulating blast count of 5,000 or greater or cellular marrow with greater than or equal to 20% blasts)
Phase II FLT3-ITD and/or FLT3-D835 mutated relapsed/refractory patients: patients should have a diagnosis of AML (de novo or transformed from hematologic malignancies); patients with high-risk myelodysplastic syndrome (MDS) (defined as having >= 10% blasts in the bone marrow) or patients with chronic myelomonocytic leukemia (CMML) (having >= 10% blasts in the bone marrow) may also be eligible after discussion with principal investigator (PI); the patients should have one of the following features: 1. patients with AML should have failed any prior induction therapy or have relapsed after prior therapy; 2. patients with high-risk MDS or high-risk CMML should have failed any prior therapy for the MDS or CMML; 3. patients with MDS or CMML who received therapy for the MDS or CMML and progress to AML are eligible at the time of diagnosis of AML regardless any prior therapy for AML; the World Health Organization (WHO) classification will be used for AML
Diagnosis of 1) AML (World Health Organization [WHO] classification definition of >= 20% blasts), or 2) high risk MDS (defined as the presence of 10% blasts)
Patients with diagnosis of AML, judged primary refractory after up to 2 courses of AML induction with therapy (> 5% blasts on day 21 [+/-7 days] bone marrow aspirate and/or biopsy from the beginning of induction chemotherapy, up to 42 days)
Disease criteria: day 21 (+/-7 days) bone marrow aspiration or biopsy from the beginning of salvage DCIA: a. in complete morphologic remission with < 5% bone marrow blasts, or b. aplastic (< 10% bone marrow cellularity), and cytopenic with an absolute neutrophil count (ANC) less than 1,000/uL, or c. low disease burden with < 30% bone marrow (BM) blasts, with recovery of peripheral blood (PB) white blood cell (WBC) (ANC > 1,000/uL) and < 5% circulating blasts
For cohort 1 only: patients with a bone marrow biopsy with < 15% cellularity, evidence of collagen fibrosis, osteosclerosis, or blasts > 10% in peripheral blood or marrow (demonstrating advanced disease)
Expression of CD-22 in >= 20% blasts
Patients with myelodysplastic syndrome (MDS) and myeloproliferative disorder (MPD) must have < 5% blasts in the bone marrow
Chronic myelogenous leukemia (CML) in second chronic phase after accelerated or blast crisis; blast crisis defined as:\r\n* Blast count >= 20% in the peripheral blood or bone marrow\r\n* Large foci of blasts on bone marrow\r\n* Presence of extra-medullary blastic infiltrate (myeloid sarcoma or chloroma)
MDS classified as follows: refractory anemia with excess blasts (RAEB)-1 (5%-9% bone marrow [BM] blasts); RAEB-2 (10%-19% BM blasts); chronic myelomonocytic leukemia (CMML) (5%-19% BM blasts); refractory anemia with excess blasts in transformation (RAEB-t) (20%-29% BM blasts) AND/OR by International Prognostic Scoring System (IPSS): intermediate-1 and high risk patients
Patients must have a diagnosis of one of the following:\r\n* MDS (Arm A)\r\n** High-risk MDS defined as: > 5% blasts in bone marrow and/or the following cytogenetic categories: presence of inv(3)/t(3q)/del(3q), -7/del(7q), complex cytogenetics (3 or more abnormalities)\r\n* AML (Arm B)\r\n** Relapsed/refractory/unable to tolerate conventional chemotherapy
RECIPIENT: Patients may have evidence of MDS with one or more peripheral blood cytopenias and greater than 5% blasts but less than 10% blasts in the bone marrow in the absence of filgrastim
Acute myeloid leukemia who fail to achieve complete remission with one course of induction chemotherapy or after relapse; patients must have less than 20% bone marrow or peripheral blood blasts
Myelodysplastic syndrome (MDS): refractory anemia (RA)/refractory cytopenia with multilineage dysplasia (RCMD) with high risk cytogenetic features or transfusion dependence, refractory anemia with excess blasts (RAEB)-1 and RAEB-2 and acute myelogenous leukemia (AML) evolved from MDS, who are not eligible for transplantation under protocol institutional review board (IRB) 08-008
Patients with CML-AP or CML-BP or Philadelphia chromosome-positive acute myeloid leukemia defined as follows: CML-AP is defined by the presence of 15-29% blasts in peripheral blood (PB) or bone marrow (BM), >= 20% basophils in PB or BM, >= 30% blasts plus promyelocytes (with blasts < 30%) in PB or BM, < 100 x 10^9/L platelets unrelated to therapy, or by clonal cytogenetics evolution (i.e., the presence of cytogenetic abnormalities other than the Philadelphia chromosome); CML-BP is defined by the presence of >= 30% blasts in the bone marrow and/or peripheral blood or the presence of extramedullary disease
Aspartate aminotransferase (AST) =< 5 x the institutional ULN, measured prior to conditioning chemotherapy; elevation secondary to leukemic involvement is not an exclusion criterion; leukemic involvement will be determined by the presence of progressive relapse defined by escalating bone marrow or peripheral blood leukemia blasts within the previous month and the absence of initiation of known hepatotoxic medication (e.g. azoles)
Subjects must have either PB or BM blasts ?5% at time of randomization.
Subjects with high PB blasts >50% AND poor ECOG PS of 2.
Subjects with evidence of relapsed or refractory acute myeloid leukemia (AML) OR treatment naive AML who are 75 years or older OR relapsed or refractory myelodysplastic syndrome (MDS)\r\n* For subjects with relapsed AML: evidence of >= 5% blasts in the bone marrow; or reappearance of blasts in the peripheral blood; or development of extramedullary disease (according to 2003 IWG criteria) who relapse after:\r\n** Allogeneic hematopoietic stem cell transplant, or\r\n** After one cycle of standard cytotoxic chemotherapy or two cycles of any hypomethylating agent-based therapy\r\n* For subjects with refractory AML: =< 2 prior induction regimens (example: patients who receive 7+3 followed by 5+2 would count as one induction regimen) or a minimum of two cycles of any hypomethylating agent-based therapy\r\n* For subjects with treatment-naive AML: must be 75 years and older with de novo or secondary AML to be considered eligible\r\n* For subjects with relapsed MDS: disease recurrence after CR, partial remission (PR) or hematologic improvement with bone marrow blasts >= 5% who relapse after:\r\n** Allogeneic hematopoietic stem cell transplant, or\r\n** After four cycles of any hypomethylating agent-based therapy\r\n* For subjects with refractory MDS: disease progression at any time after initiation of hypomethylating agent treatment or persistent bone marrow blasts >= 5% despite a minimum of four cycles of hypomethylating agent therapy
Prior hypomethylating agent (HMA) therapy is allowed, however this study excludes: (1) patients whose relapse occurred on HMA-based therapy immediately prior to this study and (2) patients who experience disease progression (see definition below) while receiving HMA-based therapy within the last 12 weeks prior to treatment start on study; disease progression is defined as either: (1) patients with MDS who have evidence of initial progression to AML (defined by the presence of >= 20% blasts in peripheral blood or bone marrow) while receiving HMA-based therapy within the last 12 weeks prior to treatment start on study; OR (2) patients with AML who have evidence of progressive disease according to European Leukemia Net (ELN) 2017 criteria (e.g. > 50% increase in marrow blasts over baseline or > 50% increase in peripheral blasts to > 25 x10^9/L [> 25,000/uL] [in absence of differentiation syndrome]) while receiving HMA-based therapy within the last 12 weeks prior to treatment start on study\r\n* (Note: Patients who relapse post-transplant who received HMA treatment prior to transplant are eligible for study)
Myelodysplastic syndrome (MDS): Refractory anemia (RA)/refractory anemia with ring sideroblasts (RARS)/refractory cytopenia with multilineage dysplasia (RCMD) with high risk cytogenetic features or transfusion dependence, as well as refractory anemia with excess blasts (RAEB)-1 and RAEB-2 and acute myelogenous leukemia (AML) evolved from MDS who are not eligible for transplantation under protocol institutional review board (IRB) 08-008
Acute leukemias (includes T lymphoblastic lymphoma); remission is defined as < 5% blasts with no morphological characteristics of acute leukemia (e.g., Auer rods) in a bone marrow with > 20% cellularity, peripheral blood counts showing ANC > 1000/ul, including patients in complete remission with incomplete platelet recovery (CRp); if the marrow has < 20% cellularity due to treatment related cytotoxicity, but still has < 5% blasts, an exception may be made to include this patient up to principal investigator (PI) discretion
Patients must have untreated AML, or high-risk myelodysplastic syndromes (MDS) (refractory anemia with excess blasts, [RAEB], or RAEB \in transformation\ [RAEB-t]) characterized by t(8;21), inv(16), or t(16;16); the presence of additional abnormalities is irrelevant
Acute myeloid leukemia/acute lymphoblastic leukemia, including biphenotypic acute leukemia or mixed-lineage leukemia: Must have < 5% morphologic marrow blasts in an evaluable marrow sample (> 25% of normal cellularity for age collected less than one month prior to start of conditioning; patients in which adequate marrow/biopsy specimens cannot be obtained to determine remission status by morphologic assessment, but have fulfilled criteria of remission by flow cytometry, recovery of peripheral blood counts with no circulating blasts, and/or normal cytogenetics (if applicable) may still be eligible; reasonable attempts must be made to obtain an adequate specimen for morphologic assessment, including possible repeat procedures; these patients must be discussed with the principal investigator prior to enrollment; patients persistently aplastic for greater than one month since completing last chemotherapy are also eligible with principal investigator (PI) approval
Myelodysplastic syndrome (MDS): Any 2001 World Health Organization (WHO) classification subtype; refractory anemia with excess blasts (RAEB)-2 patients may proceed directly to transplant, but may also be considered for induction chemotherapy before transplant; patients with >= 20% morphologic marrow blasts require induction therapy to reduce morphologic marrow blasts below 5% before transplant
Myeloproliferative disorder (MPD)\r\n* Life-threatening cytopenia(s), and/or red blood cell or platelet transfusion dependence\r\n* Patients with aplasia\r\n* Patients with excess blast less than or equal to 10% blasts in the bone marrow at work-up
Chronic myelogenous leukemia: All types, except refractory blast crisis; chronic phase patients must have failed or been intolerant to Gleevec or other tyrosine kinase inhibitors; at time of transplant, patients must have < 5% blasts in an evaluable marrow (> 25% of normal cellularity for age) by morphology within the bone marrow
Myelodysplastic syndrome (MDS): Any subtype; morphologic blasts must be less than 5% in an evaluable marrow (> 25% of normal cellularity for age); if blasts are 5% or more, patient requires induction chemotherapy pre-transplant to reduce blast count to less than 5%; patients who have a hypocellular marrow in the absence of excess blasts that is related to the underlying disease or as a result of treatment for MDS may also be eligible with the approval of the PI or designee
Acute lymphocytic leukemia (ALL) at the following stages:\r\n* High risk first remission, defined as:\r\n** Philadelphia chromosome positive (Ph+) ALL; or\r\n** Mixed lineage leukemia (MLL) rearrangement with slow early response [defined as having M2 (5-25% blasts) or M3 (> 25% blasts on bone marrow examination on day 14 of induction therapy); or\r\n** Hypodiploidy (< 44 chromosomes or deoxyribonucleic acid [DNA] index < 0.81); or\r\n** End of induction M3 bone marrow; or\r\n** End of induction M2 marrow or MRD > 1% with M2-3 marrow or MRD > 1% at day 42\r\n** High-risk infant ALL defined as age < 6 months at diagnosis with MLL (11q23) translocation\r\n* High risk second remission, defined as:\r\n** Bone marrow relapse < 36 months from induction; or > 36 months (mths) if a matched sibling donor is available\r\n** T-lineage relapse at any time; or,\r\n** Very early isolated central nervous system (CNS) relapse (< 18 months from diagnosis); or\r\n** Slow reinduction (M2-3 at Day 28) after relapse at any time\r\n* Any third or subsequent CR
Biphenotypic or undifferentiated leukemia in any CR or if in 1st relapse must have < 25% blasts in bone marrow (BM)
Greater than 30% blasts in bone marrow or greater than 5% in peripheral blood
MDS International Prognostic Scoring System (IPSS) intermediate (Int)-2 or high risk (i.e. refractory anemia with excess blasts [RAEB], RAEB in transformation [RAEBt]) or refractory anemia with severe pancytopenia or high risk cytogenetics; blasts must be < 10% by a representative bone marrow aspirate morphology
Refractory anemia with excess blasts, or leukemia
Very high risk pediatric patients with AML; patients < 21 years, however, are eligible with (M2 marrow) with < 25% blasts in marrow after having failed one or more cycles of chemotherapy; this group of patients will be analyzed separately
Myelodysplasia (MDS) International Prostate Symptom Score (IPSS) Int-2 or High risk (i.e. refractory anemia with excess blasts [RAEB], refractory anemia with excess blasts in transformation [RAEBt]) or refractory anemia with severe pancytopenia or high risk cytogenetics; blasts must be < 10% by a representative bone marrow aspirate morphology
Acute leukemias: must be in remission by morphology (< 5% blasts); note cytogenetic relapse or persistent disease without morphologic relapse is acceptable; also a small percentage of blasts that is equivocal between marrow regeneration vs. early relapse are acceptable provided there are no associated cytogenetic markers consistent with relapse
Myelodysplastic syndrome: any subtype including refractory anemia (RA) if severe pancytopenia or complex cytogenetics; blasts must be less than 5%; if 5% or more requires induction therapy pre-transplant to reduce blast count to =< 5%
Unless in post-chemotherapy and radioimmunoconjugated antibody induced aplasia, when he/she would be eligible, patients with acute leukemia in morphologic relapse/persistent disease defined as > 5% blasts in normocellular bone marrow OR any % blasts if blasts have unique morphologic markers (e.g. Auer rods) or associated cytogenetic markers that allows morphologic relapse to be distinguished are not eligible
B-cell cohort: Stage 1; ALL in second or greater relapse or refractory to 2 prior induction regimens with greater than or equal to (>=) 5 percent (%) blasts in the bone marrow and aged 1 to less than (<) 18 years. Stage 2; ALL in second or greater relapse or refractory to 2 prior induction regimens with (>=) 5% blasts in the bone marrow and aged 1 to 30 years. LL in second or greater relapse or refractory to 2 prior induction regimens and biopsy proven and with evidence of measurable disease by radiologic criteria and aged 1 to 30 years.
T-cell cohort: Stage 1; ALL in first relapse or refractory to 1 prior induction/consolidation regimen with (>=) 5% blasts in the bone marrow and aged 1 to <18 years. Stage 2; ALL in first relapse or refractory to 1 prior induction/consolidation regimen with (>=) 5% blasts in the bone marrow and aged 1 to 30 years. LL in first relapse or refractory to 1 prior induction/consolidation regimen biopsy proven and with evidence of measurable disease by radiologic criteria and aged 1 to 30 years
Acute leukemias: must be in remission by morphology (=< 5% blasts); also a small percentage of blasts that is equivocal between marrow regeneration versus (vs.) early relapse are acceptable provided there are no associated cytogenetic markers consistent with relapse
Very high risk pediatric patients with AML: patients < 21 years, however, are eligible with (M2 marrow) with < 25% blasts in marrow after having failed one or more cycles of chemotherapy
Myelodysplasia (MDS) IPSS intermediate (INT)-2 or high risk (i.e. refractory anemia with excess blasts [RAEB], refractory anemia with excess blasts in transformation [RAEBt]) or refractory anemia with severe pancytopenia, transfusion dependence, or high risk cytogenetics or molecular features; blasts must be < 10% by a representative bone marrow aspirate morphology
<5% blasts in marrow or blood at time of screening
<1% peripheral blood blasts.
<10% bone marrow blasts.
Patients may have received low-intensity treatment (e.g. azacitidine/decitabine, lenalidomide, growth factors) for antecedent low-grade myeloid neoplasm (i.e. < 10% blasts in blood and bone marrow)
Acute myeloid leukemia-intermediate risk as defined by standard World Health Organization (WHO) criteria for AML (at least 20% blasts in the peripheral blood or bone marrow) at the time of initial diagnosis\r\n* Diagnosis of AML according to WHO diagnostic criteria (at least 20% blasts in the peripheral blood or bone marrow), with French–American–British (FAB) classification other than M3 (acute promyelocytic leukemia), documented by bone marrow aspiration and biopsy performed within 14 days prior to administration of 1st dose of remission induction chemotherapy
More than 5% blasts in bone marrow
Presence of >= 5% abnormal blasts in the bone marrow
Have previously untreated AML, defined according to WHO criteria, with ? 20% leukemic blasts in the bone marrow. Subjects with extramedullary disease alone (ie, no detectable bone marrow and no detectable peripheral blood AML) are not eligible for the study.
Histologically or cytologically documented diagnosis of MDS according to the World Health Organization (WHO) classification (Vardiman 2009, Arber 2016) with >5% and <20% bone marrow blasts by morphology and a peripheral white blood cell (WBC) count of <20,000/?L
Bone marrow blasts ?20%, indicating a diagnosis of acute myeloid leukemia (AML).
Diagnosis should be made by bone marrow aspirate or biopsy demonstrating >= 25% involvement by lymphoblasts, with flow cytometry or immunohistochemistry confirming B-precursor or T-ALL phenotype\r\n* For patients with circulating blasts in the peripheral blood, flow cytometry confirmation of B-ALL or T-ALL phenotype is sufficient for registration onto the study; bone marrow aspirate and/or biopsy should be performed as soon as feasible, preferably prior to the initiation of any therapy\r\n* While myeloid co-expression on blasts determined to be primarily lymphoid is allowed, patients meeting World Health Organization (WHO) diagnostic criteria of mixed phenotype acute leukemia (MPAL) or leukemia of ambiguous lineage are not eligible; patients with mature B-cell phenotype are also not eligible
Subject had disease progression prior to Cycle 6 defined as ?50% increase in bone marrow blasts from pretreatment levels to >5%, or ?2 g/dL reduction of Hgb from pretreatment levels with transfusion dependence after at least 2 cycles of HMA. Other prior treatments for MDS such as lenalidomide, cytarabine, intensive chemotherapy, hydroxyurea, erythropoietin and other growth factors, or hematopoietic cell transplant (HCT) are allowed.
Bone marrow blasts >5% at randomization, OR
Subjects who have been diagnosed as having AML with peripheral blood or bone marrow blasts of ?20%.
Cytogenetic analysis must be performed from diagnostic bone marrow (preferred) or if adequate number of circulating blasts (> 10^9/l) from peripheral blood
Patients must have B-ALL, or previously diagnosed B lymphoblastic lymphoma (B-LL), with >= 5% (M2 or M3) bone marrow blasts with or without extramedullary disease\r\n* NOTE: Relapsed patients previously diagnosed with B-lymphoblastic lymphoma (B-LL) are eligible if they have an M2 or M3 marrow at the time of enrollment on this study
Leukemic blasts must demonstrate surface expression of CD22 at the time of relapse by local/institutional flow cytometry of a bone marrow aspirate sample; (assessment of CD22 using a bright fluorophore such as phycoerythrin [PE] is strongly recommended) \r\n* In the case of an inadequate aspirate sample (dry tap) or if bone marrow aspirate is unable to be performed due to patient clinical status, flow cytometry of peripheral blood specimen may be substituted if the patient has at least 1000/uL circulating blasts; alternatively, CD22 expression may be documented by immunohistochemistry of a bone marrow biopsy specimen
Circulating blasts < 20,000 (cytoreduction with hydroxyurea is allowed)
Patient must have one of the following:\r\n* Recurrent disease with >= 5% blasts in the bone marrow (M2/M3 bone marrow), with or without extramedullary disease.\r\n* Recurrent disease with an absolute blast count greater than 1,000 per microliter in the peripheral blood with or without extramedullary disease
For patients with circulating blasts in the peripheral blood, flow cytometry confirmation of B-precursor or T-ALL phenotype is sufficient for registration onto the study; bone marrow aspirate and/or biopsy should be performed as soon as feasible, preferably prior to the initiation of any therapy
Acute myelogenous leukemia— high risk in first complete remission (CR1) (as evidenced by preceding myelodysplastic syndrome (MDS), high risk cytogenetics such as those associated with MDS or complex karyotype, or > 2 cycles to obtain complete remission [CR]); second or greater CR; must be in remission by morphology; patients in morphologic relapse/ persistent disease defined as > 5% blasts in normocellular bone marrow OR any % blasts if blasts have unique morphologic markers (eg auer rods) or associated cytogenetic markers that allows morphologic relapse to be distinguished are not eligible for arms 2 or 3; note cytogenetic evidence of disease alone without morphologic relapse is acceptable; also a small percentage of blasts that is equivocal between marrow regeneration versus (vs) early relapse is acceptable provided there are no associated cytogenetic markers consistent with relapse
Acute lymphocytic leukemia- high risk CR1 as evidenced by high risk cytogenetics [eg t(9;22) or complex cytogenetic abnormalities] or > 1 cycle to obtain CR; second or greater CR; must be in remission by morphology; patients in morphologic relapse/persistent disease defined as > 5% blasts in normocellular bone marrow OR any % blasts if blasts have unique morphologic markers or associated cytogenetic markers that allows morphologic relapse to be distinguished are not eligible for arms 2 or 3; note cytogenetic relapse or persistent disease without morphologic relapse is acceptable; also a small percentage of blasts that is equivocal between marrow regeneration vs early relapse is acceptable provided there are no associated cytogenetic markers consistent with relapse
Participant has a hematologic malignancy that is positive for MLLr as determined by fluorescent in situ hybridization (FISH) or reverse transcriptase (RT)-PCR, and disease meets at least one of the following criteria:\r\n* Relapsed after or is refractory to chemotherapy\r\n* Relapsed after hematopoietic stem cell transplantation (HSCT)\r\n* Relapsed or refractory secondary leukemia\r\n** Relapse is defined as reappearance of leukemia cells after the attainment of complete remission and refractory is defined as >= 5% blasts at the end of induction; patients that achieved MRD negative status followed by reappearance of blasts at less than 5% are eligible
Patients must have > 5% blasts in the bone marrow at the time of study enrollment
Patients in 1st or 2nd remission with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL), who are eligible for stem cell transplant; remission defined as no circulating blasts, < 5% blasts in the bone marrow, normalization of previously detected cytogenetic abnormalities, no extramedullary disease
Must have a pathologically confirmed diagnosis by World Health Organization (WHO) criteria of MDS, CMML, or acute myeloid leukemia (AML) (except acute promyelocytic leukemia) with < 30% bone marrow blasts (refractory anemia with excess blasts in transformation [RAEB-t] by French American British criteria)
Myelodysplastic syndrome\r\n* Refractory anemia with excess blasts (RAEB)\r\n* RAEB-in transformation (T) (requires marrow and blood blasts < 10% after induction chemotherapy)
Blasts in the peripheral blood (PB) and bone marrow (BM) < 20% prior to study enrollment
Bone marrow aspirate or biopsy must have ? 5% blasts by morphology and/or flow cytometry.
Accelerated phase myeloproliferative neoplasm (MPN) as defined by 10%-19% blasts in the peripheral blood or bone marrow and evidence of dysplastic marrow features with a concomitant diagnosis of essential thrombocythemia (ET), polycythemia vera (PV) or primary myelofibrosis (PMF) or a diagnosis of acute myelogenous leukemia as defined by 20% blasts in the blood or bone marrow following a previous diagnosis of ET, PV or PMF
Leukemic transformation (> 10% blasts in peripheral blood or bone marrow biopsy).
Relapsed or refractory AML patients with at least 5% blasts by bone marrow biopsy or aspirate, or at least 1% blasts in peripheral blood, not likely to benefit from standard salvage chemotherapy.
Newly diagnosed, histologically confirmed de novo AML (bone marrow blasts ? 20%), or
Patients in the relapsed/refractory AML cohort (Cohort 2), must meet all of the following criteria:\r\n* Patient must have received at least one prior Induction chemotherapy regimen for their AML;\r\n** They may have received any type of chemotherapy\r\n** Administration of hydroxyurea to control high white blood cells (WBC) prior to, during, and after registration is permitted\r\n* Relapse or refractory disease must be documented by a bone marrow examination demonstrating > 5% blasts in the bone marrow not attributable to another cause\r\n* Patient must NOT have received chemotherapy within 14 days prior to registration
MDS: Patients must have < 10% marrow blasts; fewer than 10% marrow blasts must be documented by marrow examination within 3 weeks of initiation of conditioning
CMML: Patients with CMML1 who have not received myelosuppressive therapy must have < 10% marrow blasts; fewer than 10% marrow blasts must be documented by marrow examination within 3 weeks of initiation of conditioning; OR patients with CMML who have progressed beyond CMML1 and have received myelosuppressive chemotherapy must have < 5% marrow blasts; fewer than 5% marrow blasts must be documented by marrow examination within 3 weeks of initiation of conditioning
MPD: Patients must have < 10% marrow blasts; fewer than 10% marrow blasts must be documented by marrow examination within 3 weeks of initiation of conditioning
Atypical CML: Patients must have < 10% marrow blasts; fewer than 10% marrow blasts must be documented by marrow examination within 3 weeks of initiation of conditioning
Presence of >= 5% circulating leukemic blasts (in the peripheral blood) detected by standard pathology
Patients must have a history of relapsed/refractory CD19+ B-ALL involving the marrow to be eligible for infusion of modified T cells; please note >= 5% blasts by morphology, fluorescent in situ hybridization (FISH)/cytogenetics, molecular translocation and/or flow cytometry constitutes a bone marrow relapse on this protocol \r\n* Patients must also fulfill one of the following criteria to be eligible for infusion of modified T cells:\r\n** Second or greater (>= 2) relapse\r\n** Early first marrow relapse (1st CR < 18 months)\r\n** Intermediate/late first marrow relapse (1st CR >= 18 months from 1st CR) with poor initial response (>= 5% blasts by morphology and/or flow cytometry) following re-induction chemotherapy\r\n** Refractory disease\r\n** Ineligible for hematopoietic stem cell transplant (HSCT) as determined by the treating physician in consultation with the bone marrow transplant (BMT) service\r\n** Patient would not benefit from additional cytotoxic chemotherapy as determined by the treating physician
Aspartate aminotransferase (AST) =< 5 x the institutional ULN; elevation secondary to leukemic involvement is not an exclusion criterion; leukemic involvement will be determined by the presence of progressive relapsed defined by escalating bone marrow or peripheral blood leukemia blasts within the previous month and the absence of initiation of known hepatotoxic medication (e.g. azoles)
For a diagnosis of high-risk Myelodysplastic Syndrome RAEB 2 the patient must have 10-19% bone marrow blasts
STRATUM I:\r\n* Minimal disseminated disease (MDD) < 1% at diagnosis in T-lymphoblastic lymphoma (TLL)\r\n* No bone marrow involvement microscopically at diagnosis in B-lymphoblastic lymphoma \r\n* Patients should NOT have: \r\n** Any CNS involvement: CNS-3 status (i.e., >= 5 white blood cell [WBC]/uL of cerebrospinal fluid [CSF] with blasts or cranial nerve palsy), CNS-2 status (< 5 WBC/uL of CSF with blasts) or traumatic lumbar puncture (LP) (> 10 red blood cell [RBC]/uL of CSF with blasts) \r\n** Overt testicular involvement (evidenced by ultrasonogram)
STRATUM II:\r\n* MDD >= 1% and MRD negative (< 0.01%) on day 8 in T-lymphoblastic lymphoma \r\n* Bone marrow involvement microscopically present at diagnosis in B-lymphoblastic lymphoma \r\n* Any CNS involvement: CNS-3 status (i.e., >= 5 WBC/uL of CSF with blasts or cranial nerve palsy), CNS-2 status (< 5 WBC/uL of CSF with blasts) or traumatic LP (> 10 RBC/uL of CSF with blasts) but does not fulfill the criteria of stratum 3 \r\n* Overt testicular involvement (evidenced by ultrasonogram) but does not fulfill the criteria of stratum 3
Patients must be in morphologic leukemia-free state (marrow blasts < 5%) without evidence of extramedullary disease within 21 days of HCT
Presence of circulating leukemic blasts in the peripheral blood detected by standard morphology
Refractory anemia with excess blasts (RAEB) - defined as having 5% to 20% myeloblasts in the bone marrow.
CMML with 10% to 19% myeloblasts in the bone marrow and/or 5% to 19% blasts in the blood. OR Worl health organisation (WHO) Classifications:
RAEB 2 - defined as having 10% to 19% myeloblasts in the bone marrow and/or 5% to 19% blasts in the blood.
CMML 2 - defined as having 10% to 19% myeloblasts in the bone marrow and/or 5% to 19% blasts in the blood.
CMML 1 (Although CMML 1 is defined as having <10% myeloblasts in the bone marrow and/or <5% blasts in the blood, these participants may enroll only if bone marrow blasts >=5%.
Patients with untreated acute myeloid leukemia (AML) (> or equal to 20% blasts in bone marrow and/or peripheral blood) or high risk MDS (> or equal to 10% blasts in bone marrow); A. patients with AML and history of MDS who have received prior therapy with a hypomethylating agent (including azacytidine) and/or with lenalidomide for prior MDS are eligible if the treating physician feels that participation in the study is in the patients' best interest; B. patients should have molecular evidence of the presence of FLT3-ITD mutation with a molecular burden of at least 10%
Active AML (bone marrow blasts >= 5% by morphology, staining, or flow) and/or presence of extramedullary disease
Patients with previously untreated primary AML who meet the customary criteria for AML with >= 20% bone marrow blasts as set out in the 2008 World Health Organization (WHO) Myeloid Neoplasm Classification are eligible\r\n* Attempts to obtain bone marrow either by aspirate or biopsy must be made unless clinically prohibitive; in cases where it is clinically prohibitive, peripheral blood with an excess of 20% blasts and in which adequate flow cytometric and cytogenetics/fluorescent in situ hybridization (FISH) testing is feasible can be substituted for the marrow exam at diagnosis
Patients with < 20% bone marrow blasts are eligible if they have: \r\n* A karyotypic abnormality characteristic of de novo AML (t(8;21)(q22;q22), inv(16)(p13q22) or t(16;16)(p13;q22) or 11q23 abnormalities\r\n* The unequivocal presence of megakaryoblasts, or\r\n* Biopsy proven isolated myeloid sarcoma (myeloblastoma; chloroma, including leukemia cutis)
Patients must have measureable disease as defined the presence of >= 5% blasts in bone marrow or extramedullary leukemia
Chronic myeloid leukemia (CML) in 1st or subsequent chronic phase characterized by <10% blasts in the blood or bone marrow.
Participants must have a diagnosis of AML or MDS and must have disease that has relapsed or is refractory to chemotherapy, or that has relapsed after hematopoietic stem cell transplantation (HSCT)\r\n* Refractory disease is defined as persistent disease after at least two courses of induction chemotherapy\r\n* Patients with AML must have>= 5% leukemic blasts in the bone marrow or increasing levels of minimal residual disease (MRD) in the bone marrow as assessed by flow cytometry; if an adequate bone marrow sample cannot be obtained, patients may be enrolled if there is unequivocal evidence of leukemia in the peripheral blood
Relapsed and/or primary refractory Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS) with subtype refractory anemia with excess blasts (RAEB)-2 defined as high or very high-risk that is recurrent or refractory, or the patient is intolerant to established therapy.
Morphological disease in the bone marrow (? 5% blasts)
Chronic phase disease is defined as:\r\n* < 15% blasts in peripheral blood and bone marrow; \r\n* < 30% blasts plus promyelocytes in peripheral blood and bone marrow;\r\n* < 20% basophils in peripheral blood; \r\n* >= 100 x 10^9/L platelets (>= 100,000/mm^3); \r\n* No evidence of extramedullary disease except hepatosplenomegaly; and \r\n* No prior diagnosis of accelerated phase (AP) or blastic phase-chronic myeloid leukemia (BP-CML); patients with clonal evolution but no other criteria for accelerated phase are eligible
AML participants must have the following malignancy criteria: measurable and evaluable disease per tumor response criteria; ? 5% bone marrow blasts without alternate causality; and > 90 days since allogeneic stem cell transplantation relapse in participants relapsing after transplant
Blast phase disease (> 20% blasts in the marrow or peripheral blood)
Documented excessive leukemic myeloid blasts in the bone marrow or peripheral blood (>= 10%) in the past 6 months
Presence of < 4% blasts on hematologic studies
Patients must have histologically or cytologically confirmed: \r\n* Pathologically confirmed intermediate or poor risk newly diagnosed AML (subtypes M0, 1, 2, 4-7), but excluding newly diagnosed core-binding factor (CBF) (t(8;21) or M4eo subtype (inv(16) or t(16;16) AMLs and acute promyelocytic leukemia (acute promyelocytic leukemia [APL], M3)\r\n* MDS with high risk features as defined by intermediate (INT)-2 or high International Prognostic Scoring System (IPSS) score with > 10% blasts in the bone marrow\r\n* Chronic myelomonocytic leukemia-2 (CMML-2) defined as having > 10% blasts (including promonocytes) in the bone marrow or 5-19% blasts (including promonocytes) in the peripheral blood
All patients must meet one of the qualifications as outlined below after prior HMA therapy:\r\n* Relapse after CR/CRi or partial remission (PR) - 1 or more of the following:\r\n** Return to pretreatment bone marrow blast percentage (for initial PR)\r\n** Reappearance of bone marrow blasts (> 5%) following initial CR/CRi\r\n* Disease progression\r\n** For patients with 10% to 20% blasts: a 50% or more increase to more than 20% blasts\r\n** For patients with > 20% blasts: a 50% or more increase to more than 40% blasts\r\n* Refractory disease\r\n** No evidence of a response (CR, CRi, PR) following, at least, 6 cycles of hypomethylating agent
Subjects with a histologically confirmed diagnosis of MDS by French American British (FAB) criteria, including both MDS and refractory anemia with excess blasts in transformation (RAEB-T) (AML with 20-30% blasts and multilineage dysplasia) and chronic myelomonocytic leukemia (CMML) with at least 10% bone marrow blasts by World Health Organization (WHO) classification are eligible
Subjects must have a diagnosis of relapsed or refractory ALL with ? 5% blasts in the bone marrow (M2 or M3 disease), with or without extramedullary disease. -To be eligible, subjects must have had 1 or more prior therapeutic attempts, defined as:
Histologically confirmed AML with >20% blasts
Disease refractory or relapsed (defined as the reappearance of > 5% blasts in the bone marrow).
Diagnosis of Myelodysplastic syndrome (MDS) according to WHO classification with refractory anemia with excess blasts (subtype RAEB-1 or RAEB-2), or considered high-risk by the Revised International Prognostic Scoring System (IPSS-R), that is recurrent or refractory, or the subject is intolerant to established therapy known to provide clinical benefit for their condition (i.e., subjects must not be candidates for regimens known to provide clinical benefit), according to the treating physician and with approval of the Medical Monitor. Phase 1/Part 1 Expansion: Arm 1: Relapsed or refractory AML and age greater than or equal to 60 years or any subject with AML regardless of age who has relapsed following a Bone marrow transplant (BMT). Arm 2: Relapsed or refractory AML and age <60 years, excluding subjects with AML who have relapsed following a BMT. Arm 3: Untreated AML and age greater than or equal to 60 years that decline standard of care chemotherapy. Arm 4: Isocitrate dehydrogenase protein, 2 (IDH2)-mutated advanced hematologic malignancies not eligible for Arms 1 to 3. Phase 2: Diagnosis of AML according to World Health Organization (WHO) criteria and disease relapsed or refractory as defined by:
Diagnosis of myelodysplastic syndrome and one of the following:\r\n* Cytopenias requiring red blood cell and/or platelet transfusions or neutropenia (absolute neutrophil count [ANC] < 1 x 10^9/L)\r\n* International Prognostic Scoring System (IPSS) score of intermediate-1 (INT-1) or higher at screening\r\n* MDS with excess blasts in transformation as defined by French-American-British (FAB) criteria (20-29% bone marrow blasts) or\r\n* Chronic myelomonocytic leukemia
Previously untreated AML (>= 20% blasts); patients with high-risk MDS (defined as having >= 10% blasts in the bone marrow) or patients with chronic myelomonocytic leukemia (CMML) (having >= 10% blasts in the bone marrow) may also be eligible after discussion with principal investigator (PI); prior therapy with hydroxyurea, biological or targeted therapy (e.g. fms-related tyrosine kinase 3 [FLT3] inhibitors, other kinase inhibitors), or hematopoietic growth factors is allowed, however prior therapy with chemotherapy agents for the disease under study is not allowed; patients may have received one dose of cytarabine (up to 2 g/m^2) administered at presentation for control of hyperleukocytosis; for patients with prior MDS or CMML who transformed to AML, therapy received for MDS is not considered as prior therapy for AML
Patients with previously untreated AML are candidates if they are unable to receive anthracyclines, and have documented AML with >= 20% blasts within one week prior to enrollment
Histologically or cytologically confirmed advanced and/or aggressive hematologic malignancy (including acute myeloid leukemia [AML] in complete remission [CR] and myelodysplastic syndrome with < 10% blasts in the bone marrow) unlikely to be cured by alternative therapies
Pathological diagnosis of AML according to WHO criteria (with at least 20% blasts in the peripheral blood or bone marrow)
Acute myeloid leukemia, including biphenotypic acute leukemia or mixed-lineage leukemia\r\n* All patients must have acute myeloid leukemia (AML) that is considered best treated by stem cell transplant by the referring physician and the attending transplant physician\r\n* All patients must be in complete remission (CR) as defined by < 5% blasts by morphology/flow cytometry in a representative bone marrow sample with cellularity >= 15% for age\r\n* Patients in which adequate marrow/biopsy specimens cannot be obtained to determine remission status by morphologic assessment, but have fulfilled criteria of remission by flow cytometry, recovery of peripheral blood counts with no circulating blasts, and/or normal cytogenetics (if applicable) may still be eligible; reasonable attempts must be made to obtain an adequate specimen for morphologic assessment, including possible repeat procedures; these patients must be discussed with the principal investigator prior to enrollment
Myelodysplasia (MDS) International Prognostic Scoring System (IPSS) intermediate (Int)-2 or high risk (i.e., refractory anemia with excess blasts [RAEB], refractory anemia with excess blasts in transformation [RAEBt]) or refractory anemia with severe pancytopenia or high risk cytogenetics; blasts must be < 10% by a representative bone marrow aspirate morphology
Any acute leukemia (including prior myelodysplasia or CML blast crisis) with morphologic relapse or persistent disease >= 10% blasts in the bone marrow (BM), or doubling of the blasts in the blood in the 2 weeks preceding admission, or need for hydroxyurea in the 2 weeks prior to admission, or uncontrolled extra-medullary disease
<5% blasts in blood or marrow at screening
MDS classified as follows: refractory anemia with excess blasts (RAEB)-1 (5%-9% bone marrow [BM] blasts); RAEB-2 (10%-19% BM blasts); chronic myelomonocytic leukemia (CMML) (5%-19% BM blasts); refractory anemia with excess blasts in transformation (RAEB-t) (20%-29% BM blasts) AND/OR by International Prognostic Scoring System (IPSS): intermediate-2 and high risk patients
Myelodysplastic syndrome criteria:\r\n* Diagnosis of MDS classifiable by the World Health Organization (WHO) system as:\r\n** Refractory anemia\r\n** Refractory cytopenia with multilineage dysplasia \r\n** MDS-unclassified\r\n** Refractory cytopenias with multilineage dysplasia and ringed sideroblasts, refractory anemia with excess blasts-1\r\n** Refractory anemia with excess blasts-2\r\n** Chronic myelomonocytic leukemia (CMML)\r\n** MDS transformed to acute leukemia
Patients with advanced MDS must have < 10% marrow blasts prior to receiving conditioning with TLI/ATG; less than 10% marrow blasts must be documented by marrow examination within 1 month of starting conditioning; if necessary, a cytoreductive regimen will be determined by referring centers
Patients with evolution to AML are required to be in a morphologic leukemia free-state with blasts < 5%
Patients with MPD must have < 10% marrow blasts prior to receiving conditioning with TLI/ATG; less than 10% marrow blasts must be documented by marrow examination within 1 month of starting conditioning; if necessary, a cytoreductive regimen will be determined by referring centers
Patients with evolution to AML are required to be in a morphologic leukemia-free state with blasts less than 5% in a marrow aspirate; presence of residual dysplastic features following cytoreductive therapy is acceptable
Therapy-related myeloid neoplasms:\r\n* Patients with therapy related-MDS (t-MDS) must have < 10% marrow blasts prior to receiving conditioning with TLI/ATG; less than 10% marrow blasts must be documented by marrow examination within 1 month of starting conditioning; if necessary, a cytoreductive regimen will be determined by referring centers
Patients with t-AML are required to be in a morphologic leukemia free-state with blasts < 5%
High risk MDS (refractory anemia with excess blasts [RAEB]-1, RAEB-2, treatment related MDS) not responsive to 2 lines of therapy (including hypomethylating agent and induction chemotherapy)
The following diseases will be permitted although other diagnoses can be considered if approved by Patient Care Conference (PCC) or the participating institutions’ patient review committees and the principal investigators\r\n* Aggressive non-Hodgkin lymphomas (NHL) and other histologies such as diffuse large B cell NHL: not eligible for autologous HCT, not eligible for high-dose allogeneic HCT, or after failed autologous HCT\r\n* Mantle cell NHL: may be treated in first complete remission (CR); (diagnostic lumbar puncture [LP] required pre-transplant)\r\n* Low grade NHL: with < 6 month duration of CR between courses of conventional therapy\r\n* CLL: must have either: \r\n** Failed to meet National Cancer Institute (NCI) Working Group criteria for complete or partial response after therapy with a regimen containing FLU (or another nucleoside analog, e.g. 2-Chlorodeoxyadenosine [2-CDA], pentostatin) or experience disease relapse within 12 months after completing therapy with a regimen containing FLU (or another nucleoside analog); \r\n** Failed FLU-cyclophosphamide (CY)-Rituximab (FCR) combination chemotherapy at any time point; or \r\n** Have “17p deletion” cytogenetic abnormality; patients should have received induction chemotherapy but could be transplanted in 1st CR; or\r\n** Patients with a diagnosis of CLL (or small lymphocytic lymphoma) or diagnosis of CLL that progresses to prolymphocytic leukemia (PLL), or T-cell CLL or PLL\r\n* Hodgkin lymphoma: must have received and failed frontline therapy\r\n* Multiple myeloma: must have received prior chemotherapy; consolidation of chemotherapy by autografting prior to nonmyeloablative HCT is permitted\r\n* Acute myeloid leukemia (AML): must have < 5% marrow blasts at the time of transplant\r\n* Acute lymphocytic leukemia (ALL): must have < 5% marrow blasts at the time of transplant\r\n* Chronic myeloid leukemia (CML): patients in 1st chronic phase (CP1) must have failed or be intolerant of tyrosine-kinase inhibitors (TKI); patients beyond CP1 will be accepted if they have < 5% marrow blasts at time of transplant  \r\n* Myelodysplasia (MDS)/myeloproliferative syndrome (MPS): patients must have < 5% marrow blasts at time of transplant \r\n* Waldenstrom’s macroglobulinemia: must have failed 2 courses of therapy
Presence of circulating leukemic blasts (in the peripheral blood) detected by standard pathology for patients with AML, ALL or CML
Presence of >= 5% circulating leukemic blasts (in the peripheral blood) detected by standard pathology for patients with MDS/MPS
Blasts in Peripheral Blood or Bone Marrow ?15%
Promyelocytes and Blasts in Peripheral Blood or Bone Marrow ?30%
Thrombocytopenia <100 x 103/ml, not resulting from therapy Blast phase is defined as ?30% blasts in peripheral blood or bone marrow, or presence of extramedullary disease, except for liver or spleen.
20% blasts in bone marrow
Patients must have obtained a complete remission with chemotherapy defined by the absence of circulating blasts, and less than 5% blasts on bone marrow examination following hematopoietic recovery
With minimal residual disease (MRD) or relapse post-HSCT (for the phase I dose escalation) as evidenced by polymerase chain reaction (PCR) positivity, specific cytogenetic abnormalities, an abnormal population on flow cytometry or increased blasts on bone marrow biopsy or in the peripheral blood
Acute myeloid leukemia (AML) must have < 5% marrow blasts at the time of HCT
Acute lymphocytic leukemia (ALL) must have < 5% marrow blasts at the time of HCT
Chronic myeloid leukemia (CML) accepted if they are beyond chronic phase (CP)1 and if they have received previous myelosuppressive chemotherapy or HCT and have < 5% marrow blasts at time of transplant
Myelodysplasia (MDS)/myeloproliferative syndrome (MPS) - (> intermediate 1 [int-1] per International Prognostic Scoring System [IPSS]) after > or = 1 prior cycle of induction chemotherapy; must have < 5% marrow blasts at time of transplant
Patients with AML, MDS, ALL, or CML must not have presence of circulating leukemic blasts detected by standard pathology
The patients' leukemia or MDS blasts must express the WT1 protein detectable by immunohistopathologic analysis, or if an adequate sample is not available for testing, must have a form of leukemia (ALL, AMLs other than M5) or MDS (2 degree MDS, RAEB, RAEBT) known to overexpress WT1 in a high proportion of cases (> 60%); for patients who develop a documented relapse of leukemia or MDS following transplant, marrow aspirates should be evaluated for the proportion of blasts expressing WT1 by immunohistology or fluorescence activated cell sorting (FACS) whenever possible
Patients with advanced AML or ALL defined as beyond first remission, primary refractory disease, or evolved from myelodysplastic or myeloproliferative syndromes; or patients with MDS expressed as refractory anemia with excess blasts (RAEB), refractory cytopenia with multilineage dysplasia (RCMD), RCMD with ringed sideroblasts (RCMD-RS), or chronic myelomonocytic leukemia (CMML)
Recipients with primary or secondary acute leukemia, refractory anemia with excess blasts (RAEB), CML, or other eligible diagnosis in transformation to acute leukemia must have =< 5% blasts in bone marrow and no circulating blasts in peripheral blood at study entry; recipients who do not meet these criteria may be re-evaluated for study eligibility after receiving standard induction therapy for acute leukemia and determined to be in remission
Patients with accelerated phase chronic myelogenous leukemia may have =< 10% blasts in the peripheral smear or bone marrow at study entry
Patients must have >= 5% blasts by morphology in the bone marrow OR molecular evidence of at least 0.1% leukemic blasts in the bone marrow
Morphological evidence of disease in bone marrow (at least 5% blasts)
Patients with a diagnosis of myelodysplastic syndrome with >= 10% bone marrow blasts with no response or progression of disease after at least 4 cycles of a hypomethylating agent (5-azacytidine or decitabine)
Relapse in ALL is defined as the reappearance (in a patient who has previously achieved remission) of leukemic blasts in the bone marrow\r\n* Should flow cytometric analyses suggest relapse (by the reappearance of a similar immunophenotype to the original leukemia) in the presence of < 5% blasts morphologically, a repeat bone marrow test is recommended to confirm relapse\r\n* Molecular or genetic relapse is characterized by the reappearance of a cytogenetic or molecular abnormality
Myelodysplastic syndrome (MDS): refractory anemia (RA)/refractory cytopenia with multilineage dysplasia (RCMD) with high risk cytogenetic features or transfusion dependence, refractory anemia with excess blasts (RAEB)-1 and RAEB-2 and AML evolved from MDS, who are not eligible for a higher priority protocol
Patients must have a diagnosis of acute lymphoblastic leukemia (ALL) with ? 25% blasts in the bone marrow (M3), with or without extramedullary disease.
Patients with T-cell ALL must have greater than 25% blasts in the bone marrow with or without extramedullary disease.
Patients must have received at least one prior chemotherapy regimen for their AML and they may have received any type of chemotherapy; disease relapse or the presence of refractory disease must be documented by bone marrow examination demonstrating > 5% blasts in the bone marrow not attributable to another cause; administration of hydrea to control high white blood cell (WBC) count is permitted
For Pre-allo Part A (before stem cell transplant): Relapsed or refractory AML (greater than 5% blasts)
Bone marrow aspirate/biopsy results showing >5% blasts
Bone marrow in morphologic remission (any remission number) defined as < 5% blasts (M1 classification) performed in local institution lab
CNS 1 (< 5/?L WBCs in CSF and cytospin negative for blasts)
Patients must be in a documented CR/CRi from either their front-line or first salvage therapy as evidenced by =< 5% bone marrow blasts and absence of extramedullary disease; (for patients with prior MDS who then transformed to AML, therapy received for MDS is not considered prior therapy for AML)
Acute myeloid leukemia\r\n* Not in remission (pediatric patients < 18 years)\r\n* Not in remission (10-30% blasts in the bone marrow for adult patients >= 18 years and =< 55 years)\r\n* Evidence of pre-transplant minimal residual disease (MRD) by flow cytometry, FISH or cytogenetics
Remission will be defined as < 5% blasts in the peripheral blood and bone marrow without morphological characteristics of the original leukemia population at the time of diagnosis
Expression of CD33 on more than 30% of bone marrow blasts at screening for patients with refractory or relapsed acute myeloid leukemia is required. CD33 positive expression of bone marrow blasts at the time of initial acute myeloid leukemia diagnosis is sufficient for those patients in complete remission with high risk to relapse.
Patients with refractory or relapsed acute myeloid leukemia > 5.000 blasts in the peripheral blood.
Patients with AML in the first morphologic relapse as defined by >= 5% reappearance of leukemia blasts in the bone marrow not attributable to any other cause who have not yet received chemotherapy for the current relapse
Participants must have a diagnosis of AML or MDS and must have disease that has relapsed or is refractory to chemotherapy, or that has relapsed after hematopoietic stem cell transplantation (HSCT)\r\n* Refractory disease is defined as persistent disease after at least two courses of induction chemotherapy\r\n* Patients with AML must have >= 5% leukemic blasts in the bone marrow or have converted from negative minimal residual disease (MRD) status to positive MRD status in the bone marrow as assessed by flow cytometry; if an adequate bone marrow sample cannot be obtained, patients may be enrolled if there is unequivocal evidence of leukemia in the peripheral blood
Non-M3 acute myeloid leukemia (AML) with the presence of residual disease in the bone marrow on day 14-28 post induction (or re-induction) chemotherapy; day 14-28 residual disease is defined in this study as the presence of more than 10 % blasts in the marrow in patients, presence of between 5-10% blasts cells that are not in cluster in hypocellular marrow is ambiguous and bone marrow biopsy should be repeated in 5-7 days
Patient must have relapsed/refractory acute lymphoblastic leukemia (ALL) with ? 5 blasts in the bone marrow or biopsy confirmed extramedullary disease. Patient may have CNS 1, 2 or 3 disease. Isolated CNS relapse is not eligible.
< 5% blasts in blood or marrow at screening, except if measurable extramedullary AML is confirmed
Blasts in PB < 20% prior to study enrollment
Leukemic transformation (> 20% blasts in PB or bone marrow [BM] any time prior to hematopoietic cell transplantation [HCT])
Patients must have > 10% leukemic blasts in the bone marrow;
Newly-diagnosed AML by World Health Organization (WHO) criteria (>= 20% myeloid blasts by morphology in either blood or marrow)
High-risk myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN) including chronic myelomonocytic leukemia 2 (CMML2) as defined by 10-19% myeloid blasts in either blood or marrow
Greater than 5% blasts in bone marrow
Patients must have a strong clinical suspicion of JMML, based on a modified category 1 of the revised diagnostic criteria; specifically, eligible patients must have all of the following: \r\n* Splenomegaly\r\n* Absolute monocyte count (AMC) > 1000/uL\r\n* Blasts in peripheral blood (PB)/bone marrow (BM) < 20%
Must have one of the following diagnoses:\r\n* Pathologically confirmed chronic myelomonocytic leukemia (CMML) or myelodysplastic syndromes (MDS) with high risk features at the time of referral for trial as defined by:\r\n** Intermediate (INT)-2 or high International Prognostic Scoring System (IPSS) score\r\n** Secondary MDS (defined as MDS developing in a patient with an antecedent hematologic disorder or any patient with prior chemotherapy or radiation exposure)\r\n** INT-1 MDS with excess blasts (>= 5% blasts in bone marrow [BM]) or red blood cell (RBC) transfusion-dependency\r\n** MDS progressing to oligoblastic acute myeloid leukemia (AML) with 21-30% BM blasts\r\n** CMML with >= 5% marrow blasts, or RBC or platelet transfusion-dependency, abnormal karyotype, or proliferative features (white blood cell count >=13,000/uL, splenomegaly on physical examination, or extramedullary disease)\r\n** All patients are required to have failed to respond or relapsed after an initial response to hypomethylating agents 5-azacitidine or decitabine or have refused to receive hypomethylating therapy; failure to respond is defined as failing to achieve a CR, PR or HI after at least 4 cycles of hypomethylating therapy; these patients could have received other therapies or not, but must have received hypomethylating therapy or have refused to receive hypomethylating therapy\r\n* Pathologically confirmed AML patients who have received one or two courses of induction chemotherapy or hypomethylating agent therapy AND no plans for further chemotherapy therapy, but remain with residual disease of < 5% blasts in BM, by morphology, cytogenetics, fluorescent in situ hybridization (FISH), polymerase chain reaction (PCR) or flow cytometry
Relapsed or refractory (resistant) disease, as defined by standard criteria:\r\n* Relapsed: bone marrow blasts >= 5%; reappearance of blasts in the blood; development of extramedullary disease\r\n* Refractory (resistant): failure to achieve CR or CRi in patients who survive >= 7 days following completion of initial treatment, with evidence of persistent leukemia by blood and/or bone marrow examination
Inclusion Criteria:\n\n        Donor:\n\n          -  Donor eligibility will be determined according to applicable federal, state and local\n             regulations and institutional standards\n\n          -  18-65 years of age\n\n          -  6/6 HLA-matched sibling\n\n          -  Fulfill individual Transplant Center criteria to serve as a mobilized blood cell donor\n\n          -  Serum creatinine <2.0mg/dl\n\n        Recipient:\n\n          -  18 to 65 years of age\n\n          -  6/6 HLA antigen matched sibling willing to donate PBSC for transplant\n\n          -  Fulfill individual Transplant Center Criteria for transplant\n\n          -  One of the following diagnoses:\n\n               -  Acute myelogenous leukemia (AML) in 1st remission or beyond with <5% marrow\n                  blasts and no circulating blasts. Marrow must be done within 30 days of the start\n                  of transplant conditioning regimen in alignment with other pre-transplant\n                  assessments.\n\n               -  Acute lymphoblastic leukemia (ALL) in 1st remission or beyond with <5% marrow\n                  blasts and no circulating blasts\n\n               -  Myelodysplastic syndrome, either intermediate-1,2, or high risk by International\n                  Prognostic Scoring System or transfusion dependent\n\n               -  Chronic myelogenous leukemia (CML) failing or intolerant to tyrosine kinase\n                  inhibitor based therapy\n\n               -  Non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD) in 2nd or greater complete\n                  remission, partial remission, or in relapse (but with at least stable disease\n                  after most recent therapy)\n\n               -  Chronic lymphocytic leukemia (CLL), relapsing after at least one prior regimen,\n                  or in remission with 17p deletion\n\n          -  Serum creatinine must be <2.0mg/dl\n\n          -  Total bilirubin and AST <3x normal\n\n          -  Infectious disease marker (IDM) monitoring will be performed per institutional\n             standards\n\n          -  Karnofsky performance status of 70% or greater.\n\n          -  Patients who have undergone a prior autologous transplantation are eligible for a\n             reduced intensity transplant only\n\n        Exclusion Criteria:\n\n        Donor:\n\n          -  Donor unwilling or unable to give informed consent, or unable to comply with the\n             protocol including required follow-up and testing\n\n          -  Donor already enrolled on another investigational agent study\n\n          -  Pregnant or breast feeding females, or females not willing or able to use adequate\n             contraception if sexually active\n\n        Recipient:\n\n          -  Patient unwilling or unable to give informed consent, or unable to comply with the\n             protocol including required follow-up and testing\n\n          -  Patients with active, uncontrolled infection at the time of the transplant preparative\n             regimen\n\n          -  Pregnant or breast feeding females, or females not willing or able to use adequate\n             contraception if sexually active\n\n          -  Patients with a history of previous CNS tumor involvement showing active symptoms or\n             signs along with documented disease on lumbar puncture and MRI of the brain within 30\n             days of start of conditioning\n\n          -  A condition, which, in the opinion of the clinical investigator, would interfere with\n             the evaluation of primary and secondary endpoints.
> 10% blasts or biopsy-documented leukemia cutis or myeloid sarcoma.
Patients will be considered eligible for the study if after transplant they achieved hematologic (< 5% blasts) and cytogenetic remission
Evidence of residual disease either by increased blasts count (> 5%) or persistence of previous known cytogenetics abnormalities
Blast phase disease (>20% blasts in the marrow or peripheral blood)
Patients who are eligible for HSCT but with non-optimal AML disease control (i.e., blasts > 5%) may be enrolled into this study as a bridge-to-transplant.
Relapsed, refractory, or progressive acute leukemia in second or subsequent remission, with remission defined as < 5% bone marrow blasts morphologically
AML in second or greater remission, primary induction failure and patients with relapsed disease, peripheral blood blasts < 1000/microliter; patients > 55 years and =< 75 years need to be in morphologic remission at transplant (< 5% blasts)
Chronic myeloid leukemia (CML) >= 1st chronic phase, after failed >= 2 lines of tyrosine kinase inhibitors; in accelerated or blast phase with > 30% bone marrow blasts
Patients with AML must have less than 30% bone marrow blasts and no peripheral blood blasts
Transformed disease (bone marrow blasts are permitted; however, transformed disease indicating leukemic involvement is not permitted)
The patient's blasts cells show expression of WT1 tran-script, detected by quantitative RT-PCR.
Acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS)\r\n * Patients with AML will be eligible in first relapse or 2nd or 3rd complete remission; patients not in remission must have < 25% blasts in the bone marrow prior to admission to the hematopoietic stem cell transplant (HSCT) unit; patients with MDS will be eligible if no other suitable donor can be identified\r\n * In general, patients will be preferentially transplanted using a matched unrelated donor or umbilical cord blood; AML/MDS patients will be eligible for this study if a suitable related or unrelated donor cannot be identified, the amount of time required to identify a suitable donor is deemed unacceptable, or the patient is not eligible for a myeloablative transplant regimen\r\n * Patients who relapse following a myeloablative transplant, but cannot receive DLI (e.g. cord blood recipients, graft loss) will also be eligible; such patients must be >= 6 months post initial transplant, achieve a CR or have < 25% blasts in the bone marrow prior to admission to the HSCT unit
Leukemic relapse or disease progression: Patients with > 25% leukemic blasts in the bone marrow will not be eligible for DLI; cytoreduction with chemotherapy is permissible to reduce blast count to =< 25%
Patients must have >= 5% blasts in the bone marrow
Patients must have had histologic verification of AML at original diagnosis; AML is defined according to World Health Organization (WHO) classification with >= 5% blasts in the bone marrow (M2/M3 bone marrow), with or without extramedullary disease
Diagnosis of acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) with < 5% blasts in the bone marrow (M1) by morphology and that meets one of the following criteria:\r\n* Flow cytometric evidence of minimal residual disease (MRD) (>= 0.1% leukemic blasts for ALL or < 5% leukemic blasts for AML detected in the bone marrow) OR\r\n* Molecular/cytogenetic evidence of disease (fluorescence in situ hybridization [FISH] or polymerase chain reaction [PCR] methodology) performed within 7 days AND\r\n* With the intent of going on to an allogeneic hematopoietic cell transplantation (allo-HCT) independent of this study
Phase I (completed): Participants must have a diagnosis of AML, MDS, ALL or MPAL and must have disease that has relapsed or is refractory to chemotherapy, or that has relapsed after hematopoietic stem cell transplantation (HSCT)\r\n* Refractory disease is defined as persistent disease after at least two courses of induction chemotherapy\r\n* Patients with AML, MPAL or MDS are eligible at first or subsequent relapse, whereas patients with ALL are eligible at second or subsequent relapse or any relapse that is refractory to salvage chemotherapy\r\n* Patients with AML or ALL must have >= 5% leukemic blasts in the bone marrow or increasing levels of MRD in the bone marrow as assessed by flow cytometry; if an adequate bone marrow sample cannot be obtained, patients may be enrolled if there is unequivocal evidence of leukemia in the peripheral blood
Greater than 25% of blasts must be CD33 positive.
Greater than 25% of blasts must be CD33 positive.
Pathologically confirmed diagnosis of myelodysplastic syndrome (including secondary MDS, refractory anemia with excess blasts in transformation [RAEB-T], and chronic myelomonocytic leukemia [CMML, if white blood cells count is < 13,000/mm^3]) as defined by World Health Organization or French-American-British classifications
Patients must have documented hypoplasia from the bone marrow aspiration and biopsy 14 days +/- 2 days from the initiation of cytarabine treatment schedule (defined as < 5% blasts and < 20% cellularity)
Acute Leukemias: Must be in remission by morphology (< 5% blasts); Note cytogenetic relapse or persistent disease without morphologic relapse is acceptable; also a small percentage of blasts that is equivocal between marrow regeneration versus early relapse are acceptable provided there are no associated cytogenetic markers consistent with relapse
Myelodysplastic syndrome: any subtype including refractory anemia (RA) if severe pancytopenia or complex cytogenetics; blasts must be less than 5%; if 5% or more requires induction therapy pre-transplant to reduce blast count to =< 5%
Patients with acute leukemia in morphologic complete remission with or without hematologic recovery or with myelodysplasia (MDS) with no circulating blasts and with less than 5% blasts in the bone marrow. Patients with CMML must have a WBC count ? 10,000 cells/µL and < 5% blasts in the marrow. Patients with ? 5% blasts due to a regenerating marrow must contact the protocol chairs for review.
Subjects with acute leukemia, chronic myelogenous leukemia, or myelodysplasia must have no circulating blasts and < 5% blasts of the bone marrow.
Less than or equal to 5% blasts on bone marrow examination within 60 days of starting conditioning
EXCLUSION CRITERIA FOR ENROLLMENT (PRE-TRANSPLANT): Active leukemia (> 5% leukemic blasts in peripheral blood or bone marrow)
EXCLUSION CRITERIA (PRIOR TO IBRUTINIB ADMINISTRATION): Relapsed leukemia (> 5% leukemic blasts in peripheral blood or bone marrow after allogeneic HCT)
Patients with acute leukemia or chronic myelogenous leukemia with no circulating blasts and with less than 10% blasts in the bone marrow
Myelodysplasia (MDS) and chronic myeloid leukemia (CML): must have < 5% marrow blasts
Myeloproliferative neoplasms (MPN): must have < 5% peripheral / marrow blasts\r\n* Note: Prior use of a Janus kinase 2 (JAK2) inhibitor is allowed up to 4 weeks before day 0 of allogeneic hematopoietic cell transplantation (alloHCT)
Myelodysplasia with any of the following features: \r\n* Refractory anemia with excess blasts type I (5-10% blasts) or II (11-20% blasts) in the bone marrow (RAEB I and II)\r\n* Refractory cytopenia with multilineage dysplasia (RCMD) and poor risk cytogenetics (i.e., chromosome 7 abnormalities or complex karyotype with at least 3 abnormalities per clone)
MDS\r\n* Bone marrow with =< 5 percent myeloblasts with normal maturation of all cell lines\r\n* Peripheral blood demonstrates hemoglobin >= 11 g/dL, platelets >= 100 x 10^9/L, neutrophils >= 1 x 10^9/L, and no circulating blasts
Acute myeloid leukemia (AML) – must have < 5% marrow blasts at the time of transplant
Acute lymphocytic leukemia (ALL) – must have < 5% marrow blasts at the time of transplant
Chronic myeloid leukemia (CML) – Patients will be accepted if they have shown intolerance to tyrosine kinase inhibitors or are beyond first chronic phase (CP1) and if they have received previous myelosuppressive chemotherapy or HCT, and have < 5% marrow blasts at time of transplant
Myelodysplasia (MDS)/myeloproliferative syndrome (MPS) – Patients must have < 5% marrow blasts at time of transplant
Acute myeloid leukemia (AML) in first cytomorphological remission (< 5% blasts in the bone marrow) with Disease Risk Index (DRI) intermediate or above, or in second or higher cytomorphological remission
Acute lymphoblastic leukemia (ALL) in first or higher remission (< 5% blasts in the bone marrow)
Acute leukemias: Must be in remission by morphology (=< 5% blasts); also a small percentage of blasts that is equivocal between marrow regeneration versus early relapse are acceptable provided there are no associated cytogenetic markers consistent with relapse
Myelodysplastic syndrome: IPSS INT-2 or high risk; R-IPSS high or very high; World Health Organization (WHO) classification: RAEB-1, RAEB-2; severe cytopenias: absolute neutrophil count (ANC)0000 < 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; if >= 5% blasts, patient requires chemotherapy for cytoreduction to < 5% blasts prior to transplantation
Pre-injectable HMA (HYPOMETHYLATING AGENT) baseline bone marrow myeloblasts: a. Less than 5%: ? 100% increase to ? 8% blasts b. ? 5%: ? 50% increase to ? 10% blasts Note: ? 30% blasts is considered AML (ACUTE MYELOID LEUKEMIAT) per FAB (FRENCH-AMERICAN BRITISH)classification. Subjects known to have ? 30% blasts are not eligible for inclusion in this study. RECOG (Eastern Cooperative Oncology Group) nizing limitations of blast cell quantification, this protocol will allow subjects with pre-enrollment bone marrow blast counts up to 33% on the screening bone marrow examination to be considered for inclusion. Assessment may be made according to local bone marrow examination to facilitate enrollment of eligible subjects into the treatment phase of the study.
Acute myelogenous leukemia (AML (ACUTE MYELOID LEUKEMIA) - FAB (FRENCH-AMERICAN-BRITISH) classification: ? 30% blasts in bone marrow). Subjects known to have ? 30% blasts are not eligible for inclusion in this study. Recognizing limitations of blast cell quantification, this protocol will allow subjects with pre-enrollment (screening/baseline) bone marrow blast counts up to 33% to be considered for inclusion.
Patients with acute leukemia, chronic myelogenous leukemia, myeloproliferative disorder and myelodysplasia with no circulating blasts and with less than 5% blasts in the bone marrow within 4 weeks of the start of transplant conditioning regimen
Patients with acute leukemia, chronic myelogenous leukemia or myelodysplasia with no circulating blasts and with less than 5% blasts in the bone marrow.
CD123/IL3RA expression on the subject’s AML or MDS blasts, determined locally within 3 months of first protocol treatment
Documented diagnosis of myelodysplastic syndrome (MDS), MDS/myeloproliferative neoplasm (MPN), chronic myelomonocytic leukemia (CMML) by World Health Organization (WHO) criteria or AML with 20-30% myeloblasts (refractory anemia with excess blasts in transformation [RAEB-T] by French-American-British [FAB)] criteria)
Patients must have obtained a complete remission with chemotherapy defined by the absence of circulating blasts, and less than 5% blasts on bone marrow examination following hematopoietic recovery
The patient has a confirmed diagnosis of Philadelphia chromosome (Ph) positive chronic myelogenous leukemia in either CP or AP. Accelerated phase will be defined as disease having 1 of the following: ?15% to <30% blasts in peripheral blood or bone marrow; ?30% blasts + promyelocytes in peripheral blood or bone marrow; ?20% basophils in peripheral blood or bone marrow; platelet count <100x109/L unrelated to therapy; or clonal evolution.