Current or prior diagnosis of AML
AML as defined by the WHO Classification persisting or recurring following one or more treatment courses except promyelocytic leukemia (APML) and except AML with myelodysplasia related changes.
COHORT 2: Have received NO prior treatment for AML with the exception of hydroxyurea / leukapheresis\r\n* NOTE: Subjects may have been treated for pre-existent myeloid disorder such as myelodysplastic syndrome or myeloproliferative neoplasm including hypomethylating agents
AML SA expansion group 1: histologically or cytologically proven AML with a FLT3 ITD or TKD mutation previously determined by local testing that is R/R to standard therapy or for whom standard treatments are contraindicated
AML SA expansion group 2: histologically or cytologically proven AML with intermediate or unfavorable risk cytogenetics in the absence of a detectable FLT3 ITD or TKD mutation as previously determined by local testing that is R/R to standard therapy or for whom standard treatments are contraindicated
Participant must have metastatic CRPC or AML not amenable to curative therapy, refractory to standard of care therapy or for which standard of care therapy does not exist. Participants with AML who are candidates for stem cell transplantation must have been offered this therapeutic option. Must meet additional criteria specific for each diagnosis, metastatic CRPC and relapsing/remitting AML, as described in the protocol.
Received any previous treatment for AML
Diagnosed with APL-M3 or CBF-AML
Subject has AML secondary to prior chemotherapy.
diagnosis of AML
Pathologically-confirmed diagnoses of relapsed AML: patients with AML that have relapsed at least once or are primary induction failure will be eligible
AML as defined by the WHO Classification persisting or recurring following one or more treatment courses except promyelocytic leukemia (APML) and except AML secondary to prior myelodysplastic syndrome. For Germany only: AML as defined by the WHO Classification either persisting/refractory after at least 2 primary induction courses (ie, no response after at least 2 prior chemotherapy cycles) or recurring after having achieved an initial response to chemotherapy except promyelocytic leukemia (APML) and except AML secondary to prior myelodysplastic syndrome.
AML (with the exception of AML M3), patients with relapsed or refractory AML following treatment with cytotoxic chemotherapy or a targeted or biologic agent
AML (with the exception of AML M3):
AML unsuitable for intensive chemotherapy
Subject must have received no prior treatment for AML; hydroxyurea is not considered a treatment and is allowed
> 10% bone marrow blasts at transplant if no history of AML and > 5% if had previous progression to AML;
Patients with AML or biphenotypic or bilineage leukemia (including a myeloid component) who have failed prior therapy; patients with AML should have failed prior therapy or have relapsed after prior therapy; patients with isolated extramedullary AML are eligible
Patients diagnosed with APL, AML-M3
Previously untreated AML (de novo or secondary) defined according to World Health Organization (WHO) criteria, excluding APL [AML with t(15;17)], with locally documented IDH1 and/or IDH2 gene mutation scheduled for induction therapy followed by consolidation therapy. Secondary AML is defined as AML arising after myelodysplastic syndromes (MDSs) or other antecedent hematologic disorders (AHDs) or AML arising after exposure to genotoxic injury including radiation and/or chemotherapy. Subjects may have had previous treatment for MDS or other AHD, including hypomethylating agents (HMAs), provided that the last dose of administration is ? 14 days prior to study drug initiation
AML associated with inv(16); t(16;16); t(8;21) or t(15;17)
Patients who have had prior chemotherapy for AML
> 14 days since any prior therapy for AML excluding hydroxyurea
A new diagnosis of de novo, secondary or treatment-related AML
Only patients who are relapsed, refractory, or intolerant of standard AML therapy will be eligible for Part 1 (minimum of 1 prior line of AML-directed therapy)
Inclusion Criteria:\n\n        AML confirmed subjects aged ? 60 years who have achieved complete remission (CR or CRi)\n        after induction/consolidation Ara-C based therapy, that have MRD positive status and are\n        not planned for stem cell transplantation.\n\n        Exclusion Criteria:\n\n        Subjects diagnosed with acute promyelocytic leukemia or with extramedullary AML or subjects\n        who have achieved CR or CRi following treatment for AML. Subjects who have received\n        treatment with hypomethylating agents.
Patients with active (blood or bone marrow blasts > 5%) relapsed or refractory CD33+ acute myeloid leukemia (AML) de novo, or secondary. a. Relapsed AML is defined as patients that had a first complete remission (CR) before developing recurrent disease. b. Refractory AML defined as patients that have not achieved a CR after 2 cycles of induction chemotherapy.
FOR AML ONLY: Obtained =< 14 days prior to registration: No ANC restriction
AML ONLY: Acute promyelocytic leukemia (PML-RARA rearranged- AML-M3)
Patients must have newly diagnosed AML or ALL without previous treatment; hydroxyurea will be allowed to control peripheral blast count as clinically indicated but would need to be stopped prior to initiation of tyrosine kinase inhibitor [TKI]); all-trans retinoic acid (ATRA) is permitted during the period prior to ruling out a diagnosis of APL; previous radiation treatment is allowable; patients must be deemed eligible for treatment with cytotoxic induction chemotherapy with cytarabine and idarubicin for AML or hyper-cyclophosphamide, dexamethasone, doxorubicin, vincristine sulfate (CVAD) for ALL; patients newly diagnosed with ALL must have received no prior treatment for their ALL with the exception of steroids (i.e. prednisone, dexamethasone); intrathecal methotrexate or cytarabine, allowed prior to and throughout the enrollment period for AML and ALL
Therapy-related AML (defined as occurrence of AML due to prior exposure to chemotherapy or radiation for malignancy)
Secondary AML (defined as development of AML in patients with an antecedent hematological malignancy)
Diagnosis of AML according to World Health Organization (WHO) 2008 criteria; therapy related AML may be included if in complete response and off treatment for their prior malignancy for more than 2 years; AML arising after documented myeloproliferative disease (MPD) are excluded
Patients must have histologic evidence of high risk acute myeloid leukemia defined as one of the following:\r\n* Primary refractory non-M3 AML\r\n** Residual leukemia after a minimum of 2 prior courses of chemotherapy (same or different)\r\n** Evidence of leukemia recurrence after a nadir bone marrow biopsy demonstrates no evidence of residual leukemia\r\n** Evidence of leukemia after induction therapy which, in the opinion of the investigator, would be appropriate for reinduction with sirolimus/MEC therapy\r\n* Relapsed non-M3 AML\r\n* Previously untreated non-M3 AML age > 60 with no evidence of favorable karyotype defined by presence of t(8;21)(q22;q22) [AML1-ETO], inversion (inv)16(p13;q22), or t(16;16)(p13;q22) [core-binding factor (CBF)beta; myosin, heavy chain (MYH)11] by cytogenetics, fluorescence in situ hybridization (FISH), or real time-polymerase chain reaction (RT-PCR)\r\n* Previously untreated secondary AML (from antecedent hematologic malignancy or following therapy with radiation or chemotherapy for another disease) with no evidence of favorable karyotype defined by presence of t(8;21)(q22;q22) [AML1-ETO], inv16(p13;q22), or t(16;16)(p13;q22) [CBFbeta;MYH11] by cytogenetics, FISH, or RT-PCR
AML secondary to any prior chemotherapy unrelated to leukemia
Patients must meet one of the three treatment history criteria:\r\n* Relapsed AML who have failed at least 1 line of salvage therapy\r\n* De novo AML who have not achieved CR after 2 lines of therapy\r\n* AML evolving from myelodysplastic syndrome (MDS) or myeloproliferative disorder who have failed hypomethylating agent or induction chemotherapy\r\n* Patients who have relapsed after allogeneic hematopoietic cell transplant (HCT) are eligible if they are at least 3 months after HCT, do not have active graft vs. host disease (GVHD) and are off immunosuppression except for maintenance dose of steroids (prednisone 10 mg/day or less)
ARM 1 SALVAGE COHORT: Patients with AML or biphenotypic or bilineage leukemia who have failed prior therapy; patients with AML should have failed prior therapy or have relapsed after prior therapy will be eligible for Arm 1;
Recipients with AML in CR1 must have one of the following:\r\n* Adverse cytogenetics (as evaluated by history) as defined as complex karyotype (> 3 abnormalities); inv(3) or t(3;3); t(6;9); t(6;11); monosomy 7; trisomy 8, alone or with an abnormality other than t(8;21), t(9;11), inv(16) or t(16;16); or t(11;19)(q23;p13.1)\r\n* Cytogenetically normal AML (CN-AML) with mutations in FMS-like tyrosine kinase 3 (FLT3), deoxyribonucleic acid (DNA) methyl transferase 3A (DMNT3A), or additional sex coombs like 1 (ASXL1)\r\n* Primary induction failure, defined as failure to achieve CR with primary induction chemotherapy\r\n* Secondary AML, defined as AML related to antecedent myeloid neoplasm or cytotoxic chemotherapy\r\n* Hyperleukocytosis, white blood cell (WBC) > 100,000, at diagnosis
ARM 1 - AML: Research patients enrolled are those patients with relapsed or refractory CD123+ AML de novo, or secondary OR participant who are at high risk for disease recurrence\r\nNOTE: CD123+ biphenotypic acute leukemia or CD123+ acute lymphoblastic leukemia (ALL) may also be considered but only after discussion with the study principal investigator (PI)\r\n* Relapsed AML is defined as patients that had a first complete remission (CR) before developing recurrent disease (increased bone marrow blasts)\r\n* Refractory AML is defined as patients that have not achieved a first CR after 2 cycles of induction chemotherapy; for patients with AML evolving from myelodysplastic syndrome, they should have completed at least one cycle of induction chemotherapy
Diagnosis of AML associated with the following karyotypes: inversion (inv)(16), t(16;16), t(8;21), t(15;17), or t(9;22)
DIAGNOSIS REQUIREMENT FOR PHASE II PATIENTS: Refractory AML without CR after induction therapy (primary induction failure) or relapsed AML after obtaining a CR; favorable-risk core binding factor (CBF) mutated AML and acute promyelocytic leukemia (APL) will be excluded
Initial diagnosis of poor -risk AML or MDS, treated with either stem cell transplant or cytarabine-based consolidation chemotherapy, within the past 60-185 days; the original diagnosis of AML or MDS must have been confirmed by bone marrow aspirate and/or biopsy review by a Johns Hopkins Hospital (JHH) hematopathologist; poor-risk AML is defined as disease that is therapy-related or arises from a previous marrow disorder, or de novo AML that is associated with any of the following characteristics: patient age 60 years or greater,\r\ntrilineage dysplasia, disease status greater than or equal to second complete remission (CR2), fms-related tyrosine kinase 3 (FLT3)/internal tandem duplication (ITD) mutations, detectable disease at time of consolidation chemotherapy or SCT, or poor-risk cytogenetics, which include abnormalities of chromosome 3, 5, or 7, trisomy 8, 11q23 abnormalities, t(6;9), 20q-, and complex karyotype
Secondary AML in 1st remission
Subjects with relapsed/refractory AML must have received either induction chemotherapy for AML or hypomethylating agents for hematologic disease before AML.
Received more than 2 cycles of induction therapy for AML. Investigational agents as part of front-line therapy for AML may by acceptable following discussion with the Medical Monitor. Hydroxyurea is permitted (see #5 below).
Group C: Cohort C1A: Subjects age ? 18 years with relapsed/refractory AML by WHO criteria; Cohort C2: Subjects age ? 18 years with relapsed/refractory AML with MLL; Cohort C3: Subjects with previously untreated AML by WHO criteria and who would have met disease eligibility criteria for Group A or B but refuse or are unable to receive chemotherapy and hypomethylating agent as determined by the treating physician
AML in 1st remission - for patients whose AML does not have 'good risk' cytogenetic features (i.e. t 8;21, t15;17, inv 16)
Secondary AML in 1st remission
Patients with therapy-related AML whose prior malignancy has been in remission for at least 12 months
Patients with relapsed or refractory AML. Relapsed AML is defined as relapse after achieving a response to initial therapy and refractory AML is defined as failure to achieve a response after one previous line of therapy. Response is defined as per IWG criteria (CR, CRi or CRp). Patients who are not candidates to receive or who decline standard of care therapy are also eligible.
AML either de novo or secondary who either :
Prior malignancy (other than basal cell carcinoma and cervical in situ carcinoma) unless treated with a curative intend and without evidence of malignant disease for 1 year before screening. Patients with prior hematologic malignancies that have progressed to AML (such as Myelodysplastic syndrome, myeloproliferative neoplasms, bi-phenotypic leukemias, AcuteLymphocyticLeukemia) or AML that has relapsed are eligible;
Patient with AML-M3 (APL)
Secondary AML in CR
secondary AML and ALL in 1st or 2nd relapse or primary refractory
Has FLT3-ITD mutant (> 3% FLT3-ITD/total FLT3) AML (primary AML or secondary to myelodysplastic syndrome [MDS]) that have failed any prior induction therapy regimen or have relapsed after prior induction/consolidation therapy, have not received more than one salvage therapy, and have not received more than one FLT3 inhibitor during prior AML treatment(s)
FLT3-ITD mutant (> 3% FLT3-ITD/total FLT3) AML (primary AML or secondary to MDS) is ineligible for intensive induction chemotherapy by meeting at least 1 of the protocol-defined criteria
Patients who have received any therapy other than hydroxyurea with the purpose of treating their AML are not eligible
ESCLATION COHORT: Patients must have a diagnosis of newly diagnosed and/ or relapsed/refractory AML with any of the following:\r\n* Confirmed translocation involving 11q23\r\n* Partial tandem duplication(PTD) of the MLL gene (on 11q23)\r\n* FLT3-ITD (internal tandem duplication)\r\n* Increased Fgf2 in serum (2 standard deviations above control serum samples)\r\n* HOX(A9/A10) over-expression in bone marrow ( 2 standard deviations above control values in CD34+ cells from normal subjects)\r\n* Note: Relapsed or refractory AML is defined as either: \r\n** Recurrence of disease after a complete remission (CR), or \r\n** Failure to achieve CR with initial therapy
EXPANSION COHORT: Patients must have a diagnosis of newly diagnosed AML with any of the following:\r\n* Confirmed translocation involving 11q23\r\n* Partial tandem duplication (PTD) of the MLL gene (on 11q23)\r\n* FLT3-ITD (internal tandem duplication)\r\n* Increased Fgf2 in serum (2 standard deviations above control serum samples)\r\n* HOX(A9/A10) over-expression in bone marrow (2 standard deviations above control values in CD34+ cells from normal subjects)\r\n* Note: Patients with secondary AML are eligible for enrollment into the trial (in both cohorts); secondary AML is defined as AML that has developed in a person with a history of antecedent blood count abnormalities, or myelodysplastic syndromes (MDS), or a myeloproliferative disorder (excluding chronic myeloid leukemia); or a history of prior chemotherapy or radiation therapy for a disease other than AML
Treatment-related AML and secondary AML in morphological remission (CR1 or beyond) with minimal residual disease as quantified either by flow cytometry, or by cytogenetics or molecular markers
Patients must have relapsed/refractory disease; patients with secondary AML (including those progressing from MDS or myeloproliferative neoplasm [MPN], and those with AML secondary to chemotherapy or radiotherapy for other malignancies) are eligible whether they have received prior therapy for AML or not
Have received any prior treatment for AML with the exception of hydroxyurea.
Cohort Inclusion Criteria - Group B: Subjects must have relapsed or refractory AML according to the WHO classification. For study purposes, refractory AML is defined as failure to ever achieve CR or recurrence of AML within 6 months of achieving CR; relapsed AML is defined as all others with disease after prior remission. (Group B is not currently recruiting. Expected to begin recruiting in 3rd quarter 2017.)
Specifically, for participants in Cohorts A3 and A4: Treatment naïve participants unfit for induction chemotherapy for AML as defined by the following: Age >= 70 or age 65 to 69 years with at least one of the following: ECOG performance status of 2, Intermediate I/II or adverse risk cytogenetic and molecular alterations per ELN 2010 guidelines or secondary AML, or other comorbidity judged incompatible with intensive chemotherapy
Any approved AML-related therapy within 14 days prior to enrollment
Patients may not have received prior chemotherapy for AML with the exception of hydroxyurea for increased blast count or leukapheresis for leukocytosis; patients who have received a limited and short-term exposure of ATRA (all trans retinoid acid) while AML-M3 (acute promyelocytic leukemia) was being ruled out, and which has been discontinued, will be eligible
>= 55 years of age with AML of any risk classification, or 18-54 years of age with high-risk AML disease based on one of the following:\r\n* Antecedent hematologic disorder including myelodysplasia (MDS)-related AML (MDS/AML) and prior myeloproliferative disorder (MPD)\r\n* Treatment-related myeloid neoplasms (t-AML/t-MDS)\r\n* AML with FLT3-ITD\r\n* Myeloid sarcoma\r\n* AML with multilineage dysplasia (AML-MLD)\r\n* Adverse cytogenetics (defined as -5/-5q; -7/-7q; abnormal 3q, 9q, 11q, 20q, 21q or 17p; t(6;9); t(9;22); trisomy 8; trisomy 13; trisomy 21; complex karyotypes (>= 3 clonal abnormalities); monosomal karyotypes
Patients with untreated AML and the presence of FLT3 mutation (Cohort A only); untreated AML patients > 60 years who are not candidates for intensive chemotherapy and patients with relapsed or refractory FLT3-mutated AML may enroll to Cohort B
Patients with secondary AML or therapy related disease (t-AML) are eligible
Patients with core-binding factor AML (inv[16], t[8;21]) or t(15;17) (Cohort A only)
AML with favorable risk cytogenetic abnormalities including t(15;17), t(8;21) or inv(16)
Patients must have histologically or cytologically confirmed acute myeloid leukemia (AML) by World Health Organization (WHO) criteria in the blood and/or marrow AND age >= 60 and not candidates/refuse standard induction treatment OR who have one of the following: poor risk cytogenetics, AML following antecedent hematologic disorder, or therapy-related AML
Patients must have histologic proof of active AML at time of enrollment
Refractory to first-line AML therapy is defined as:
AML secondary to prior chemotherapy for other neoplasms, except AML secondary to prior Myelodysplastic Syndrome (MDS).
Subject must have received no prior treatment for AML with the exception of hydroxyurea
Subject has favorable risk cytogenetics as categorized by the National Comprehensive Cancer Network Guidelines Version 2, 2014 for AML.
No prior therapy for AML, except for hydroxyurea, in this setting is allowed.
A diagnosis of renal AML > 3 cm confirmed on pre-enrollment DCE-MRI; a previous diagnosis or treatment of a different AML lesion is allowed
Patients must not have received any prior treatment for AML
Treatment-related AML, except if it is associated with favorable cytogenetics (e.g., inversion 16, t(16;16), t(8;21), t(15;17)).
Treatment-related AML, except if it is associated with favorable cytogenetics (e.g., inversion 16, t(16;16), t(8;21), t(15;17)).
Diagnosis of AML according to WHO criteria 2016.
AML (including secondary AML) diagnosed as per WHO criteria
AML with inv(16), t(8;21), t(16;16), t(15;17), or t(9;22) or molecular evidence of such translocations
AML secondary to exposure to potentially leukemogenic therapies or agents (eg, radiation therapy, alkylating agents, topoisomerase II inhibitors) with the primary malignancy in remission for at least 2 years.
Absolute WBC count ? 15 × 109/L. AML Cohort:
For AML patients, no more than 1 prior salvage therapy.
Patients with AML\r\n* Patients with therapy-related myeloid neoplasms are allowed\r\n* Patients with AML that has evolved from an antecedent hematologic disorder are allowed\r\n* Patients will be eligible regardless of their ultimate plans or candidacy for allogeneic stem cell transplant
AML patients include de novo AML, AML evolving from MDS or other AHD and AML after previous cytotoxic therapy or radiation (secondary AML)
Patients with AML or biphenotypic or bilineage leukemia who have failed at least one prior therapy; patients with AML should have failed prior therapy or have relapsed after prior therapy
AML without complete remission (CR/CRc/CRi) after at least 2 induction therapies OR AML that has relapsed within 6 months after obtaining a CR OR AML that has relapsed more than 6 months after obtaining a CR, and has treatment failure (TF) or progressive disease (PD) following at least 1 re-induction regimen OR AML that has relapsed post-allogeneic transplantation
Relapsed/refractory AML (>= 5% blasts in bone marrow or extramedullary leukemia) or newly diagnosed AML patients who are not candidates for (age >= 70 years; adverse cytogenetics, e.g., as defined by the Medical Research Council [MRC] Prognostic Groupings; secondary AML; organ dysfunction arising from significant co-morbidities not directly linked to leukemia; Eastern Cooperative Oncology Group [ECOG] = 2) or not willing to undergo intensive chemotherapy; Note that both relapsed/refractory and newly diagnosed AML patients will be eligible for the dose escalation part of the study, but only newly diagnosed patients will be eligible for the dose expansion cohort
Patients with previously untreated AML with core binding factor (CBF) chromosomal aberrations (inv[16]/t[16;16] or t[8;21]); Note that patients with relapsed or refractory AML with CBF chromosomal aberrations will be eligible
Subject has received previous therapy for AML, with the exception of the following:
Subject has clinically significant coagulation abnormality unless secondary to AML.
Diagnosed with AML
Patients with secondary AML or therapy related disease (t?AML) are eligible; patients who received decitabine or 5?azacytidine as prior treatment for myelodysplastic syndrome (MDS) or AML remain eligible; however, none of these agents is permitted within 6 months of study entry
We will define patients as high risk AML and thus eligible if they meet one or more of the following criteria:\r\n* Secondary AML (from underlying MDS or therapy related)\r\n* Presence of complex cytogenetic abnormalities (>= 3 cytogenetic abnormalities), all monosomies, del 5q, del 7q, inv3, t(3;3), t(6;9), t(9;22), abn 11q23 (excluding t[9;11])\r\n* Fms-related tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) mutation positive\r\n* Age >= 65 years
Subject has received previous therapy for AML, with the exception of the following:
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:
Patients with AML must have either: (a) relapsed or refractory leukemia after receiving at least one prior conventional induction therapy. Those in early first relapse must not have a matched donor and/or they must not be a candidate for allogeneic stem cell transplantation (usually this would mean the patient is too ill, obese, has a co-morbid condition or is over the age of 55 years) or (b) poor-risk AML as defined below: (i) Treatment related AML, except if it is associated with favorable cytogenetics (e.g., inversion 16, t(16;16), t(8;21), t(15;17), and not a candidate for stem cell transplantation, or (ii) AML with an antecedent hematologic disease (e.g., MDS, myelofibrosis, polycythemia vera, etc.), and not a candidate for stem cell transplantation. (iii) De novo AML > 70 years of age. (iv) AML with unfavorable cytogenetics regardless of age (>18 years), if patients are not candidates for allogeneic transplantation. Unfavorable cytogenetics are the following: complex (>3 abnormalities), -7, -5, 7q-, 5q-, abnormalities of 11q23 excluding t(9;11), t(9;22), inversion 3, t(3;3), t(6;9). (c) Patients older than 60 years of age who had AML (i.e., > 20% bone marrow blasts) and no 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
Newly diagnosed AML (according to the World Health Organization [WHO] 2008 classification) except t(15;17), including:\r\n* De novo AML\r\n* Secondary AML\r\n* Secondary AML arising from previously diagnosed myelodysplastic syndromes (MDS) or other antecedent hematologic malignancy treated with deoxyribonucleic acid (DNA) methyltransferase inhibitor (DNMTi) (i.e., decitabine or azacitidine)
Patients must have one of the following disease characteristics:\r\n* Therapy-related myeloid neoplasm (t-MN) age >= 18 years\r\n** Patients must have received cytotoxic chemotherapy, radiation, or a drug known to affect the properties of deoxyribonucleic acid (DNA) or cell growth, prior to current diagnosis of t-MN; this broad definition is meant to include any prior therapy with chemicals that affect DNA replication, DNA integrity, or DNA structure, or chemicals that alter cell growth; this includes traditional cytotoxic chemotherapy, newer immunologic agents that have been shown to have cytotoxic activities in addition to immunosuppressive functions, and other chemicals; note that patients with primary AML could be diagnosed with a t-MN if morphology/cytogenetic analysis clearly indicated that the second process is not a relapse of the original disease\r\n* AML arising from an antecedent hematological disorder age >= 18 years\r\n* De novo AML in patients age >= 60 years\r\n* Relapsed and/or refractory AML >= 18 years
Investigator considers patient ineligible for intensive remission induction therapy based on documented medical reasons (e.g. disease characteristics like AML genetics, type of AML (de novo or secondary), and patient characteristics like performance score, concomitant diagnoses, organ dysfunctions).
Therapy related AML: t-AML must have a documented history of prior cytotoxic therapy or ionizing radiotherapy for an unrelated disease
Prior treatment intended for induction therapy of AML; only hydroxyurea is permitted for control of blood counts. For example, a patient with MDS that changes HMA dose and schedule after the diagnosis of AML is excluded. AML-type therapy, such as cytarabine alone (>1g/m2/day) or cytarabine plus an anthracycline as well as prior HSCT are also excluded.
Confirmed primary AML relapsed or refractory after prior therapy, AML secondary to antecedent chemotherapy or radiation therapy, or AML due to prior myelodysplastic syndrome (MDS)/ myeloproliferative neoplasm (MPN) as defined by WHO criteria with presence of either FLT3 ITD and/or other FLT3 activating mutations
Patients with secondary AML should have failed no more than two (2) prior regimens
AML that is considered to be therapy-related
Patients with evolution to AML are required to be in a morphologic leukemia free-state with blasts < 5%
Patients with t-AML are required to be in a morphologic leukemia free-state with blasts < 5%
Relapsed AML or secondary AML (from myelodysplastic syndromes [MDS] or treatment related): not in CR after 1 or more cycles of standard re-induction therapy
AML relapsed > 2 months after transplant
Male or female patient ? 18 years of age with newly diagnosed, histologically confirmed, AML including de novo, secondary to antecedent hematologic disorders, or treatment-related disease with intermediate or unfavorable-risk cytogenetics
AML-associated inv(16)/t(16;16)/del(16q), t(15;17) (i.e. promyelocytic leukemia) with/without secondary aberrations; t(8;21) lacking del (9q) or complex karyotypes
Previous chemotherapy for AML except for the following, which are allowed:
Patients with AML at initial diagnosis or at first relapse
For subjects Age < 65\r\n* Refractory AML\r\n* OR AML relapse within six months of attaining remission\r\n* OR AML relapse more than six months after achieving a remission, who cannot achieve a second remission \r\n* OR Untreated subjects who develop AML after preexisting hematologic disease \r\n* OR Secondary AML\r\nFor subjects Age >= 65\r\n* De novo AML not candidates for induction chemotherapy\r\n* OR Refractory AML\r\n* OR AML relapse within six months of attaining remission\r\n* OR AML relapse more than six months after achieving a remission, who cannot achieve a second remission\r\n* OR Untreated subjects who develop AML after preexisting hematologic disease \r\n* OR Secondary AML
Recipients with AML in first complete remission (CR1) must have one of the following:\r\n* Adverse cytogenetics with residual disease detectable by flow cytometry, cytogenetic analysis, fluorescence in situ hybridization (FISH), or polymerase chain reaction (PCR); adverse cytogenetics in AML are defined as complex karyotype (>= 3 abnormalities); inversion (inv)(3) or t(3;3); t(6;9); t(6;11); monosomy 7; trisomy 8, alone or with an abnormality other than t(8;21), t(9;11), inv(16) or t(16;16); or t(11;19 (q23;p13.1) \r\n* Primary induction failure, defined as failure to achieve CR with primary induction chemotherapy \r\n* Secondary AML, defined as AML related to antecedent MDS, MPD, or cytotoxic chemotherapy\r\n* Hyperleukocytosis, white blood cells (WBC) >= 100,000, at diagnosis\r\n* Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene (FLT3-LM; FLT internal tandem duplication [ITD]s)
Patients must have histologically confirmed relapsed or refractory AML and meet the following criteria:\r\n* Relapsed disease is defined as AML is in 1st or greater marrow relapse\r\n* Refractory disease is defined as AML which failed to go into remission after 1st or greater relapse, OR AML which failed to go into remission after two or more induction attempts from original diagnosis
AML associated with favorable risk karyotypes including inv(16), t(8;21), t(16;16), or t(15;17)
Secondary AML
The original diagnosis of AML must have been confirmed by bone marrow aspirate and/or biopsy review by a Johns Hopkins (JH) hematopathologist; patients are eligible if they have AML that is not classified as poor-risk or APL; poor-risk AML is defined as therapy-related, arising from a previous marrow disorder, or de novo AML associated with any of the following characteristics: trilineage dysplasia, fms-related tyrosine kinase 3 (FLT3)/internal tandem duplication (ITD) mutation, poor risk cytogenetics including: chromosome 3, 5, or 7 abnormalities, t(6;9), and complex karyotype
MDS or high-risk AML, morphologically confirmed and based on World Health Organization criteria), who are transplant candidates with an available human leukocyte antigen (HLA)-matched sibling or unrelated donor with at least 8/8 match\r\n* Definition of high-risk AML:\r\n** Age >= 60 years\r\n** Age < 60 years with any of the following:\r\n*** Secondary AML\r\n*** Poor risk cytogenetics, which include abnormalities of chromosome 3, 5, or 7, trisomy 8, 11q23 abnormalities, t(6;9), 20q-, and complex karyotype\r\n*** Fms-related tyrosine kinase 3 (FLT3) mutation\r\n*** Disease status >= second complete remission (CR2) at time of HCT\r\n*** Detectable disease at time of HCT
Histologically proven non-M3 AML:\r\n* Refractory/relapsed AML OR\r\n* Initial diagnosis of AML in patient >= 60 years old
Age ? 60 years with relapsed/refractory AML of any type except for acute promyelocytic leukemia (APL; AML M3), after at least 1 prior AML therapy , who have never undergone, and who are not currently eligible for, stem cell transplantation, and are currently deemed unfit for intensive chemotherapy.
RR-AML
Patient must have one of the following histologically or cytologically documented measurable (may be measureable by tumor markers only, such as quantitative RT-PCR for WT1 transcript for AML, or CA-125 for ovarian carcinoma) advanced stage malignancies: non-small cell lung, ovarian, glioblastoma, and AML (not including acute promyelocytic leukemia), known to overexpress the WT1 protein.
Patient must have histologically or cytologically documented measurable (may be measurable by tumor markers only, such as quantitative RT-PCR for WT1 transcript for AML) advanced stage glioblastoma or AML (not including acute promyelocytic leukemia), known to overexpress the WT1 protein. Note: Determination of WT1 expression will not be assessed prior to patient enrollment.
Patients with secondary AML or therapy related disease (t-AML) are eligible
Histologically or cytologically confirmed AML, other than acute promyelocytic leukemia, as defined by the 2008 World Health Organization (WHO) criteria that is relapsed or refractory to standard chemotherapy; Note: newly-diagnosed AML patients who are 60 years or older and are not candidates for or have refused standard chemotherapy are also eligible for this trial
Diagnosed with AML according to the WHO 2008 classification. Note: subjects with secondary AML following Myelodysplastic syndrome or secondary to previous leukemogenic therapy are allowed provided that a record of previous MDS history or leukemogenic therapy history is available.
Previous AML treatment (other than hydroxyurea).
Patients diagnosed with AML meeting one of the following criteria:\r\n* Newly diagnosed, age 60 and older\r\n* High risk cytogenetics and molecular abnormalities (National Comprehensive Cancer Network [NCCN] criteria)\r\n* Relapsed or refractory to prior chemotherapy\r\n* Secondary AML
Patient must not have received definitive treatment for AML, defined as any prior chemotherapy with antileukemic activity
The patient has a diagnosis of AML associated with karyotype t(15;17).
Patients with FLT3 ITD positive AML or AML patients with other cytogenetic abnormalities who are eligible for trials of other targeted investigational agents from which the investigator feels there is greater benefit.
Morphologically documented primary AML, prior-chemotherapy-related AML or AML secondary to an antecedent hematologic disorder (e.g., Myelodysplastic Syndrome) as defined by WHO criteria, confirmed by pathology review. For Cohort Expansion Phase (Part 2) only: Bone marrow involvement is required.
Have either relapsed or refractory AML, or who have newly diagnosed Flt3-ITD positive AML but either refuse or are considered by the Investigator not to be an appropriate candidate for standard chemotherapy.
65+ yrs with AML not eligible for standard frontline chemo
The leukemia is a de novo or secondary AML.
The patient has cytologically proven AML, as defined by the WHO classification. The pretreatment AML karyotype should be documented.
The leukemia could be a de novo or secondary AML.
Hospitalized patients with high-risk AML, defined as:\r\n* Newly diagnosed patients with AML \r\n* Newly diagnosed AML with antecedent hematologic disorder\r\n* Newly diagnosed therapy-related AML\r\n* Relapsed AML\r\n* Primary refractory AML
Patients must have one of the following diagnoses and/or treatment plans:\r\n* Newly diagnosed de novo AML\r\n* First or subsequent relapse of AML\r\n* Secondary AML\r\n* Treatment with institutional standard AML therapy in those without AML (for example, myelodysplastic syndrome, bone marrow blasts > 5% or biphenotypia)\r\n* Note: Patients with a history of prolonged antifungal therapy (example, relapsed AML) are eligible
Newly diagnosed, morphologically documented primary AML or AML secondary to myelodysplastic syndrome or a myeloproliferative neoplasm, based on the World Health Organization (WHO) 2008 classification (at Screening);
Diagnosis of AML secondary to prior chemotherapy or radiotherapy for other neoplasms;
Prior treatment for AML, except for the following allowances:
Previous chemotherapy for AML
Prior AML therapy, with the exception of intrathecal chemotherapy or emergent radiation for myeloid sarcoma.
Patients with secondary or relapsed AML or APL should be excluded
Patients must have AML at initial diagnosis or at first relapse
diagnosis of AML
Prior chemotherapy for AML