For AML and MDS patients: patients with a dry tap on bone marrow aspiration during screening
Patients must have previously untreated MDS or AML according to the WHO  classification.
. Written informed consent must be obtained prior to any screening procedures\n\n          . Male or female patients ?  years of age who present with one of the following:\n\n             Arms -:\n\n               -  Refractory/relapsed AML following ? prior therapies and are deemed by the\n                  investigator not to be candidates for standard therapy, including re-induction\n                  with cytarabine or other established chemotherapy regimens for patients with AML\n                  (patients who are suitable for standard re-induction chemotherapy or\n                  hematopoietic stem cell transplantation and willing to receive it are excluded)\n\n               -  De novo AML patients who are suitable for treatment with decitabine (patients who\n                  are suitable for standard induction chemotherapy or hematopoietic stem cell\n                  transplantation and willing to receive it are excluded)\n\n               -  High risk MDS (patients who are suitable for standard re-induction chemotherapy\n                  or hematopoietic stem cell transplantation and willing to receive it are\n                  excluded)\n\n             Arms -:\n\n               -  Refractory / relapsed AML following ? prior therapies (Arms a & a)\n\n               -  High risk MDS who have failed hypomethylating agent therapy (Arms b & b) (Note:\n                  hypomethylating agent failure is defined as progressive disease on\n                  hypomethylating agent therapy or lack of clinically meaningful response as deemed\n                  by investigator after at least  cycles of hypomethylating agent therapy.)\n\n          . Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ? \n\n          . Patient must be a candidate for serial bone marrow aspirate and/or biopsy according to\n             the institutions guidelines and be willing to undergo a bone marrow aspirate\n             and/biopsy at screening, during and at the end of therapy on this study. Exceptions\n             may be considered after documented discussion with Novartis.\n\n          . Arms -: Patients must be fit for standard treatment with decitabine as determined by\n             the investigator and as per local decitabine package insert.
AML/MDS combination treatment (dose escalation and expansion): histologically or cytologically proven AML or MDS as defined by WHO criteria and IPSS-R, respectively, that is: R/R to standard therapy, or AML: who are unfit for, or unwilling to receive standard induction therapy, or MDS: eligible to receive azacitidine
Previous treatment for MDS or AML with intensive chemotherapy regimen (induction chemotherapy) or hypomethylating agent
Pathologically confirmed myelodysplastic syndrome (MDS) diagnosis (regardless of initial International Prognostic Scoring System [IPSS] risk category) or oligoblastic acute myeloid leukemia (AML) with -% 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 (-% 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  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 > % blasts in bone marrow or white blood cells (WBC) >  x ^/L
Phase  (expansion) subjects must have either MDS or relapsed/refractory AML
Patients with the TPwt hematological tumors (AML, ALL, HR-MDS) who have failed prior therapies or who are considered inappropriate candidates for standard induction therapy.
Patients with MDS who transform to AML while on hypomethylator agents or patients with AML who progress on hypomethylator agents could be considered for arm A of this trial if \r\n* They choose not to be treated on or are ineligible for our competing trial of sEPHB-HSA + hypomethylator (L--) \r\n* They are appropriate for high dose cytarabine treatment
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 >= % bone marrow blasts) may also be eligible after discussion with the PI.
AML patients with prior history of MDS or CMML who received therapy for the MDS or CMML and progressed to AML, are eligible at the time of diagnosis of AML regardless of any prior therapy for MDS; the World Health Organization (WHO) classification will be used for AML
Patients with high-risk MDS, and chronic myelomonocytic leukemia (CMML) with bone marrow blasts between % and %, relapsed or refractory to prior hypomethylating agent (HMA) therapy, defined as prior receipt of  cycles of HMA therapy with failure to attain a response, or relapse after prior response to HMA therapy
ARMS A-G: RR AML: Patients with AML who are refractory or relapsed (any salvage) with no available therapies or not candidates for available therapies. For patients with prior MDS or chronic myelomonocytic leukemia (CMML) or myeloproliferative neoplasm (MPN) who transformed to AML, therapy received for MDS, CMML, or MPN is NOT considered as prior therapy for AML.
Patients with previously untreated AML (except acute promyelocytic leukemia [APL]) who have at least one of the following:\r\n* Adverse genetic features as per the European Leukemia Net guidelines\r\n* Treatment related AML or AML with antecedent myelodysplastic syndrome (MDS); (patient who have received treatment with hypomethylating agents for MDS and have now transformed to AML are eligible)\r\n* Are over the age of  years and considered fit for chemotherapy\r\n* Patients with AML with MDS-related changes
Patients must have advanced AML, ALL or high-risk MDS meeting one of the following descriptions:\r\n* AML or ALL beyond first remission (i.e., having relapsed at least one time after achieving remission in response to a treatment regimen)\r\n* AML or ALL representing primary refractory disease (i.e., having failed to achieve remission at any time following one or more prior treatment regimens)\r\n* AML evolved from myelodysplastic or myeloproliferative syndromes\r\n* MDS expressed as refractory anemia with excess blasts (RAEB)\r\n* Chronic myelomonocytic leukemia (CMML) by French-American-British (FAB) criteria
Patients must have: a. Relapsed and/or refractory non-APL AML that has failed to achieve a complete remission (CR) or partial remission (PR) following standard induction therapy, or has relapsed after any duration of CR or PR i. Patients must have measurable disease with bone marrow blasts ?%at screening b. Relapsed and/or refractory higher-risk MDS (High / Very High Risk, as defined by the Revised International Prognostic Scoring System (IPSS-R)) that has failed to achieve a CR or PR, or any hematologic improvement (HI, per IWG  criteria) after standard therapy with hypomethylating agents (e.g., azacitidine, decitabine), or has relapsed after any duration of CR or PR or HI i. Patients must have measurable disease with bone marrow blasts >% at screening c. Newly diagnosed, treatment-nave non-APL AML in patients who, at the time of study entry are unlikely to tolerate standard intensive chemotherapy due to age, performance status, or comorbidities based on at least one of the following criteria (Ferrara et al, ): i. Age ?  years old ii. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of  iii. Cardiac history of congestive heart failure (CHF) or documented ejection fraction (EF) ? % iv. Pulmonary disease with DLCO ? % or FEVI ? % v. Creatinine clearance ?  mL/min to <  mL/min vi. Hepatic impairment with total bilirubin > . to ? . x upper limit of normal (ULN) vii. Any other comorbidity that the Investigator judges to be incompatible with intensive chemotherapy, and reviewed and approved by the Sponsor prior to enrollment d. Transfusion dependent lower-risk MDS without the del q abnormality, in patients refractory to erythropoietin treatment or unlikely to respond to erythropoietin treatment (EPO >). i. Lower-risk MDS: Very Low /Low / Intermediate Risk, as defined by IPSS-R. ii.Red blood cell (RBC) transfusion dependent anemia defined as no eight consecutive weeks without RBC transfusions within the  weeks prior to study entry, or ? RBC transfusions within the  weeks prior to study entry. iii.Refractory to or ineligible for ESAs is defined as RBC-Transfusion Dependence despite ESA treatment of ?, units/week recombinant human erythropoietin for  weeks or an equivalent dose of darbepoetin ( g/week) or serum EPO level > mU/mL in patients not previously treated with ESAs.
>  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 ?% bone marrow blasts;
Patients with AML who are refractory (up to salvage ) or relapsed (up to nd relapse); for patients with prior myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML) or myeloproliferative neoplasm (MPN) who transformed to AML, therapy received for MDS, CMML, or MPN is NOT considered as prior therapy for AML
May have previously received monotherapy with demethylating agents for MDS or AML or treatment with a mitoxantrone- or cladribine-based regimen for MDS or AML, including G-CLAM, but not demethylating agent as priming for or in combination with chemotherapy
Patients who have received prior chemotherapy for AML with the exception of hydroxyurea or leukapheresis for leukocytosis; prior hypomethylating or immunomodulatory agents for MDS are allowed
Patients with a secondary AML (defined as a history of prior radiation therapy or systemic chemotherapy, antecedent MDS, MPN or CMML)
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  cycles of hypomethylating agents -azacitidine or decitabine +/- other therapies +/- bone marrow transplant OR with de novo MDS but have refused to receive hypomethylating therapy: \r\n** Intermediate (INT)- 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- IPSS or intermediate R-IPSS MDS with excess blasts (>= % blasts in bone marrow [BM]) or transfusion-dependency or\r\n** MDS progressing to oligoblastic AML with -% BM blasts or\r\n** CMML or MDS/MPN with >= % marrow blasts, transfusion-dependency, abnormal karyotype, or proliferative features (white blood cell count >= ,/uL, splenomegaly on physical examination, or extramedullary disease)
Newly diagnosed disease with either a diagnosis of high-risk MDS (>= % blasts in marrow or blood), high-risk myeloproliferative neoplasm (MPN; >= % blasts in blood or bone marrow), or AML other than acute promyelocytic leukemia (APL) with t(;)(q;q) or variants according to the  World Health Organization (WHO) classification; patients with biphenotypic AML are eligible; such high-risk MDS or MPN have natural history much closer to AML than to lower risk MDS or MPN and have responded similarly to AML-type therapy
Patient population (histological or cytologically confirmed diagnosis):\r\n* Untreated elderly (>  years) AML if in the intermediate and poor-risk cytogenetic group and not candidates (as judged by treating doctor of medicine [MD]) for or willing to undergo standard induction therapy (i.e. elderly unfavorable cytogenetic AML) or any untreated AML age >  years\r\n** Note: previous therapy with a hypomethylating agent (HMA) for a diagnosis of MDS is allowed\r\n* Relapsed or refractory AML (>=  years)\r\n* Any MDS (>=  years) having failed or been intolerant to prior hypomethylating agent (HMA) treatment\r\n** Failure is defined as any disease progression while on HMA, relapse after HMA treatment or no response after  cycles of -Azacitidine or decitabine\r\n** Patients with isolated q-/q- syndrome must have failed, not tolerated, or lenalidomide in addition to having failed or been intolerant to HMA treatment\r\n*** Note: patients with chronic myelomonocytic leukemia (CMML) and MDS/myeloproliferative neoplasms (MPN) overlap are allowed if meeting other study eligibility criteria\r\n*** Note: for all patient groups, therapy as part of a plan as a bridge to transplant is allowed
Prior chemotherapy treatment for AML (prior treatment with hydroxyurea and/or leukapheresis to control white blood cell count, or all-trans retinoic acid [ATRA] for suspected acute promyelocytic leukemia [APML] is acceptable); prior chemotherapy for MDS or myeloproliferative neoplasms (MPN) such as azacitidine, decitabine, and thalidomide, is permitted, but such treatments once MDS or MPN has transformed to AML is not permitted
Phase II FLT-ITD and/or FLT-D 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 >= % blasts in the bone marrow) or patients with chronic myelomonocytic leukemia (CMML) (having >= % blasts in the bone marrow) may also be eligible after discussion with principal investigator (PI); the patients should have one of the following features: . patients with AML should have failed any prior induction therapy or have relapsed after prior therapy; . patients with high-risk MDS or high-risk CMML should have failed any prior therapy for the MDS or CMML; . 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
Patients must meet one of the three treatment history criteria:\r\n* Relapsed AML who have failed at least  line of salvage therapy\r\n* De novo AML who have not achieved CR after  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  months after HCT, do not have active graft vs. host disease (GVHD) and are off immunosuppression except for maintenance dose of steroids (prednisone  mg/day or less)
In the phase I portion, patients with relapsed or refractory AML/MDS are also eligible, as per the treating physicians discretion
Patients with myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (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; prior therapy for MDS or CMML will not be considered as a prior therapy for AML
In the phase I portion of the study all patients with relapsed or refractory AML are eligible; for the Phase II portion of the study, patients must have AML progressing from prior MPN (MPN-BP) or have myelodysplastic syndrome (MDS)/MPN with more than % blasts; temporary prior measures to control blood counts, such as apheresis or Hydrea are allowed; patients with newly diagnosed or previously treated disease are eligible as long as prior therapy does not include hypomethylating agents; prior therapy for ruxolitinib for MPN is allowed
PHASE II -- Patients aged  and older with newly diagnosed primary or secondary AML according to WHO classification, without any prior therapy for AML with the exception of (a) emergency leukapheresis and (b) emergency treatment for hyperleukocytosis with hydroxyurea that is allowed until  hours before start of the trial treatment; Note: prior therapy for preexisting hematological condition e.g. MDS or myeloproliferative disease (MPD), including but not limited to hypomethylating agents is allowed until at least  weeks have elapsed from completion of that agent before the first dose of MEK ; patients with relapsed AML, and relapsed MDS and CMML, after prior hypomethylating therapy are also eligible to participate
For Phase I Only: Refractory or relapsed disease defined as follows: Patients with MDS or CMML should have failed prior therapy (e.g., with a hypomethylating agent, clofarabine, and/or with lenalidomide); Patients with AML should have failed any prior induction therapy or have relapsed after prior therapy; Patients (any age) with MDS or CMML who received therapy with a hypomethylating agent and progress to AML are eligible at the time of diagnosis of AML regardless any prior therapy for AML. The WHO classification will be used for AML; Patients with any of the eligible diagnoses who have received no prior therapy are eligible if not candidates to receive standard intensive therapy (ie, high-dose cytarabine-based chemotherapy).
For Phase II Only: Patients with MDS, CMML or AML who are either: Age  years or older and newly diagnosed, previously untreated. Prior therapy with hydroxyurea or single agent ara-C for the purpose of control of WBC is acceptable.; Age  years or older and with refractory or relapse disease who have received no more than one prior treatment regimen and will be receiving first salvage. For this purposes, a second induction cycle with the same drugs used during the first cycle, consolidation chemotherapy or stem cell transplant in CR (or CRp or CRi) will be considered part of the prior regimen. Prior therapy for MDS (or other malignancies) is not considered a prior regimen for AML in patients who progress from MDS (or other malignancies).;
Patients must have a diagnosis of one of the following:\r\n* MDS (Arm A)\r\n** High-risk MDS defined as: > % blasts in bone marrow and/or the following cytogenetic categories: presence of inv()/t(q)/del(q), -/del(q), complex cytogenetics ( or more abnormalities)\r\n* AML (Arm B)\r\n** Relapsed/refractory/unable to tolerate conventional chemotherapy
Clonal cytogenetic abnormalities associated with MDS or AML on bone marrow examination.
Patients with >=  years of age with relapsed/refractory leukemia with a confirmed diagnosis of acute myelogenous leukemia (AML) or acute lymphoblastic leukemia (ALL) who meet the following criteria: \r\n* Age -: Salvage treatment failures only - defined as relapsed or refractory to after least  cycle of salvage therapy\r\n* Age >= : Refractory to or have relapsed after induction chemotherapy defined as no response to initial therapy\r\n** Given the clinical activity and use of hypomethylating agents in AML patients, for all AML populations, initial therapy and salvage therapy may include hypomethylating agents; furthermore, patients >=  with hematologic malignancies including chronic myelomonocytic leukemia (CMML) or myelodysplasia (MDS) that transform to acute leukemia while actively receiving hypomethylating agents (i.e. decitabine or azacytidine) will be considered induction failures and thus are eligible; for Philadelphia positive (Ph+) ALL, initial therapy and salvage therapy may include steroids and imatinib or dasatinib or nilotinib
Patients with previously untreated AML or high risk myelodysplastic syndrome (MDS) (>=  % blasts or International Prognostic Scoring System [IPSS] >= intermediate-); prior therapy with hydroxyurea, hematopoietic growth factors, azacytidine, all-trans retinoic acid (ATRA), or an isolated dose of cytarabine up to  g is allowed; patients with history of MDS transformed to AML are eligible regardless of their prior therapy for MDS provided this will be their first induction therapy for AML
Patients with active AML or MDS at the time of the study (anything less than a complete remission) are not eligible for this protocol
Subjects with evidence of relapsed or refractory acute myeloid leukemia (AML) OR treatment naive AML who are  years or older OR relapsed or refractory myelodysplastic syndrome (MDS)\r\n* For subjects with relapsed AML: evidence of >= % blasts in the bone marrow; or reappearance of blasts in the peripheral blood; or development of extramedullary disease (according to  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: =<  prior induction regimens (example: patients who receive + followed by + 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  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 >= % 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 >= % despite a minimum of four cycles of hypomethylating agent therapy
A histologically or pathologically confirmed diagnosis of AML based on WHO classification which is previously untreated by systemic therapy or is in first relapse after achieving a complete remission to initial induction, consolidation and/or maintenance therapy or MDS with IPSS scores of intermediate - or higher risk risk which has been previously treated with hypomethylating agents
Having received more than one induction systemic therapy for AML or having received a standard dose or high dose ara-C containing regimen for MDS
Confirmed diagnosis of refractory/relapsed AML or high-risk MDS
Meets one of the following disease criteria:\r\n* Primary (de novo) AML or higher-risk MDS with induction failure: No complete remission (CR) after  or more induction attempts with high dose chemotherapy or hypomethylating agents +/- other agents. Higher risk MDS defined as risk score > . based on the revised International Prognostic Scoring System (IPSS) criteria\r\n* Secondary AML (from antecedent hematologic malignancy or treatment-related): Not in CR after  or more cycles of chemotherapy\r\n* Relapsed AML: Blast count >= % in bone marrow or peripheral blood after prior attainment of CR; relapse at any time but >=  days following allogeneic hematopoietic cell transplantation (HCT)\r\n* Relapsed MDS: Morphologic evidence of relapse or increase in blasts >= % in bone marrow or peripheral blood after prior attainment of CR; relapse at any time but ? days following allogeneic HCT
Previously treated MDS or CMML, defined as prior treatment with at least one hypomethylating agent (HMA; azacitidine and/or decitabine) for intermediate or high risk MDS or CMML whose disease progressed or relapsed as follows:
TREATMENT: Patients with treatment-related acute myeloid leukemia (AML) (t-AML)/myelodysplastic syndrome (MDS), or with features suggestive of AML/MDS, or who have had prior allogeneic bone marrow transplant or double umbilical cord blood transplantation, should not receive veliparib due to reports of MDS and leukemia secondary to oncology therapy on Cancer Therapy Evaluation Program (CTEP)-sponsored studies utilizing veliparib
Patients with AML, relapsed or refractory to standard therapy or elderly patients with AML (age  or over). Patients who have AML and are younger than age  but considered unfit for conventional chemotherapy are eligible. Patients with de novo or treated MDS or chronic myelomonocytic leukemia (CMML) INT- or above are eligible. Patients may have had prior exposure to azacitidine but no more than one cycle of decitabine. Patients must have been off chemotherapy for  weeks prior to entering this study and have recovered from the toxicities of that therapy; a caveat to this is in the case of rapidly progressive disease. Hydroxyurea is permitted for control of elevated white blood cell (WBC) prior to treatment and can be continued for the first  weeks of therapy. Erythropoiesis stimulating agents (ESAs) and granulocyte colony stimulating factor (GCSF) are allowed before therapy. ESAs, GCSF or other growth factors are permitted on therapy.
Patients with MDS that has evolved to AML must be in remission
Patients with MDS evolved into AML that is not in remission
Subject has AML secondary to prior chemotherapy for other neoplasms (except for MDS).
For patients registered to the relapsed/refractory cohort (Cohort ), patients must have a previous morphologically confirmed diagnosis of acute myeloid leukemia (AML)\r\n* For patients registered to the myelodysplastic syndromes (MDS) transformed to AML cohort (Cohort ), patients must have a previous morphologically confirmed diagnosis of MDS/chronic myelomonocytic leukemia (CMML); patients may have received previous non-intensive therapy (e.g. azacitidine, decitabine, low-dose cytarabine [LDAC], lenalidomide) given for treatment of MDS/CMML (with up to % blasts); at the time of registration they must have a morphologically confirmed diagnosis of AML\r\n* Note: This protocol uses the World Health Organization (WHO) diagnostic criteria for AML; patients with acute promyelocytic leukemia (APL, French American British [FAB], M) or blastic transformation of chronic myelogenous leukemia are not eligible
Patients with prior malignancy (other than AML and MDS/CMML) are eligible; however, the patient must be in remission from the prior malignancy and have completed all chemotherapy and radiotherapy at least  months prior to registration; except for AML and MDS treatment, all treatment related toxicities must have been resolved; NOTE: for patients with prior history of malignancy who have received anthracyclines or mediastinal/pericardial radiation in the past, the risk versus benefit of therapy should be weighed, particularly in the setting of receiving consolidation therapy
Diagnosis of MDS, CMML, or RAEB-t/non-proliferative AML (as defined by -% BMBL, WBC ? , x ^/L and stable for at least  weeks without intervention) according to World Health Organization (WHO) criteria or French American British (FAB) classification either previously treated or previously untreated. The diagnosis must be confirmed via BM aspirate and/or biopsy within  weeks prior to Screening. Note: patients with RAEB-t/non-proliferative AML (as defined by -% BMBL, WBC ? , x ^/L and stable for at least  weeks without intervention) are not eligible for the Phase II Part  RPTD component of the study and patients with CMML will not be eligible for Phase II Part  Expansion of the study.
Off all other treatments for MDS, CMML, or AML including an erythropoiesis-stimulating agent (ESA), for at least  weeks prior to Screening. Filgrastim (G-CSF) is allowed before and during the study, as clinically indicated.
Anemia due to factors other than MDS, CMML, or AML (including hemolysis or gastrointestinal bleeding).
Patients with AML or RAEB  High Risk MDS who are newly diagnosed according to the WHO  Classification and previously untreated.
Patients with AML (arising from an antecedent hematologic disease [AHD]) or MDS who may have had one prior regimen with commercially available agents for the treatment of their prior hematologic disease. The patients may not have had a prior therapy for their AML.
Patients who have received prior induction chemotherapy for AML or myelodysplastic syndrome (MDS); temporary prior measures such as apheresis or hydroxyurea are allowed; patients who have received a limited and short-term exposure of ATRA (all trans retinoic acid) while AML-M (acute promyelocytic leukemia) was being ruled out, and which has been discontinued, will be eligible
Participants with MDS, CMML, or low blast AML, whose only site of disease is extramedullary, example, the skin.
Patients with myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (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
To be considered at high risk for induction mortality patients must have  or  of the following risk factors (patients >=  must have at least  risk factor, patients <  must have at least  risk factors) present; at least one risk factor in every patient must be an AML-related factor: \r\n* AML-related factors include: \r\n** Antecedent hematologic disorder (AHD) (MDS, chronic myelomonocytic leukemia [CMML], or MPD) or history of exposure to cytotoxic chemotherapy [therapy-related (t)-AML]), or WHO-defined AML with MDS-related changes or apparent de novo AML with MDS-associated karyotype\r\n** Unfavorable cytogenetics as defined by the European Leukemia Net\r\n* Patient-related factors:\r\n** Age >= \r\n** ECOG performance status (PS) >= \r\n* Co-morbidities:\r\n** Serum creatinine > . g/dL
Patients with untreated acute myeloid leukemia (AML) (> or equal to % blasts in bone marrow and/or peripheral blood) or high risk MDS (> or equal to % 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 FLT-ITD mutation with a molecular burden of at least %
AML participants ?  years old in first relapse with a disease-free interval <  months, or further relapse. First relapse is also applicable to AML post-MDS patients who have received prior treatment for MDS, but have not received prior treatment for AML.
Patients with one of the following diagnoses:\r\n* Intermediate, high and very high risk (per International Prognostic Scoring System [IPSS]-revised [R]) untreated MDS or any MDS with >= % marrow blasts (by French American British [FAB] and World Health Organization [WHO] diagnostic criteria); NOTE: MDS/MPN overlap is allowed\r\n* CMML requiring treatment per doctor of medicine (MD) judgment\r\n* Low and very low risk MDS patients symptomatic and/or transfusion dependent, (>=  U red blood cells [RBC] over the preceding  week period) who have failed erythropoietin-stimulating agents (ESAs) or who have a low likelihood of responding to ESAs\r\n* MDS and CMML patients relapsed/refractory to hypomethylating agents as evidenced by one of the following:\r\n** Progressed at any time during treatment with hypomethylating agents\r\n** Failed to achieve a response after  cycles of -azacytidine or  cycles of decitabine\r\n** Progressed after treatment with hypomethylating agents had been discontinued\r\n*** NOTE: MDS/MPN overlap is allowed\r\n* Relapsed or refractory AML exposed to =<  prior regimens (note, induction and consolidation including stem cell transplantation count as one regimen)\r\n* For exploratory phase I LDE days - with azacitidine or LDE days - with decitabine cohorts only: untreated AML/CMML/MDS/MPN overlap or relapsed/refractory AML/CMML/MDS/MPN overlap WITHOUT prior exposure to a hypomethylating agent (HMA)\r\n* Elderly (age >= ) untreated AML and not a candidate for induction therapy\r\n* Untreated AML <  year of age who are not candidates to undergo standard induction chemotherapy\r\n* Primary myelofibrosis (PMF) and post essential thrombocytopenia (ET)/polycythemia vera (PV) MF with a Dynamic International Prognostic Scoring System (DIPSS)-plus score of intermediate or high, or a > % blasts in the marrow and who are in need of therapy and who have failed previous treatment with a janus kinase  (JAK) inhibitor and, if appropriate, have failed Interferon based treatment
Pathological diagnosis of AML (by World Health Organization [WHO] criteria) or higher risk MDS (includes intermediate [int]- and high risk MDS by International Prognostic Scoring System (IPSS) along with one of the following:\r\n* Patients with de novo or secondary MDS with progression/refractoriness after HMA treatment who have not transformed to AML\r\n* Patients with MDS and prior HMA treatment for MDS who transformed to AML \r\n* Patients with AML who are refractory/relapsed after HMA therapy for their AML are eligible
Patients who have had conventional intensive cytotoxic induction chemotherapy for treatment of specifically MDS or AML are excluded
Previously untreated AML (>= % blasts); patients with high-risk MDS (defined as having >= % blasts in the bone marrow) or patients with chronic myelomonocytic leukemia (CMML) (having >= % 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  [FLT] 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  g/m^) 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
Prior or concomitant chemotherapy for AML (with the exception of hydroxyurea and/or corticosteroid therapy for no more than  days (cumulative)). Please note that any prior therapy for MDS is allowed.
Patients must meet one of two disease criteria:\r\n* Acute myelogenous leukemia within one of the following categories:\r\n** Primary induction failure (PIF): patients who have not achieved a complete remission following initial diagnosis and after at least two induction cycles of chemotherapy consisting of cytarabine and an anthracycline or high-dose cytarabine\r\n** Relapsed AML: Patients are defined as having relapsed disease if they entered a complete remission confirmed with a bone marrow biopsy following initial treatment, and then were found to have morphological or cytogenetic evidence of recurrent disease on a subsequent bone marrow exam\r\n** Any complete remission (CR) or greater: CR must be defined using a bone marrow exam taken at least  days since the last chemotherapy (including a methyltransferase inhibitor), and may include CRp (morphologic CR without peripheral platelet recovery)\r\n** CR with high-risk features: includes patients with treatment-related AML, secondary AML (following myelodysplastic syndrome [MDS] or myeloproliferative neoplasms [MPN]), high-risk cytogenetic or molecular phenotype (by National Comprehensive Cancer Network [NCCN] criteria)\r\n** Untreated AML (> % blasts on a bone marrow) arising from a previous confirmed diagnosis of MDS or MPN (excluding breakpoint cluster region [BCR]-Abelson murine leukemia viral oncogene homolog  [ABL] positive disease)\r\n* Myelodysplastic syndromes within one of the following categories:\r\n** High-risk MDS at diagnosis as defined by the International Prognostic Scoring System (IPSS) or World Health Organization (WHO) classification based Prognostic Scoring System (WPSS)\r\n** Transfusion dependent MDS (either red blood cells [RBC] or platelet dependent) without a hematologic response to at least  months of MTI therapy; hematological response is defined as transfusion independence for two or more months\r\n** Progressive MDS following at least  months of MTI therapy; progression is defined as resumption of transfusion dependence after at least two months of transfusion independence OR increase of marrow blasts by % from pretreatment OR overall blasts over % of marrow cells at any time after treatment
AML with a history of myelodysplasia: MDSAML must have bone marrow documentation of prior MDS
Patients with antecedent MDS/MPN, defined by WHO criteria, without any prior therapy for AML, regardless of the number of therapies for MDS/ MPN
For the phase I portion of the study patients should have failed any number of prior therapies, which should include at least the following: . Patients with MDS should have failed prior therapy with a hypomethylating agent and/or with lenalidomide. . Patients with AML should have failed any prior induction therapy or have relapsed after prior therapy. . Patients with MDS who received therapy with a hypomethylating agent and progress to AML are eligible at the time of diagnosis of AML regardless of any prior therapy for AML. . Patients with any of the eligible diagnoses who have received no prior therapy are eligible if not candidates to receive standard therapy or if they refuse standard chemotherapy.
For the phase II Portion of the study, only patients who are previously untreated for AML. . Patients with history of MDS who received therapy for MDS and progressed to AML are eligible at the time of diagnosis of AML. Only induction chemotherapy administered for AML will be considered for considerations of eligibility regarding prior therapy. Patients who received therapy for MDS before transforming to AML (e.g., with hypomethylating agents or lenalidomide) are eligible.
Isolated myeloid sarcoma not meeting bone marrow criteria for AML or MDS
Patients must have advanced AML, ALL or high-risk MDS meeting one of the following descriptions:\r\n* AML or ALL beyond first remission (i.e., having relapsed at least one time after achieving remission in response to a treatment regimen)\r\n* AML or ALL representing primary refractory disease (i.e., having failed to achieve remission at any time following one or more prior treatment regimens)\r\n* AML evolved from myelodysplastic or myeloproliferative syndromes; or \r\n* MDS expressed as refractory anemia with excess blasts (RAEB) or chronic myelomonocytic leukemia (CMML) by French-American-British (FAB) criteria
Key Inclusion Criteria (Phase ):\n\n        - Confirmed hematologic malignancy, including Acute Myeloid Leukemia (AML), Chronic\n        Lymphocytic Leukemia (CLL), Chronic Myelogenous Leukemia (CML), Acute Lymphocytic Leukemia\n        (ALL), Myelodysplastic Syndrome (MDS), Multiple Myeloma (MM), Myelofibrosis (MF),\n        Myeloproliferative Neoplasms (MPN) or MDS/MPN overlap diseases. (Once Phase  has started\n        subjects with AML will be eligible for inclusion in the Phase  portion of the study only\n        if their malignancy has been shown to have c-Cbl mutation, trisomy , trisomy , inv(),\n        or elevated FLT. [Other AML and subjects with MDS will no longer be eligible for\n        inclusion in the Phase  portion of the study]).\n\n        Key Inclusion Criteria (Phase ):\n\n          -  Part A: AML or MDS patients with an acceptable level of EphA expression\n\n          -  Part B: MF patients with an acceptable level of EphA expression\n\n        Key Inclusion Criteria (Both Phases):\n\n          -  Confirmed hematologic malignancy refractory to or progressed following standard\n             treatments, or subjects not considered medically suitable to receive standard of care\n             treatment or who refuse standard of care treatment\n\n          -  Acceptable level of EphA expression\n\n          -  Eastern Cooperative Oncology Group (ECOG) ?\n\n          -  Acceptable laboratory results\n\n        Key Exclusion Criteria (Both Phases):\n\n          -  For subjects with AML, more than  prior therapies for AML (induction and\n             consolidation with or without a hypomethylating agent given in a maintenance setting\n             are considered  therapy)\n\n          -  History of or current central nervous system (CNS) involvement that may increase risk\n             of bleeding\n\n          -  Recent major surgery\n\n          -  Ongoing surgical or wound healing complications\n\n          -  Active clinically significant bleeding\n\n          -  Uncontrolled hypertension\n\n          -  Significant intercurrent illness\n\n          -  Known history of prolonged bleeding times or platelet dysfunction\n\n          -  Active infection requiring IV antibiotics, IV antifungals, or IV antivirals within \n             weeks prior to Cycle , Day 
Key Inclusion Criteria (Phase ):\n\n        - Confirmed hematologic malignancy, including Acute Myeloid Leukemia (AML), Chronic\n        Lymphocytic Leukemia (CLL), Chronic Myelogenous Leukemia (CML), Acute Lymphocytic Leukemia\n        (ALL), Myelodysplastic Syndrome (MDS), Multiple Myeloma (MM), Myelofibrosis (MF),\n        Myeloproliferative Neoplasms (MPN) or MDS/MPN overlap diseases. (Once Phase  has started\n        subjects with AML will be eligible for inclusion in the Phase  portion of the study only\n        if their malignancy has been shown to have c-Cbl mutation, trisomy , trisomy , inv(),\n        or elevated FLT. [Other AML and subjects with MDS will no longer be eligible for\n        inclusion in the Phase  portion of the study]).\n\n        Key Inclusion Criteria (Phase ):\n\n          -  Part A: AML or MDS patients with an acceptable level of EphA expression\n\n          -  Part B: MF patients with an acceptable level of EphA expression\n\n        Key Inclusion Criteria (Both Phases):\n\n          -  Confirmed hematologic malignancy refractory to or progressed following standard\n             treatments, or subjects not considered medically suitable to receive standard of care\n             treatment or who refuse standard of care treatment\n\n          -  Acceptable level of EphA expression\n\n          -  Eastern Cooperative Oncology Group (ECOG) ?\n\n          -  Acceptable laboratory results\n\n        Key Exclusion Criteria (Both Phases):\n\n          -  For subjects with AML, more than  prior therapies for AML (induction and\n             consolidation with or without a hypomethylating agent given in a maintenance setting\n             are considered  therapy)\n\n          -  History of or current central nervous system (CNS) involvement that may increase risk\n             of bleeding\n\n          -  Recent major surgery\n\n          -  Ongoing surgical or wound healing complications\n\n          -  Active clinically significant bleeding\n\n          -  Uncontrolled hypertension\n\n          -  Significant intercurrent illness\n\n          -  Known history of prolonged bleeding times or platelet dysfunction\n\n          -  Active infection requiring IV antibiotics, IV antifungals, or IV antivirals within \n             weeks prior to Cycle , Day 
Patients must have one of the following, histologically or cytologically confirmed:\r\n* Acute myeloid leukemia (AML) [non- acute promyelocytic leukemia (APL) AML]\r\n** If previously treated:\r\n*** AML that is relapsed or refractory to at least one prior line of therapy\r\n** If previously untreated, must meet all of the following:\r\n*** >=  years of age\r\n*** Secondary or therapy-related AML\r\n*** Does NOT bear favorable cytogenetic and/or molecular features, eg, core-binding factor abnormalities, FLT Internal Tandem Duplication (FLT-ITD) negative/NPM mutated, biallelic CCAAT/enhancer binding protein alpha (CEBPA) mutation without FLT-ITD\r\n* Chronic myeloid leukemia blast crisis (CML-BC)\r\n** Relapsed or refractory to at least one Bcr-Abl-TKI-containing regimen\r\n* Myelodysplastic syndrome (MDS), must meet all of the following:\r\n** Higher risk MDS [intermediate- or high risk by the original International Prognostic Scoring System (IPSS)]\r\n** Relapsed, refractory, or intolerant to at least one prior line of therapy containing hypomethylating agents (deoxyribonucleic acid [DNA] methyltransferase inhibitors)
Patients must be in a documented CR/CRi from either their front-line or first salvage therapy as evidenced by =< % 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)
Bone marrow blast < % if MDS or ? % if AML; and
Diagnosis of untreated high-risk MDS (>= % blasts) or AML other than acute promyelocytic leukemia (APL) with t(;)(q;q) or variants according to the  World Health Organization (WHO) classification; patients with biphenotypic AML are eligible; outside diagnostic material is acceptable as long as peripheral blood and/or bone marrow slides are reviewed at the study institution and cytogenetic/molecular information is available\r\n* Prior hydroxyurea for AML is permitted but should be discontinued prior to start of CPX- treatment\r\n* Azacitidine, decitabine, lenalidomide, and growth factors are permitted for low-risk MDS (< % blasts); all treatments for MDS should be discontinued prior to start of CPX- treatment
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)- 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- MDS with excess blasts (>= % blasts in bone marrow [BM]) or red blood cell (RBC) transfusion-dependency\r\n** MDS progressing to oligoblastic acute myeloid leukemia (AML) with -% BM blasts\r\n** CMML with >= % marrow blasts, or RBC or platelet transfusion-dependency, abnormal karyotype, or proliferative features (white blood cell count >=,/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 -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  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 < % blasts in BM, by morphology, cytogenetics, fluorescent in situ hybridization (FISH), polymerase chain reaction (PCR) or flow cytometry
May have previously received monotherapy with demethylating agents for MDS or AML
May have previously received chemotherapy with MEC for MDS or AML
Acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS)\r\n * Patients with AML will be eligible in first relapse or nd or rd complete remission; patients not in remission must have < % 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 >=  months post initial transplant, achieve a CR or have < % blasts in the bone marrow prior to admission to the HSCT unit
Patients should have a diagnosis of AML (de novo or transformed from hematologic malignancies), myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML) with one of the following features: (A) patients with MDS or CMML should have failed prior therapy with a hypomethylating agent and/or with lenalidomide (cohorts  and ); (B) patients with AML should have failed any prior therapy or have relapsed after prior therapy (cohorts  and ); for patients in cohort  prior therapy should have included a FLT inhibitor; (C) patients with MDS or CMML who received therapy with a hypomethylating agent 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; these patients will be assigned to cohort ; patients with MDS, CMML or AML who have received no prior therapy are eligible if age  and greater or if, at the time of enrollment, are not candidates to receive or refuse standard therapy (cohort  only)
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 >= % 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
Patients with AML or high-risk MDS receiving non-intensive therapy including hypomethylating agents, single-agent chemotherapy, targeted therapy agents, single or combination non-intensive agents offered on a clinical trial, or any other chemotherapy offered for patients with AML and high-risk MDS that does not require a prolonged - week hospitalization including the following populations:\r\n* Newly diagnosed AML\r\n* Relapsed or primary refractory AML\r\n* Newly diagnosed high-risk MDS\r\n* Relapsed or primary refractory high-risk MDS
Patients with secondary AML arising out of myelodysplastic syndrome (MDS) (all subtypes under WHO classification), chronic myelomonocytic leukemia (CMML); therapy-related AML and those with a prior autologous hematopoietic cell transplantation are eligible
Secondary AML arising out of myeloproliferative neoplasms (as per the revised  WHO classification of myeloid neoplasms and acute leukemias) and MDS/myeloproliferative (MPD) neoplasms other than CMML (as per the revised  WHO classification of myeloid neoplasms and acute leukemias); refractory anemia with ringed sideroblasts with thrombocytosis (RARS-T) classified as MDS/myeloproliferative neoplasm (MPN) neoplasm, unclassifiable will be excluded; AML patients with presenting features suspicious of underlying unrecognized MPD such as marked splenomegaly (>=  cm) and or thrombocytosis (> , per microliter) will be excluded; patients with relapsed or refractory AML will be excluded
Untreated AML, including patients with an antecedent hematologic disorder or secondary disease. Patients with prior MDS may have received therapy with immunomodulatory agents or hypomethylating agents for this diagnosis. Patients with other prior cancer diagnoses are allowed as long as they have no measurable disease, are not undergoing active therapy, and have a life expectancy of ?  months.
Untreated AML, including patients with an antecedent hematologic disorder or secondary disease. Patients with prior MDS may have received therapy with immunomodulatory agents for this diagnosis.
Patients must have or be anticipated to have neutropenia (absolute neutrophil count [ANC] < . x ^/L) () for >=  days as a result of treatment of their AML/MDS
Treatment-nave/ Unfit Cohorts: Previously untreated patients with histological confirmation of AML who are ineligible for treatment with a standard cytarabine and anthracycline induction regimen; or previously untreated patients with intermediate, high, or very high risk MDS. Prior and concurrent therapy with hydroxyurea, oral etoposide, erythroid and/or myeloid growth factors is allowed.
CD/ILRA expression on the subjects AML or MDS blasts, determined locally within  months of first protocol treatment
With relapsed or refractory AML (hydroxyurea is not considered a prior treatment regimen) OR with treatment-naive AML who decline intensive induction chemotherapy or who are unfit due to co-morbidity or other factors OR with MDS and >= % myeloblasts in the bone marrow
Use of cytotoxic chemotherapeutic agents, or experimental agents (agents that are not commercially available) for the treatment of MDS, MDS/MPN, CMML or AML within  days of the first day of study drug treatment
In the Dose Expansion Segment, hypomethylating agent (HMA) treatment-nave MDS subjects (including CMML), and intermediate- or high-risk MDS subjects (including CMML) relapsed or refractory to prior HMA treatment are allowed, and treatment-nave AML subjects who are at least  years of age will be allowed if they also have at least one of the following criteria
Patients with treatment-related acute myeloid leukemia (AML) (t-AML)/myelodysplastic syndrome (MDS), or with features suggestive of AML/MDS, or who have had prior allogeneic bone marrow transplant or double umbilical cord blood transplantation, should not receive veliparib due to reports of MDS and leukemia secondary to oncology therapy on Cancer Therapy Evaluation Program (CTEP)-sponsored studies utilizing veliparib