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9L-11-8: HLA-mismatched allogeneic cellular therapy (HMMACT) after Chemotherapy in High Risk Acute Myeloid Leukemia

Description

There have been no major new drugs for acute leukemia in 30 years. There are approximately 12,000 new cases of Acute myeloid leukemia in the US per year, and allogeneic stem cell transplant may cure 35-50% of these cases.It is believed that HLA-mismatched allogeneic cellular therapy (HMMACT) harnesses a powerful immunologic tool for achieving complete remission in acute leukemias without fewer risks of transplantation or limitations as nearly all patients will have an available donor.The primary objective of this study is to assess the feasibility of cytarabine based chemotherapy and HLA-mismatched allogeneic cellular therapy (HMMACT) in patients with high risk AML, with feasibility measured by induction mortality (IM) and complete response rate.Eligible AML patients will receive induction chemotherapy with mitoxantrone (IV, 3 days) and cytarabine (IV, 7 days) and receive HLA-mismatched G-PBSCs on day 9 or 10. Family donors will concurrently be HLA typed and best available donor will undergo donor screening.This is a Pilot/Feasability study. The primary measures of feasibility will be (1) induction mortality (IM) and (2) complete remission (CR or CRi). Secondary assessments of feasibility will involve safety as measured by the occurrence of serious infections (Grade 4), time to recovery of absolute neutrophil counts and platelets, and incidence of graft versus host disease (GvHD). An additional assessment of feasibility will be the ability to identify a suitable donor in this elderly population. It is expected that between 60% and 80% patients will have a suitable donor; therefore it is anticipated (assuming that only 60% of patients have a donor) that 33-35 patients will be initially recruited to the trial. The number of 20 patients (who actually receive a stem cell infusion) was selected to permit preliminary estimates of toxicities, CRR, EFS and OS. Standard errors (based on 20 patients) for the proportion of patients who experience a CR or IM or GvHD will be 0.11.Follow-up for survival will be done monthly for 3 years or until death. Those no longer followed at our center would be followed by phone call follow-up by the research RN.

Phase

Phase 1 - a new treatment that has not been tested, and researchers are looking for the best way to administer the treatment and how much can be given safely. Phase I trials are usually offered only to patients with advanced disease who would not be helped by other known treatments. Some patients are helped by these treatments, although in this early stage physicians don’t really know if the treatment will be effective.

Inclusion and Exclusion Criteria

  • Patients must have a histologically and cytological confirmed acute myeloid leukemia, high risk AML defined as:
  • Age > 60, or
  • Presence of complex cytogenetic abnormalities (with > 3 cytogenetic abnormalities), del (7q, -5, -7), t(9,22), 11q(23) or high risk mutations by FISH eg MLL, FLT-3 +
  • Secondary AML, or
  • A white blood cell count of > 50 x10^9/L
  • Patients must be medically ineligible for allogeneic stem cell transplant (alloSCTx) or not have a known fully HLA matched sibling for planned sibling transplant.
  • Patients must have measurable or evaluable disease
  • Diagnosis of AML according to World Health Organization (WHO) diagnostic criteria (at least 20% blasts in the peripheral blood or bone marrow), with French-American-British Cooperative group (FAB) classification other than M3 (acute promyelocytic leukemia), documented by bone marrow aspiration and biopsy performed within 14 days prior to administration of 1st dose of remission induction chemotherapy; if a bone marrow aspirate and biopsy were obtained within 28 days prior to the first dose of remission induction therapy then these tests may be submitted for review at University of Southern California (USC) and a repeat screening bone marrow does not need to be conducted;
  • Cohort A: newly diagnosed AML, no prior cytotoxic chemotherapy
  • Cohort B: newly diagnosed AML, failed to achieve Complete remission (CR) with single standard Induction chemo.
  • Patient has at least one medically fit family member expected to be HLA mismatched at 1-9/10; more commonly and preferred: 4-6/10 loci (parent, sibling, niece/nephew, etc but adult children preferred)
  • Absolute neutrophil count (ANC) > 1500, unless due to direct bone marrow involvement of disease
  • Platelets > 75,000, unless due to direct bone marrow involvement of disease
  • Hemoglobin > 8.0 gm/dL, transfusion allowed
  • Serum creatinine < 2.0 x the upper limits of institutional normal (ULN)
  • Total bilirubin < 1.5 x the upper limits of institutional normal
  • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT )< 2.5 x the upper limits of institutional normal (=< 5 x ULN for patients with liver involvement of leukemia)
  • Cardiac left ventricular ejection fraction (LVEF) > 45%
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
  • Estimated survival of at least 3 months
  • Patients must be able to understand and agree to sign an Institutional Review Board (IRB)-approved informed consent form
  • Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) prior to study entry, for the duration of study, and for two months after study participation
  • DONOR: Donor screening; all donors will meet the standard blood donor criteria established by the participating local blood center, American Association of Blood Banks (AABB)
  • DONOR: Donors will be selected from among the subject's relatives, adult children preferred
  • DONOR: Infectious disease testing will be done per Hemacare policy and AAAB guidelines
  • DONOR: Donor and intended recipient red cell type and compatibility will be determined
  • DONOR: Donors will be pre-selected on the basis of HLA haploidentity
  • DONOR: If patient is cytomegalovirus (CMV)-negative, donors who are CMV-negative will be preferred; CMV serology of the donor will be tested prior to the allogeneic cell donation; donations from CMV-positive donors to CMV-negative recipients will be given if no CMV negative donor is available, and CMV surveillance and pre-emptive treatment given

  • Cohort A: Patients who have received prior cytotoxic chemotherapy, such as anthracyclines and cytarabine not permitted; but prior treatment with demethylating agents (azacytidine or decitabine, lenalidomide, etc) ALLOWED.
  • Cohort B: Patients who have received prior fludarabine, clorarabine or drugs known to target T cells not permitted; but prior standard induction with anthracylines and cytarabine ALLOWED including after demethylating agents.
  • Have uncontrolled systemic infections, coagulation disorders, or other major medical illnesses of the cardiovascular or respiratory systems
  • Pregnant and/or lactating
  • Patients who have had non-biopsy surgery in the last 10 days
  • Active central nervous system (CNS) disease; patients with previously treated leptomeningeal disease without evidence of remaining leukemia cells by spinal fluid will be eligible
  • Known active autoimmune disorder
  • Known to be human immunodeficiency virus (HIV)-positive or have active hepatitis B or C
  • Patients concurrently taking the following drugs are excluded: mycophenolate, cyclosporine, prednisone > 20mg/day, or immunosuppressive agents
  • DONOR: Personal or family history of severe sickle cell disease or variant (unless donor has tested negative); testing for the presence of hemoglobin S is not required
  • DONOR: Positive infectious disease test as dictated by blood collection center's standard operating procedure (SOP)
  • DONOR: Current uncontrolled hypertension
  • DONOR: Diabetes mellitus
  • DONOR: Active peptic ulcer disease
  • DONOR: Pregnant or breast-feeding
  • DONOR: Currently taking lithium therapy
  • DONOR: History of autoimmune disease
  • DONOR: History of coronary disease

Sites

  • California

    • USC Norris Comprehensive Cancer Center, Los Angeles, California, 90033
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