Patient case: 1-year-old male with acute myeloid leukemia; genetic feature: IDH1

Clinical trial: Laboratory-Treated Donor Cord Blood Cell Infusion Following Combination Chemotherapy in Treating Younger Patients With Relapsed or Refractory Acute Myeloid Leukemia

Summary: This pilot clinical trial studies infusion of laboratory-grown donor cord blood cells following combination chemotherapy in treating younger patients with acute myeloid leukemia that has returned or that does not respond to treatment. Chemotherapy drugs work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Chemotherapy also kills healthy infection-fighting cells, increasing the risk of infection. The infusion of laboratory-grown cord blood cells may be able to replace blood-forming cells that were destroyed by chemotherapy. This may decrease the risk of infection following chemotherapy, and allow for more chemotherapy to be given so that more cancer cells are killed.

Detailed description: PRIMARY OBJECTIVES:
  I. Assess the safety of infusing "off-the-shelf" non-human leukocyte antigen (HLA) matched expanded cord blood cells as supportive care following administration of FLAG (fludarabine phosphate, cytarabine, and filgrastim) consolidation or reinduction chemotherapy in pediatric and young adult patients with acute myeloid leukemia (AML) or acute leukemia of ambiguous lineage.
  SECONDARY OBJECTIVES:
  I. Assess the kinetics of autologous recovery when compared to historical cohorts.
  II. Assess the ability of the product to provide transient myeloid engraftment/recovery.
  III. Examine the in vivo persistence of the ex vivo expanded cord blood cells by determining the kinetics and durability of potential engraftment.
  IV. Develop understanding of the underlying immune interaction between the patient (host) and the infused expanded cord blood cells (donor) by performing in vitro analyses to assess host-mediated rejection of the non HLA-matched expanded cells.
  V. Estimate the incidence of clinically significant infections (e.g. bacterial, viral, or fungal) observed in patients treated with FLAG consolidation or reinduction chemotherapy followed by "off-the-shelf" non-HLA matched expanded cord blood cells.
  VI. Assess the percentage of patients that achieve complete remission (CR)/complete remission with incomplete blood count recovery (CRi)/complete remission with partial recovery of platelet count (CRp) with this therapy approach.
  VII. Assess long term efficacy (overall survival [OS]/disease free survival [DFS]) of FLAG consolidation or reinduction chemotherapy followed by "off-the-shelf" non HLA matched expanded cord blood cells in pediatric AML or acute leukemia of ambiguous lineage patients during long term follow up.
  OUTLINE:
  Patients receive filgrastim subcutaneously (SC) or intravenously (IV) on days 1-7, fludarabine phosphate IV over 30 minutes on days 2-6, cytarabine IV over 4 hours on days 2-6, and ex vivo-expanded cord blood progenitor cells IV over 30 minutes on day 8.
  After completion of study treatment, patients are followed up every 6 months for 2 years.

Eligibility: Inclusion Criteria:
  -  Patients must have a diagnosis of AML or acute leukemia of ambiguous lineage according to World Health Organization (WHO) classification with >= 5% of disease in bone marrow (BM); patients with blast count < 5% are eligible if immunophenotype, molecular or cytogenetic signature are consistent with AML as determined by primary treating oncologist; patients with extramedullary disease, or biopsy-proven isolated myeloid sarcoma (myeloblastoma, chloroma, including leukemia cutis) are eligible regardless of marrow involvement
  -  AML or acute leukemia of ambiguous lineage:
  -  If relapse AML or acute leukemia of ambiguous lineage:
  -  Must have a prior diagnosis of AML or acute leukemia of ambiguous lineage and be in 1st or greater relapse as evidenced by morphology, immunophenotype, molecular or cytogenetic signature
  -  Must not have received prior reinduction therapy for this relapse
  -  If primary refractory AML or acute leukemia of ambiguous lineage:
  -  Must have had a prior diagnosis of AML or acute leukemia of ambiguous lineage and
  -  Must not have received more than 3 previous induction attempts
  -  If primary AML or acute leukemia of ambiguous lineage newly diagnosed or in remission
  -  Primary treating oncologist must have deemed patient unable to complete standard treatment therapy and selected FLAG as appropriate alternative regimen
  -  If prior diagnosis of acute lymphoblastic leukemia must have evidence of transformation to AML or acute leukemia of ambiguous lineage as evidenced by morphology, immunophenotype, molecular or cytogenetic signature
  -  Patients meeting above criteria are eligible regardless of central nervous system (CNS) classification
  -  Recipients of prior allogeneic hematopoietic stem cell transplantation for AML or acute leukemia of ambiguous lineage are eligible if they do not have graft-versus-host disease (GVHD) or they have quiescent GVHD whether or not they are receiving immunosuppressive therapy
  -  Must have a Lansky or Karnofsky performance status of >= 50; use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age
  -  Patients must have recovered from the acute toxicity of all prior chemotherapy; patients may not have received cytotoxic chemotherapy within 2 weeks of first dose of G-CSF (filgrastim) therapy, with exception of hydroxyurea, which is allowed for up to 24 hours prior to first dose of G-CSF, and intrathecal chemotherapy, which is allowed prior to, or in the 1st 72 hours after start of G-CSF therapy
  -  The following amounts of time must have elapsed prior to entry on study:
  -  2 weeks from local radiation therapy (XRT)
  -  8 weeks from prior craniospinal or if > 50% of the pelvis has been irradiated
  -  6 weeks must have elapsed if other bone marrow radiation has occurred
  -  Creatinine within normal range for age (per institutional defined lab value ranges)
  -  Direct bilirubin =< 1.5 upper limit of normal (ULN) age unless elevation thought to be due or hepatic infiltration by the hematologic malignancy
  -  Alanine aminotransferase (ALT) < 5 x ULN age
  -  Adequate cardiac function as defined as shortening fraction of > 27% OR ejection fraction of > 50%
  -  Patients must have a corrected QT (QTc) interval < 450 ms on baseline electrocardiogram (EKG)
  -  Patients must demonstrate a respiratory rate that is within normal limits for age, measured when afebrile and at rest (measured for a full minute) and pulse oximetry >= 93% on room air
  -  Signed informed consent
  -  Patient must have a life expectancy of at least 2 months
  -  Females of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of treatment
  -  Females of childbearing potential and males should agree to use adequate contraception (barrier method of birth control) prior to study entry and for the duration of study participation
  Exclusion Criteria:
  -  Recipients of prior allogeneic hematopoietic stem cell transplant (HSCT) with active acute or chronic GVHD
  -  Patients with history of Down's syndrome, Fanconi anemia or other known marrow failure condition
  -  Patients currently receiving other investigational drugs are not eligible
  -  Current concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol with the exception of intrathecal chemotherapy; this includes the tyrosine kinase inhibitor sorafenib which must not be initiated until patient demonstrates count recovery
  -  Patients with a systemic fungal, bacterial, viral, or other infection not controlled despite appropriate antibiotics or other treatment; uncontrolled systemic infections require infectious disease consultation for verification
  -  Patients who are platelet refractory prior to initiation of protocol therapy; platelet refractoriness is defined by platelet count < 50 K when platelet count is obtained 1 hour post platelet transfusion
  -  Pregnant or lactating patients
  -  Any significant concurrent disease, illness, or psychiatric disorder that would compromise patient safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results

Relevance to patient case: not relevant