Patient case: 4-year-old female with leukemia; genetic feature: ABL1

Clinical trial: Alemtuzumab, Busulfan, and Cyclophosphamide Followed By a Donor Stem Cell Transplant in Treating Patients With Hematologic Cancer

Summary: RATIONALE: Monoclonal antibodies, such as alemtuzumab, can find cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. Giving chemotherapy drugs, such as busulfan and cyclophosphamide, before a donor stem cell transplant helps stop the growth of cancer cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving tacrolimus and methotrexate after the transplant may stop this from happening.
  PURPOSE: This phase I/II trial is studying the best dose of alemtuzumab when given together with busulfan and cyclophosphamide followed by a donor stem cell transplant and to see how well it works in treating patients with hematologic cancer.

Detailed description: OBJECTIVES:
  Primary
  -  Identify the lowest dose of alemtuzumab that is associated with day 180 transplant-related mortality ≤ 45%.
  Secondary
  -  Determine the incidence of life-threatening infection in patients receiving this treatment.
  -  Determine the incidence of grades III-IV acute graft-vs-host disease (GVHD) in patients receiving this treatment.
  -  Determine the survival at 1 year in patients receiving this treatment.
  -  Determine the incidence of disease relapse at 1 year in patients receiving this treatment.
  -  Determine the incidence of extensive chronic GVHD at 1 year in patients receiving this treatment.
  -  Determine the incidence of graft failure at day 100 in patients receiving this treatment.
  OUTLINE:
  -  Chemotherapy: Patients receive alemtuzumab IV over 2 hours on days -10 to -6, busulfan IV over 3 hours on days -7 to -4, and cyclophosphamide IV on days -3 and -2.
  -  Peripheral blood stem cell (PBSC) transplantation: Patients undergo allogeneic filgrastim (G-CSF)-mobilized PBSC transplantation on day 0.
  -  Graft-vs-host disease prophylaxis: Patients receive tacrolimus IV continuously or orally twice daily on days -1 to 50 and methotrexate IV on days 1, 3, 6, and 11.
  After completion of study therapy, patients are followed periodically.

Eligibility: DISEASE CHARACTERISTICS:
  -  Confirmed diagnosis of one of the following:
  -  Primary acute myeloid leukemia (AML) meeting any of the following criteria:
  -  First complete remission (CR; defined as < 5% blasts in marrow) with high-risk features as defined by failure to achieve remission by day 21 after induction chemotherapy, or the presence of chromosomal abnormalities involving any of the following:
  -  -5/del(5q)
  -  -7/del(7q)
  -  Inversion 3q
  -  Abnormalities of 11q23, 20q, 21q, del(9q),
  -  Translocation 6;9
  -  Translocation 9;22
  -  Abnormalities of 17p
  -  Complex karyotype with ≥ 3 abnormalities
  -  Second CR or subsequent in remission
  -  Refractory or relapsed disease
  -  Secondary AML in remission or relapse
  -  Chronic myelogenous leukemia (CML) in accelerated or blast phase meeting the following criteria:
  -  Accelerated phase is defined by any one of the following:
  -  Blasts 10% to 19% of peripheral blood white cells or bone marrow cells
  -  Peripheral blood basophils ≥ 20%
  -  Persistent thrombocytopenia (< 100,000/mm³) unrelated to therapy, or persistent thrombocytosis (> 1,000,000/mm³) unresponsive to therapy
  -  Increasing spleen size and increasing WBC count unresponsive to therapy
  -  Cytogenetic evidence of clonal evolution (i.e., the appearance of an additional genetic abnormality that was not present in the initial specimen at the time of diagnosis of chronic phase CML)
  -  Blast phase is defined by any of the following:
  -  Blasts ≥ 20% of peripheral blood white cells or bone marrow cells
  -  Extramedullary blast proliferation
  -  Large foci or clusters of blasts in bone marrow biopsy
  -  Primary myelodysplastic syndromes (MDS) with an IPSS score > 1.5
  -  Secondary MDS with any IPSS score
  -  Primary acute lymphoblastic leukemia meeting any of the following criteria:
  -  First CR (< 5% blasts in marrow) with high-risk features as defined by 1 of the following:
  -  Failure to achieve remission after first induction chemotherapy
  -  Presence of chromosomal abnormalities including hypodiploidy or abnormalities of 11q23 or translocation 9;22
  -  Second CR or subsequent in remission
  -  Refractory or relapsed disease
  -  No patients for whom a suitable HLA genotypically identical sibling or fully matched HLA-A, -B, -C, and -DRB1 unrelated donor is available
  -  No active CNS involvement with disease
  -  Donors must meet the following criteria:
  -  Unrelated volunteer donors who are mismatched for more than one HLA-class I alleles or antigens or for one HLA-class I antigen, but matched by high-resolution typing at HLA-DRB1 and -DQB1, OR who are mismatched for one or more HLA-class II alleles or antigens, but matched by high-resolution typing at HLA-A, -B, and -C
  -  No two-antigen mismatch at a single HLA-A, -B, or -C locus
  -  No mismatching of class I and class II HLA
  -  Matching must be based on results of high-resolution typing at HLA-A, -B, -C, - DRB1, and -DQB1
  PATIENT CHARACTERISTICS:
  -  Karnofsky performance status 50-100%
  -  No symptomatic coronary artery disease or symptomatic congestive heart failure
  -  No hepatic disease with transaminases or bilirubin > 2 times upper limit of normal except for isolated hyperbilirubinemia attributed to Gilbert's syndrome
  -  No severe hypoxemia with room air P_AO_2 < 70, supplemental oxygen-dependence, or DLCO < 60% predicted
  -  No impaired renal function with creatinine > 2 times upper limit of normal or creatinine clearance < 50% normal
  -  Not HIV seropositive
  -  Not pregnant or breast-feeding
  -  Fertile patients must use effective contraception
  -  No active infections that are untreated or failing to respond to appropriate therapy
  PRIOR CONCURRENT THERAPY:
  Inclusion criteria:
  -  See Disease Characteristics
  Exclusion criteria:
  -  Prior allogeneic or autologous bone marrow, peripheral blood stem cell, or umbilical cord blood transplantation using a high-dose total-body irradiation regimen

Relevance to patient case: not relevant