Patient case: 13-year-old male with acute myeloid leukemia; genetic feature: FLT3

Clinical trial: Total Marrow and Lymphoid Irradiation and Chemotherapy Before Donor Stem Cell Transplant in Treating Patients With High-Risk Acute Lymphocytic or Myelogenous Leukemia

Summary: This phase II trial studies the safety and efficacy of total marrow and lymphoid irradiation (TMLI) in combination with two chemotherapy drugs, etoposide and cyclophosphamide, as a preparative regimen before donor stem cell transplant in treating patients with high-risk acute lymphocytic leukemia (ALL) or acute myeloid leukemia (AML) who have failed previous therapy. Intensity-modulated radiation therapy (IMRT) uses imaging to provide a three-dimensional view of the area to be irradiated. Doctors can then shape and direct the radiation beams at the area from multiple directions while avoiding, as much as possible, nearby organs. TMLI is a method of using IMRT to direct radiation to the bone marrow. Radiation therapy is given before transplant to suppress the immune system, prevent rejection of the transplanted cells, and wipe out any remaining cancer cells. TMLI may allow a greater radiation dose to be delivered to the bone marrow as a preparative regimen before transplant while causing fewer side effects than standard radiation therapy.

Detailed description: PRIMARY OBJECTIVES: I. Following a patient safety lead-in, evaluate the anti-tumor activity of the allogeneic hematopoietic cell transplant (alloHCT) preparative regimen - TMLI, cyclophosphamide (Cy) and etoposide (VP-16), as assessed by 2-year progression-free survival (PFS).
  SECONDARY OBJECTIVES: I. Estimate overall survival (OS), cumulative incidence (CI) of relapse/progression, and non-relapse mortality (NRM) at 100 days, 1 year and 2 years.
  II. Evaluate early and late toxicities/complications by organ and severity, and characterize by organ dose/dose volume, including acute/chronic graft-versus-host-disease (GVHD), infection, and longer-term complications (via protocol #s 07173 and 00029).
  OUTLINE: Patients undergo image guided TMLI on days -9 to -5, receive etoposide intravenously (IV) on day -4 and cyclophosphamide IV on day -2, and undergo allogeneic peripheral blood stem cell or bone marrow transplant on day 0.
  After completion of study treatment, patients are followed up for 5 years.

Eligibility: Inclusion Criteria:
  -  Acute lymphocytic leukemia or acute myelogenous leukemia who are not in first remission or second remission i.e. after failing induction therapy, or in relapse or beyond second remission
  -  Karnofsky performance status (KPS) >= 70%
  -  Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for six months following duration of study participation; should a woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately
  -  Patients with acute lymphocytic leukemia or acute myelogenous leukemia who are not in first remission or second remission i.e. after failing remission induction therapy or in relapse or beyond second remission
  -  All candidates for this study must have a human leukocyte antigen (HLA) (A, B, C, DR) identical siblings who is willing to donate bone marrow or primed blood stem cells or a 10/10 allele matched unrelated donor; a single allele mismatch at A, B, C, DR or DQ and a killer immunoglobulin-like receptor (KIR) mismatch at C will be allowed; all ABO blood group combinations of the donor/recipient are acceptable since even major ABO compatibilities can be dealt with by various techniques (red cell exchange or plasma exchange)
  -  Prior therapy with VP-16 and Cytoxan is allowed
  -  A cardiac evaluation with an electrocardiogram showing no ischemic changes or abnormal rhythm and an ejection fraction of >= 50% established by multi gated acquisition scan (MUGA) or echocardiogram
  -  Patients must have a serum creatinine of less than or equal to 1.3 mg/dL or creatinine clearance > 80 ml/min
  -  A bilirubin of less than or equal to 1.5 mg/dL; excluding patients with Gilberts disease
  -  Patients should also have a serum glutamic oxaloacetic transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) less than 5 times the upper limit of normal
  -  Pulmonary function tests including diffusion capacity of the lung for carbon monoxide (DLCO) will be performed; forced expiratory volume of the lung in one second (FEV1) and DLCO should be greater than 50% of predicted normal value
  -  The time from the end last induction or re-induction attempt should be greater than or equal to 14 days
  -  All subjects must have the ability to understand and the willingness to sign a written informed consent
  -  Signed informed consent form approved by the Institutional Review Board (IRB) is required; the patient, family member and transplant staff physician (physician, nurse, and social worker) meet at least once prior to starting the transplant procedure; during this meeting all pertinent information with respect to risks and benefits to donor and recipient will be presented; alternative treatment modalities will be discussed; the risks are explained in detail in the enclosed consent forms
  -  The time from the end of last induction, re-induction, or consolidation regimen should be greater than or equal to 14 days; note: chemotherapy given within 14 days of planned study enrollment for the purpose of controlling counts is permitted
  Exclusion Criteria:
  -  Patients should not have any uncontrolled illness including ongoing or active infection
  -  Patients may not be receiving any other investigational agents, or concurrent biological, chemotherapy, or radiation therapy; maintenance therapy with Food and Drug Administration (FDA)-approved targeted therapies (e.g. tyrosine kinase inhibitors for Ph+ acute lymphoblastic leukemia [ALL], and FLT inhibitors for FLT3+ patients) will be allowed after day 60 disease assessment
  -  History of allergic reactions attributed to compounds of similar chemical or biologic composition to etoposide
  -  Prior radiation therapy that would exclude the use of TMLI
  -  Relapsed patients who have undergone autologous or allogeneic hematopoietic stem cell transplantation previously
  -  Patients with psychological or medical condition that patients physician deems unacceptable to proceed to allogeneic hematopoietic stem cell transplantation
  -  Electrocardiogram (EKG) showing ischemic changes or abnormal rhythm and/or an echocardiogram or MUGA scan showing abnormal wall motion or ejection fraction < 50%
  -  Patients who have been treated with chemotherapy or radiation for the purpose of induction, re-induction or consolidation, within two weeks of planned study enrollment
  -  Patients with other active malignancies are ineligible for this study, other than localized malignancies
  -  Subjects, who in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study

Relevance to patient case: not relevant