Total Marrow Irradiation for Refractory Acute Leukemia

OBJECTIVES:

Primary

• Determine the maximum tolerated dose of total marrow irradiation (TMI) delivered by image-guided tomographic intensity-modulated radiotherapy when administered in combination with myeloablative chemotherapy in patients undergoing double umbilical cord blood (UCB) transplantation or hematopoietic stem cell for refractory acute leukemia.

Secondary

• Determine the incidence of engraftment (defined as achievement of neutrophil count > 500/uL at 42 days after transplantation).
• Determine the incidence of platelet engraftment at 6 months and at 1 year after transplantation.
• Evaluate the incidence of complete donor chimerism and the relative contribution of each UCB unit to donor engraftment within the first 100 days after transplantation.
• Determine the incidence of transplantation-related mortality (TRM) at 6 months after treatment with a TMI-containing myeloablative conditioning regimen.
• Determine the incidence of grade II-IV and grade III-IV acute graft-versus-host disease (GVHD) at 100 days after transplantation.
• Determine the incidence of chronic GVHD at 1 year after transplantation.
• Determine the incidence of relapse at 1 year after transplantation.
• Determine the survival and disease-free survival at 1 and 2 years after transplantation.
• Assess the durability of remission based on presence of rapid early response (defined by clearance of leukemic blasts from the bone marrow at 21 days after transplantation).

OUTLINE: This is a dose-escalation study of total marrow irradiation (TMI).

• Myeloablative conditioning regimen: Patients receive fludarabine phosphate IV over 1 hour once daily for 3 days between days -12 and -6 and cyclophosphamide IV once daily for 2 days between days -11 and -6. Patients undergo TMI once daily for 4-8 days between days -8 and -1.
• Donor umbilical cord blood (UCB) transplantation: Patients undergo single-unit or double-unit donor UCB transplantation on day 0. Patients receive filgrastim (G-CSF) IV or subcutaneously once daily beginning on day 1 and continuing until blood counts recover.
• Related Donor: Related donor bone marrow will be collected (target cell dose 5x10^8 nucleated cells/kg recipient weight, minimum 3x10^8 nucleated cells/kg recipient weight) and infused without processing on day 0.
• Graft-versus-host disease (GVHD) prophylaxis: Patients receive cyclosporine IV over 2 hours or orally 2-3 times daily beginning on day -3 and continuing until day 100, followed by a taper until day 180, in the absence of GVHD. Patients also receive mycophenolate mofetil IV or orally 2-3 times daily beginning on day -3 and continuing until day 30 (or 7 days after engraftment), in the absence of acute GVHD.

Patients are followed periodically for up to 2 years after transplantation.

Inclusion criteria

• Acute lymphoblastic leukemia

• ≥ Complete remission 2 (CR2) (adults ≥ 18 years and ≤ 55 years)
• CR2 in pediatrics (defined as <18 years) and <12 months duration of first remission
• ≥ CR3 or not in remission (pediatric patients <18 years)
• T cell leukemia ≥ CR2
• Evidence of pre-transplant minimal residual disease (MRD) by flow cytometry, FISH or cytogenetics
• Myelodysplastic syndrome

• ≤ 55 years of age and ≥ 10% blasts, not responsive to hypomethylating agents and/or conventional therapy
• Acute myeloid leukemia

• Not in remission (pediatric patients <18 years)
• Not in remission (10-30% blasts in the bone marrow for adult patients ≥18 years and ≤ 55 years)
• Evidence of pre-transplant minimal residual disease (MRD) by flow cytometry, FISH or cytogenetics
• Multiple myeloma

• No prior autologous transplant and fitting into one of the following disease categories:

• Early disease stage (CR1/PR1) with high-risk molecular features
• Early disease stage (CR1/PR1) with high-risk clinical features
• Late disease stage (CR2/PR2+) with high-risk clinical features
• Other high risk hematologic malignancies - to be approved by 2 or more hematology/oncology and BMT physicians
• Patients with prior CNS involvement are eligible provided that it has been treated and is in remission. CNS therapy (chemotherapy or radiation) should continue as medically indicated during the protocol.
• Have acceptable organ function within 14 days of study registration defined as:

• Renal: glomerular filtration rate > 60ml/min/1.73m2
• Hepatic: bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), Alkaline phosphatase (ALP) < 5 x upper limit of normal (ULN)
• Pulmonary function: Carbon Monoxide Diffusing Capacity corrected (DLCOcorr) > 50% of normal, (oxygen saturation [>92%] can be used in child where pulmonary function tests (PFT's) cannot be obtained)
• Cardiac: left ventricular ejection fraction ≥ 45% by echocardiogram (ECHO) or multi gated acquisition scan (MUGA)
• Karnofsky performance status (PS) >80% for ages 16 years and older or Lansky Play Score >50 for < 16 years
• An acceptable source of stem cells according to current University of Minnesota BMT program guidelines:

• UCB graft will be composed of two partially HLA matched units. Each unit must be matched at 4-6 HLA loci to the recipient and to each other. If two matched units are not available, then a single HLA 4-6 matched unit may be used if of adequate cell dose - total graft dose must be >3 x 107 MNC/kg
• HLA-matched related donor (6/6 or 5/6 antigen match)
• HLA-matched unrelated adult donor (if previously identified)
• Women of childbearing potential must agree to use adequate contraception (diaphragm, birth control pills, injections, intrauterine device [IUD], surgical sterilization, subcutaneous implants, or abstinence, etc.) for the duration of treatment.
• Voluntary written consent

Exclusion criteria

• Active uncontrolled infection at time of enrollment or documented fungal infection within 3 months.
• Evidence of Human immunodeficiency virus (HIV) infection
• Pregnant or breast feeding. The agents used in this study may be teratogenic to a fetus and there is no information on the excretion of agents into breast milk. All females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy.
• Prior myeloablative transplant within the last 6 months
• Prior total body irradiation (TBI) making total marrow irradiation (TMI) not feasible