High-Dose Unrelated Donor Umbilical Cord Blood Transplant with T-cell Depleted Peripheral Blood Stem Cell Infusion in Treating Patients with High-Risk Hematologic Malignancies
This phase II trial studies how well high-dose unrelated donor umbilical cord blood transplant with T-cell depleted peripheral blood stem cell infusion works in treating patients with hematologic malignancies that are likely to come back or spread (high-risk). Giving chemotherapy and total-body irradiation before a donor umbilical cord blood transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from an unrelated donor that do not exactly match the patient's blood are infused into the patient, they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. The donated stem cells may also replace the patient’s immune cells and help destroy any remaining cancer cells.
Inclusion Criteria
- Diagnosis of severe aplastic anemia: eligibility to be discussed with principal investigator (PI) and service chief; such patients will be assessed in Arm B
- Diagnosis of high risk hematological malignancy: * Any acute leukemia in first complete remission (CR) considered at high risk for relapse, or second or third CR, or relapse/refractory less than 10% blasts in bone marrow, or aplasia post-therapy; this includes de novo acute leukemia or acute leukemia that is therapy related or arising from an antecedent hematologic disorder including myelodysplasia (MDS), chronic myeloid leukemia (CML) or other myeloproliferative disorder * Juvenile myelomonocytic leukemia (JMML) in CR, or relapse with less than 10% bone marrow blasts * CML with tyrosine kinase inhibitor failure in chronic or accelerated phase or evolved to acute leukemia (blast crisis, see above) * MDS or other myeloproliferative disorder with life-threatening cytopenia(s), and/or red blood cell or platelet transfusion dependence, or patients with aplasia, or patients with excess blasts less than 10% blasts in the bone marrow at work-up * Aggressive lymphoma: patients in first complete remission (CR1) with disease at high risk of relapse or CR2-3 * Indolent lymphoma or chronic lymphocytic leukemia (CLL): any disease status provided any transformed component is in CR * Hodgkin lymphoma that is primary refractory or relapsed not suitable for other therapy and in partial remission (PR) or CR or small volume stable disease
- Karnofsky score >= 70 or Lansky score >= 70
- Resting left ventricular ejection fraction (LVEF) >= 50%
- Spirometry (forced expiratory volume in one second [FEV1] and forced vital capacity [FVC]) & corrected diffusing capacity of lungs for carbon monoxide (DLCO) >= 50% predicted; in small children use history and physical computed tomography (CT) scan to determine pulmonary status
- Total bilirubin =< 1.5 mg/dL (unless benign congenital elevated bilirubin)
- Alanine aminotransferase (ALT) =< 3 x upper limit of normal (ULN)
- Calculated creatinine (calc. creat.) clearance >= 60 ml/min
- Albumin >= 3.0
- Graft: * Cryopreserved dose will be >= 1.5 x 10^7 total nucleated cells (TNC)/kilogram in each unit for double unit CB grafts; this will be the CB graft for the majority of patients * In select patients with access to CB units that have high TNC (> 5.0 x 10^7/kg), and are from good quality CB banks a single unit could be considered with a back-up CB unit on standby * In select patients who have a very poor search and only have one suitable CB unit available, this unit could be given as a single unit; this unit must have a TNC >= 2.0 x 10^7 TNC/kilogram and a cluster of differentiation (CD)34+ cell dose >= 1.5 x 10^5 CD34+/kilogram * Haplo-identical donors who are 5/10 or better but not HLA-identical will be used
- HAPLO-IDENTICAL DONOR: A HLA-haplo-identical related donor will be selected as available as per standard MSKCC adult bone marrow transplantation (BMT) guidelines; mismatched family members who are matched at more than 5 of 10 HLA-loci are permitted; factors to be taken into account when selecting a haplo-identical donor will include donor age, weight, health status and comorbidities, compliance, venous access, recipient donor specific HLA-antibody status, and natural killer (NK) cell alloreactivity
- HAPLO-IDENTICAL DONOR: The donor must meet criteria outlined in the Functional Assessment of Cancer Therapy (FACT)-approved standard operating procedure (SOP) for "DONOR EVALUATION AND SELECTION FOR ALLOGENEIC TRANSPLANTATION" in the Blood and Marrow Transplant Program Manual, document E-1
- HAPLO-IDENTICAL DONOR: The donor must have adequate peripheral venous catheter access for leukapheresis or must agree to placement of a central catheter
- HAPLO-IDENTICAL DONOR: The donor must be > 25 kg in weight
Exclusion Criteria
- Active central nervous system (CNS) leukemia
- Any acute leukemia (including prior myelodysplasia or CML blast crisis) with morphologic relapse or persistent disease >= 10% blasts in the bone marrow (BM), or doubling of the blasts in the blood in the 2 weeks preceding admission, or need for hydroxyurea in the 2 weeks prior to admission, or uncontrolled extra-medullary disease
- Two prior stem cell transplants of any kind
- One prior autologous stem cell transplant within the preceding 12 months
- One prior allogeneic stem cell transplant within the preceding 24 months
- Prior radiation therapy with 400 cGy or more of TBI; if 200 cGy of prior TBI then only 400 cGy of TBI on this protocol is permitted
- Uncontrolled viral, bacteria or fungal infection at time of study enrollment
- Sero-positive or nucleic acid test (NAT) positive for human immunodeficiency virus (HIV)
- Females who are pregnant or breast feeding
- Patient or guardian unable to give informed consent or unable to comply with the treatment protocol including appropriate supportive care, follow-up, and research tests
- HAPLO-IDENTICAL DONOR: Evidence of active infection (including active urinary tract infection, or upper respiratory tract infection) or evidence of viral hepatitis exposure on screening unless only hepatitis B surface antibody (HbsAB)+ and hepatitis B virus (HBV) deoxyribonucleic acid (DNA) negative
- HAPLO-IDENTICAL DONOR: Medical or physical reason which makes the donor unlikely to tolerate or cooperate with growth factor therapy and leukapheresis
- HAPLO-IDENTICAL DONOR: Factors which place the donor at increased risk for complications from leukapheresis or granulocyte colony-stimulating factor (G-CSF) therapy (e.g., active autoimmune disease, sickle cell trait, symptomatic coronary artery disease requiring therapy)
- HAPLO-IDENTICAL DONOR: Pregnancy (positive serum or urine beta-human chorionic gonadotropin [HCG]) or breastfeeding; women of childbearing age must avoid becoming pregnant while on the study
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT01682226.
PRIMARY OBJECTIVES:
I. To obtain an estimate of the speed of neutrophil recovery after double-unit cord blood transplantation (CBT) with a T-cell depleted haplo-identical allograft.
SECONDARY OBJECTIVES:
I. The incidence of sustained cord blood-derived neutrophil engraftment.
II. The speed of platelet recovery and incidence of platelet engraftment by day 180.
III. The contribution of the haplo-identical peripheral blood stem cells (PBSC) to initial and sustained engraftment by assessment of chimerism in blood and bone marrow.
IV. The contribution of each cord blood (CB) unit to initial and sustained engraftment by assessment of chimerism in blood and bone marrow.
V. The incidence and severity of acute graft-versus-host disease (GVHD) at 100 days.
VI. The incidence and severity of chronic GVHD at 1 year.
VII. The incidence of day 100 and 180 transplant-related mortality (TRM).
VIII. The length of initial hospitalization post-CBT.
IX. The number of days hospitalized from day 0 to day 100 post-CBT.
X. Immune recovery after transplant.
XI. The incidence of malignant relapse at 1 and 2 years.
XII. The probabilities of overall and disease-free survival at one and 2 years after CBT.
XIII. Graft characteristics potentially associated with engraftment.
OUTLINE: Patients are assigned to 1 of 3 treatment arms.
ARM I (high-dose conditioning): Patients receive fludarabine phosphate intravenously (IV) over approximately 30 minutes on days -6 to -4 and cyclophosphamide IV over 30-60 minutes on days -6 and -5. Patients undergo total body irradiation (TBI) thrice daily (TID) on days -3 to -1 and twice daily (BID) on day 0, followed by CBT on day 0 and haplo-identical PBSC infusion on day 0 or 1. Patients receive cyclosporine IV over 2-4 hours beginning day -3 to 6 months with a taper to 12 months and mycophenolate mofetil IV every 8-12 hours or orally (PO) from day -3 to day 100 with a taper to 6 months.
ARM II (reduced intensity conditioning): Patients receive fludarabine phosphate IV over 30-60 minutes on days -6 to -2, cyclophosphamide IV on day -6, and thiotepa IV over 4 hours on days -5 and -4. Patients undergo TBI on days -2 and -1, CBT on day 0, and haplo-identical PBSC infusion on day 0 or 1. Patients receive cyclosporine and mycophenolate mofetil as in Arm I.
ARM III (higher intensity conditioning): Patients receive fludarabine phosphate IV as in Arm II, cyclophosphamide IV on day -5, and thiotepa IV over 4 hours on day -4. Patients undergo TBI, CBT and haplo-identical PBSC as in Arm II. Patients receive cyclosporine and mycophenolate as in Arm I.
After completion of study treatment, patients are followed up at days 21, 28, 60, 100, at 6 and 9 months, 1 year, 18 months, and 2 years.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationMemorial Sloan Kettering Cancer Center
Principal InvestigatorJuliet Naomi Barker
- Primary ID12-153
- Secondary IDsNCI-2012-01707
- ClinicalTrials.gov IDNCT01682226