Disease-Specific High-Dose Conditioning Regimens in Treating Patients Undergoing T-cell Depleted Peripheral Blood Stem Cell Transplantation for Hematologic Malignancies or Other Lethal Hematologic Disorders
This phase II trial studies how well disease-specific high-dose conditioning regimens work in treating patients undergoing T-cell depleted peripheral blood stem cell transplant for hematologic malignancies or other lethal hematologic disorders. Giving high doses of chemotherapy and total body irradiation before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem 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 antithymocyte globulin and removing the T-cells from the donor cells before transplant may stop this from happening.
Inclusion Criteria
- Malignant conditions or other life threatening disorders correctable by transplant for which CD34+ selected, T-cell depleted allogeneic hematopoietic stem cell transplantation is indicated such as:
- AML in 1st remission - for patients whose AML does not have 'good risk' cytogenetic features (i.e. t 8;21, t15;17, inv 16)
- Secondary AML in 1st remission
- AML in 1st relapse or >= 2nd remission
- ALL/CLL in 1st remission clinical or molecular features indicating a high risk for relapse; or ALL/CLL >= 2nd remission
- Chronic myelogenous leukemia (CML) failing to respond to or not tolerating imatinib or dasatinib in first chronic phase of disease; CML in accelerated phase, second chronic phase, or in CR after accelerated phase or blast crisis
- Non-Hodgkin’s lymphoma with chemoresponsive disease in any of the following categories: * Intermediate or high grade lymphomas who have failed to achieve a first CR or have relapsed following a 1st remission who are not candidates for autologous transplants * Any non-Hodgkin lymphoma (NHL) in remission which is considered not curable with chemotherapy alone and not eligible/appropriate for autologous transplant
- Myelodysplastic syndrome (MDS): Refractory anemia (RA)/refractory anemia with ring sideroblasts (RARS)/refractory cytopenia with multilineage dysplasia (RCMD) with high risk cytogenetic features or transfusion dependence, as well as refractory anemia with excess blasts (RAEB)-1 and RAEB-2 and acute myelogenous leukemia (AML) evolved from MDS who are not eligible for transplantation under protocol institutional review board (IRB) 08-008
- Chronic myelomonocytic leukemia: CMML-1 and CMML-2
- Multiple myeloma with disease in the following categories: * Patients with relapsed multiple myeloma following autologous stem cell transplantation who have achieved at least partial response following additional chemotherapy * Patients with high risk cytogenetics at diagnosis must have achieved at least a partial response following autologous stem cell transplantation; patients must have complex karyotype, del17p, t4;14 and/or t14;16 by fluorescent in situ hybridization (FISH) and/or del13 by karyotyping
- Other rare lethal disorders of hematopoiesis and lymphopoiesis for which a T-cell depleted transplant is indicated (e.g. hemophagocytic lymphohistiocytosis; refractory aplastic anemia or congenital cytopenias; non-severe combined immunodeficiency [SCID] lethal genetic immunodeficiencies such as Wiskott Aldrich syndrome, CD40 ligand deficiency or, autoimmune lymphoproliferative syndrome [ALPS], as well as refractory autoimmune cytopenias, paroxysmal nocturnal hemoglobinuria [PNH], metabolic storage diseases or heavily transfused congenital hemoglobinopathies)
- Accrual to each treatment arm will include standard risk and poor risk patients, except for Regimen D; all patients on Arm D will be poor risk by virtue of risks of relapse and/or transplant related mortality
- Standard risk patients will include eligible patients, as defined above, who are receiving transplants as treatment for MDS in RA/RCMD, RARS, AML in 1st or 2nd remission, ALL in 1st CR, NH in 1st remission, MM in 1st remission, very good partial response, or 1st partial response on the CML in the first chronic phase or 1st remission
- All other patients, including those with treatment related malignancies and/or those who have AML derived from MDS, will have received extensive prior chemo/radiotherapy and, therefore, will be considered to be at poor risk of conditioning and transplant related morbidities, and potentially transplant related mortality; patients with life threatening non-malignant genetic and acquired disorders will also, by virtue of their history of, optional transfusions and/or infection be considered poor risk; stopping rules for non-relapse related mortality in these heavily treated patients are, therefore, slightly less stringent than patients in the poor risk transplant groups; stopping rules for the principal endpoints of graft failure and GvHD are the same for all groups
- Patients may be of either gender or any ethnic background
- Patients must have a Karnofsky (adult) or Lansky (pediatric) performance status >= 70%
- Cardiac: asymptomatic or if symptomatic then left ventricular ejection fraction (LVEF) at rest must be >= 50% and must improve with exercise
- < 3 x upper limit of normal (ULN) aspartate aminotransferase (AST)
- =< 1.5 total serum bilirubin, unless there is congenital benign hyperbilirubinemia or if the hyperbilirubinemia is directly caused by the disease in which the patient is receiving a transplant (e.g. AML chloroma obstructing the biliary tree); patients with higher bilirubin levels due to causes other than active liver disease are also eligible with principal investigator (PI) approval e.g. patients with paroxysmal nocturnal hemoglobinuria (PNH), Gilbert's disease or other hemolytic disorders
- Serum creatinine =< 1.2 mg/dL or if serum creatinine is outside the normal range, then creatinine clearance (CrCl) > 40 ml/min (measured or calculated/estimated)
- Pulmonary: asymptomatic or if symptomatic, diffusion capacity of the lung for carbon monoxide (DLCO) >= 50% of predicted (corrected for hemoglobin)
- Each patient must be willing to participate as a research subject and must sign an informed consent form
- DONOR: Each donor must meet criteria outlined by institutional guidelines
- DONOR: Donor should agree to undergo general anesthesia and bone marrow harvest collection if peripheral blood stem cell (PBSC) yield is inadequate or otherwise not transplantable for whatever reason
Exclusion Criteria
- Female patients who are pregnant or breast-feeding
- Active viral, bacterial or fungal infection
- Patient seropositive for human immunodeficiency virus (HIV)-I/II; human t-lymphotrophic virus (HTLV) -I/II
- Presence of leukemia in the central nervous system (CNS)
- DONOR: If donors do not meet institutional guidelines, exclusion will be considered
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT01119066.
PRIMARY OBJECTIVES:
I. To assess the incidence of durable hematopoietic engraftment for T-cell depleted transplants fractionated by the CliniMACS system administered after each of the four disease targeted cytoreduction regimens.
II. To assess the incidence and severity of acute and chronic graft-versus-host disease (GVHD) following T-cell depleted, cluster of differentiation (CD)34+ progenitor cell enriched transplants fractionated by the CliniMACS system.
III. To assess the incidence of non-relapse mortality (transplant-related mortality) following each cytoreduction regimen and a transplant fractionated by the CliniMACS system.
IV. To estimate the probability of survival and disease-free survival (DFS) at 6 months, and yearly through at least 5 years and thereafter as clinically indicated post transplant for life for each disease-targeted cytoreduction regimen when used with a T-cell depleted graft fractionated by the CliniMACS system.
SECONDARY OBJECTIVES:
I. To determine the proportion of patients receiving optimal CD34+ (> 5 x 10^6/kg) and CD3+ (< 1 x 10^5/kg) cell doses the proportion recurring suboptimal doses (< 2 x 10^6/kg) CD34+cells; and the proportion of patients receiving CD3+ T-cell doses > 1 x 10^5/kg.
II. To correlate doses of CD34+ progenitors and CD3+ T cells with engraftment, graft vs. host disease and non-relapse mortality.
OUTLINE: Patients are assigned to 1 of 4 preparative cytoreduction treatment regimens.
REGIMEN A: Patients with high-risk acute lymphocytic leukemia (ALL) or acute myeloid leukemia (AML) in 1st or 2nd complete response (CR), diffuse large B-cell lymphoma (DLBCL), or other malignant disorders treated with a T-cell depleted graft undergo hyperfractionated total-body irradiation three times daily (TID) on days -9 to -6. Patients also receive thiotepa intravenously (IV) over 4 hours on days -5 and -4 and cyclophosphamide IV over 30 minutes on days -3 and -2. Patients also receive antithymocyte globulin (ATG) IV on days -4 and -3*.
REGIMEN B: Patients with multiple myeloma, AML >= 2nd CR, myelodysplastic syndromes (MDS), or who cannot receive total body irradiation or cyclophosphamide, receive busulfan IV over 2 hours every 6 hours on days -9 to -7, melphalan IV over 30 minutes on days -6 and -5, and fludarabine phosphate IV over 30 minutes on days -6 to -2. Patients also receive ATG IV on days -3 and -2**.
REGIMEN C: Patients with ALL after 1st relapse, infants and young children with high-risk AML in 1st CR, or ALL or DLBCL at risk for toxicities associated with irradiation or cyclophosphamide receive clofarabine IV over 2 hours on days -9 to -5, thiotepa IV over 4 hours on day -4, and melphalan IV over 30 minutes on days -3 and -2. Patients also receive ATG IV on days -3 and -2**.
REGIMEN D: Patients with congenital acquired cytopenias, aplastic anemia, immune deficiencies, and immune disorders receive fludarabine IV over 30 minutes on days -6 to -2, melphalan IV over 30 minutes on days -8 and -7, thiotepa IV over 4 hours on days -6 and -5, and ATG IV on days -3 and -2**.
NOTE: * Patients with human leukocyte antigen (HLA)-mismatched donors also receive ATG on day -2.
NOTE: ** Patients with HLA-mismatched donors also receive ATG on day -1.
All patients undergo T cell-depleted peripheral blood stem cell transplantation on day 0.
After completion of study treatment, patients are followed up at day 100, at 6, 12, and 24 months, and then yearly thereafter.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationMemorial Sloan Kettering Cancer Center
Principal InvestigatorRichard J. O'Reilly
- Primary ID10-050
- Secondary IDsNCI-2010-01240
- ClinicalTrials.gov IDNCT01119066