Low-Dose Donor Bone Marrow Transplant in Treating Patients with Hematologic Malignancies
This phase I/II trial studies the side effects and the best way to give low-dose donor bone marrow transplant (BMT) and to see how well it works in treating patients with hematologic malignancies (blood cancers). Giving low-doses of chemotherapy, such as fludarabine phosphate and cyclophosphamide, before a donor bone marrow transplant helps stop the growth of cancer 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 bone marrow cells. When the healthy stem cells from a related or unrelated donor, that do not exactly match the patient's blood, are infused into the patient they may help 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 (called graft-versus-host disease). Giving cyclophosphamide, tacrolimus, and mycophenolate mofetil (MMF) after transplant may stop this from happening.
Inclusion Criteria
- Absence of a suitable related or unrelated bone marrow or peripheral stem cell donor who is molecularly matched at HLA-A, -B, -Cw, -DRB1, and -DQB1
- Absence of a suitable partially HLA-mismatched (haploidentical), first-degree related donor; Note: determination of matching is based on allele or allele group level typing; to be considered haploidentical, the donor and recipient must be identical at least one allele of each of the following genetic loci: HLA-A, -B, -Cw, -DRB1, and –DQB1; a minimum match of 5/10 is therefore required, and will be considered sufficient evidence that the donor recipient share one HLA haplotype; donors who are homozygous for the CCR5delta32 polymorphism are given preference
- Relapsed or refractory acute leukemia (acute myeloid leukemia or acute lymphoblastic leukemia or lymphoma) in second or subsequent remission, with remission defined as < 5% bone marrow blasts morphologically
- Poor-risk acute leukemia in first remission, with remission defined as < 5% bone marrow blasts morphologically: * Acute myeloid leukemia (AML) with at least one of the following: ** AML arising from myelodysplastic syndrome (MDS) or a myeloproliferative disorder, or secondary AML ** Presence of fms-related tyrosine kinase 3 (Flt3) internal tandem duplications ** Poor-risk cytogenetics: complex karyotype [>= 3 abnormalities], inv(3), t(3;3), t(6;9), myeloid/lymphoid or mixed-lineage leukemia (MLL) rearrangement with the exception of t(9;11), or abnormalities of chromosome 5 or 7 ** Primary refractory disease * Acute lymphoblastic leukemia (ALL) (leukemia and/or lymphoma) with at least one of the following: ** Adverse cytogenetics such as t(9;22), t(1;19), t(4;11), or MLL rearrangement ** Clear evidence of hypodiploidy ** Primary refractory disease * Biphenotypic leukemia
- MDS with at least one of the following poor-risk features: * Poor-risk cytogenetics (7/7q minus or complex cytogenetics) * International Prognostic Scoring System (IPSS) score of intermediate (INT)-2 or greater * Treatment-related MDS * MDS diagnosed before age 21 years * Progression on or lack of response to standard deoxyribonucleic acid (DNA)-methyltransferase inhibitor therapy * Life-threatening cytopenias, including those generally requiring greater than weekly transfusions
- Interferon- or imatinib-refractory chronic myelogenous leukemia (CML) in first chronic phase, or non-blast crisis CML beyond first chronic phase
- Philadelphia chromosome negative myeloproliferative disease
- Chronic myelomonocytic leukemia
- Juvenile myelomonocytic leukemia
- Low-grade non-Hodgkin lymphoma (including small lymphocytic lymphoma [SLL] and chronic lymphocytic leukemia [CLL]) or plasma cell neoplasm that has progressed after at least two prior therapies (excluding single agent rituximab and single agent steroids), or in the case of lymphoma undergone histologic conversion; patients with transformed lymphomas must have stable disease or better
- Poor-risk CLL or SLL as follows: 11q deletion disease that has progressed after a combination chemotherapy regimen, 17p deletion disease, or histologic conversion; patients with transformed lymphomas must have stable disease or better
- Aggressive non-Hodgkin lymphoma as follows, provided there is stable disease or better to last therapy: * Natural killer (NK) or NK-T cell lymphoma, peripheral T-cell lymphoma (including angioimmunoblastic T-cell lymphoma, hepatosplenic T-cell lymphoma, subcutaneous panniculitic T-cell lymphoma, and other variants), T-cell prolymphocytic leukemia, or blastic/blastoid variant of mantle cell lymphoma; or * Hodgkin or aggressive non-Hodgkin lymphoma that has failed at least one multiagent regimen, and the patient is either ineligible for autologous BMT or autologous BMT is not recommended; eligible subtypes of aggressive non-Hodgkin lymphoma include: ** Mantle cell lymphoma ** Follicular grade 3 lymphoma ** Diffuse large B-cell lymphoma or its subtypes, excluding primary central nervous system (CNS) lymphoma ** Primary mediastinal large B-cell lymphoma ** Large B-cell lymphoma, unspecified ** Anaplastic large cell lymphoma, excluding skin-only disease ** Burkitt’s lymphoma or atypical Burkitt’s lymphoma (high-grade B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt’s), in complete remission
- Patients with CLL, SLL, or prolymphocytic leukemia must have < 20% bone marrow involvement by malignancy (to lower risk of graft rejection)
- One of the following, in order to lower risk of graft rejection: * Cytotoxic chemotherapy, an adequate course of 5-azacitidine or decitabine, or alemtuzumab within 3 months prior to start of conditioning; or * Previous BMT within 6 months prior to start of conditioning * Note: patients who have received treatment outside of these windows may be eligible if it is deemed sufficient to reduce graft rejection risk; this will be decided on a case-by-case basis by the Principal Investigator (PI) or co-PI
- Any previous BMT must have occurred at least 3 months prior to start of conditioning
- No active extramedullary leukemia or known active CNS involvement by malignancy; such disease treated into remission is permitted
- Left ventricular ejection fraction >= 35%, or shortening fraction > 25%, unless cleared by a cardiologist
- Bilirubin =< 3.0 mg/dL (unless due to Gilbert’s syndrome or hemolysis)
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 5 x upper limit of normal (ULN)
- Forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) >= 40% of predicted; or in pediatric patients, if unable to perform pulmonary function tests due to young age, oxygen saturation > 92% on room air
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 or Karnofsky or Lansky score >= 60
- Not pregnant or breast-feeding
- No uncontrolled bacterial, viral, or fungal infection (infection is permitted if there is evidence of response to medication) * Note: human immunodeficiency virus (HIV)-infected patients are potentially eligible; eligibility of HIV-infected patients will be determined on a case-by-case basis
- DONOR: Potential donors consist of: * Unrelated donors * Second-degree relatives * First cousins
- DONOR: Donor must not be HLA identical to the recipient
- DONOR: The donor and recipient must be identical at least 5 HLA alleles based on high resolution typing of HLA-A, -B, -Cw, -DRB1, and -DQB1, with at least one allele matched for a HLA class I gene (HLA-A, -B, or -Cw) and at least one allele matched for a class II gene (HLA-DRB1 or -DQB1)
- DONOR: Meets institutional selection criteria and medically fit to donate
- DONOR: Lack of recipient anti-donor HLA antibody; Note: in some instances, low level, non-cytotoxic HLA specific antibodies may be permissible if they are found to be at a level well below that detectable by flow cytometry; this will be decided on a case-by-case basis by the PI and one of the immunogenetics directors; pheresis to reduce anti-HLA antibodies is permissible; however eligibility to proceed with the transplant regimen would be contingent upon the result
- DONOR: Has not donated blood products to recipient
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT01203722.
PRIMARY OBJECTIVES:
I. In reduced-intensity, partially human leukocyte antigen (HLA) mismatched allogeneic BMT from unrelated or non-first-degree related donors, identify a transplant regimen associated with acceptable rates of severe acute graft-versus-host disease (GVHD) (=< 25%) and transplant-related non-relapse mortality (NRM) (=< 20%) by day 100. (Phase I)
II. With the selected transplant regimen, as a measure of immunologic efficacy, estimate the 6-month probability of survival without having had acute grade III-IV GVHD or evidence of graft failure. (Phase II)
SECONDARY OBJECTIVES:
I. Estimate the progression-free survival, disease-free survival, overall survival, cumulative incidence of progression or relapse, and cumulative incidence of NRM.
II. Estimate the cumulative incidence of acute grade II-IV GVHD, acute grade III-IV GVHD, and chronic GVHD.
III. Determine the need for systemic immunosuppressive treatment for GVHD beyond the originally planned prophylaxis regimen; estimate the cumulative incidence of systemic steroid initiation for GVHD, cumulative incidence of non-steroid immunosuppressant use, and cumulative incidence of discontinuation of systemic immunosuppression for GVHD treatment; describe the types of immunosuppression used for GVHD treatment; and evaluate GVHD composite endpoints (GVHD-free relapse-free survival, chronic GVHD-free relapse-free survival).
IV. Describe graft failure frequency, kinetics of T-cell donor chimerism and total leukocyte donor chimerism in peripheral blood, and kinetics of neutrophil and platelet recovery.
V. Characterize immune reconstitution and the immunobiology of sirolimus and post-transplantation Cy (cyclophosphamide) by analyzing peripheral blood mononuclear cells collected prospectively at defined time points.
OUTLINE: Patients are assigned to 1 of 3 regimens.
REGIMEN B: Patients receive fludarabine phosphate intravenously (IV) once daily (QD) over 30-60 minutes on days -6 to -2 and cyclophosphamide IV QD over 1-2 hours on days -6 to -5. Patients undergo total-body irradiation (TBI) on day -1. Patients undergo allogeneic BMT on day 0. Patients then receive high-dose cyclophosphamide IV QD over 1-2 hours on days 3-4, MMF PO thrice daily (TID) on days 5-35, and sirolimus PO QD on days 5-180 in the absence of disease progression or unacceptable toxicity.
REGIMEN B2: Patients receive fludarabine phosphate, cyclophosphamide, TBI, high-dose cyclophosphamide, MMF, and sirolimus as in Regimen B. Patients also undergo hematopoietic stem cell transplant (HSCT) on day 0 in the absence of disease progression or unacceptable toxicity.
REGIMEN C: Patients receive fludarabine phosphate, cyclophosphamide, TBI, high-dose cyclophosphamide, and MMF as in Regimen B. Patients undergo allogeneic BMT on day 0, and also receive tacrolimus IV QD or PO BID on days 5-180 in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at least yearly.
Trial PhasePhase I/II
Trial Typetreatment
Lead OrganizationJohns Hopkins University/Sidney Kimmel Cancer Center
Principal InvestigatorRichard F. Ambinder
- Primary IDJ1055
- Secondary IDsNCI-2011-00377, CRMS-33771, NA_00039823, NA-00039823
- ClinicalTrials.gov IDNCT01203722