Low-Dose Donor Bone Marrow Transplant in Treating Patients with Hematologic Malignancies
- 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
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)
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 Phase Phase I/II
Trial Type Treatment
Johns Hopkins University / Sidney Kimmel Cancer Center
Richard F. Ambinder
- Primary ID J1055
- Secondary IDs NCI-2011-00377, NA_00039823, CRMS-33771
- Clinicaltrials.gov ID NCT01203722