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A Multi-Center, Phase III, Randomized Trial of Reduced Intensity (RIC) Conditioning and Transplantation of Double Unrelated Umbilical Cord Blood (dUCB) versus HLA-Haploidentical Related Bone Marrow (Haplo) for Patients with Hematologic Malignancies
|Blood & Marrow Transplant (BMT)
- The primary objective is to compare progression-free-survival at 2 years post-randomization between patients who receive unrelated double cord blood unit transplantation versus HLA-haploidentical related bone marrow transplantation.
- Patients enrolled in this study will also be followed for the following endpoints: neutrophil recovery, graft failure, platelet recovery, donor cell engraftment, acute graft-versus-host-disease (GVHD) and chronic GVHD, overall survival, treatment-related mortality, infections, hospital admission and length of stay, health related quality of life, relapse/progression and cost effectiveness (see companion 1101 study document for ancillary cost effectiveness protocol).
- Patients ≥ 18 and ≤ 70 years old
- Patients must have available both:
- One or more potential related mismatched donors (biologic parent (s) or siblings (full or half) or children). Low resolution using DNA based typing at HLA-A, -B and -DRB1 for potential haplo-identical donors is required.
- At least two potential umbilical cord blood units identified.
- Each unit must have a minimum of 1.5 x 10^7/kg pre-cryopreserved total nucleated cell dose. For non-red blood cell depleted units, the minimum pre-cryopreserved total nucleated cell dose of each unit must be at least 2.0 x 10^7/kg
- Units must be HLA matched at a minimum of 4/6 to the recipient at HLA-A, HLA-B (at low resolution using DNA based typing) and HLADRB1 (at high resolution using DNA based typing). Confirmatory typing is not required for randomization.
- Patients must have received either:
- At least one cycle of at least one of the following cytotoxic chemotherapy regimens (or regimen of similar intensity) within 3 months of enrollment (measured from the start date of chemotherapy): a) Multi-agent chemotherapy (e.g. CVP+/-R, CHOP+/-R, ICE+/-R, DHAP+/-R, ESHAP+/-R) b) Chemotherapy regimens like those that are given as induction or consolidation of acute leukemia (7+3, HiDAc, mitoxantrone+etoposide, FLAG, FLIG, and others), c) Single drug alkylator agent (cyclophosphamide ≥ 1.5g/m^2 or equivalent), d) Bendamustine, e) Single agent alemtuzumab or brentuximab vedotin
- Antineoplastic agents that are not considered adequate cytotoxic chemotherapy include: a)Single agent steroids, b)Single agent monoclonal antibody +/- steroids with the exception of alemtuzumab, c) Single agent hypomethylating agent (e.g. azacytidine), d) Single agent antimetabolite +/- steroids (e.g. low dose methotrexate, low dose cytarabine), e) Single agent proteasome inhibitor +/- monoclonal antibody (except for alemtuzumab or brentuximab vedotin) +/- steroids, f) Hydroxyurea, g) Localized radiation therapy, h) Interferon
- Autologous hematopoietic stem cell transplantation > 6 months and < 2 years prior to enrollment.
- Please consult with the protocol chairs for any drugs or regimens not listed above.
- Acute Leukemias (includes T lymphoblastic lymphoma):
- Acute Lymphoblastic Leukemia (ALL) in first complete remission (CR1) (see remission definition in Chapter 3) that is NOT considered favorable-risk as defined by the presence of at least one of the following:
- Adverse cytogenetics such as t(9;22), t(1;19), t(4;11), other MLL rearrangements,
- White blood cell counts of greater than 30,000/mcL (B-ALL) or greater than 100,000/mcL (T-ALL) at diagnosis,
- Recipient age older than 30 years at diagnosis,
- Time to CR greater than 4 weeks
- Acute Myelogeneous Leukemia (AML) in first complete remission (CR1) (see remission definition in Chapter 3) that is NOT considered as favorable-risk. Favorable risk is defined as having one of the following:
- t(8,21) without CKIT mutation
- inv(16) without CKIT mutation or t(16;16)
- Normal karyotype with mutated NPM1 and not FLT-IND
- Normal karyotype with double mutated CEBPA
- APL in first molecular remission at end of consolidation
- Acute Leukemias in 2nd or subsequent CR (see remission definition in Chapter 3).
- Biphenotypic/Undifferentiated/Prolymphocytic Leukemias in first or subsequent CR, adult T-cell leukemia/lymphoma in first or subsequent CR
- Burkitts lymphoma: second or subsequent CR.
- Lymphoma fulfilling the following criteria:
- Chemotherapy-sensitive (complete or partial response; see response criteria in Chapter 3) lymphomas that have failed at least 1 prior regimen of multi-agent chemotherapy and are INELIGIBLE for an autologous transplant.
- Marginal zone B-cell lymphoma or follicular lymphoma that has progressed after at least at least two prior therapies (excluding single agent Rituxan).
- Performance status: Karnofsky score ≥ 70%
- Patients with suitably matched related or unrelated donor. An unrelated donor search is not required for a patient to be eligible for this protocol, or a search and donor mobilization may be abandoned, if the clinical situation dictates an urgent transplant. Clinical urgency is defined as 6-8 weeks from referral to transplant or a low-likelihood of finding a matched, unrelated donor.
- Recipients of prior autologous hematopoietic stem cell transplantation are ineligible if disease recurrence occured < 6 months from their autologous hematopoietic stem cell transplant.
- Current uncontrolled bacterial, viral or fungal infection (currently taking medication with evidence of progression of clinical symptoms or radiologic findings).
- Prior allogeneic hematopoietic stem cell transplant.
- Patients with history of primary idiopathic myelofibrosis or any severe marrow fibrosis.
- Planned use of prophylactic donor lymphocyte infusion (DLI) therapy.
- Anti-donor HLA antibodies. Positive anti-donor HLA antibody is defined as a positive crossmatch test of any titer (by complement-dependent cytotoxicity or flow cytometric testing) or the presence of anti-donor HLA antibody with mean fluorescence intensity > 1000 by solid phase immunoassay
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