Partially HLA Mismatched (Haploidentical) Allogeneic Bone Marrow Transplantation
Condition: Hematologic Malignancies
MeSH terms: Neoplasms; Hematologic Neoplasms
Intervention: Haploidentical Transplant; Fludarabine; Busulfan; Total Body Irradiation; Cyclophosphamide
Intervention description: Subjects will be dosed with pre-transplant Fludarabine (180mg/m2)and Busulfan total AUC 2400 μmol*min/L or 6.4mg/kg. Subjects will then undergo total body irradiation 2Gy. Subjects will undergo haploidentical allogeneic bone marrow transplant, followed by Cyclophosphamide, Tacrolimus and MMF based GVHD prophylaxis.; Subjects in this trial will receive Fludarabine 30 mg/m2 IV QD, adjusted for CrCl from Days -8 through -3.; Subjects in this trial will receive Busulfan total AUC 2400 μmol*min/L or 6.4mg/kg in 4 doses with seizure prophylaxis from Days -6 through -3.; Subjects in this trial will receive total body irradiation (2Gy fractionated) from Day -2 or -1.; Subjects in this trial will receive Cyclophosphamide 50 mg/kg IV QD on Days 3 and 4 post-transplant.
Intervention MeSH terms: Cyclophosphamide; Busulfan; Fludarabine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 3.0
Sex: All
Minimum age: 10 Years
Maximum age: 75 Years
Healthy volunteers: No

Summary:

      Allogeneic stem cell transplantation is a potentially curative treatment for patients with
      many hematologic malignancies (e.g. leukemia, lymphoma, and myeloma with high risk of
      relapse). This process requires a suitable donor. The best case scenario involves an Human
      Leukocyte Antigen (HLA) matched sibling donor. However, this type of donor is not always
      available. Donor registries can provide another source for matched unrelated donors, but this
      may take valuable time delaying treatment for the transplant recipient. Donor availability
      remains a significant barrier to the use of allogeneic (from a donor) stem cell transplant.
      This issue disproportionately affects patients of minority backgrounds. Novel strategies to
      improve outcomes using alternative donors are desperately needed.

      Haploidentical transplants are an alternative which provides a readily available donor in the
      form of a partially HLA matched family member. This provides for more potential donors and
      the donors can be selected based on other factors that can play a role in transplant success
      (e.g. age, gender, KIR alloreactivity). Recent advances in transplant techniques have greatly
      improved success rates with haploidentical transplants although disease relapse has remained
      as issue.

      This trial aims to provide an alternative transplant option for patients with hematologic
      malignancies who require bone marrow transplantation but lack an HLA identical donor. The
      investigational component of this study is the combination of the Fludarabine/ Busulfan/
      Total Body Irradiation conditioning regimen and the HLA Haploidentical Transplant with
      post-transplant Cyclophosphamide.
    

Eligibility criteria:

        Inclusion Criteria:

          1. First-degree related donor or half-sibling who is at minimum HLA haploidentical

          2. Lack of fully matched donor (related or unrelated). Patients with a matched unrelated
             donor may only be enrolled if they require an urgent transplant. Urgency of transplant
             will judged by PI and co-investigators.

          3. Eligible diagnoses are listed below:

               1. Low-grade non-Hodgkin's lymphoma or plasma cell neoplasm that has progressed
                  during multiagent therapy including follicular lymphoma, Marginal zone (or MALT)
                  lymphoma, lymphoplasmacytic lymphoma / Waldenstrom's macroglobulinemia, Hairy
                  cell leukemia, Small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia
                  (CLL), Prolymphocytic leukemia, Multiple myeloma and Plasma cell leukemia

               2. Poor-risk SLL or CLL

               3. Aggressive lymphoma that has failed at least one prior regimen of multiagent
                  chemotherapy, and patient is either ineligible for autologous BMT or autologous
                  BMT is not recommended including Hodgkin lymphoma, high grade Follicular
                  lymphoma, Mantle cell lymphoma, Diffuse large B-cell lymphoma, Burkitt's
                  lymphoma/leukemia, Anaplastic large cell lymphoma, Plasmablastic lymphoma,
                  Peripheral T-cell lymphoma

               4. Relapsed or refractory acute leukemias.

               5. Poor-risk acute leukemia in first remission:

             i. Acute myeloid leukemia (AML) with at least one of the following:

               -  AML arising from myelodysplastic syndrome (MDS) or a myeloproliferative disorder

               -  Presence of FLT3 internal tandem duplications

               -  Poor-risk cytogenetics

             ii. Acute lymphoblastic leukemia and/or lymphoma (ALL) with at least one of the
             following:

               -  Poor risk cytogenetics

               -  Primary refractory disease

             iii. Biphenotypic leukemia

             f. MDS with at least one of the following poor-risk features: i. Poor-risk
             cytogenetics ii. Int-2 or high IPSS score iii. Treatment-related MDS iv. MDS diagnosed
             before age 21 years v. Progression on or lack of response to standard hypomethylator
             therapy vi. Life-threatening cytopenias

             g. Imatinib-refractory chronic myelogenous leukemia (CML) in accelerated or chronic
             phase

             h. Philadelphia chromosome negative myeloproliferative neoplasm

             i. Chronic myelomonocytic leukemia

        5. Adequate end-organ function as measured by:

          1. Left ventricular ejection fraction ≥ 35%

          2. Bilirubin ≤ 3.0 mg/dL and ALT and AST < 5 x ULN

          3. FEV1 and FVC > 40% of predicted

             6. Karnofsky score > 60

             7. Lack of recipient anti-donor HLA antibody