Total Body Irradiation/Fludarabine Based Ablative Haploidentical Transplant for Hematologic Diseases
Condition: Chronic Leukemia; Acute Leukemia; Hodgkin's Disease; Non-Hodgkin's Lymphoma; Myelodysplastic Syndrome
MeSH terms: Leukemia; Hodgkin Disease; Myelodysplastic Syndromes
Study type: Interventional
Phase: Phase 2

Summary: 
      In this study, patients will receive a myeloablative preparative regimen consisting of
      fludarabine and total body irradiation (TBI), followed by a T cell replete, mobilized
      peripheral blood stem cell (PBSC) allograft from a partially matched related donor. All
      patients will receive post-transplant Cy in addition to standard post transplant
      immunosuppression with tacrolimus and MMF. The treatment protocol will be essentially
      identical to the prior study, with the exception of the substitution of TBI for Busulfan. The
      investigators hypothesize that this change will significantly reduce the risk of HC, while
      maintaining the efficacy of the transplant.
    

Detailed description: 
      Historically, haploidentical HSCT has been associated with significant risks of graft
      rejection and severe graft versus host disease (GVHD), leading to high treatment related
      mortality and poor outcomes. The risk of engraftment failure and GVHD may be reduced in
      intensively conditioned recipients of grafts that have been rigorously depleted of T cells,
      but the risks of serious infection and death from prolonged immune compromise in these
      patients remains high. Recently, investigators from Johns Hopkins University demonstrated a
      new approach to haploidentical transplantation, utilizing a nonmyeloablative preparative
      regimen, followed by a T cell-replete bone marrow infusion and post-transplantation
      immunosuppression with high dose Cyclophosphamide (Cy), tacrolimus, and MMF. Clinical studies
      have shown this approach to be safe and effective with a low incidence of graft rejection,
      GVHD, and treatment-related mortality. Relapse represents the major cause of treatment
      failure in these patients, particularly with high-risk myeloid malignancies.

      In order to decrease this relapse risk in high-risk patients, the investigators initiated a
      myeloablative haploidentical HSCT study in January 2009 utilizing Busulfan-based
      conditioning, post-transplant Cy, and PBSC, instead of BM, as the stem cell source. Outcomes
      of the 15 patients transplanted to date have been promising with 100% engraftment, low rates
      of treatment-related mortality, relapse and GVHD, and excellent survival rates. An unexpected
      outcome of the study was a higher-than-expected rate of BK virus-induced hemorrhagic cystitis
      (HC) occurring in 7 of 14 evaluable patients. Although there were no deaths attributable to
      HC, it was associated with significant morbidity in some patients.

      HC is a recognized complication of allogeneic transplant therapy. Late onset HC, occurring
      after engraftment, is due almost exclusively to reactivation of the polyoma BK virus (BKV).
      Other important risk factors associated with HC include Busulfan-based conditioning, acute
      GVHD, HLA mismatched transplants, and use of bone marrow as the stem cell source. TBI-based
      conditioning, prior to myeloablative allogeneic transplant, has been associated with
      significantly less HC than Busulfan-based conditioning in both retrospective and prospective
      randomized trials.

      Eighteen patients will be accrued to this study. The primary end point of this study is the
      incidence of HC. The investigators will also examine the incidence of acute and chronic GVHD,
      engraftment, degree of donor-host chimerism, transplant related morbidity and mortality, as
      well as disease-free and overall survival. Stopping rules will minimize the risk of untoward
      or unexpected side effects.
    

Intervention name(s): Peripheral Blood Stem Cell Transplant
Intervention type(s): Procedure
Intervention description(s): Total Body Irradiation 1200cGy (150cGy given in 8 fractions twice a day six hours apart on days -4, -3, -2 and -1.
Fludarabine 30 mg/m^2 given once a day for 3 days on days -7, -6 and -5 Cyclophosphamide 50mg/kg given one a day on days +3 and +4
Other intervention name(s): TBI; Fludara; Cytoxan
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: CML; CLL; AML; ALL; MDS; HD; NHL; MFB; P.vera; Essential Thrombocytosis