Patient case: 4-year-old female with leukemia; genetic feature: ABL1

Clinical trial: Stem Cell Transplantation From HLA Partially-Matched Related Donors for Patients With Hematologic Malignancies

Summary: This clinical pilot trial is intended to evaluate the feasibility, efficacy and safety of hematopoietic stem cell transplantation (HSCT) from Human Leukocyte Antigen (HLA)-mismatched related donors for children and young adults with hematologic malignancies who lack a suitably matched related or unrelated donor. The methodology will be one that has been successfully utilized in adult patients at Thomas Jefferson University.

Detailed description: Allogeneic HSCT is a potentially curative therapy for a number of malignancies. A barrier to the institution of this potentially curative strategy in hematologic malignancies is the availability of donors. Only 30% of patients in North America or Europe who may benefit from allogeneic HSCT will have an available HLA matched sibling donor. The ability to find a matched sibling donor is proportional to the number of children in the family. Because of the decreasing size of nuclear families, it is becoming less likely for patients to have an HLA identical matched sibling. Registries can provide a matched unrelated allogeneic stem cell graft for an additional 30% of patients. However this is not an option for patients who do not have a match in the registry, or whose disease status precludes them from waiting to identify an appropriate unrelated donor. The ability of finding a well matched unrelated donor is even more limited for segments of the population with mixed race ancestry as well as for African Americans who, because of a higher degree of HLA diversity, will be unlikely to find an unrelated donor who matches their HLA type.
  In these settings it is easier and faster to identify a partially HLA-matched (or haploidentical) family member as a stem cell donor. The use of haploidentical donors broadens the application of HSCT because it is not as limited by family size or racial/ethnic HLA diversity. Because parents and children, as well as siblings can be used as haploidentical donors, this type of transplant enfranchises almost every segment of the population.
  Since, in this study, the donor lymphoid and stem cell portions of the graft are collected and administered at different time points during the conditioning regimen, this approach to haploidentical HSCT is referred to as a 2 Step regimen. The approach does not involve ex vivo T cell depletion, but uses cyclophosphamide to tolerize donor lymphocytes within the framework of a myeloablative conditioning regimen. Preliminary experience with this approach in adult patients at Thomas Jefferson University for myeloablative haploidentical HSCT dates back to 2005 with the first trial using myeloablative conditioning formally launched in 2006. That initial trial met its accrual goals and the current trial is one of the successor trials derived from that experience.
  The conditioning regimen includes total body irradiation (TBI) (1.5 Gray x 8) and CY (60 mg/kg x 2). Tacrolimus and Mycophenolate Mofetil (MMF) are used as post-transplant immunosuppression in relatively standard fashion.
  The novel aspect of the regimen is in the administration of the graft. If one considers that a standard allograft consists of two components, a lymphoid portion and a stem cell portion, what is unique here is the administration of these two portions separately, at different time points during the conditioning regimen rather than together. The lymphoid portion, including a fixed dose of CD3+ cells/kg is administered prior to cyclophosphamide while the hematopoietic stem cell (HSC) portion of the graft is administered after cyclophosphamide has been metabolized and eliminated. Thus, the transplant occurs in 2 steps.

Eligibility: Inclusion Criteria:
  -  Acute lymphoblastic leukemia
  -  Acue myelogenous leukemia
  -  Myelodysplastic syndrome
  -  Non-Hodgkin lymphoma
  -  Chronic myelogenous leukemia
  -  Adequate lung, liver, renal, cardiac function
  -  Performance status >70
  -  Available related donor who is mismatched at ≥ 2 HLA alleles
  Exclusion Criteria:
  -  Available HLA-identical related donor
  -  HIV positive
  -  Active uncontrolled infection
  -  Pregnancy
  -  Performance status ≤70

Relevance to patient case: not relevant