Making transplant safer and available to all patients in need
Hematopoietic cell transplantation (HCT) from HLA identical related or unrelated donors or from umbilical cord blood units can cure malignant and non-malignant hematologic, immune and metabolic disorders. Major limitations for wider use of HCT remain timely identification of suitable donors and risk of transplant related morbidity and mortality.
The likelihood of finding an optimal donor varies with racial and ethnic background. According to data from the NMDP, the highest probability is among whites of European descent at 75%, with a much lower probability in ethnic minorities such as African Americans at 19% or Hispanics at 34%. Optimal cords are only found in a small proportion of patients, 17% for white Europeans, 1% for African Americans and 5% for Hispanics. By using suboptimal donors and suboptimal cord-blood units, a donor may be found in 90% of patients. However, the use of suboptimal donors (mismatched adult or cord-blood units) is associated with a higher rate of complications (graft failure, graft vs. host disease, infection) and lower survival. Patients from ethnic/race minorities more frequently suffer this burden.
HLA haplotypes (HLA-A, HLA-B, HLA-C, HLA-DR) are tightly linked genes that are jointly inherited. A familiar potential donor that shares one haplotype with the recipient (4/8 identical), usually a sibling, a parent or a child is available in over 95% of patients. Haploidentical familiar donors in general, are rapidly identified, readily available and highly motivated to donate. Such donors can be selected at the time siblings are HLA typed and before an unrelated donor search is formally started. Furthermore, haploidentical familiar donors are available for any patient independent of ethnic/racial background.
The fundamental obstacle of crossing the HLA barrier in haploidentical transplantation arises from the intense bidirectional responses from T-cells reacting to allogeneic HLA molecules resulting in overwhelmingly high incidence of GVHD and graft rejection. Over the past 2 decades, different strategies including profound T-cell depletion and post-transplant immunosuppression were attempted to overcome these limitations without major success. More recently, T-cell replete haploidentical transplantation emerged as an attractive option owing to the development of stronger and more effective GVHD-preventive strategies. The use of a short course of cyclophosphamide early after graft infusion targets and rapidly depletes donor and host alloreactive T-cells. With the implementation of post-transplant cyclophosphamide (PtCy), haploidentical transplantation has become a safe and viable option for many patients in need of a donor. Several single center and multicenter studies have duplicated and expanded this approach with promising results. Comparisons with sibling, unrelated and umbilical cord blood transplantation have shown at least comparable outcomes, with low incidence of GVHD and non-relapse mortality.
At Moffitt Cancer Center, we adopted haploidentical transplantation as a strategy to increase patient access in a timely manner to allogeneic transplantation. We will further expand this experience using both, myeloablative and reduced intensity conditioning and peripheral blood stem cell grafts to allow our patients to have a safe and comprehensive approach that will be applicable within a large range of age and comorbidities. In addition, this approach would mitigate the impact of race and ethnicity in the availability of suitable donors and would allow more patients to access HCT.
Our first haploidentical transplantation was done on November/2014. To date we have completed 14 haploidentical transplants for different malignant and non-malignant conditions like aplastic anemia. So far, we have no transplant related fatalities and low incidence of relapse. This early experience has been highly rewarding. In addition, we are planning to use this platform to answer fundamental research questions in transplant tolerance and to improve GVHD prevention after haploidentical transplantation.
In summary, haploidentical transplantation has emerged as a safe and effective transplant alternative that addresses several shortcoming of sibling and unrelated donor transplant and has open a new era in bone marrow transplantation for hematologic disorders. By using haploidentical transplantation, Moffitt cancer center continues to be at the forefront of clinical care and research for hematologic disorders.
- Luznik L, O'Donnell PV, Fuchs EJ. Post-transplantation cyclophosphamide for tolerance induction in HLA-haploidentical bone marrow transplantation. Seminars in oncology 2012; 39(6): 683-93.
- Bashey A, Solomon SR. T-cell replete haploidentical donor transplantation using post-transplant CY: an emerging standard-of-care option for patients who lack an HLA-identical sibling donor. Bone marrow transplantation 2014; 49(8): 999-1008.