by Asad Bashey, M.D., Ph.D.
From ATLANTA Medicine, 2013, Transplantation, Vol. 84, No. 1
Hematopoietic (marrow or peripheral blood stem cell) transplants from allogeneic donors (allo-HCT) can cure several hematological malignancies and some non-malignant diseases of the bone marrow or lymphoid system that are incurable with standard therapies. Traditionally, donors for allo-HCT have comprised either a matched (HLA-genoidentical) sibling (MRD) or an HLA-matched unrelated volunteer (MUD). Only one of every four full siblings will be a MRD and thus given the size of the average American family, MRD are available for only 25-30% of patients. Best results using MUD are achieved when the donor is fully matched with the recipient at least 8 of 8 HLA-A, B, C and DRB1 loci. Suitably matched MUD may be available for 70% of Caucasian patients if sufficient time is available to complete a formal donor search which can take up to 4-6 months.
However, many patients are in short-lived remissions from their malignancy and cannot afford to wait for the time required. For patients from ethnic minorities and mixed-race backgrounds optimally matched MUD are much less commonly found and this problem is particularly severe for African American patients.
Cryopreserved umbilical cord blood (UCB) has been used as an alternative donor source for such patients. However, single UCB units often contain insufficient cells for an adult recipient. Two UCB units have been used to overcome this problem but the acquisition of two such units can be prohibitively expensive. Furthermore, UCB transplants can be associated with slow immunological recovery in adult recipients with associated prolonged risk of opportunistic infections and other post-transplant complications.
Partially-matched related donors, i.e. family donors with whom the patient shares an HLA-haplotype (also known as haploidentical donors) have also been investigated as an alternative donor source in patients who lack MRD and MUD. Almost all patients who need an allo-HCT have a first degree relative with whom they share a HLA-haplotype.
Original studies performed in Seattle in the 1970s and 80s demonstrated that un-manipulated allo-HCT from such haploidentical donors using the same regimens used for MRD and MUD transplants resulted in unacceptable rates of graft rejection and severe graft-versus-host disease (GVHD) due to aggressive bidirectional alloreactivity against the mismatched HLA-antigens. This led to the abandonment of haploidentical donor transplantation for several years. Subsequently, investigators in Perugia, Italy developed an approach to allo-HCT from haploidentical donors that utilizes stringent depletion of T-cells from the graft to prevent GVHD and very intensely cytotoxic preparative regimens with anti-thymocyte globulin to prevent graft-rejection. Although such transplants have been shown to be feasible and can cure some patients with acute leukemia, they are associated with high-rates of regimen-related toxicity and very slow immunological recovery with associated high rates of treatment related mortality1,2. Furthermore, the procedure is relatively complex and not easily replicated in other centers.
More recently an alternative approach to allo-HCT from haploidentical donors has been developed initially by Ephraim Fuchs and colleagues at Johns Hopkins University which uses unmanipulated (T-cell replete) bone marrow as the stem cell source in conjunction with a reduced-intensity (non-myeloablative) preparative regimen. The procedure relies instead on the use of post-transplant cyclophosphamide (ptCy) to control bi-directional T-cell alloreactivity. Cyclophosphamide is an alkylating agent that is relatively sparing to hematopoietic stem cells and seems to preferentially target T-cells that are undergoing activation and expansion in response to antigen stimulation. The approach administers high-dose cyclophosphamide on day +3 and +4 following the transplant when alloreactive T-cells are proliferating in response to the presence of mismatched HLA-antigens.
This process appears to selectively eliminate alloreactive T-cells responsible for graft-rejection and GVHD, while preserving other T-cells that are important for immunologic recovery3,4. Haplo-ptCy have been shown to result in low rates of GVHD, infections and treatment related mortality in single and multi-center trials including a parallel phase-II comparison to UCB transplantation conducted by the Blood and Marrow Transplantation Clinical Trials Network (BMT-CTN)5. However, Haplo-ptCy have not been formally compared to allo-HCT performed using conventional MRD or MUD donors.
Successful haploidentical donor transplantation would be of particular benefit to the population of metropolitan Atlanta because of the relatively large proportion of minority, and in particular African-American, patients who reside in this area. At the BMT Program at Northside Hospital, we have studied the use of Haplo-ptCy transplants since 2005. In addition to the non-myeloablative regimen originally developed at Johns Hopkins University, we have pioneered myeloablative regimens for Haplo-ptCy in patients with more aggressive and refractory malignancies in whom the non-myeloablative approach is unsatisfactory. We have demonstrated that the approach can be safe and effective with a low treatment related mortality and excellent disease-free survival in patients with advanced and refractory malignancies6.
However, despite the promising results of phase II studies of Haplo-ptCy transplantation, it has been unclear how the outcomes of such transplants compare to allogeneic hematopoietic transplants performed using optimally matched MRD and MUD. In order to address this question we analyzed outcomes of 271 consecutive first allo-HCT performed for hematologic malignancy at Northside hospital between February 2005 and October 2010. Specifically, we compared outcomes following 53 consecutive Haplo-ptCy to 117 consecutive allo-HCT from MRD and 101 from MUD respectively performed at our center.
All transplants were performed contemporaneously at Northside Hospital using identical supportive care measures. The patients undergoing allo-HCT from the three types of donor were well matched with respect to age, gender, diagnosis, risk-profile of malignancy and co-morbidities. Haplo-ptCy patients were more likely to receive bone marrow rather than peripheral blood stem cell grafts and more likely to receive reduced intensity versus myeloablative preparative conditioning for transplant. A Cox proportional hazards analysis was conducted and outcome measures were adjusted for any difference in confounding variables between the three groups. The results demonstrated that patients who underwent Haplo-ptCy transplants had similar overall and disease-free survival to patients transplanted from MRD and MUD.
Adjusted 24-month estimated survival rates were 76%, 67% and 64% for MRD, MUD and Haplo donor transplants respectively (p=n.s.). The corresponding 24-month rates of disease-free survival were 53%, 52% and 60% respectively. Cumulative incidences of non-relapse-mortality and relapse of malignancy were also not significantly different between the three groups. Rates and severity of acute GVHD were similar but cumulative incidence of extensive and severe chronic GVHD were lower in Haplo-ptCy transplant patients. These results were presented at an oral session at the 53rd annual meeting of the American Society of Hematology meeting (December 2011, San Diego, CA, Abstract 833; Blood vol 118 (21) p380)
This study is the first to compare a large number of allo-HCT performed using Haplo-ptCy to contemporaneous allo-HCT performed from MRD and MUD at the same center. It shows that Haplo-ptCy transplantation produces similar outcomes to transplants performed from conventional donors. Thus, it establishes Haplo-ptCY transplantation as a valid standard of care in patients who lack a conventional donor. Because Haplo-ptCy transplantation avoids the purchase expense of an unrelated donor graft or unrelated cord blood units, and it does not require expensive ex-vivo T-cell depletion, its use has the potential to significantly alter the algorithm for donor selection for allo-HCT. Haplo-ptCy transplantation is being compared to double UCB transplantation in an ongoing randomized phase III trial conducted by the Blood and Marrow Transplantation Clinical Trials Network (BMT-CTN trial 1101). Haplo-ptCy hematopoietic cell transplantation is also being explored as a means of establishing graft tolerance in recipients prior to solid organ transplantation.
References
1. Aversa F, Terenzi A, Tabilio A, et al: Full haplotype-mismatched hematopoietic stem-cell transplantation: a phase II study in patients with acute leukemia at high risk of relapse. J Clin Oncol 23:3447-54, 2005
2. Ciceri F, Labopin M, Aversa F, et al: A survey of fully haploidentical hematopoietic stem cell transplantation in adults with high-risk acute leukemia: a risk factor analysis of outcomes for patients in remission at transplantation. Blood 112:3574-81, 2008
3. Kasamon YL, Luznik L, Leffell MS, et al: Nonmyeloablative HLA-haploidentical bone marrow transplantation with high-dose posttransplantation cyclophosphamide: effect of HLA disparity on outcome. Biol Blood Marrow Transplant 16:482-9, 2010
4. Luznik L, O’Donnell PV, Symons HJ, et al: HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant 14:641-50, 2008
5. Brunstein CG, Fuchs EJ, Carter SL, et al: Alternative donor transplantation after reduced intensity conditioning: results of parallel phase 2 trials using partially HLA-mismatched related bone marrow or unrelated double umbilical cord blood grafts. Blood 118:282-8, 2011
6. Solomon SR, Matthews RH, Barreras AM, et al: Outpatient myeloablative allo-SCT: a comprehensive approach yields decreased hospital utilization and low TRM. Bone Marrow Transplant 45:468-75, 2010
