Improving Transplant Outcomes for Patients without a Match

Abstract & Commentary

By William B. Ershler, MD

Synopsis: In a retrospective review of consecutive patients treated at a single institution, recipients of cells from haploidentical donors were compared to those receiving cells from matched related or matched unrelated donors. All patients, including, those with haploidentical match, received non-T-cell depleted infusions. Haploidentical recipients did receive post-transplant cyclophosphamide. Results were comparable in terms of non-relapse mortality, relapse, and the occurrence and severity of graft-versus-host disease.

Source: Bashey A, et al. T-cell-replete HLA-haploidentical hematopoietic transplantation for hematologic malignancies using post-transplantation cyclophosphamide results in outcomes equivalent to those of contemporaneous HLA-matched related and unrelated donor transplantation. J Clin Oncol 2013,31:1310-1316.

For patients requiring allogeneic hematopoietic cell transplantation (HCT), it is commonly understood that HLA-matched siblings or HLA-matched unrelated donors (MUDS) are optimal donors. However, there remain a substantial number of patients for whom a matched donor is not available. Current research at a number of transplant centers has focused on this issue and there have developed a number of strategies in which haploidentical marrow is used. Recognizing that severe graft-versus-host disease (GVHD) would be unacceptable, methods of depleting donor T cells from the infused stem cell preparation have been tested but, unfortunately, such approaches have been associated with slow immune reconstitution and a high rate of nonrelapse mortality (NRM).1,2 Recently, an alternative approach to haploidentical allogeneic HCT was developed, in which T cells were not removed or altered from the donor sample but immune reactivity was regulated post-transplant with cyclophosphamide.3 This approach has demonstrated promising results in Phase 2 trials,4-6 but a direct comparison with fully HLA matched donations had not been reported.

To address this question, Bashey and colleagues from Northside Hospital in Atlanta provide a retrospective review of their single institution experience in which consecutive patients received first transplantation for hematologic malignancy with either matched (related or unrelated) or haploidentical marrow. There were 271 patients, all with hematologic malignancy presenting between February 2005 and October 2010, included in this analysis and all underwent T-cell–replete allogeneic hematopoietic cell transplantation. Of the 271 patients, 117 had matched related donors (MRD), 101 had MUD, and 53 had haploidentical donors.

Patients receiving MRD or MUD were treated by institutional protocols, either myeloablative, reduced-intensity conditioning, or nonmyeloablative stem cell transplantation. The 53 patients using haploidentical donors received one of two regimens. Thirty-five patients received a nonmyeloablative regimen consisting of fludarabine 30 mg/m2 intravenously (IV) once per day on days -6 to -2; total-body irradiation (TBI) 2 Gy on day -1, and cyclophosphamide 14.5 mg/kg IV once per day on days -6 and -5 and 50 mg/kg once per day on days 3 and 4 with a bone marrow graft. Eighteen patients were treated on an institutionally developed myeloablative protocol using fludarabine 25 mg/m2 IV once per day on days -6 to -2, busulfan 110 to 130 mg/m2 IV once per day on days -7 to -4, and cyclophosphamide 14.5 mg/kg IV once per day on days -3 and -2 and 50 mg/kg once per day on days 3 and 4, with granulocyte, colony-stimulating, factor-mobilized peripheral blood stem cells (PBSCs; target CD34-cell count, 5-106/kg) as the graft. No pharmacokinetic adjustment of busulfan dose was performed. All patients received tacrolimus from days 5 to 180, with a target level of 5 to 15 ng/mL, and mycophenolate mofetil (maximum dose, 3 g per day in divided doses) on days 5 to 35. Filgrastim 5 mcg/kg was administered from day 5 until neutrophil recovery. Overall and disease-free survival (DFS) were adjusted for effects of significant patient-, disease-, and transplantation-related covariates using a stratified Cox model.

Patient characteristics were similar between the three donor groups. For patients undergoing MRD, MUD, and haploidentical transplantation, 24-month cumulative incidences of nonrelapse mortality were 13%, 16%, and 7%, and of relapse were 34%, 34%, and 33%, respectively (P not significant [NS]). Cumulative incidences of grades 3 to 4 acute GVHD at 6 months were 8%, 11%, and 11%, respectively (P NS); extensive chronic GVHD occurred in 54%, 54%, and 38% of patients, respectively (P < 0.05 for those undergoing haploidentical donor vs MRD or MUD transplantation). Adjusted 24-month probabilities of survival were 76%, 67%, and 64%, and of DFS were 53%, 52%, and 60%, respectively; these were not significantly different among the three donor groups.

Commentary

Haploidentical hematopoietic stem cell transplantation is an alternative transplant strategy for patients without an HLA-matched donor. Currently, as many as half of all patients who might benefit from transplantation are unable to find an HLA-matched related or unrelated donor. Yet, for many in this situation a haploidentical donor is readily available. Early studies of haploidentical transplantation resulted in intolerable GVHD, high rejection rate, and transplant-related mortality. In recent years, there have been important advances including partial ex vivo or in vivo alloreactive T cell depletion and post-transplant cell therapy resulting in improved immune reconstitution in recipients of haploidentical transplants (for review, see reference 7). Further, results of unmanipulated stem-cell transplantation using ATG and combined immunosuppression in haploidentical transplant settings are promising. The current encouraging report indicates that post-transplantation cyclophosphamide also may be effective in this regard.

An alternative for patients without a match is transplantation of hematopoietic stem cells prepared from umbilical cord blood (e.g., double umbilical cord blood [DUCB]). In a Phase 2 study, dUCB transplantation in a similar setting (matched marrow not available) gave results comparable to haploidentical marrow.4 A future prospective randomized trial comparing modern haploidentical HCT with dUCB would seem a reasonable next step in the promotion of effective management of selective hematological malignancies.

References

1. Aversa F, 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 2005;23:3447-3454.

2. Ciceri 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 2008;112:3574-3581.

3. O’Donnell PV, et al. Nonmyeloablative bone marrow transplantation from partially HLA-mismatched related donors using posttransplantation cyclophosphamide. Biol Blood Marrow Transplant 2002;8:377-386.

4. Brunstein CG, 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 2011;118:282-288.

5. Kasamon YL, et al. Nonmyeloablative HLA-haploidentical bone marrow transplantation with high-dose posttransplantation cyclophosphamide: Effect of HLA disparity on outcome. Biol Blood Marrow Transplant 2010;16:482-489.

6. Huang XJ. Haploidentical hematopoietic stem cell transplantation without in vitro T-cell-depletion for the treatment of hematologic diseases. Chimerism 2013 [Epub ahead of print].

7. Alshemmari S, et al. Haploidentical hematopoietic stem-cell transplantation in adults. Bone Marrow Res 2011;2011:303487.