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Is Post-Transplantation Cyclophosphamide Disruptive Technology?



If chronic graft-vs-host disease rates are reduced without an increase in relapse rates, post-transplant cyclophosphamide may not only extend a transplant option to virtually everybody who stands to benefit from it, but it may also replace standard graft-vs-host disease prophylaxis and eliminate the need for oral immunosuppressants for the majority of transplant recipients.
— Matt Kalaycio, MD, FACP

There was a time when transplantation across human leukocyte antigen (HLA) barriers was fraught with so much difficulty that many thought it was impossible and we should stop trying. However, most patients do not have an HLA-matched sibling donor, and death was therefore certain if they had a hematologic malignancy that would otherwise be curable. That dismal reality prompted investigators to continue trying different techniques to extend the possibility of cure to a larger number of patients.

Searching for an Effective Technique

The most effective method to date has been high-resolution tissue typing, which opened the door to unrelated-donor transplantation for most white patients but not others and is complicated by the time required to secure a donor.1

Other investigators tried to circumvent HLA restriction through ex vivo T-cell depletion, but these efforts failed to generate much enthusiasm due to an increased risk of relapse, failure to prevent graft-vs-host disease, graft failure, or some combination of these problems.2,3 T-cell depletion is also complex and expensive.

The recognition that umbilical cord blood cells could engraft in an HLA-mismatched host was a major breakthrough.4 Umbilical cord blood transplants extend the opportunity for cure to those without sibling or unrelated donors across HLA barriers but are complicated by poor immune recovery, inconsistent engraftment, and high cost. Yet, in the absence of an alternative, their use increased substantially over the past 10 years.

More recently, the transplant group at Johns Hopkins discovered a novel approach to avoiding HLA barriers. By administering cyclophosphamide after the marrow transplant, reactive T cells are destroyed, and regulatory T cells are spared, not only allowing transplant across HLA barriers but also allowing immune surveillance with preservation of graft-vs-malignancy effects.5 Published results with this approach in the setting of haplo-identical transplantation have been remarkably good.6,7

As reviewed in this issue of The ASCO Post, the most recent example of promising results with post-transplant cyclophosphamide comes from the Center for International Blood and Marrow Research. Nilanjan Ghosh, MD, PhD, and colleagues queried the Center for International Blood and Marrow Research database to compare reported results with haplo-identical transplant using post-transplant cyclophosphamide with those reported with standard-of-care matched sibling-donor transplant in patients with lymphoma.8 As a registry study, it comes with all the caveats that attend such studies, but the outcomes for the two techniques in reasonably comparable patient populations are quite similar. There is, however, one very important difference. As has been demonstrated in several other studies, post-transplant cyclophosphamide reduces the risk of chronic graft-vs-host disease, even after HLA-mismatched transplant.

The Goal of Transplant Science

T cells are both scourge and savior of allogeneic bone marrow transplantation, being responsible for both graft-vs-host disease and graft-vs-leukemia effects. Since the primacy of T cells was recognized, separating graft-vs-host disease from graft-vs-leukemia has been the goal of transplant science.9 Post-transplant cyclophosphamide represents the latest, and most promising, technique to achieve this elusive goal.

Prospective, randomized trials such as the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 1101 will clarify the advantages and disadvantages of haplo-identical transplant with post-transplant cyclophosphamide compared with other options such as umbilical cord blood transplant. However, studies like the one from the Center for International Blood and Marrow Research generate consistently impressive data supporting post-transplant cyclophosphamide as a viable option for graft-vs-host disease prophylaxis. Many centers across the world now commonly administer post-transplant cyclophosphamide to allow transplants from haplo-identical donors when matched sibling or unrelated donors are unavailable.

The Next Question

In fact, the next question is already being asked in another Blood and Marrow Transplant Clinical Trials Network trial. The PROGRESS I trial (BMT CTN 1203) randomizes patients with matched sibling and unrelated donors to post-transplant cyclophosphamide or more conventional graft-vs-host disease prophylaxis. If chronic graft-vs-host disease rates are reduced without an increase in relapse rates, post-transplant cyclophosphamide may not only extend a transplant option to virtually everybody who stands to benefit from it, but it may also replace standard graft-vs-host disease prophylaxis and eliminate the need for oral immunosuppressants for the majority of transplant recipients. ■

Disclosure: Dr. Kalaycio reported no potential conflicts of interest.

References

1. Petersdorf EW, Hansen JA, Martin PJ, et al: Major-histocompatibility-complex class I alleles and antigens in hematopoietic-cell transplantation. N Engl J Med 345:1794-1800, 2001.

2. Wagner JE, Thompson JS, Carter SL, Kernan NA, Unrelated Donor Marrow Transplantation Trial: Effect of graft-versus-host disease prophylaxis on 3-year disease-free survival in recipients of unrelated donor bone marrow (T-cell Depletion Trial): A multi-centre, randomised phase II-III trial. Lancet 366:733-741, 2005.

3. Aversa F, Tabilio A, Velardi A, et al: Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype. N Engl J Med 339:1186-1193, 1998.

4. Gluckman E, Rocha V, Boyer-Chammard A, et al: Outcome of cord-blood transplantation from related and unrelated donors. Eurocord Transplant Group and the European Blood and Marrow Transplantation Group. N Engl J Med 337:373-381, 1997.

5. Luznik L, Fuchs EJ: High-dose, post-transplantation cyclophosphamide to promote graft-host tolerance after allogeneic hematopoietic stem cell transplantation. Immunol Res 47:65-77, 2010.

6. Ciurea SO, Zhang MJ, Bacigalupo AA, et al: Haploidentical transplant with posttransplant cyclophosphamide vs matched unrelated donor transplant for acute myeloid leukemia. Blood 126:1033-1040, 2015.

7. Kanakry CG, Tsai HL, Bolaños-Meade J, et al: Single-agent GVHD prophylaxis with posttransplantation cyclophosphamide after myeloablative, HLA-matched BMT for AML, ALL, and MDS. Blood 124:3817-3827, 2014.

8. Ghosh N, Karmali R, Rocha V, et al: Reduced-intensity transplantation for lymphomas using haploidentical related donors versus HLA-matched sibling donors: A Center for International Blood and Marrow Transplant Research analysis. J Clin Oncol. June 6, 2016 (early release online).

9. Horowitz MM, Gale RP, Sondel PM, et al: Graft-versus-leukemia reactions after bone marrow transplantation. Blood 75:555-562, 1990.


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Reduced-Intensity Related-Donor Haploidentical vs HLA-Matched Sibling-Donor Hematopoietic Cell Transplantation in Lymphoma


[Reduced intensity or nonmyeloablative conditioning] followed by haplo-hematopoietic cell transplantation with [post-transplantation cyclophosphamide] should be considered an acceptable option for patients with lymphoma without matched sibling donors.
— Nilanjan Ghosh, MD, ...


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