Teaching a Young Dog New Tricks: Modifications to the Post-Transplantation Cyclophosphamide Haploidentical Transplantation Platform
Year: 2018
Type: article
Abstract: In this issue of Biology of Blood and Marrow Transplantation, Chiusolo et al. [1Chiusolo P. Bug G. Olivieri A. et al.A modified post-transplant cyclophosphamide regimen for unmanipulated haploidentical marrow transplantation in acute myeloid leukemia: a multicenter study.Biol Blood Marrow Transplant. 2018; 24: 1243-1249Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar] report retrospective outcomes of 150 patients with acute myeloid leukemia transplanted with an HLA-haploidentical hematopoietic cell transplantation (HCT) platform using post-transplantation cyclophosphamide (PTCy). This platform was adapted from the Johns Hopkins (Baltimore) regimen [2Luznik L. O'Donnell P.V. Symons H.J. et al.HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide.Biol Blood Marrow Transplant. 2008; 14: 641-650Abstract Full Text Full Text PDF PubMed Scopus (1203) Google Scholar] with the major modifications being the incorporation of myeloablative conditioning and the timing of the immunosuppression. The changes to the immunosuppression included starting cyclosporine (CsA) on day 0 and mycophenolate mofetil on day +1 and spacing the days of PTCy from +3 and +4 to +3 and +5. Despite these alterations, graft-versus-host disease (GVHD) and overall transplant outcomes were excellent. The cumulative incidence of grade III to IV acute GVHD of 5% was identical with that found using the Johns Hopkins regimen, and the incidence of grade II to IV acute GVHD was actually lower (17% versus 30%) [3McCurdy S.R. Kanakry C.G. Tsai H.L. et al.Acute graft-versus-host disease and higher nucleated cell graft dose improve progression-free survival after hla-haploidentical transplant with post-transplant cyclophosphamide.Biol Blood Marrow Transplant. 2017; Google Scholar]. The incidence of moderate/severe chronic GVHD was low at 15%, although it was higher than patients treated with the Johns Hopkins regimen (3%), and thus the percent of patients remaining on immunosuppression at 1 year (37%) also was higher than has been seen with the Johns Hopkins approach (22%) [3McCurdy S.R. Kanakry C.G. Tsai H.L. et al.Acute graft-versus-host disease and higher nucleated cell graft dose improve progression-free survival after hla-haploidentical transplant with post-transplant cyclophosphamide.Biol Blood Marrow Transplant. 2017; Google Scholar]. Even so, malignancy control was very encouraging, with 4-year survival and cumulative incidence of relapse being 73% and 13%, respectively, for patients in remission at transplant. These relapse and survival outcomes are markedly better than reported with the Johns Hopkins regimen, although the use of myeloablative conditioning here likely contributed [4Scott B.L. Pasquini M.C. Logan B.R. et al.Myeloablative versus reduced-intensity hematopoietic cell transplantation for acute myeloid leukemia and myelodysplastic syndromes.J Clin Oncol. 2017; 35: 1154-1161Crossref PubMed Scopus (383) Google Scholar]. Despite myeloablative conditioning, the engraftment rates were not better than those seen with the Johns Hopkins regimen, and importantly, only 1 of 6 patients failing to engraft after the myeloablative conditioning could be salvaged. Nevertheless, overall this approach seemed to preserve most of the positive effects of the original approach in terms of low rates of acute and chronic GVHD as well as nonrelapse mortality, while providing encouraging disease control that compares favorably with other myeloablative HLA-haploidentical HCT studies using PTCy [5Kanakry C.G. Fuchs E.J. Luznik L. Modern approaches to HLA-haploidentical blood or marrow transplantation.Nat Rev Clin Oncol. 2016; 13: 10-24Crossref PubMed Scopus (197) Google Scholar]. The use of PTCy was developed clinically at Johns Hopkins to overcome historical barriers to HLA-haploidentical HCT including high rates of graft failure, severe acute GVHD, and consequent nonrelapse mortality [5Kanakry C.G. Fuchs E.J. Luznik L. Modern approaches to HLA-haploidentical blood or marrow transplantation.Nat Rev Clin Oncol. 2016; 13: 10-24Crossref PubMed Scopus (197) Google Scholar]. Critical to this development was pioneering work in murine models [6Berenbaum M.C. Brown I.N. Prolongation of homograft survival in mice with single doses of cyclophosphamide.Nature. 1963; 200: 84Crossref PubMed Scopus (92) Google Scholar, 7Aisenberg A.C. Studies on cyclophosphamide-induced tolerance to sheep erythrocytes.J Exp Med. 1967; 125: 833-845Crossref PubMed Scopus (88) Google Scholar, 8Owens Jr, A.H. Santos G.W. The effect of cytotoxic drugs on graft-versus-host disease in mice.Transplantation. 1971; 11: 378-382Crossref PubMed Scopus (61) Google Scholar, 9Mayumi H. Umesue M. Nomoto K. Cyclophosphamide-induced immunological tolerance: an overview.Immunobiology. 1996; 195: 129-139Crossref PubMed Scopus (110) Google Scholar, 10Luznik L. Jalla S. Engstrom L.W. Iannone R. Fuchs E.J. Durable engraftment of major histocompatibility complex-incompatible cells after nonmyeloablative conditioning with fludarabine, low-dose total body irradiation, and posttransplantation cyclophosphamide.Blood. 2001; 98: 3456-3464Crossref PubMed Scopus (240) Google Scholar], particularly studies in major histocompatibility complex (MHC)–matched skin allografting models [9Mayumi H. Umesue M. Nomoto K. Cyclophosphamide-induced immunological tolerance: an overview.Immunobiology. 1996; 195: 129-139Crossref PubMed Scopus (110) Google Scholar]. Interestingly, the use of PTCy was unsuccessful at inducing tolerance to MHC-mismatched skin allografts in contrast to the preclinical [10Luznik L. Jalla S. Engstrom L.W. Iannone R. Fuchs E.J. Durable engraftment of major histocompatibility complex-incompatible cells after nonmyeloablative conditioning with fludarabine, low-dose total body irradiation, and posttransplantation cyclophosphamide.Blood. 2001; 98: 3456-3464Crossref PubMed Scopus (240) Google Scholar] and current major clinical application of PTCy in MHC-mismatched HCT. Although more recent work has contributed scientific insight [11Kanakry C.G. Ganguly S. Zahurak M. et al.Aldehyde dehydrogenase expression drives human regulatory T cell resistance to posttransplantation cyclophosphamide.Sci Transl Med. 2013; 5: 211ra157Crossref PubMed Scopus (227) Google Scholar, 12Ross D. Jones M. Komanduri K. Levy R.B. Antigen and lymphopenia-driven donor T cells are differentially diminished by post-transplantation administration of cyclophosphamide after hematopoietic cell transplantation.Biol Blood Marrow Transplant. 2013; 19: 1430-1438Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar, 13Ganguly S. Ross D.B. Panoskaltsis-Mortari A. et al.Donor CD4+ Foxp3+ regulatory T cells are necessary for posttransplantation cyclophosphamide-mediated protection against GVHD in mice.Blood. 2014; 124: 2131-2141Crossref PubMed Scopus (128) Google Scholar], much of the current model of understanding of how PTCy prevents GVHD still is directly derived from this work in MHC-matched skin allografting [14Luznik L. O'Donnell P.V. Fuchs E.J. Post-transplantation cyclophosphamide for tolerance induction in HLA-haploidentical bone marrow transplantation.Semin Oncol. 2012; 39: 683-693Crossref PubMed Scopus (225) Google Scholar]. In these MHC-matched skin allografting models, it was critical that a calcineurin inhibitor not be given before administration of PTCy [15Nomoto K. Eto M. Yanaga K. Nishimura Y. Maeda T. Nomoto K. Interference with cyclophosphamide-induced skin allograft tolerance by cyclosporin A.J Immunol. 1992; 149: 2668-2674PubMed Google Scholar]; the administration of CsA starting 3 days before cell transfer (5 days before PTCy) and continuing through the day before PTCy interfered with tolerance induction and resulted in skin graft rejection [15Nomoto K. Eto M. Yanaga K. Nishimura Y. Maeda T. Nomoto K. Interference with cyclophosphamide-induced skin allograft tolerance by cyclosporin A.J Immunol. 1992; 149: 2668-2674PubMed Google Scholar]. This graft rejection was accompanied by higher persistence of alloreactive T cells and mixed lymphocyte in vitro proliferative responses. Based on these data, when PTCy was translated clinically in HCT, it was considered a cardinal rule that no immunosuppression, particularly calcineurin inhibitors, be given before the completion of PTCy. Thus, when the Johns Hopkins regimen was finalized as PTCy on days +3 and +4, the adjunct immunosuppression of tacrolimus and mycophenolate mofetil was started on day +5 [2Luznik L. O'Donnell P.V. Symons H.J. et al.HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide.Biol Blood Marrow Transplant. 2008; 14: 641-650Abstract Full Text Full Text PDF PubMed Scopus (1203) Google Scholar]. Based on initial reports of successful translation of PTCy toward safely facilitating HLA-haploidentical HCT, other investigative groups began to test the use of PTCy for their own patients. When the Genova group began to use PTCy, they consciously decided to space the 2 doses to days +3 and +5 to try to minimize potential toxicity. However, they were unaware of the cardinal rule and continued their normal practice from HLA-matched HCT regarding the other immunosuppressants. Thus, the CsA began on day 0 and the mycophenolate mofetil (given twice daily instead of the thrice daily in the Johns Hopkins approach) began on day +1. Surprisingly, the effectiveness of PTCy in preventing GVHD was not hindered [1Chiusolo P. Bug G. Olivieri A. et al.A modified post-transplant cyclophosphamide regimen for unmanipulated haploidentical marrow transplantation in acute myeloid leukemia: a multicenter study.Biol Blood Marrow Transplant. 2018; 24: 1243-1249Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar, 16Raiola A.M. Dominietto A. Ghiso A. et al.Unmanipulated haploidentical bone marrow transplantation and posttransplantation cyclophosphamide for hematologic malignancies after myeloablative conditioning.Biol Blood Marrow Transplant. 2013; 19: 117-122Abstract Full Text Full Text PDF PubMed Scopus (264) Google Scholar]. Based on these and other clinical observations as well as our completed and ongoing laboratory work, we are increasingly recognizing that the mechanisms previously delineated for the efficacy of PTCy in murine MHC-matched skin allografting models may not fully apply to HLA-haploidentical HCT using PTCy. The original studies suggested that suppressor T cells were important for the efficacy of PTCy only in the late stages of tolerance induction and were predominately CD8+ [17Eto M. Mayumi H. Tomita Y. Yoshikai Y. Nishimura Y. Nomoto K. Sequential mechanisms of cyclophosphamide-induced skin allograft tolerance including the intrathymic clonal deletion followed by late breakdown of the clonal deletion.J Immunol. 1990; 145: 1303-1310PubMed Google Scholar, 18Tomita Y. Mayumi H. Eto M. Nomoto K. Importance of suppressor T cells in cyclophosphamide-induced tolerance to the non-H-2-encoded alloantigens. Is mixed chimerism really required in maintaining a skin allograft tolerance?.J Immunol. 1990; 144: 463-473PubMed Google Scholar], although a later study by the same group suggested that the critical suppressor T cells were instead CD4+ [19Kong Y.Y. Eto M. Omoto K. Umesue M. Hashimoto A. Nomoto K. Regulatory T cells in maintenance and reversal of peripheral tolerance in vivo.J Immunol. 1996; 157: 5284-5289PubMed Google Scholar]. Our prior work showed that CD4+Foxp3+ regulatory T cells (Tregs) recover rapidly after PTCy in HLA-matched HCT, are resistant to mafosfamide (an in vitro analogue of cyclophosphamide) in HLA-mismatched mixed lymphocyte culture in vitro, and are necessary for GVHD prevention immediately post-HCT in xenogeneic and MHC-matched murine HCT models [11Kanakry C.G. Ganguly S. Zahurak M. et al.Aldehyde dehydrogenase expression drives human regulatory T cell resistance to posttransplantation cyclophosphamide.Sci Transl Med. 2013; 5: 211ra157Crossref PubMed Scopus (227) Google Scholar, 13Ganguly S. Ross D.B. Panoskaltsis-Mortari A. et al.Donor CD4+ Foxp3+ regulatory T cells are necessary for posttransplantation cyclophosphamide-mediated protection against GVHD in mice.Blood. 2014; 124: 2131-2141Crossref PubMed Scopus (128) Google Scholar]. In the course of that work, we also tested in HLA-mismatched mixed lymphocyte cultures the impact of CsA given either before or after mafosfamide on the frequency of surviving Tregs [11Kanakry C.G. Ganguly S. Zahurak M. et al.Aldehyde dehydrogenase expression drives human regulatory T cell resistance to posttransplantation cyclophosphamide.Sci Transl Med. 2013; 5: 211ra157Crossref PubMed Scopus (227) Google Scholar]. In the original publication, we had not included the data on CsA before mafosfamide so as not to unnecessarily complicate a point that was already tangential to the main thrust of that publication, see Figure S8 in Kanakry et al. [11Kanakry C.G. Ganguly S. Zahurak M. et al.Aldehyde dehydrogenase expression drives human regulatory T cell resistance to posttransplantation cyclophosphamide.Sci Transl Med. 2013; 5: 211ra157Crossref PubMed Scopus (227) Google Scholar]. We found that CsA given either before or after mafosfamide did not interfere with the increase in the percentages of naïve or effector Tregs [20Miyara M. Yoshioka Y. Kitoh A. et al.Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor.Immunity. 2009; 30: 899-911Abstract Full Text Full Text PDF PubMed Scopus (1646) Google Scholar] after mafosfamide, Figure 1 and Figure S8 in Kanakry et al. [11Kanakry C.G. Ganguly S. Zahurak M. et al.Aldehyde dehydrogenase expression drives human regulatory T cell resistance to posttransplantation cyclophosphamide.Sci Transl Med. 2013; 5: 211ra157Crossref PubMed Scopus (227) Google Scholar]. Yet, when CsA was given before mafosfamide rather than afterwards, it resulted in a significant reduction in the overall numbers of effector Tregs that were comparable to CsA treatment without mafosfamide [Figure 1]. Whether this relative sparing of Tregs while overall minimizing their absolute numbers contributes to improved malignancy control in patients treated with PTCy is unknown. Alternatively, as the authors suggest, it is possible that CsA reduces the proliferation of alloreactive T cells, thus diminishing the impact of PTCy on them, enabling their continued elimination of tumor without resulting in high rates of severe GVHD. Very possibly, both mechanisms may be active. Regardless, the use of CsA and/or other immunosuppressants before PTCy is a promising approach for HLA-haploidentical HCT, as it appears to largely preserve the positive impact on GVHD and toxicity while seemingly augmenting the graft-versus-tumor efficacy of this approach. Other groups also have modified the adjunct immunosuppression used for PTCy-based HCT and have shown encouraging results, and further modifications to the PTCy platform may continue to improve outcomes. Ultimately, direct comparisons between platforms in homogeneous patient populations will be necessary to confirm which approach may be optimal. Financial disclosure: The authors have no relevant disclosures. Conflict of interest statement: There are no conflicts of interest to report.
Authors: Christopher G. Kanakry, Leo Luznik
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,650
OpenAlex ID: W2797531265