Graft-versus-Host Disease Prophylaxis with Post-Transplantation Bendamustine in Patients with Refractory Acute Leukemia: A Dose-Ranging Study

Moiseev, Ivan S.; Bondarenko, Sergey N.; Morozova, Elena; Vlasova, Yulia; Dotsenko, Anna A.; Epifanovskaya, Olga S.; Babenko, Elena V.; Botina, Anna; Baykov, Vadim; Суркова, Е. А.; Лапин, С. В.; Beynarovich, Anastasiya; Borzenkova, E.; Golosgchapov, Oleg; Kanunnikov, Mikhail; Kudyasheva, Olga; Ovechkina, Varvara N.; Pirogova, Olga V.; Porunova, Valentina V.; Rudakova, Tatyana; Smikova, Olesya; Smirnova, Anna G.; Afansyev, Boris

doi:10.1016/j.jtct.2021.03.032

Cited by 4 publications

(8 citation statements)

References 29 publications

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“…This may parallel the ascites secondary to liver failure that developed in our BEN-treated mice. Ultimately, our results and the recent clinical study ( 18 ) suggest the need for caution in considering BEN as a suitable, safe, and effective alternative to PTCy until more mature clinical data are available.…”

Section: Discussionmentioning

confidence: 74%

“…Indeed, early results from a PTCy dose de-escalation clinical study at our institution suggest that intermediate-dose PTCy maintains excellent protection against acute GVHD ( 62 ). Whether such results also are true for other chemotherapeutics is unknown, but is important to understand, particularly given the recent attempts to implement post-transplantation bendamustine clinically ( 17 , 18 ).…”

Section: Discussionmentioning

confidence: 99%

“…An additional interesting finding of this study is that BEN was ineffective in ameliorating severe and fatal GVHD in our MHC-haploidentical HCT model. Recently, post-transplantation BEN has shown promise in pre-clinical murine HCT studies ( 16 ) and mixed results in early phase clinical trials ( 17 , 18 ). It is possible that our conflicting findings may be explained in part due to differences in models or relative doses of CY or BEN, which were higher in the CB6F1→CAF1/J model ( 16 ) than we have determined to be optimal at preventing GVHD in our B6C3F1→B6D2F1 model ( 5 ).…”

Section: Discussionmentioning

confidence: 99%

“…It is possible that our conflicting findings may be explained in part due to differences in models or relative doses of CY or BEN, which were higher in the CB6F1→CAF1/J model ( 16 ) than we have determined to be optimal at preventing GVHD in our B6C3F1→B6D2F1 model ( 5 ). Additionally, a recent clinical study examining post-transplantation BEN showed that patients developed severe cytokine release syndrome, often manifesting with liver dysfunction, at unacceptably high rates ( 18 ). This may parallel the ascites secondary to liver failure that developed in our BEN-treated mice.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, the relative effects of PTCy compared with other chemotherapeutics on T-cell subsets have not been examined. The only exception has been recent interest in post-transplantation bendamustine (BEN), which has been shown in pre-clinical studies to produce engraftment and GVHD prevention results similar to PTCy, while maintaining the graft-versus-leukemia effect ( 16 – 18 ); yet, phase I/II trials thus far have shown mixed results ( 17 , 18 ).…”

Section: Introductionmentioning

confidence: 99%

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Post-Transplantation Cyclophosphamide Uniquely Restrains Alloreactive CD4+ T-Cell Proliferation and Differentiation After Murine MHC-Haploidentical Hematopoietic Cell Transplantation

et al. 2022

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Post-transplantation cyclophosphamide (PTCy) reduces the incidence and severity of graft-versus-host disease (GVHD), thereby improving the safety and accessibility of allogeneic hematopoietic cell transplantation (HCT). We have shown that PTCy works by inducing functional impairment and suppression of alloreactive T cells. We also have identified that reduced proliferation of alloreactive CD4+ T cells at day +7 and preferential recovery of CD4+CD25+Foxp3+ regulatory T cells (Tregs) at day +21 are potential biomarkers associated with optimal PTCy dosing and timing in our B6C3F1→B6D2F1 MHC-haploidentical murine HCT model. To understand whether the effects of PTCy are unique and also to understand better the biology of GVHD prevention by PTCy, here we tested the relative impact of cyclophosphamide compared with five other optimally dosed chemotherapeutics (methotrexate, bendamustine, paclitaxel, vincristine, and cytarabine) that vary in mechanisms of action and drug resistance. Only cyclophosphamide, methotrexate, and cytarabine were effective in preventing fatal GVHD, but cyclophosphamide was superior in ameliorating both clinical and histopathological GVHD. Flow cytometric analyses of blood and spleens revealed that these three chemotherapeutics were distinct in constraining conventional T-cell numerical recovery and facilitating preferential Treg recovery at day +21. However, cyclophosphamide was unique in consistently reducing proliferation and expression of the activation marker CD25 by alloreactive CD4+Foxp3- conventional T cells at day +7. Furthermore, cyclophosphamide restrained the differentiation of alloreactive CD4+Foxp3- conventional T cells at both days +7 and +21, whereas methotrexate and cytarabine only restrained differentiation at day +7. No chemotherapeutic selectively eliminated alloreactive T cells. These data suggest that constrained alloreactive CD4+Foxp3- conventional T-cell numerical recovery and associated preferential CD4+CD25+Foxp3+ Treg reconstitution at day +21 may be potential biomarkers of effective GVHD prevention. Additionally, these results reveal that PTCy uniquely restrains alloreactive CD4+Foxp3- conventional T-cell proliferation and differentiation, which may explain the superior effects of PTCy in preventing GVHD. Further study is needed to determine whether these findings also hold true in clinical HCT.

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Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%