A phase 1 trial utilizing TMI with fludarabine-melphalan in patients with hematologic malignancies undergoing second allo-SCT

Misha C Tran, Yasmin Hasan, Amy Wang, Kamil Yenice, Julien Partouche, Wendy Stock, Richard A Larson, Satyajit Kosuri, James L LaBelle, Justin Kline, Peter A Riedell, Andrew S Artz, Ralph Weichselbaum, Michael R Bishop, Bulent Aydogan, Hongtao Liu, Misha C Tran, Yasmin Hasan, Amy Wang, Kamil Yenice, Julien Partouche, Wendy Stock, Richard A Larson, Satyajit Kosuri, James L LaBelle, Justin Kline, Peter A Riedell, Andrew S Artz, Ralph Weichselbaum, Michael R Bishop, Bulent Aydogan, Hongtao Liu

Abstract

Relapse after allogeneic stem cell transplantation (allo-SCT) remains the primary cause of treatment failure. A second SCT can result in long-term survival in a subset of patients, but the relapse rate remains high. We conducted a single-center, phase 1, modified 3 + 3 dose-escalation study of the feasibility of combining intensity-modulated total marrow irradiation (IM-TMI) with fludarabine and melphalan for conditioning. Between December 2015 and May 2020, 21 patients with relapsed hematologic disease undergoing second or greater allo-SCT were treated with IM-TMI doses of 6 Gy, 9 Gy, or 12 Gy. Dose-limiting toxicity was defined as a grade 3 or higher treatment-related adverse event; mucositis was the primary dose-limiting toxicity. The median times to neutrophil and platelet engraftment were 10 and 18 days, respectively. The 1-year cumulative incidence of graft-versus-host disease was 65% (95% confidence interval CI, 38-83). The nonrelapse mortality at 2 years was 17% (95% CI, 4-39). Cumulative incidence of relapse at 2 years was 35% (95% CI, 13-58). Two-year progression-free survival and overall survival were 48% and 50%. We conclude that combining IM-TMI with fludarabine-melphalan is feasible. We recommend 12 Gy of IM-TMI with fludarabine-melphalan for second SCT, although 9 Gy may be used for older or underweight patients.

Conflict of interest statement

Conflict-of-interest disclosure: H.L. has research support from Karyopharm and Bristol Myers Squibb; served at the advisory board meeting for Agios, Pfizer, Nkarta, and CTI Biopharm; consultant for NGM Biopharma; and received consulting fees from BeiGene. Other co-authors reported research funding and membership on advisory boards from different companies but reported no conflicts of interest with this study. The remaining authors declare no competing financial interests.

© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

Figures

Graphical abstract
Graphical abstract
Figure 1.
Figure 1.
Cumulative incidences of relapse, NRM, and GVHD. (A) Cumulative incidences of relapse at 1 year and 2 years were 28% (95% CI, 9-50) and 35% (95% CI, 13-58%), respectively. The NRM at 1 year and 2 years were both 17% (95% CI, 4-39). (B) The cumulative incidence of any GVHD at 1 year was 65% (95% CI, 38-83).
Figure 2.
Figure 2.
PFS and OS. Estimated 2-year PFS (A) and OS (B) were 48% and 50%, respectively, with IM-TMI.

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