Peritransplantation ruxolitinib administration is safe and effective in patients with myelofibrosis: a pilot open-label study

Haris Ali, Ni-Chun Tsai, Timothy Synold, Sally Mokhtari, Weimin Tsia, Joycelynne Palmer, Tracey Stiller, Monzr Al Malki, Ibrahim Aldoss, Amandeep Salhotra, Syed Rahmanuddin, Vinod Pullarkat, Ji-Lian Cai, Anthony Stein, Stephen J Forman, Guido Marcucci, Matthew Mei, David S Snyder, Ryotaro Nakamura, Haris Ali, Ni-Chun Tsai, Timothy Synold, Sally Mokhtari, Weimin Tsia, Joycelynne Palmer, Tracey Stiller, Monzr Al Malki, Ibrahim Aldoss, Amandeep Salhotra, Syed Rahmanuddin, Vinod Pullarkat, Ji-Lian Cai, Anthony Stein, Stephen J Forman, Guido Marcucci, Matthew Mei, David S Snyder, Ryotaro Nakamura

Abstract

We report results of our prospective pilot trial evaluating safety/feasibility of peritransplantation ruxolitinib for myelofibrosis treatment. Primary objectives were to determine safety and maximum tolerated dose (MTD) of ruxolitinib. Ruxolitinib was administered at 2 dose levels (DLs) of 5 and 10 mg twice daily, with fludarabine/melphalan conditioning regimen and tacrolimus/sirolimus graft-versus-host disease (GVHD) prophylaxis. We enrolled 6 and 12 patients at DL1 and DL2, respectively. Median age at transplantation was 65 years (range, 25-73). Per Dynamic International Prognostic Scoring System, 4 patients were high and 14 intermediate risk. Peripheral blood stem cells were graft source from matched sibling (n = 5) or unrelated (n = 13) donor. At each DL, 1 patient developed dose-limiting toxicities (DLTs): grade 3 cardiac and gastrointestinal with grade 4 pulmonary DLTs in DL1, and grade 3 kidney injury in DL2. All patients achieved engraftment. Grade 2 to 4 and 3 to 4 acute GVHD cumulative incidence was 17% (95% confidence interval [CI], 6-47) and 11% (95% CI, 3-41), respectively. Cumulative incidence of 1-year chronic GVHD was 42% (95% CI, 24-74). With 22.6-month (range, 6.2-25.8) median follow-up in surviving patients, 1-year overall and progression-free survival were 77% (95% CI, 50-91) and 71% (95% CI, 44-87), respectively. Causes of death (n = 4) were cardiac arrest, GVHD, respiratory failure, and refractory GVHD of liver. Our results show peritransplantation ruxolitinib is safe and well tolerated at MTD of 10 mg twice daily and associated with dose-dependent pharmacokinetic and cytokine profile. Early efficacy data are highly promising in high-risk older patients with myelofibrosis. This trial was registered at www.clinicaltrials.gov as #NCT02917096.

© 2022 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.
Conditioning regimen and engraftment. (A) Study schema. Peri-HCT ruxolitinib administration was from day −3 pre-HCT to day +30 post-HCT. Neutrophil (B) and platelet (C) engraftment post-HCT. aGVHD, acute GVHD; PO, orally; QD, once daily.
Figure 2.
Figure 2.
Ruxolitinib pharmacokinetics. Days −2 to +4 (A) and +5 (B). AUC, area under the plasma concentration–time curve; BID, twice daily; CL/F, oral clearance; Cmax, maximum plasma concentration; PK, pharmacokinetics; T1/2, terminal-phase elimination half-life.
Figure 3.
Figure 3.
Comparison of immune reconstitution. Reconstitution of DL1 (5 mg twice daily) vs DL2 (10 mg twice daily) on days 21, 35, and 100 post-HCT for CD3+ T cells (A), CD3+ T cells (B), CD8+ T cells (C), Foxp3+ Tregs (D), CD27+ B cells (E), and CD56+ NK cells (F).

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