A Prospective Pilot Study of Graft-versus-Host Disease Prophylaxis with Post-Transplantation Cyclophosphamide and Ruxolitinib in Patients with Myelofibrosis

Abstract

<b><i>Introduction:</i></b> This prospective study evaluated a calcineurin inhibitor-free graft-versus-host disease (GVHD) prophylaxis regimen of ruxolitinib in combination with post-transplant cyclophosphamide (PTCy). <b><i>Patents and Methods:</i></b> Twenty patients with primary or secondary myelofibrosis were prospectively enrolled. Reduced intensity conditioning was performed, followed by allogeneic stem cell transplantation from related (<i>n</i> = 7) or unrelated (<i>n</i> = 13) donors. GVHD prophylaxis included only PTCy and ruxolitinib (45 mg) from day–7 to day–2, and 15 mg from day+5 to day+100. This trial was registered at www.clinicaltrials.gov as #NCT02806375. <b><i>Results:</i></b> Primary engraftment was documented in 17 patients. One patient experienced primary graft failure and 2 died before engraftment. Eleven patients demonstrated severe poor graft function (SPGF), which required ruxolitinib dose reduction. The regimen was well tolerated, with grade 3–4 non-haematological toxicity in 30%, viral reactivation in 45%, and severe sepsis in 15% of patients. The incidence of acute GVHD grade II–IV was 25%, grade III-IV GVHD was 15%, and moderate chronic GVHD was 20%, with no severe cases. Only 2 patients required systemic steroids. Haematological relapse was documented in 1 patient. Two-year non-relapse mortality was 15%, 2-year overall survival was 85%, and 2-year event-free survival was 72%. <b><i>Conclusion:</i></b> GVHD prophylaxis with PTCy and ruxolitinib is associated with low toxicity, good acute and chronic GVHD control, and low relapse incidence. However, the relatively high rate of SPGF should be taken into account. SPGF could possibly be mitigated by ruxolitinib dose reduction.

Use of the JAK Inhibitor Ruxolitinib in the Treatment of Hemophagocytic Lymphohistiocytosis

“…Ruxolitinib (Jakafi®) is an oral, potent, highly bioavailable JAK1/2 inhibitor that is approved by the Food and Drug Administration (FDA) for use in patients with myeloproliferative neoplasms and steroid refractory graft-vs.-host-disease (GVHD), where it has shown to induce responses, even in those with the most advanced disease ( 32 – 34 ). Currently, ruxolitinib is being trialed as GVHD prophylaxis for patients undergoing allogeneic HSCT ( 35 , 36 ). In addition, ruxolitinib has been reported to lessen inflammation in patients with pathogenic germline STAT1 or STAT3 gain-of-function (GOF) variants.…”

Allogeneic Transplantation for Myelofibrosis with Novel Graft-versus-Host Disease Prophylaxis

“…In this issue of Acta Haematologica , Morozova et al [1] report a single-center prospective study of allogeneic transplant for MF patients in Russia, employing a reduced-intensity conditioning (RIC) regimen with peripheral blood stem cell graft use, and studying a combination PTCy and ruxolitinib primary GVHD prophylaxis. The authors enrolled 20 patients, using 14 matched donors and 6 mismatched donors (4 haploidentical and 2 mismatched unrelated donors).…”

A Novel Combination for Graft-versus-Host-Disease Prophylaxis: Lessons Learned from the Birth of Sushi Burrito!

“…Innovation has no boundaries, and to achieve a goal in research, one must discover, create, or invent something, or use various combinations of the existing armamentarium (if present) for innovation/discovery. The latter approach is the tale of a novel prophylaxis regimen demonstrated in this issue of Acta Haematologica , where Mo­rozova et al [1] present data on a pilot trial using the commonly used drugs cyclophosphamide and ruxolitinib for the prevention of graft-versus-host-disease (GVHD) to which this commentary refers to. I use the metaphor of a novel cuisine to demonstrate the novelty of this GVHD regimen.…”

“…The Hopkins group has championed the approach of alleviating the risk of both acute and chronic GVHD by using post-transplant cyclophosphamide (PTCy) [4], the use of which has skyrocketed over the past decade given its effectiveness in matched related, matched unrelated, and haploidentical transplantations [5-7]. To exploit this approach, Morozova et al [1] developed a novel regimen for GVHD prophylaxis by utilizing only PTCy and ruxolitinib (45-mg dose given from day 7 to day 2, and 15 mg from day +5 to day +100 of HCT) after a reduced-intensity conditioned transplant in myelofibrosis patients. They report that out of 20 patients on the trial, 11 patients had severe poor graft function, 1 engraftment failure, and 1 relapse.…”

“…In a phase II multicenter trial of 103 patients with myelofibrosis conditioned with busulfan and fludarabine, the incidence of acute GVHD grade II–IV was 27%, and for chronic GVHD it was 43% [9]. The results of the study by Morozova et al [1] compare favorably to the results from the larger studies concerning the incidence of chronic GVHD, without a significant difference in the risk of relapse. However, before applying the novel GVHD prophylaxis regimen in practice, certain issues need to be dealt with first.…”