Prevention is better than cure Free

In this issue of Blood, DeFilipp et al report on the use of ruxolitinib as graft-vs-host disease (GVHD) prophylaxis after allogeneic hematopoietic stem cell transplantation (alloSCT) and describe low rates of clinically significant chronic GVHD (cGVHD).¹ 

“Prevention is better than cure!” It was Christoph Wilhelm Hufeland who formulated this sentence in his book, Macrobiotics or the Art of Prolonging Human Life, published in 1832.² Since then, the strong belief in prevention has spread to all medical disciplines, especially oncology. The advantage of prevention as opposed to curative treatment is evident to patients living with cGVHD, which is the major cause of late morbidity and nonrelapse mortality, occurring in up to 70% of alloSCT recipients.³ Typical cGVHD manifestations have a strong negative impact on the quality of life and include skin fibrosis, sicca syndrome, gastrointestinal symptoms, liver disease, respiratory insufficiency, and joint stiffness. The standard immunosuppressive treatments for cGVHD often have significant cumulative toxicity, but complete remissions are uncommon, emphasizing the old adage that an ounce of prevention is worth a pound of cure.

Therapeutic JAK1/2 blockade by ruxolitinib could be a promising strategy to prevent GVHD. The storyline of ruxolitinib in GVHD started in 2014, focusing on prevention, then moving to mainly therapeutic strategies, and now returning to prevention in the work by DeFilipp and colleagues. As usual in the alloSCT field, the initial work was performed in murine models and showed that inhibition of JAK1/2 signaling suppressed proliferation of effector T cells and proinflammatory cytokine production, resulting in prevention of target-organ acute GVHD (aGVHD).⁴ In the human setting, ruxulitinib was then very successfully developed as GVHD therapy and is now recommended as standard treatment for steroid-refractory aGVHD and chronic GVHD.⁵ To our knowledge, the first solid evidence for ruxolitinib as a drug for GVHD prophylaxis came from a pilot study in alloSCT patients with myelofibrosis, a disease in which ruxolitinib is an approved treatment.⁶ That prospective study evaluated a calcineurin inhibitor–free GVHD prophylaxis regimen of ruxolitinib (before alloSCT and from day +5 to day +100) with posttransplantation cyclophosphamide (PTCy) and found low toxicity and effective control of aGVHD (grades 2 to 4: 25%) as well as cGVHD (no severe cases, moderate at 20%). The same authors presented positive results of a randomized multicenter trial evaluating ruxolitinib and PTCy in unrelated and haploidentical alloSCT at the 2024 EBMT annual meeting.⁷ One hundred twenty-eight adult alloSCT recipients with acute leukemia in complete remission received standard GVHD prophylaxis with PTCy 50 mg/kg on days +3 and +4. They were randomized 1:1 to either tacrolimus and mycophenolate mofetil (control) or ruxolitinib (15 mg/day on days +5 to 21, and 10 mg/day on days 22 to 150, PTCy-ruxolitinib). The study met its primary end point of aGVHD grade 2 to 4 noninferiority (aGVHD incidence 11.4% PTCy-ruxolitinib vs 19.7% control). Of note, the cumulative incidence of nonrelapse mortality in the PTCy-ruxolitinib and control groups was 8.2% vs 23.5% and overall survival 91.8% vs 72.4%, respectively. In addition, reduced incidences of cytomegalovirus reactivation, kidney toxicity, and transplant-associated microangiopathy were observed in the PTCy-ruxolitinib arm.

Another conference report highlighted a multicenter, open-label, 1:1 randomized, phase 3 clinical trial including 206 haploidentical alloSCT recipients at 5 sites in China.⁸ GVHD prophylaxis was performed with PTCy, cyclosporine, and methotrexate. The control group received mycophenolate mofetil, and in the experimental arm ruxolitinib was given at 5 mg twice daily until day +90 (start of taper at day +60). The incidence of grade 2 to 4 aGVHD was significantly lower in the ruxolitinib group (7.8% vs 36.9%). Moderate to severe cGVHD was also significantly lower in the ruxolitinib group (3.3% vs 19.6%).⁸ Additional evidence of the feasibility of ruxolitinib GVHD prophylaxis came from a retrospective study. In 35 alloSCT recipients with aplastic anemia, the addition of ruxolitinib led to a significantly lower incidence of moderate to severe aGVHD as well as lower treatment-related mortality when compared with historic controls.⁹ 

Taken together with prior evidence, this report by DeFilipp et al demonstrates that ruxolitinib has great potential as GVHD prophylaxis and should be investigated in different alloSCT settings. This could be a meaningful step toward addressing the medical need for more effective GVHD prevention.

Conflict-of-interest disclosure: O.P. has received honoraria or travel support from Gilead, Jazz, Merck Sharp & Dohme (MSD), Novartis, Pfizer, and Therakos; research support from Incyte and Priothera; and is a member of the advisory boards of Equillium Bio, Jazz, Gilead, Novartis, MSD, Omeros, Priothera, Sanofi, Shionogi, and Sobi.