The impact of JAK inhibitor use on HSCT outcome in patients with MPN

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potential curative option for patients with myeloproliferative neoplasms (MPN), which acts through donor T-cell mediated clearance of malignant host cells and modulation of the inflammatory processes in the bone marrow microenvironment. However, graft-versus-host disease (GvHD) and engraftment failure are common and potentially lethal complications of allo-HSCT in these patients.

Activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is crucially involved in the development of MPN but is also positioned centrally in a myriad of inflammatory pathways which are initiated and maintained in GvHD. Not surprisingly, JAKs have been targeted therapeutically, and the JAK inhibitor ruxolitinib is approved both for the treatment of MPN and steroid-refractory acute GvHD, however its role in GvHD prophylaxis is not well understood.¹

Barabanshikova and colleagues analyzed outcomes of patients with MPN undergoing allo-HSCT with or without prior JAK inhibitor treatment and recently presented their work at the 46^th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT).²

Study design and patient characteristics²

This retrospective study included 54 patients with MPN with a median age of 49 years (range, 20–61). Of these, 27 patients who had received JAK inhibitor therapy for their underlying disease for 7 months prior to transplantation (myelofibrosis, MF+ group) were compared to 27 patients not treated with JAK targeted therapy (MPN– group). In 25 patients in the MF+ group, ruxolitinib was administered at 30–45 mg daily until D–1. Table 1 indicates the GvHD prophylaxis treatment schedules for the two groups.

Allo-HSCT was performed using granulocyte colony-stimulating factor mobilized peripheral blood progenitor cells (n = 43) or bone marrow (n = 11) from the following donors:

• Unrelated n = 37
• Related n = 10
• Haploidentical n = 7

The median number of CD34+ cells/kg transferred was 6.4 x 10⁹ (range, 1.4–11.9).

In 20 patients, ruxolitinib concentration from peripheral blood was analyzed at D0, D+7, D+14, D+21, D+30, D+60, and D+100.

Table 1. JAK inhibitor use and GvHD prophylaxis treatment schedule²

Results²

The median follow-up in this study was 32 months (range, 2–126) with primary engraftment documented in 77% of patients. Graft failure was more common in the MPN– group, although this result did not achieve significance. Ruxolitinib concentrations were found to accumulate from Day 7 to Day 14 before stabilizing. There were five deaths in the MF+ group due to infection (n = 4) and hemorrhage (n = 1). Although the incidence of both acute and chronic GvHD were higher in the MPN– group, the results did not achieve significance. However, both 3-year overall survival and progression-free survival were significantly higher in MF+ patients. See Table 2 for the patient outcomes in this study.

Table 2. Post-allo-HSCT patient outcomes²

Case studies³

In another EBMT poster presentation, Sami Brake discussed three cases of patients with myelofibrosis undergoing allo-HSCT who received ruxolitinib 6 months prior to transplant, ceasing 2 weeks before the procedure.

All three patients had splenomegaly and pancytopenia following engraftment and required frequent transfusions of donor blood products. Despite well-matched donor profiles and appropriate prophylaxis, all three patients experienced severe Grade 4 steroid-refractory GvHD, which responded well to ruxolitinib re-initiation. The authors postulate that the rapid onset of severe GvHD around 109–140 days post cessation of ruxolitinib was due to the lack of JAK-STAT signaling inhibition, potentially leading to increased proliferation and activation of immune cells and higher production of proinflammatory cytokines.

Conclusion

Results from both clinical trials and case studies indicate that the continuous use of JAK1/JAK2 inhibitors in the pre- and posttransplant period could improve the outcome of allo-HSCT and may reduce the risk of GvHD in patients with MPN. Promising results with ruxolitinib as GvHD prophylaxis in patients with MPN have also been reported from another study, and a phase II study comparing posttransplant cyclophosphamide (PTCy) + ruxolitinib with PTCy + tacrolimus + mycophenolate mofetil in patients with acute leukemia is underway.