Ruxolitinib treatment pre-, during-, and post-transplant for patients with MF

Myelofibrosis (MF) is clonal myeloproliferative disorder characterized by splenomegaly, bone marrow fibrosis, and risk of transformation to acute myeloid leukemia. Patients with intermediate- and high-risk disease benefit more from hematopoietic stem cell transplant (HSCT), while patients with asymptomatic favorable-risk disease are observed and those with symptomatic favorable-risk may be given a JAK 1/2 inhibitor, such as ruxolitinib.

Retrospective studies of ruxolitinib prior to transplantation for intermediate/high risk MF suggest that patients who respond in terms of splenomegaly have improved transplant outcomes.¹ Additionally, ruxolitinib has been approved by the U.S. Food and Drug Administration (FDA)  for posttransplant treatment of graft-versus-host disease (GvHD) in chronic GvHD (cGvHD) and steroid-refractory acute GvHD (aGvHD). A previous phase I study showed peritransplant use of ruxolitinib was safe and well tolerated, producing promising survival rates in patients with MF.² There is variation in practice regarding tapering ruxolitinib prior to HSCT, and a question around the safety and efficacy of ruxolitinib throughout the transplant setting.¹

At the 63rd American Society of Hematology (ASH) Annual Meeting and Exposition, Gabriela Hobbs presented interim data from a phase II study investigating the safety and efficacy of ruxolitinib treatment pre-, during-, and post-HSCT in patients with primary and secondary MF (NCT03427866). We summarize key findings below.¹

Study design

This was a phase II, multi-center, investigator-initiated trial, with ruxolitinib treatment given up to 1-year following HSCT. A summary of the study design is illustrated in figure 1.

Figure 1. Study design*

aGvHD, acute graft versus host disease; cGvHD, chronic graft versus host disease; GRFS, GvHD free and relapse free survival; OS, overall survival, PFS, progression-free survival.
Conditioning consisted of a reduced intensity regimen with fludarabine (30mg/m²/day × 5 days) and melphalan (100mg/m² or 140mg/m² × 1 day). GvHD prophylaxis consisted of methotrexate and tacrolimus.
*Adapted from Hobbs¹

Inclusion criteria for this study included:

• Age ≥18 years
• World Health Organisation (WHO) defined primary or secondary myelofibrosis
• DIPSS+ intermediate-1 (with adverse risk molecular markers) or > int-2

Results

Out of a total of 26 patients enrolled, the majority were male (75%), had DIPSS+ intermediate-2 or high-risk (92%) classification, and half of patients were receiving ruxolitinib before transplant (Table 1).

Table 1. Baseline characteristics (N = 26)*

As expected, the most common mutation present prior to transplant was JAK2 (58%), while 12% of patients carried CALR mutations and 12% carried MPL, and finally 35% of patients carried ASXL1 mutation.

Safety

No unexpected adverse events were reported, and treatment was well tolerated. The most common Grade 3/4 hematologic events were anemia and thrombocytopenia (table 2).

Table 2. Grade 3/4 hematologic adverse events*

Engraftment

Hobbs reported engraftment of [defined as absolute neutrophil count >0.5 × 10⁹] in all but one patient (23/²4) by Day 30, who then went on to achieve engraftment by Day 60. The median time to neutrophil engraftment was 15 days.

Delayed engraftment of platelets was observed, with 14/23 patients achieving engraftment in the first 30 days (defined as 20 × 10⁹ for the first 13 and >10 × 10⁹ for the rest), while a further four patients achieved engraftment by Day 60, and by Day 150, all patients had achieved engraftment.

Survival outcomes

Clinical outcomes posttransplant with ruxolitinib are summarized in Table 3.

In terms of the primary endpoint, 65% of patients were GvHD free and relapse free at 12 months.

Table 3. Clinical outcomes with post-transplant ruxolitinib treatment*

In terms of tolerability, the median number of cycles of ruxolitinib treatment was nine (range, 2–17 cycles), each lasting a month.

Comparison of mutational profile before and after HSCT

Next-generation sequencing was performed before and 100 days post-HSCT. All patients cleared their mutations except for one patient who had detectable JAK2 mutation. However, this patient remained in remission after 1 year.

Conclusion

The interim data from this study provides evidence for the safety of ruxolitinib treatment pre- during and post-HSCT for patients with MF. Notably, PFS, OS, and, GRFS with ruxolitinib treatment were superior to historical observations with minimal incidence of severe aGvHD and cGvHD.  

Hobbs concluded by highlighting next steps which include completing this phase II study, which will include 45 patients, followed by further research into in depth testing of clonal dynamics pre and posttransplant to better understand changes to the mutational profile, and be able to predict relapse to enable timely intervention.