Outcomes of Allogeneic Hematopoietic Cell Transplantation in Patients with Myelofibrosis with Prior Exposure to Janus Kinase 1/2 Inhibitors

Abstract

The impact of JAK1/2 inhibitor therapy prior to allogeneic hematopoietic cell transplantation (HCT) has not been studied in a large cohort in myelofibrosis (MF). In this retrospective multicenter study, we analyzed outcomes of patients who underwent HCT for MF with prior exposure to JAK1/2 inhibitors. One hundred consecutive patients from participating centers were analyzed, and based on clinical status and response to JAK1/2 inhibitors at the time of HCT, patients were stratified into five groups: (a) clinical improvement (n=23), (b) stable disease (n=31), (c) new cytopenia/increasing blasts/intolerance (n=15), (d) progressive disease: splenomegaly (n=18), and (e) progressive disease: leukemic transformation (LT) (n=13). Overall survival (OS) at two years was 61% (95%CI, 49–71). This was 91% (95% CI, 69–98) for those who experienced clinical improvement, and 32% (95% CI, 8–59) for those who developed LT on JAK1/2 inhibitors. In multivariable analysis, response to JAK1/2 inhibitors (p=0.03), DIPSS score (p=0.003), and donor type (p=0.006) were independent predictors of survival. Among the 66 patients who remained on JAK1/2 inhibitors until stopped for HCT, two patients developed serious adverse events necessitating delaying of HCT, and another 8 patients had symptoms with lesser severity. Adverse events were more common in patients who started tapering or abruptly stopped their regular dose ≥6 days prior to conditioning therapy. We conclude that prior exposure to JAK1/2 inhibitors did not adversely affect post-transplant outcomes. Our data suggest that JAK1/2 inhibitors should be continued near to the start of conditioning therapy. The favorable outcomes of patients who experienced clinical improvement with JAK1/2 inhibitor therapy prior to HCT were particularly encouraging, and need further prospective validation.

JAK2 inhibitors for myeloproliferative neoplasms: what is next?

“…157,158 Although the timing of allo-HCT in patients receiving ruxolitinib is not known with certainty, retrospective studies suggest that prior ruxolitinib therapy does not compromise allo-HCT outcomes and that the drug should be continued almost up until the time of conditioning. 159 A plethora of other targeted agents are being studied in MPNs, mostly in MF, both alone and in combination with ruxolitinib. Thus far, some of the combinations have been more promising than others, but in general, both insufficient activity (over that expected with ruxolitinib alone) and additive or overlapping toxicity are of concern.…”

Myelofibrosis: to transplant or not to transplant?

“…In the largest retrospective study so far on the use of JAK 1/2 inhibitors in HCT for MF, 38 higher survival (91% vs 56%) and lower NRM were observed in patients who had clinical improvement on JAK inhibitor therapy at the time of HCT (n 5 23) compared with those who had either stable disease or developed clinical issues such as significant cytopenenias, increasing blasts, or loss of response to JAK inhibitor therapy at HCT. It is not possible to discern whether JAK inhibitor therapy influences HCT outcomes directly through clinical improvement, or indirectly by identifying patients with clinical improvement as those with favorable disease biology.…”

“…37 However, importantly several studies have found no significant difference in outcomes between MSDs and wellmatched URDs. 17,34,38 The availability of an MSD or well-matched URD may prompt earlier consideration for HCT in a patient. Conversely, HCT may be delayed for patients without an MSD or well-matched URD, and may be more appropriate for patients who have failed nontransplant therapies, are unlikely to do well with JAK 1/2 inhibitor therapy (Table 1), or are at higher risk of LT.…”

“…36,38,[41][42][43][44][45][46] The key questions have been how to best integrate JAK inhibitor therapy into HCT protocols prior to transplant and whether there is any role in the posttransplant setting.…”

Hematopoietic stem cell transplantation and other therapeutic options in primary myelofibrosis: a review and two case reports

“…Recently Shanavas et al has reported results of large multicenter retrospective study, which tested efficacy of pretransplant JAK1/2 inhibitors therapy [35]. 100 patients with MF who undergo alloHSCT after JAK1/2 inhibitors therapy were included in this study.…”