Since its FDA approval in 2011, the Janus kinase 1/2 (JAK 1/2) inhibitor ruxolitinib has become a routine treatment for myelofibrosis, a type of myeloproliferative neoplasm.
However, allogeneic hematopoietic stem cell transplant (SCT) remains the only treatment with curative potential. Unfortunately, only a small number of patients are eligible for this approach due to the advanced age of many patients with this disease.
"The development of reduced intensity conditioning regimens with limited toxicity has allowed clinicians to offer allogeneic hematopoietic stem cell transplant to a growing number of older patients," Gupta, et al, wrote. "The availability of JAK 1/2 inhibitors allows clinicians to provide symptom relief and improved quality of life of myelofibrosis patients" (Biol Blood Marrow Transplant 2014;20(9):1274-1281).
Given the growing utilization of JAK 1/2 inhibitors for myelofibrosis treatment and the impact these agents could have on decisions regarding the timing of allogeneic hematopoietic stem cell transplant, further research is needed on JAK 1/2 inhibitors and their effect on outcomes after SCT. "The identification of indications for the use of JAK1/2 inhibitors in the context of transplantation may lead to new therapeutic strategies for patients with myelofibrosis," noted Gupta et al.
Previous Research
In one study, researchers investigated early outcomes after allogeneic SCT in 22 patients with myelofibrosis who received ruxolitinib prior to transplantation in order to reduce spleen size and constitutional symptoms (Blood 2013;122:392).
"At time of transplantation 86 percent had improvement of constitutional symptoms and 45 percent had major response (>50% palpable) of spleen size, 28 percent had response of spleen size which was less than 50 percent, and 27 percent had no response or progressive spleen size after ruxolitinib treatment," investigators reported.
The research team concluded that, "ruxolitinib reduces spleen size and constitutional symptoms in the majority of patients before allogeneic stem cell transplantation. Discontinuation of ruxolitinib at start of conditioning did not induce rebound phenomenon and did not negatively impact engraftment after transplantation. Longer follow-up is needed to determine late outcome."
Another study also took a closer look at the outcomes of allogeneic hematopoietic cell transplantation among this patient population following treatment with a JAK 1/2 inhibitor (Biol Blood Marrow Transplant 2016;22(3):432-440). The data showed that overall survival at 2 years was 61 percent.
"Among the 66 patients who remained on JAK 1/2 inhibitors until stopped for allogeneic hematopoietic cell transplantation, two patients developed serious adverse events necessitating delay of [stem cell transplantation] and another eight patients had symptoms with lesser severity," the researchers reported. "Adverse events were more common in patients who started tapering or abruptly stopped their regular dose >=6 days before conditioning therapy."
The investigators concluded that "prior exposure to JAK1/2 inhibitors did not adversely affect post-transplantation outcomes. The favorable outcomes of patients who experienced clinical improvement with JAK1/2 inhibitor therapy before hematopoietic cell transplantation were particularly encouraging, and need further prospective validation."
"While a survival benefit has been observed in some trials with the use of JAK1/2 inhibitors, these survival benefit data must be confirmed in long-term follow-up studies and across the class of these drugs," according to Gupta, et al.
Study Methodology
Early data has been mixed and the number of studies comparing patients who received JAK 1/2 inhibitors to those who did not at the same centers is limited, according to researchers who conducted a recent study that aimed to fill this void (J Clin Oncol 36, 2018 (suppl; abstr 7072)).
With this goal in mind, the research team conducted a retrospective analysis of patients who underwent SCT for primary or secondary myelofibrosis to assess the impact of receiving pre-SCT JAK 1/2 inhibitors on outcomes, specifically overall survival (OS), progression-free survival (PFS), and GVHD-free and relapse-free survival (GRFS).
Investigators identified 132 myelofibrosis patients who received allogeneic SCT between 2004 and 2017 at Massachusetts General Hospital or Dana-Farber Cancer Institute. Eighty-three (63%) did not receive JAK 1/2 inhibitors and 49 (37%) did receive them.
Eligible patients were those with primary or secondary myelofibrosis. The study included patients "who were staged at DIPSS plus intermediate-1, intermediate-2, and high-risk prior to SCT," according to study authors. Due to small sample size, five low-risk patients were excluded.
The research team fit Cox proportional hazard regressions to estimate the association between the use of pre-SCT JAK 1/2 inhibitors and OS, PFS, and GRFS after SCT, adjusting for baseline ECOG performance status, conditioning intensity, and DIPSS status.
Key Findings
In the overall analysis, data showed an increased 4-year OS among patients who received JAK 1/2 inhibitors (69% vs. 43%) as well as increased 4-year PFS (67% vs. 44%); however, there was not in 8-month GRFS in unadjusted models.
Researchers reported a stronger survival effect in the intermediate subgroups (OS 75% vs. 42%; PFS 72% vs 44%) compared to the high-risk cohort (OS 48% vs. 46%; PFS 51% vs. 46%).
"In models adjusted for baseline ECOG performance status, conditioning regimen intensity, and DIPPS status, the use of JAK 1/2 inhibitors prior to SCT was associated with a marginally-significant improvement in PFS [hazard ratio (HR)=0.54, 95% CI 0.27-1.07, p=.075] and OS [HR=0.53, 95% CI 0.26-1.07, p=.077], and was not associated with an improvement in GRFS [HR=0.77, CI 0.49-1.23, p=.28]," according to the researchers.
Conclusions, Next Steps
The data suggests that utilizing JAK 1/2 inhibitors may slightly improve survival outcomes, but do not improve rates of GVHD development for patients with myelofibrosis who undergo SCT, researchers reported.
"Interestingly, the most benefit from JAK 1/2 inhibitors was seen in intermediate risk groups and not the high risk group," study authors concluded. "However, further investigation with a larger sample size is needed to better understand the effect of JAK 1/2 inhibitor use on patient outcomes after SCT and how the effect differs according to risk group."
The research team noted that future investigation should also focus on the use of post-SCT JAK 1/2 inhibitors given their exhibited activity for GVHD.
Catlin Nalley is associate editor.