Ruben A. Mesa, MD
In September 2019, Dr. Claire Harrison and colleagues, myself among them, presented two new analyses regarding the use of the JAK2 and FLT3 inhibitor fedratinib in myelofibrosis at the Society of Hematologic Oncology (SOHO) Annual Meeting, with resulting publication in Clinical Lymphoma, Myeloma & Leukemia.1,2 The two analyses were nicely summarized in the October 10, 2019, issue of The ASCO Post. The first assessed responses to fedratinib in patients with low baseline platelet counts (between 50 and 100 x 109/L), and the second is a modern reanalysis of the JAKARTA2 study efficacy by current standards of assessing ruxolitinib failure.
The timeliness of these two reports was significant, given the U.S. Food and Drug Administration approval of fedratinib days before. This approval is significant in that although fedratinib had a positive phase III trial in myelofibrosis compared with placebo (JAKARTA study3) and a positive phase II study in second-line treatment (ruxolitinib failures in JAKARTA24), the discovery of a low incidence of central nervous system (CNS) toxicity (< 1%) led to a clinical hold and a long period of the agent being in development limbo. The lack of other approved options for myelofibrosis led to a further analysis of CNS toxicity to clarify a pathway for fedratinib’s FDA approval with certain precautions (thiamine supplementation, monitoring for Wernicke’s encephalopathy). Given the lengthy interval between the JAKARTA and JAKARTA2 studies, understanding the relevance of these reports requires some reflection of our current state of options for myelofibrosis and how the treatment landscape evolved during this interval.
The JAK1/2 inhibitor ruxolitinib has become the clear standard of care for patients with intermediate- and high-risk myelofibrosis on the basis of the positive randomized phase III trials of COMFORT-I (ruxolitinib vs placebo) and COMFORT-II (ruxolitinib vs best alternative therapy). Both of these studies demonstrated a clear benefit in improvement of myelofibrosis-associated symptoms (ie, splenomegaly) and likely survival, with multiple corresponding studies and analyses validating these observations. Ruxolitinib had become the clear standard in most international guidelines, including the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for those myelofibrosis patients not felt to be better treated with stem cell transplantation.
Prior to the approval of fedratinib, the solitary availability of ruxolitinib was very helpful, yet gaps existed especially among patients with myelofibrosis who failed to respond to ruxolitinib (due to intolerance, resistance, or disease progression) or patients with marked thrombocytopenia (ruxolitinib is not approved for patients with platelet counts < 50 x 109/L and is frequently modestly dosed in those with platelet counts between 50 and 100 x 109/L). It is precisely in these two areas of therapeutic gaps that the studies by Harrison et al looked to provide further insight regarding the benefits of fedratinib.
Myelofibrosis With Baseline Moderate Thrombocytopenia
JAK inhibitors, with the possible exception of the still investigational pacritinib, have tended to lead to thrombocytopenia due to the on-target impact of inhibition of JAK2. The updated analysis of the JAKARTA and JAKARTA2 studies by Harrison et al is relevant because patients with myelofibrosis who have baseline platelet counts between 50 and 100 x 109/L still remain a challenging group. Ruxolitinib is approved in this group, but it is frequently dosed modestly and perhaps has suboptimal efficacy.
The reported results by Harrison et al were that efficacy and safety (according to adverse events) were comparable in patients with modest thrombocytopenia (50–100 x 109/L) and that dosing intensity could be preserved. Although there are no randomized data comparing fedratinib and ruxolitinib in patients with modest thrombocytopenia, these findings at least raise the consideration of fedratinib in this group as front-line therapy (as both agents have nearly identical front-line indications).
Second-Line Therapy for Myelofibrosis
“Patients with myelofibrosis who have baseline platelet counts between 50 and 100 × 109/L still remain a challenging group.”— Ruben A. Mesa, MD
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The approval of fedratinib created a second approved therapeutic option for myelofibrosis, in the same class of therapy (JAK inhibitor) and with nearly an identical indication. This latter situation is common in our field (azacitidine and decitabine for myelodysplastic syndromes; nilotinib and dasatinib for chronic myeloid leukemia), however rarely with the long lag period between approval of the two agents as we had here (almost 8 years). The dynamic among ruxolitinib-treated patients in the United States is that there are two groups—the first is doing well and responding to ruxolitinib, and the second is still on ruxolitinib but with a suboptimal response or toxicity. When we add the patients who have already come off ruxolitinib to the latter group, we have a reasonably sized population of patients with inadequate therapy for myelofibrosis who fail to respond to ruxolitinib.
The natural question for this latter group is whether to switch them to fedratinib. Harrison and colleagues’ second presentation at the SOHO meeting sought to answer this question with the only data available, from the JAKARTA2 trial. Two things impacted the application of the initial JAKARTA2 data to patients in 2019. The first centers on the question of what constitutes ruxolitinib failure (more lenient in the era of JAKARTA2 and more stringent in 2019). The second is the trial concluded prematurely due to the clinical hold (limiting our understanding of the durability of second-line therapy, long-term toxicity, and efficacy data).
Thus, Harrison et al reanalyzed JAKARTA2, applied stringent 2019 ruxolitinib failure criteria, and then assessed a cohort that received a sufficient duration of therapy (ie, not curtailed by the clinical hold) to assess safety and efficacy. Given those conditions, they reported that a solid one-third of patients with myelofibrosis responded to second-line fedratinib therapy, as assessed by spleen volume response. These results are significant, given the lack of other available treatment options as well as the published poor outcomes and survival of patients who have failed to respond to ruxolitinib.
Closing Thoughts
This pair of reports helps bring some modern context to the consideration of fedratinib in patients with myelofibrosis who have thrombocytopenia and in second-line treatment for those who fail to respond to ruxolitinib. Although treatment guidelines have not yet been updated in myelofibrosis to include fedratinib, undoubtedly both of these situations will be listed among considerations to be contemplated (along with appropriate clinical trials or salvage stem cell transplantation in appropriate candidates).
Dr. Mesa is Director, Mays Cancer Center at UT Health San Antonio MD Anderson Cancer Center, San Antonio, Texas. He was the senior author of the two abstracts featured in Clinical Lymphoma, Myeloma and Leukemia, presented at the 2019 Society of Hematologic Oncology Meeting, and reviewed in the October 10 issue of The ASCO Post.
DISCLOSURE: Dr. Mesa has had a consulting or advisory role with Novartis, Sierra Oncology, and La Jolla Pharmaceutical and has received research funding from Celgene, Incyte, AbbVie, Samus, Genotech, Promedior, and CTI BioPharma.
REFERENCES
1. Harrison C, Schaap N, Vannucchi A, et al: Fedratinib induces spleen responses and reduces symptom burden as first-line or salvage therapy in patients with myeloproliferative neoplasm-associated intermediate- or high-risk myelofibrosis and low platelet counts. Clinical Lymphoma, Myeloma & Leukemia 19(suppl 1):S355, 2019. Abstract MPN-352.
2. Harrison C, Schaap N, Vannucchi A, et al: Fedratinib induces spleen responses in patients with myeloproliferative neoplasm-associated intermediate- or high-risk myelofibrosis resistant or intolerant to ruxolitinib: An updated analysis of the phase II JAKARTA2 study. Clinical Lymphoma, Myeloma & Leukemia 19(suppl 1):S356, 2019. Abstract MPN-353.
3. Pardanani A, Harrison C, Cortes JE, et al: Safety and efficacy of fedratinib in patients with primary or secondary myelofibrosis: A randomized clinical trial. JAMA Oncol 1:643-651, 2015.
4. Harrison CN, Schaap N, Vannucchi AM, et al: Janus kinase-2 inhibitor fedratinib in patients with myelofibrosis previously treated with ruxolitinib (JAKARTA-2). Lancet Haematol 4:e317-e324, 2017.
