Comparison of clinical outcomes between transplant and nontransplant therapies in myelofibrosis following failure of first‐line JAK‐inhibitor

To the Editor: Following Food and Drug Administration (FDA) approval of ruxolitinib in 2011, medical management of symptomatic MF with JAK-inhibitor (JAKi) therapy has become the standard of care. JAKi therapy does not have clear impact on modifying disease course or improving survival and clinical benefit is variable with most patients experiencing JAKi therapy failure by 3 years with subsequent poor survival of 11–16 months. Reasons for JAKi failure are varied, with proposed Canadian MPN Group criteria serving as a guide to classify the pattern of failure. The FDA approval of additional JAKi, fedratinib and pacritinib, along with the development of novel therapies has broadened the available options; but it is not clear if second-line therapies have improved the poor prognosis. At our center, our approach has been to consider the option of allogeneic hematopoetic cell transplantation (HCT) in all eligible patients with failure of first-line JAKi therapy in a shared-decision model. There is limited information on efficacy of HCT in comparison to nontransplant therapies in patients following first-line JAKi therapy failure. A prior study based on a small number of patients following ruxolitinib discontinuation suggested improved survival in patients undergoing HCT, though did not adjust for confounding factors that determine fitness for transplant. To address this knowledge gap, we sought to compare outcomes in transplant-eligible patients with MF between those who underwent HCT and patients managed with best available nontransplant therapies (BAT) following first-line JAKi therapy failure. We conducted a retrospective review of patients with MF from a prospective MPN registry (NCT02760238) treated at the Princess Margaret Cancer Centre in Toronto, Canada between January 1, 2011 and February 28, 2022. Patients were included if they had a diagnosis of chronic phase Primary (overt or prefibrotic), (MF) or MF following previous diagnosis of essential thrombocythemia or polycythemia vera and experienced first-line JAKi failure as per definitions from the Canadian MPN Group (Table S1). Patients were excluded from study if they had progressed to an accelerated (10%–19% peripheral/bone marrow blasts) or blast phase (≥20% blasts) or were not candidates for HCT (Table S2). Patients for whom a hematopoietic cell donor was not found or declined HCT based on preference but were otherwise medically fit for transplant were included in the best-available therapy (BAT) group. Baseline clinical and laboratory data at the time of JAKi failure were collected. We used the age-adjusted Dynamic International Prognostic Scoring System (aaDIPSS) to better estimate disease-related risk given the younger age of the study cohort. Patients were analyzed with an intention-to-treat basis according to the main second-line therapy received: either HCT or BAT. The HCT group included patients who received bridging therapy (second-line JAKi or splenectomy) with the intent of optimization prior to HCT. The BAT group included patients who received second-line therapy with alternative JAKi or clinical trial novel agent (alone or in combination with JAKi); or best supportive care with hydroxyurea, transfusion support, danazol, growth factors (recombinant erythropoietin), splenectomy, or continuation of first line JAKi. The primary outcomes of interest were overall survival (OS) from time of JAKi failure to last follow-up or death. A key secondary outcome is transformation-free survival (TFS) defined as the time from JAKi therapy failure to last follow-up, death, or transformation AP/BP. Statistical methods are described in the Appendix A. Of the 641 patients with MF in our database, 323 (50.4%) were treated with first-line JAKi and 122 under the age of 70 years met the definition of JAKi therapy failure. Of these patients, 88 patients met the study eligibility criteria (Figure S1), and outcomes were compared between the HCT (n = 41), and BAT (n = 47) groups. Baseline variables are described in Table S3. The median [range] follow-up from time of JAKi failure in survivors was 39 [6–126] months. Of the 47 patients who received BAT, 38 (81%) patents had donor searches initiated and 35 had a donor identified. Second line treatments in the BAT arm were: fedratinib (n = 7), momelotinib (n = 6), ruxolitinib (n = 3), pacritinib (n = 3), investigational agent added to ruxolitinib (n = 3), continuation of first-line JAKi (n = 18), splenectomy (n = 6), and splenic radiation (n = 1). Two patients in the BAT group underwent salvage HCT following failure of second-line treatment. In the HCT group, 8 (20%) patients received second-line bridging treatment prior to HCT: fedratinib (n = 4), ruxolitinib after first-line momelotinib (n = 2), and splenectomy (n = 2). Compared to the BAT cohort, the HCT cohort was younger, had smaller median palpable spleen size, less frequent constitutional symptoms, and higher proportion of low/int-1 aaDIPSS. There were no observed significant differences in blood counts, peripheral blasts, [Correction added on March 30, 2023, after first online publication: The copyright line was changed. ] Received: 6 December 2022 Revised: 15 February 2023 Accepted: 20 February 2023