New drugs in myelofibrosis: Critical assessment of additional value to monotherapy with <scp>JAK</scp> inhibitors
Authors: Naseema Gangat, Ayalew Tefferi
Journal: American Journal of Hematology (2024)

Ruxolitinib in combination with navitoclax or pelabresib in myelofibrosis: activity in JAKi-naïve patients. Among the JAK2 mutation-prevalent myeloproliferative neoplasms, myelofibrosis (MF) is prognostically the worst with median survival estimates ranging from less than 2 years to over 10 years, depending on the presence or absence of specific genetic and clinical risk factors.1 Moreover, quality of life (QoL) in MF is severely compromised by progressive anemia, splenomegaly, and constitutional symptoms. At present, the only treatment modality in MF with the potential to cure the disease or prolong survival is allogeneic hematopoietic stem cell transplant.2 On the other hand, current drug therapy, including that with JAK inhibitors (JAKi), has been shown to be effective in improving QoL by way of alleviating constitutional symptoms, reducing spleen size, reversing cachexia, and, in some instances, resulting in resolution of red cell transfusion need.3 Ruxolitinib was the first JAKi to receive the United States Food and Drug Administration (FDA) approval in 2011, followed by approval of three additional JAKi, namely, fedratinib (2019), pacritinib (2022), and momelotinib (2023), the latter two in the context of thrombocytopenia (platelet count <50 × 109/L), and anemia, respectively.4 All four FDA-approved JAKi alleviate splenomegaly and constitutional symptoms, in a dose-dependent and variable fashion. On the other hand, their impact on anemia is less impressive, especially for ruxolitinib and fedratinib, which often result in exacerbation of the condition. The recent approval of momelotinib was facilitated by its favorable erythropoietic effect, which is currently attributed to its inhibitory activity against activin A receptor, type 1 (ACVR1).5, 6 None of the currently available JAKi have been shown to express selective anti-clonal activity by way of major cytogenetic, molecular, or morphologic remissions. Similarly, data on their impact on survival are less than convincing and not enough to warrant their assignment as being disease-modifying.7-9 More recent clinical trials in MF have solicited new agents as monotherapy or in combination with ruxolitinib, with the intent to fill the gap in ongoing unmet needs (Table 1 and Table S1). In the current editorial, we critically review findings from two recently completed phase 3 randomized placebo-controlled studies in MF with pelabresib, an oral bromodomain and extra-terminal domain (BET) inhibitor,10 or navitoclax, an oral bcl-x/bcl-2 inhibitor, in combination with ruxolitinib,11 and provide our perspectives on the evolving treatment landscape in MF. IPSS High 58% Intermediate-2 41% DIPSS-plus High 10% Intermediate-2 83% Intermediate-1 6% DIPSS-plus High 9% Intermediate-2 87% Intermediate-1 4% DIPSS High 5% Intermediate-2 35% Intermediate-1 60% DIPSS High 7% Intermediate-2 34% Intermediate-1 59% 20 mg BID (Plts >200 × 109/L) 15 mg BID (Plts 150–200 × 109/L) Days 1–21 Ruxolitinib 10–15 mg BID (median dose 29.3 mg daily) + Days 1–14 Pelabresib 125 mg QD Days 1–21 Ruxolitinib 10–15 mg BID (median dose 31.3 mg daily) + Days 1–14 Placebo Anemia 96% Grade ≥3 Anemia 45% Thrombocytopenia 70% Grade ≥3 thrombocytopenia 13% Neutropenia 19% Grade ≥3 neutropenia 7% Diarrhea 23% Anemia 60% Grade ≥3 Anemia 46% Thrombocytopenia 90% Grade ≥3 thrombocytopenia 51% Neutropenia 45% Grade ≥3 neutropenia 38% Diarrhea 34% Anemia 49% Grade ≥3 Anemia 39% Thrombocytopenia 50% Grade ≥3 thrombocytopenia 15% Neutropenia 6% Grade ≥3 neutropenia 4% Diarrhea 14% Anemia 44% Grade ≥3 Anemia 23% Thrombocytopenia 32% Grade ≥3 thrombocytopenia 9% Diarrhea 23% Dysgeusia 18% Anemia 56% Grade ≥3 Anemia 38% Thrombocytopenia 23% Grade ≥3 thrombocytopenia 6% Diarrhea 19% Dysgeusia 4% The MANIFEST-2 study was a global phase 3 randomized double-blind study of pelabresib + ruxolitinib (N = 214) versus placebo + ruxolitinib (N = 216), in 430 JAKi-naïve patients with MF; 59% of study patients were intermediate-1 risk by Dynamic International Prognostic Scoring System (DIPSS), 37% harbored high molecular risk mutations, and only 14% were transfusion-dependent, at baseline.10 Treatment consisted of either pelabresib (median daily dose; 108 mg, Days 1–14) + ruxolitinib (median daily dose; 29.3 mg, Days 1–21) or placebo + ruxolitinib (median daily dose; 31.3 mg, Days 1–21). During a median follow-up of 45.4 weeks, treatment discontinuation rates were 27.1% (pelabresib + ruxolitinib) and 25% (placebo + ruxolitinib), mainly due to adverse events in 11% and 7% of patients, respectively. The key findings from the study included a 2-fold higher spleen response rate with pelabresib + ruxolitinib combination therapy; spleen volume reduction ≥35% (SVR35) at Week 24, was achieved in 65.9% of patients treated with pelabresib + ruxolitinib versus 35.2% on placebo + ruxolitinib (p < .001).10 On the other hand, total symptom score improvements of ≥50% (TSS50) at Week 24, did not significantly differ among the treatment arms (52.3%, pelabresib + ruxolitinib, vs. 46.3%, placebo + ruxolitinib) (p = .22).10 Furthermore, anemia response with hemoglobin increase of ≥1.5 g/dL, in the absence of transfusions, was observed in only 9.3% of patients receiving pelabresib + ruxolitinib versus 5.6% on placebo + ruxolitinib.10 In regard to toxicity, ≥grade 3 anemia and thrombocytopenia were documented in 23% and 9% of patients in the pelabresib + ruxolitinib arm, which was akin to hematological toxicities observed in patients on placebo + ruxolitinib.10 Similarly, gastrointestinal adverse events including diarrhea, constipation, and nausea were comparable in the two treatment arms, except for dysgeusia which was more prominent in pelabresib-treated patients (18% vs. 4%).10 Correlative studies demonstrated the reduction of inflammatory cytokines and modest improvements in bone marrow fibrosis (≥grade 1 fibrosis; 39% vs. 24%) with pelabresib + ruxolitinib compared to placebo + ruxolitinib.10 In another phase 3 trial (TRANSFORM-1), navitoclax + ruxolitinib was compared to placebo + ruxolitinib, in 252 JAKi naïve patients with MF; the majority (85%) of patients were classified as DIPSS-plus intermediate-2 risk and only nine (3.5%) patients were transfusion-dependent at study entry.11 Treatment schedule included navitoclax 100/200 mg once daily with ruxolitinib 15 or 20 mg twice daily based on platelet count. At a median follow-up of 14.9 months, one-third of the study patients discontinued treatment, primarily due to adverse events in 14% and 11% of patients in the navitoclax/ruxolitinib versus placebo/ruxolitinib treatment arms, respectively.11 Similar to the MANIFEST-2 trial, spleen response rate (SVR35 at Week 24) was significantly higher with navitoclax/ruxolitinib versus placebo/ruxolitinib (63.2% vs. 31.5%; p < .0001), however, symptom response was not significantly different in the two treatment arms (TSS50 reduction; 39.2% vs. 41.7%).11 Importantly, incidence of ≥grade 3 thrombocytopenia (51% vs. 15%) and neutropenia (38% vs. 4%) was markedly higher with navitoclax/ruxolitinib compared to placebo/ruxolitinib.11 Not surprisingly, adverse events, mainly thrombocytopenia, led to ruxolitinib dose reductions or interruptions in 90% and 63% of patients in the navitoclax arm.11 Table 1 provides a comparative assessment of efficacy and toxicity data from the MANIFEST-2 and TRANSFORM-1 studies and also includes information on the ruxolitinib arm of the COMFORT-1 study (ruxolitinib vs. placebo),12 as a reference. The MANIFEST-2 and TRANSFORM-1 studies suggest significant enhancement of spleen response by combining navitoclax or pelabreseib with ruxolitinib but also raise a number of questions regarding study design on selection of study patients and endpoints. The key question is whether or not pelabresib or navitoclax will conjure additional therapeutic value, without added toxicity, to what is already achievable with currently available JAKi. In this regard, it is to be recalled that momelotinib (another JAKi) was recently added to the treatment armamentarium for MF and is known to provide erythropoietic effect, in addition to the JAKi class-wide effect on spleen and constitutional symptoms.4 Neither pelabresib nor navitoclax, each combined with ruxolitinib, was shown to improve anemia or outperform ruxolitinib monotherapy, in terms of constitutional symptoms (Table 1). Furthermore, both drugs, in combination with ruxolitinib, were associated with a higher prevalence of severe thrombocytopenia, which was most apparent for navitoclax, which was also associated with grade ≥3 neutropenia (38% vs. 7% with ruxolitinib monotherapy; Table 1). Grade ≥3 anemia was observed in 46% of patients treated with navitoclax + ruxolitinib and 23% of those treated with pelabresib + ruxolitinib, which is noteworthy, considering the fact that only a minority of study patients in both clinical trials were transfusion dependant at study entry (4% navitoclax and 16% pelabresib; Table 1). The difficulty in tolerating these drug combinations is also reflected by the relatively high discontinuation rates after a median follow-up of only 11.3–14.9 months (25%–35%; Table 1). Other issues of concern regarding the aforementioned phase-3 studies, from our standpoint, include the fact that (i) only a minority of high-risk and transfusion-dependent patients were enrolled in the MANIFEST-2 and TRANSFORM-1 studies, which limits comparison across prior phase 3 studies involving JAKi and (ii) relatively lower doses of ruxolitinib were used in both the active and comparator arms of both studies. In other words, it is reasonable to assume higher response rates might have occurred with higher doses of ruxolitinib monotherapy, if one were to justify the associated higher degree of myelosuppression. The fact that ruxolitinib dose matters was recently exemplified by a real-world study that showed no additional benefit from treatment with fedratinib in patients failing adequately dosed ruxolitinib therapy.13 Both MANIFEST-2 and TRANSFORM-1 trials were focused primarily on spleen response.10, 11 However, we are not convinced that additional spleen response, over and above that is achievable with optimal, toxicity-adjusted dosing of currently available JAKi, represents an ongoing unmet need in MF. Furthermore, given the relatively short follow-up duration (~1 year), and nontrivial discontinuation rates in both studies, the durability of spleen response is not guaranteed and remains to be determined. In other words, we would have been more impressed with anti-clonal treatment activity, improvement in anemia, or dual spleen/symptoms advantage without additional toxicity than is expected from monotherapy with ruxolitinib. None of these goals were achieved in either the MANIFEST-2 or TRANSFORM-1 study. Unfortunately, disease-modifying activity appears to also elude other new drugs in MF currently under investigation, which are also spleen-directed with limited anemia benefit (Table S1); the latter include inhibitors of PIM1 kinase (TP-3654),14 nuclear export (selinexor + ruxolitinib),15 lysine-specific demethylase-1 (LSD) (bomedemstat + ruxolitinib),16 and BET (BMS-986158 + ruxolitinib/fedratinib and INCB057643 ± ruxolitinib).17, 18 On the other hand, preliminary data are encouraging regarding a few investigational agents with potential to ameliorate anemia, including luspatercept (transforming growth factor-beta ligand trap),19 zilurgisertib (ACVR1 inhibitor),20 and DISC-0974 (anti-hemojuvelin antibody).21 Taken together, the ruxolitinib add-on value derived from pelabresib or navitoclax, in terms of spleen response, does not appear to be coupled with additional value in symptom response and might come at a cost of hematological and other toxicities, particularly in navitoclax treated patients. Patients with suboptimal spleen response to a specific JAKi might be better served by dose escalation or switching to an alternative JAKi with more potent spleen effect, such as fedratinib.1, 22 Furthermore, for MF patients with anemia, momelotinib might be the first-line JAKi of choice, given its ability to induce anemia, spleen, and symptom response.3, 4 Accordingly, it is currently difficult to construct a scenario where combination therapy with pelabresib or navitoclax might be preferable to JAKi monotherapy. NG and AT co-wrote the paper. The authors declare no conflicts of interest. Data available by email to the corresponding author. Table S1. Summary of investigational agents in phase 1/2 clinical trials in myelofibrosis. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.