Clinical Effectiveness and Safety of Momelotinib Compared with Continued Ruxolitinib or Best Available Therapy in Patients with Myelofibrosis Who Required RBC Transfusions: Subgroup Analysis of the Phase 3 Simplify-2 Study
Authors: Harrison Claire N , Vannucchi Alessandro Maria , Recher Christian , Passamonti Francesco , Gerds Aaron T. , Hernandez Boluda Juan Carlos , Yacoub Abdulraheem , Sirhan Shireen , Kawashima Jun , Patel Bharat , Strouse Bryan , Platzbecker Uwe 
Published: December 2023

Introduction:
Splenomegaly, constitutional symptoms, and anemia are key clinical features of myelofibrosis (MF); approximately one-third of patients (pts) are anemic at diagnosis, and most develop anemia over time. While Janus kinase (JAK) inhibitors such as ruxolitinib (RUX) and fedratinib (FED) may address symptoms and splenomegaly, they do not manage and may exacerbate anemia. Treatments for anemia include erythropoiesis-stimulating agents (ESAs), often in combination with RUX or FED, and androgens such as danazol; however, these have shown limited efficacy. Red blood cell (RBC) transfusions are the mainstay of anemia management in MF, but transfusion dependency is associated with diminished quality of life and is a negative prognostic factor for survival. Treatments that address anemia as well as spleen volume and symptoms are needed.
Momelotinib (MMB), a JAK1/JAK2/activin A receptor type 1 inhibitor, has demonstrated clinically meaningful and durable improvements in anemia, splenomegaly, and symptoms in pts with MF across 3 phase 3 trials. To evaluate outcomes in pts who switched to MMB vs continuing RUX or best available therapy (BAT) despite transfusion requirement, we present a descriptive subgroup analysis of pts enrolled in SIMPLIFY-2 (NCT02101268) who were considered transfusion dependent (TD; ≥4 units of RBC transfusions in the previous 8 wk or hemoglobin [Hb] level &lt;8 g/dL) or transfusion requiring (TR; receiving transfusions but not meeting TD criteria) at baseline (BL).
Methods:
SIMPLIFY-2 was an international, multicenter, open-label, phase 3 clinical trial investigating the efficacy and safety of MMB vs BAT in pts with MF who had suboptimal responses or hematologic toxicities while receiving RUX. Pts (N=156) were randomized 2:1 to receive open-label MMB or BAT, which was RUX in 88.5% of pts. Treatment washout from prior RUX was not permitted before study enrollment. The primary endpoint was spleen volume reduction ≥35% (SVR35). Total Symptom Score (TSS) response rate (≥50% reduction; TSS50) and transfusion independence response (TI-R; no RBC transfusions for ≥12 wk immediately before the end of wk 24, with all Hb levels ≥8 g/dL) were key secondary endpoints. This post hoc, descriptive analysis focused on pts treated with either MMB or BAT, who were considered non-transfusion-independent (non-TI), defined as either TD or TR, at BL.
Results:
In SIMPLIFY-2, 72 of 104 pts (69%) in the MMB arm and 33 of 52 pts (63%) in the BAT arm were non-TI at BL, and BL characteristics were balanced between both patient groups. Mean duration of prior treatment with RUX was 64.6 and 59.5 wk in non-TI pts in the MMB and RUX arms, respectively. Average BL TSS for this subpopulation was 18.6. All pts randomized to the MMB arm received a starting dose of 200 mg daily. In the BAT arm, 29 of 33 pts (88%) were treated with RUX, with 59% receiving a BL dose of ≤20 mg daily. ESAs were administered to 5 pts in the BAT arm.
At wk 24, SVR35 was observed in 7 of 72 pts (10%) treated with MMB and 1 of 33 pts (3%) treated with BAT. TSS50 was achieved in 21 of 72 pts (29%) treated with MMB, but there were no responses in the BAT arm. Additionally, TI-R was achieved in 25 of 72 pts (35%) treated with MMB compared with only 1 of 33 (3%) treated in the BAT arm on RUX. Many responders with MMB achieved 2 or all 3 endpoints (16 of 36 responders [44%]) (Figure); there were no dual or triple responses in the BAT arm. Of the 5 pts in the BAT arm who received ESAs, only 1 pt each (different pts per response) achieved SVR35, TSS50, or TI. Safety outcomes were consistent with those previously reported for the intent-to-treat (ITT) population.
Conclusions:
In RUX/BAT-treated pts with MF who required RBC transfusions, continued treatment with RUX/BAT in most pts resulted in poor treatment outcomes compared with MMB. Specifically, treatment with MMB demonstrated an ability to deliver higher SVR, TI, and TSS response rates. The lower SVR35 rate in both arms, similar to the overall ITT population, was likely a result of lack of washout from prior JAK inhibitor treatment. While pt numbers were limited, similar findings were observed compared with pts who received ESAs. Overall, these data support MMB as a potential alternative treatment option for pts with MF who require RBC transfusions.
Figure. Responses at Week 24 for Non-TI Patients at Baseline