Transfusion independence and improvements in symptoms and splenomegaly in two patients with PMF and anaemia treated with a JAK inhibitor

Case 1: A JAK inhibitor– naïve patient with PMF
History and presentation
A 52-year-old female presented with leukocytosis and thrombocyto­sis, and was diagnosed with primary myelofibrosis (PMF) in 2019. She had no significant past medical history and no anaemia at initial diagnosis. Molecular testing identified a type 2 calreticulin (CALR) mutation, and risk stratification using Dynamic Inter­national Prognostic Scoring System (DIPSS)-plus classified her as having very low-risk PMF. At that time, she was considered to be in the early phase of the disease.

The patient started treatment with pegylated interferon in 2019. However, since 2022, she developed progressive anaemia over a 2-year period, eventually requiring regu­lar transfusions. She required two units of packed red blood cells per month for >3 consecutive months, thereby meeting the criteria for transfusion-dependent anaemia.¹ The patient’s DIPSS risk category worsened to intermediate-2. Despite being eligible, she refused allogeneic haematopoietic stem cell transplan­tation (HSCT), citing concerns about the associated risks.

Treatment with momelotinib
In August 2024, momelotinib 200 mg QD was initiated without the need for dose modification. Before momelotinib treatment, the patient had palpable splenomegaly, measur­ing approximately 15 cm below the left costal margin. Her haemoglobin (Hb) level was 6.9 g/dL, platelet count was 90 x 10⁹/L, and white blood cell (WBC) count was 25 x 10⁹/L. (Table 1)

By 12-week follow-up (F/U), her Hb level had increased by 1.6 g/dL, meaning no transfusion was required. This improvement was sustained, with Hb level maintained at 8.4 g/dL at week 24, and she was rendered transfusion-independent. (Table 1)

By week 24, there was >50 per­cent reduction in palpable spleen length, measuring approximately 7 cm below the left costal margin. A reduction in white blood cell (WBC) count was also observed, with plate­let counts remaining stable. Further­more, the patient reported improve­ments across all seven symptom domains on the Myelofibrosis Symp­tom Assessment Form (MFSAF), with significant reductions in night sweats, pruritus, and pain under the left rib margin. (Table 1)

The patient tolerated momelo­tinib well. During the initial 2 weeks of treatment, she experienced mild postural dizziness that resolved spontaneously without requiring dose reduction. There was no evidence of peripheral neuropathy, documented postural hypotension or infections.

As of her last F/U in August 2025, the patient remained transfusion-independent while continuing momel­otinib therapy.

Case 2: A JAK inhibitor– experienced patient with PMF
History and presentation
In 2006, a 46-year-old female with no comorbidities was diagnosed with low-risk PMF according to DIPSS. Since 2016, she developed progressive splenomegaly accom­panied by worsening constitutional symptoms. As a result, she was initi­ated on ruxolitinib (15 mg twice daily) in September 2018, which however failed, as evidenced by progressively increasing transfusion requirement, which had reached approximately three units per month. In addition, the patient did not achieve adequate control of splenomegaly or symptom burden, and her condition deteriorat­ed to high-risk PMF. She had throm­bocytopenia (platelet count, <100 x 10⁹/L) when treated with ruxolitinib 10 mg twice daily, which precluded dose escalation.

Treatment with momelotinib
The patient was switched to momelotinib 200 mg QD in Sep­tember 2024. Following treatment initiation, her Hb level gradually in­creased to 9.9 g/dL by 24-week F/U, at which point she was deemed transfusion-independent. Her plate­let counts remained stable, and WBC counts were within normal limits during momelotinib therapy. (Table 2)

Splenomegaly, which measured 12 cm below the left costal margin at treatment initiation, decreased to 7 cm by week 24, indicating a fa­vourable treatment response. Im­provement was also observed in MFSAF total symptom score, which decreased from 10 at baseline to 4 at week 24, with improvements not­ed in the same symptom domains as in patient case 1. (Table 2)

The patient experienced no hae­matological or nonhaematological adverse events, and no dose modi­fications were required.

Her most recent visit was in Au­gust 2025, with F/U visits taking place every 4 weeks. She harbours a JAK^2V617F mutation, with no other high-risk mutations identified. Given her older age (currently, 66 years), the risks associated with allogene­ic HSCT are considered high, and therefore it is not being pursued.

Discussion
Treatment goals in PMF
Pharmacological treatment of PMF typically targets its key clinical manifestations, including anaemia, splenomegaly, and constitutional symptoms. Among these, improving anaemia, and thereby achieving and maintaining transfusion indepen­dence (TI), is a central therapeutic goal, as it can improve symptoms, enhance quality of life (QoL), pro­long survival, and potentially delay disease progression. For patients ineligible for allogeneic HSCT, which is the only curative option for PMF, the current standard of care con­sists of approved Janus kinase (JAK) inhibitors.^2,3

In the head-to-head SIMPLI­FY-1 trial comparing momelotinib and ruxolitinib in JAK inhibitor–naïve patients (n=432), momelotinib was noninferior to ruxolitinib in achieving a ≥35 percent reduction in spleen volume (SVR35) at week 24 (26.5 vs 29.0 percent; p=0.011) and was nominally superior in achieving TI (66.5 vs 49.3 percent; p<0.001).⁴

Responses by baseline platelet counts

A post-hoc analysis of the sub­set of patients with anaemia (base­line Hb <10 g/dL; n=180) from the SIMPLIFY-1 trial demonstrated that rates of SVR35 and dual SVR35 plus TI responses were notably higher with momelotinib vs ruxolitinib among pa­tients with baseline platelet counts <200 × 10⁹/L (SVR35: 39 vs 17 per­cent; SVR35 + TI: 33 vs 2 percent). These improvements were even more pronounced in the subgroup with platelet counts ≥50–<100 x 10⁹/L (thrombocytopenia).⁵ (Table 3)

In SIMPLIFY-1, most patients with anaemia and thrombocytope­nia were able to initiate and maintain full or near-full doses of momelotinib over time, whereas dose reductions, which can compromise clinical effi­cacy, were commonly required with ruxolitinib.^5,6 Similar to this subgroup, our patient case 1 was transfusion-dependent, had significant spleno­megaly, and a baseline platelet count <100 × 10⁹/L. These clinical features supported the selection of momelo­tinib over ruxolitinib as first-line ther­apy, as ruxolitinib was unlikely to be titrated to an optimal dose capable of achieving meaningful SVR and TI.³ Remarkably, our patient achieved multiple clinical objectives on momel­otinib without any dose adjustments, including TI, substantial spleen size reduction, and improvement in con­stitutional symptoms.

The SIMPLIFY-1 post-hoc anal­ysis also showed that the overall SVR35 rate with momelotinib (31 percent) was largely maintained among patients who achieved TI at week 24, with a dual SVR35 + TI rate of 27 percent. In contrast, only 7 per­cent of patients receiving ruxolitinib achieved dual responses, despite an SVR35 rate of 33 percent, reflecting the high transfusion burden in the ruxolitinib arm.⁵

Hb >10 g/dL linked to better OS
Transfusion dependence is a ma­jor adverse prognostic indicator in PMF. Achieving TI, either alone or in combination with SVR35, is as­sociated with prolonged survival. Among patients randomized to re­ceive momelotinib in the SIMPLIFY-1 trial, those who achieved TI by week 24 demonstrated a significantly high­er 3-year overall survival (OS) rate vs those who did not (77.2 vs 51.6 percent; hazard ratio [HR], 0.323; p<0.0001).^3,5,7

Another post-hoc analysis of the SIMPLIFY-1 and MOMENTUM (mom­elotinib vs danazol in JAK inhibitor– experienced, symptomatic, anaemic patients) trials investigated the im­pact of raising Hb levels to >10 g/dL on OS in patients with moderate-to-severe anaemia at baseline who were treated with momelotinib.^8,9

In SIMPLIFY-1, 69 percent of patients with moderate anaemia at baseline and 50 percent with severe anaemia at baseline achieved Hb >10 g/dL by week 24. In MOMEN­TUM, 47 and 24 percent of patients with moderate and severe anaemia at baseline, respectively, achieved Hb >10 g/dL by week 24. Of note, achieving Hb >10 g/dL by week 24 was associated with longer OS re­gardless of baseline anaemia severity or JAK inhibitor experience.⁸ (Figure)

Importance of early treatment with momelotinib
Although the majority of patients achieved the Hb threshold with mom­elotinib, those with moderate base­line anaemia (≥8 to <10 g/dL) were numerically more likely to achieve it and reached it more rapidly vs those with severe baseline anaemia (<8 g/ dL). This highlights the importance of initiating treatment early, before anaemia progresses, to maximize the likelihood of attaining TI and improv­ing OS.⁸

Our second patient became transfusion-dependent while receiv­ing ruxolitinib, and had suboptimal control of splenomegaly and symp­toms. After switching to momelo­tinib, she experienced improvements in spleen size, anaemia (achieving TI) and symptoms, consistent with the triple therapeutic benefits ob­served in many patients switching to momelotinib in the MOMENTUM trial. Similarly, in the open-label extension phase of SIMPLIFY-1, 23 percent of ruxolitinib nonresponders with base­line Hb <10 g/dL and platelet counts <200 x 10⁹/L achieved a SVR35 re­sponse after switching to momelo­tinib. As these patients had received lower doses of ruxolitinib, the find­ings further underscore the need for full-dose JAK inhibition to achieve optimal spleen responses.^5,9

PMF patients with anaemia on ruxolitinib therapy, particularly those receiving low doses, can safely transition to momelotinib without the need for tapering. Switching to momelotinib may lead to rapid im­provement in anaemia, an increased likelihood of achieving TI, and main­tenance or enhancement of spleen and symptom responses.¹⁰

Key takeaways
PMF treatment goals should be personalized based on each pa­tient’s clinical profile and individual needs. Effective disease manage­ment requires careful consideration of the interplay between anaemia, symptom burden, and splenomega­ly, with a focus on improving OS and QoL. In patients with moderate-to-severe anaemia, particularly those with baseline thrombocytopenia in whom optimal dosing of ruxolitinib is not feasible, early initiation of momelotinib should be considered. Additionally, in patients previously treated with ruxolitinib who become transfusion-dependent, an early switch to momelotinib is a reasonable and potentially beneficial strategy.

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