JAK1/2 inhibitor provides rapid and durable disease control in a patient with myelofibrosis

History, presentation and initial management
A 67-year-old man was diagnosed with polycythaemia vera (PV) in 2005. Over the next several years, he re­ceived various cytoreductive agents, including anagrelide, pegylated inter­feron (IFN) and hydroxyurea.

In 2016, the patient developed progressive anaemia, with haemoglo­bin (Hb) declining from a baseline level of approximately 14 g/dL to around 10–11 g/dL. After further assess­ments, including a bone marrow (BM) examination, disease progression to myelofibrosis (MF) was confirmed.

The COVID-19 pandemic led to a 3-year default in follow-up from 2021 to 2023, since the patient was residing in Macau.

In early 2023, the patient present­ed to our clinic with marked fatigue (grade 2–3), poor appetite, a palpable spleen 8 cm below the left costal mar­gin, and an elevated white blood cell (WBC) count of 37 x 10⁹/L. Previous BM examination performed in Macau showed moderate fibrosis (MF-2 on a 0–3 scale). Cytogenetics were normal and molecular data were unavailable as next-generation sequencing (NGS) could not be performed at the time. He was assessed to have an intermediate-2 Dynamic International Prognostic Scoring System (DIPSS) risk score.

Subsequent treatment with ruxolitinib and response
The patient was recommended to receive the Janus kinase (JAK) 1/2 inhibitor, ruxolitinib. He was put on pegylated IFN while awaiting reim­bursement approval. In the meantime, screening for hepatitis B (HBV) and tu­berculosis (TB) infections, performed in accordance with recommended safety protocols before initiating ruxolitinib therapy, showed negative results.¹

In February 2025, reimbursement for ruxolitinib was approved, and the patient started treatment at 20 mg BID. After 3 months, substantial clinical improvements were noted. The spleen became non-palpable, constitutional symptoms such as fa­tigue and lack of appetite resolved, WBC count improved to 25–27 x 10⁹/L, and Hb stabilized at 11 g/dL. His platelet count remained stable at approximately 500 x 10⁹/L.

At the time of writing, the patient had been on ruxolitinib for 7 months and did not experience any adverse events (AEs). His treatment is ongoing, and he is regularly followed up with pe­riodic monitoring of blood counts and assessments of spleen size and symp­toms using the Myelofibrosis Symptom Assessment Form.

Discussion
Allogeneic haematopoietic stem-cell transplantation (HSCT) is current­ly the only definitive cure for patients with MF. However, only a small pro­portion are eligible for HSCT.^2,3 Among pharmacologic options, ruxolitinib has emerged as a cornerstone treatment for MF due to a clear rationale for JAK inhibition, robust clinical trial evidence, and measurable improvements in pa­tient outcomes.^1-5

Rationale for JAK inhibition in MF
The pathogenesis of MF is close­ly tied to aberrant activation of the JAK signal transducer and activa­tor of transcription (STAT) pathway. The most common driver mutation in MF is JAK2^V617F, which occurs in ap­proximately 50 percent of patients with primary MF, followed by muta­tions in CALR and MPL, all of which cause constitutive activation of JAK-STAT signalling that leads to abnor­mal cytokine production and mar­row fibrosis central to MF’s clinical manifestations.^2,3

Ruxolitinib in MF: Clinical impact and evidence from the COMFORT trials
The therapeutic goals in MF centre on controlling splenomegaly, alleviat­ing disease-related symptoms, and improving overall survival.⁶ Ruxoli­tinib, a potent inhibitor of both JAK1 and JAK2, is approved for adults with primary, post-PV and post-essential thrombocythemia MF pre­senting with symptomatic splenomeg­aly or disease-related symptoms.¹ Approval was based on data from the pivotal phase III COMFORT (Con­trolled Myelofibrosis Study with Oral JAK Inhibitor Treatment) trials, which demonstrated ruxolitinib’s superiority vs placebo and best available therapy (BAT) in terms of durable reductions in spleen volume and symptom bur­den, leading to improved quality of life (QoL) and extended survival.^2,5-8

COMFORT-I was a random­ized, double-blind, placebo-con­trolled trial that enrolled patients with intermediate-2 and high-risk MF. Rux­olitinib led to a significant ≥35 percent reduction in spleen volume in 41.9 per­cent of treated patients at 24 weeks, vs 0.7 percent with placebo (p<0.001). Symptom burden also improved sig­nificantly, with 45.9 vs 5.3 percent of patients in the ruxolitinib vs placebo group achieving ≥50 percent reduction in total symptom score at 24 weeks (p<0.001). Ruxolitinib’s benefits were durable, with 67 percent maintaining spleen response at ≥48 weeks.²

In addition, overall survival (OS) was notably improved with ruxolitinib vs placebo (hazard ratio [HR], 0.50; 95 percent confidence interval [CI], 0.25–0.98; p=0.04).²

The most common AEs, name­ly, anaemia and thrombocytopaenia, primarily occurred early and rarely led to treatment discontinuation.^2,6 Long-term follow-up results also showed that ruxolitinib consistently improved symptoms and QoL in patients with MF.^7,8

COMFORT-II, which compared ruxolitinib vs BAT, revealed ruxoli­tinib’s value for broader MF subtypes, including post-PV MF. At 48 weeks, 28 percent of ruxolitinib patients achieved ≥35 percent spleen volume reduction vs no patients in the BAT arm (p<0.001).⁵ The probability of maintaining response at 5 years was 48 percent for patients on ruxolitinib. Median OS was not reached in the ruxolitinib group vs 4.1 years with BAT, reflecting a 33 percent reduction in risk of death (HR, 0.67; 95 percent CI, 0.44–1.02; p=0.06).⁹

Extended duration of and contin­uous therapy with ruxolitinib also led to improved QoL and role functioning. The most common grade ≥3 haema­tologic abnormalities in either group were thrombocytopaenia and anae­mia, which were managed with dose reductions, interruption of treatment, or transfusions. While there was a sin­gle treatment discontinuation in each group due to thrombocytopaenia, no patients discontinued treatment due to anaemia.^5,9

Pooled 5-year analysis of COMFORT-I and -II also demonstrat­ ed a significant OS benefit with rux­olitinib in patients with intermediate-2 or high-risk MF, regardless of anaemia or transfusion status. Median OS was 5.3 vs 3.8 years for ruxolitinib and con­trol groups, respectively (HR, 0.70; 95 percent CI, 0.54–0.91; p=0.0065). (Figure 1A) After correcting for crossover using the rank-preserving structural failure time method, me­dian OS was 5.3 vs 2.3 years, favouring ruxolitinib (HR, 0.35; 95 per­cent CI, 0.23–0.59).¹⁰ (Figure 1B)

The COMFORT trial results affirm the robust clinical efficacy of ruxoli­tinib in patients with MF, aligning with the positive experience of our patient. Initiation of ruxolitinib in our patient led to a rapid and durable reduction in spleen size, resolution of consti­tutional symptoms, and stabilization of blood counts, as seen in both COMFORT-I and COMFORT-II, where ruxolitinib provided significant and lasting improvements in splenomegaly and MF symptom burden.^2,5

Practical recommendations for anaemia management
Although our patient did not ex­perience any AEs during ruxolitinib treatment, anaemia is a relatively common side effect of the JAK in­hibitor drug class.^1-3,5 With ruxolitinib, treatment-induced anaemia typically peaks at 8–12 weeks after initiation, with Hb levels stabilizing or gradually recovering within 3–6 months.⁴

Importantly, treatment‑related anaemia may not diminish ruxolitinib efficacy and will uncommonly require permanent treatment discontinua­tion. For instance, patients with new-onset anaemia in COMFORT‑I showed comparable spleen and symptom re­sponses to those without anaemia.²

Thus, to ensure maximum clinical benefit, early dose reductions should be avoided during the initial 3 months. Maintaining the highest tolerated ruxoli­tinib dose during this period may cor­relate with better spleen and symptom responses and optimize survival out­comes.^2,5 Any consideration of dose re­duction should be balanced against rux­olitinib’s benefits on symptom burden and splenomegaly. For patients with anaemia who are symptomatic or transfusion-dependent, erythropoietin-stimulating agents, danazol, and thalidomide can be used either alone or in combination with a JAK inhibitor.^3,4

In patients with both splenomegaly and anaemia where splenomegaly re­mains refractory to the JAK inhibitor, low-dose splenic irradiation or splenec­tomy may be considered.^3,4 However, splenectomy has considerable surgical risk and must be evaluated on an indi­vidual basis. Furthermore, the effects of splenic irradiation on anaemia improve­ment may be short-lived.³

If anaemia persists beyond 6 months, alternative causes should be considered before ruxolitinib dose titra­tion. Dose modifications may be nec­essary in patients experiencing non-haematologic toxicities.⁴

Practical approaches and consider­ations in managing anaemia in patients with MF are summarized in the Table.

Summary
In summary, our patient’s rapid spleen size reduction, symptom resolu­tion and stable blood counts with rux­olitinib closely reflect the durable clin­ical benefits and safety demonstrated in the pivotal COMFORT trials. These findings highlight ruxolitinib’s central role in effectively and safely managing MF in real-world practice.

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