Efficacy and safety of a novel dosing strategy for ruxolitinib in the treatment of patients with myelofibrosis and anemia: The REALISE phase 2 study

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Patients with myelofibrosis (MF) have reduced survival and poor quality of life due to symptoms derived from splenomegaly, constitutional symptoms (weight loss, night sweats, low-grade fever), and anemia. Ruxolitinib is a Janus kinase (JAK)1/JAK2 inhibitor approved for the treatment of MF-related splenomegaly or symptoms.1 While ruxolitinib is highly effective in controlling splenomegaly and constitutional symptoms, anemia tends to worsen during the first few months of therapy.2 Of note, ruxolitinib dosing is dictated by the patient’s platelet count, regardless of their hemoglobin (Hb) level.2 It has been suggested that a lower starting dose (10 mg twice daily [b.i.d.]) could reduce the impact of treatment-related anemia while maintaining therapeutic response in anemic MF patients.4

 The REALISE open-label, single-arm, phase 2 study evaluated the efficacy and safety of a novel dosing strategy of ruxolitinib, consisting of a reduced starting dose with delayed up-titration in MF patients with Hb levels <10 g/dl. Patients received a 10 mg oral dose of ruxolitinib b.i.d. for the first 12 weeks (regardless of their platelet counts), after which up-titrations of up to 25 mg b.i.d. were permitted (Figure 1). The primary endpoint was the proportion of patients achieving ≥50% reduction in spleen length at week 24. Secondary endpoints included changes in Hb, transfusion requirements, safety, and patient-reported outcomes.

Figure 1. Diagram of up-titration procedure in the REALISE phase 2 study. b.i.d. twice daily; BSL baseline spleen length; PLT platelets; RUX ruxolitinib; SL spleen length.

The main features of the 51 eligible patients at study entry are summarized in the table.

Table 1
aBaseline values presented. Values obtained at screening may vary.
bJAK2 and CALR, n=1; JAK2 and MPL, n=1; CALR and MPL, n=1.
cTriple negative status was defined as lack of positive result for JAK2, CALR, or MPL mutation
dConstitutional symptoms included weight loss, fever, and night sweats.
ePatient included in study based on screening values.
fDefined according to IWG-MRT criteria as 6 or more transfusions in the 12 weeks prior to baseline.
CALR calreticulin; DIPSS Dynamic International Prognostic Scoring System; ECOG Eastern Cooperative Oncology Group; Hb hemoglobin; IWG-MRT International Working Group for Myeloproliferative Neoplasms Research and Treatment; JAK2 Janus kinase 2; MF myelofibrosis; MPL myeloproliferative leukemia protein; PET post-essential thrombocythemia; PMF primary myelofibrosis; PPV post-polycythemia vera; SL spleen length; TD transfusion-dependent; WBC, white blood count

Twenty-eight patients completed the study and one was considered as treatment ongoing at time of data cut-off. During the study, the median daily dose of ruxolitinib was 20 (range 8–36) mg. At final data cut-off, 12% (6/50) of patients had received dose increases and 30% (15/50) had maintained their starting dose. The majority of patients who maintained the starting dose achieved ≥50% reduction in spleen length at week 12 or later (11/15 patients). Overall, 56% of patients (n/N = 28/50) had a ≥50% reduction in spleen length by week 24 (Figure 2).

Figure 2. Best response according to spleen length from baseline for individual patients.

A higher proportion of patients who received an increased ruxolitinib dose had greater palpable spleen length (median 14 cm vs 9 cm) than patients who did not receive a dose increase. Of the 15 patients receiving an increased dose at 12 weeks, 47% achieved a ≥50% reduction in spleen size at week 24. Median Hb levels remained reasonably constant throughout the study (Figure 3).

Figure 3. Median hemoglobin levels over time. Boxes indicate 25th–75th percentiles and median daily dose is indicated as a horizontal line.

Based on these results, we propose that this new dosing strategy of ruxolitinib may be appropriate for MF patients commencing therapy due to splenomegaly and/or MF-associated symptoms who have Hb levels <10 g/dl. In anemic patients in need of JAK inhibition, the choice of the initial ruxolitinib dose (i.e. the standard dose, as dictated by platelet counts, or a lower dose with escalation at 12 weeks, if needed) could be based on the need to achieve a rapid spleen reduction. In case of moderate-to-marked, but not massive, splenomegaly, a 2-step dosing policy could be considered. Additionally, in anemic patients with constitutional symptoms without marked splenomegaly a lower starting dose (i.e. 10 mg b.i.d) seems reasonable.

In conclusion, the results demonstrate that an alternative dosing regimen of ruxolitinib in anemic MF patients is effective and well-tolerated, reinforcing that it is not necessary to delay or withhold treatment with ruxolitinib because of co-existent or treatment-emergent anemia

References

  1. Cervantes F. How I treat myelofibrosis. Blood 2014;124:2635–2642.
  2. Harrison C, Kiladjian J-J, Al-Ali HK, Gisslinger H, Waltzman R, Stalbovskaya V, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med 2012;366:787–798.
  3. Al-Ali HK, Griesshammer M, Foltz L, Palumbo GA, Martino B, Palandri F, et al. Primary analysis of JUMP, a phase 3b, expanded-access study evaluating the safety and efficacy of ruxolitinib in patients with myelofibrosis, including those with low platelet counts. Br J Haematol 2020;189:888–903.
  4. Al-Ali HK, Stalbovskaya V, Gopalakrishna P, Perez-Ronco J, Foltz L. Impact of ruxolitinib treatment on the hemoglobin dynamics and the negative prognosis of anemia in patients with myelofibrosis. Leuk Lymphoma 2016;57:2464–2467.

Francisco Cervantes

Senior Consultant & Professor, Hospital Clínic, IDIBAPS, University of Barcelona