JAK inhibition in MPN: Updates from phase I/II trials at ASH 2022

Several exciting updates on developments in Janus kinase inhibitor (JAKi) therapies in myeloproliferative neoplasms (MPN) were presented at the 64th American Society of Hematology (ASH) Annual Meeting and Exposition. Here, the MPN Hub summarizes key findings from our selected top ASH abstracts reporting phase I and II trial data on JAK inhibition in both monotherapy and combination settings.

JAKi monotherapy

MAJIC-PV: Ruxolitinib vs BAT in PV

MAJIC-PV (ISRCTN61925716) is a randomized phase II trial of ruxolitinib vs best available therapy (BAT) in patients with polycythemia vera (PV) resistant/intolerant to hydroxycarbamide.¹

• The primary outcome was complete response (CR) per European LeukemiaNet criteria within 1 year.¹
• Secondary outcomes included duration of response, event-free survival, symptom response, and molecular response.¹

Claire Harrison presented 5-year analysis results from the study, demonstrating superior CR rate, CR duration, and time to discontinuation of first treatment with ruxolitinib vs BAT (Table 1).¹

Table 1. MAJIC-PV responses at 5-year analysis*

Event-free survival for major thrombosis, hemorrhage, transformation, and death were all superior with ruxolitinib, but with statistically significantly superiority only for thrombosis (hazard ratio, 0.56; 95% confidence interval, 0.32–1.00; p = 0.05).¹ Symptom responses were also improved with ruxolitinib vs BAT, and durable to a mean of 52 months.²

At the last time point tested, a >50% reduction in JAK2^V617F variant allele frequency was observed in 56% of patients receiving ruxolitinib, compared with 25% of patients receiving BAT (p < 0.001).² Molecular response at 1 year was associated with improved outcomes; attaining CR, improved progression-free survival (p = 0.001), event-free survival (p = 0.001), and overall survival (p = 0.01),¹ and clearance of MPN stem cells (a 72–100% reduction in JAK2^V617F stem/progenitor cells was demonstrated in three patients treated with ruxolitinib through targeted single-cell genotyping).²

Adverse events (AEs) of interest were deemed to be infections and malignancy. Bacterial and viral infections and skin cancers occurred more frequently in the ruxolitinib arm, but the majority of events were lower grade.¹

RuxoBEAT: Ruxolitinib vs BAT in ET

RuxoBEAT (NCT02577926) is a phase IIb trial investigating ruxolitinib vs BAT in patients with high-risk PV or high-risk essential thrombocytopenia (ET).³ Steffen Koschmieder presented results from a prespecified interim analysis of 95 patients with ET (75% of whom were pretreated) randomized 1:1 to ruxolitinib vs BAT.³ The primary endpoint was clinicohematologic CR rate at Month 6.³ In this prespecified interim analysis, the primary endpoint was not reached, with the study showing that ruxolitinib was not superior to BAT in inducing CRs in ET (Table 2).³

Table 2. Clinicohematologic responses*

At Month 6, there was a significant difference between the two treatment groups in the median number of platelets, median hemoglobin values, and median spleen size, but not in the median number of white blood cells (Table 3). Patient-reported outcome measures (PROMs) were significantly in favor of ruxolitinib vs BAT for headache and concentration problems, and there was a trend for improvement for pruritus, but no significant difference for dizziness (Table 3).

Table 3. Clinical responses and PROMs at Month 6*

Whilst the primary study endpoint was not reached, the results suggest that ruxolitinib was more effective in reducing ET-associated spleen size and symptoms, such as headache and concentration problems. The authors noted that the low CR rate may be in part due to the strict application of 0 PROM points, as well as the early assessment time point.³

Safety analysis revealed 147 AEs in the ruxolitinib group and 211 AEs in the BAT group (6% and 11% were Grade ≥3, respectively).³ There was no significant difference in the percentage of Grade ≥3 AEs between both groups (p = 0.08), and no new safety signals were identified. Overall, the results indicate that neither treatment was better than the other in this setting.³

JAKi-based combination therapies

RUXOPeg: Ruxolitinib + INFα⁵

Jean-Jacques Kiladjian presented final results of RUXOPeg (NCT02742324), a phase I/II trial designed to assess the efficacy and safety of different dose combinations of ruxolitinib and pegylated interferon alpha (IFNα)-2a in JAKi- and IFNα-naïve patients with myelofibrosis (MF). A total of 18 patients were recruited to the phase I safety cohort and 19 to the phase II efficacy cohort (N = 37).

• Phase I tolerance criterion was the occurrence of dose-limiting toxicities within 45 days.
• Phase II primary efficacy criterion was ≥50% reduction in spleen length (≥50% SLR) by palpation within 24 weeks.

The combination produced significant decreases in JAK2^V617F mutant allele burden (from 84% at screening to 56% after 12 months). In addition, biomarker analysis showed that cellularity improved in 57% of patients and megakaryocyte morphology improved in 25%. The majority of patients experienced a decrease in inflammatory cytokine profile, an increase in the proportion of B cells, and decreased NK cells.

Very few Grade 3 or 4 toxicities were observed (7.5% and 0.5%, respectively), and the most frequent toxicities were hematologic as expected (anemia, 18.7%; thrombocytopenia, 13.7%). Notably, there was a low incidence of expected INFα events, suggesting ruxolitinib may improve INFα tolerance. The primary endpoint (≥50% SLR) was reached in 70% of patients; a marked improvement when compared with the 40% rate in ≥50% SLR with ruxolitinib monotherapy reported from the COMFORT-I trial (NCT00952289).

MANIFEST Arm 3: Ruxolitinib + pelabresib

In the ongoing phase II MANIFEST study (NCT02158858), pelabresib (an investigational BET inhibitor) is under investigation as monotherapy and in combination with ruxolitinib in patients with MF.⁶ John Mascarenhas presented results from Arm 3 of MANIFEST, which investigated ruxolitinib + pelabresib in JAKi-naïve patients with MF. In total, 84 patients received ≥1 dose of the combination.⁶

• The primary endpoint was ≥35% spleen volume reduction from baseline (SVR35) after 24 weeks of treatment.⁶
• Secondary endpoints included ≥50% total symptom score reduction from baseline, duration of splenic response, pharmacokinetics, and safety.⁷

At Week 24, 68% of patients achieved the primary end point of SVR35, with a median spleen volume reduction (SVR) of 50% and mean SVR of 48%.⁶ A total of 80% of patients achieved SR35 at any time during the study.⁶ Spleen response and change in total symptom score over time are shown in Table 4.

Table 4. Spleen volume and symptom burden reduction responses over time*

The most common any grade AEs were hematologic; thrombocytopenia in 55% of patients (18% Grade ≥3) and anemia in 43% of patients (34% Grade ≥3).⁶ Serious adverse events reported in ≥2 patients were anemia, pyrexia, and COVID-19 (3 patients each); gastrointestinal hemorrhage, multiorgan failure, COVID-19 pneumonia, pneumonia, and respiratory tract infections, urinary tract infection, fall, and respiratory failure (2 patients each).⁶ Treatment-emergent AEs (TEAEs) that led to pelabresib  discontinuation occurred in 14% of patients, and eight Grade 5 (TEAEs) reported in 7 patients.⁶

Conclusion

The MAJIC-PV trial demonstrates novel benefits for ruxolitinib in patients with high-risk PV resistant/intolerant to hydroxycarbamide, whilst confirming existing evidence of hematologic control and symptom response efficacy.¹ Attainment of a 50% JAK2^V617F reduction (more frequent with ruxolitinib than BAT), was associated with important clinical benefits and clearance of MPN stem cells. These data support the benefit of targeted therapy and molecular monitoring in PV.¹ RuxoBEAT trial data suggest that ruxolitinib is not superior to BAT in inducing CRs in ET, but that it may be more effective in reducing ET-associated spleen size and symptoms; the trial is ongoing.³

Regarding ruxolitinib-based combinations in MF, the RUXOPeg trial demonstrates that ruxolitinib + INFα may be a safe combination that can provide high rates of spleen length reductions and JAK2^V617F allele burden, and may improve IFNα tolerance.⁵ Arm 3 of the MANIFEST trial showed that ruxolitinib + pelabresib can offer durable improvements in spleen volume, total symptom score, and bone marrow fibrosis, and is generally well tolerated.⁶

Together, results from these trials confirm and expand upon the important role of JAKi therapies in MPN treatment and highlight the need for further investigation across disease subtypes and treatments settings to ensure clinical trial data translate into the best possible patient outcomes in clinical practice.