The MPN landscape is shifting from JAKi monotherapy to the combination of new agents

With more than 10 active and ongoing Phase 3 trials worldwide, new treatments are being combined with JAK inhibitors to develop new treatment strategies for patients with myeloproliferative neoplasms (MPNs).1

In a presentation at the 14th Annual International Congress on Myeloproliferative Neoplasms, Naveen Pemmaraju, MD, Associate Professor, Department of Leukemia, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, discussed agents currently under review for NMPs, beyond ruxolitinib (Jakafi).

MPN landscape in 2022

There are currently very few treatment options for patients with polycythemia vera (PV) that can both control hematocrit levels, reduce the need for phlebotomy, and reduce the incidence of thrombosis.

In November 2021, the FDA granted approval to ropeginterferon alfa-2b-njft (Besremi) for the treatment of adults with PV. Long-acting monopegylated interferon has been approved based on results from the Phase 3 PROUD/CONTINUATION-PV clinical trial (NCT01949805; NCT02218047). The data revealed that ropeginterferon alfa-2b-njft had a high and durable hematological response in patients over 36 months, compared to hydroxyurea (Siklos).

There is also rusfertide (PTG-300), which has undergone several clinical trials in PV patients and received Breakthrough Therapy designation as a treatment option for PV patients in June 2021.

Two of these trials are the Phase 2 studies REVIVE (NCT04057040) and PACIFIC (NCT04767802), which were placed on clinical hold by the FDA in September 2021 after a nonclinical finding was identified in a mouse model study. 26-week-old rasH2 transgenic showing benign and malignant subcutaneous skin tumors.

However, the suspension was lifted in October 2021 following an FDA review. New safety and stopping rules have been added to study protocols for the protection of patients in ongoing studies. No other unexpected safety signals were reported during the review.

There have also been approvals in rarer disease spaces, including FDA approval for avapritinib (Ayvakit) for the treatment of patients with advanced systemic mastocytosis, including patients with aggressive systemic mastocytosis , systemic mastocytosis with associated hematological neoplasm and mast cell leukemia and pemigatinib (Pemazyre) for the treatment of adults with relapsed or refractory myeloid/lymphoid neoplasms (MLN) and FGFR1 rearrangement.2

In the field of myelofibrosis (MF), there are new JAK inhibitors that go beyond ruxolitinib (Jakafi). For thrombocytopenic patients with intermediate- or high-risk MF, the FDA approved pacritinib (Vonjo), a JAK2/IRAK1 inhibitor, in February 2022. Next, momelotinib is another JAK 1/2 inhibitor in clinical development advanced for anemic and symptomatic patients with MF. This agent has demonstrated significant improvements in measures of anemia, spleen size and symptoms7 in the ongoing pivotal Phase 3 MOMENTUM trial (NCT04173494). Experts remain hopeful that momelotinib may soon receive regulatory approval as a treatment for anemic patients with MF.


Two phase 3 trials led to the approval of ruxolitinib: COMFORT-I (NCT00952289) and COMFORT-II (NCT00934544). COMFORT-1 was a randomized study between ruxolitinib and placebo, while COMFORT-2 evaluated ruxolitinib against the best available treatment. Most COMFORT-2 patients received hydroxyurea.3

Both trials revealed a favorable splenic response with an approximate 42% response rate in the spleen in COMFORT-I (odds ratio, 134.4; 95% CI, 18.0-1004.9; P

With respect to survival benefit, with an additional 4 months of follow-up after the primary analysis, the median OS of the pooled data from the two COMFORT trials showed an extension of lifespan to approximately one and a half years (5 ,3 years [4.7- not estimable] against 3.8 years [3.2-4.6]; HR, 0.70; 95% CI, 0.54-0.91; P = .0065).

Although the JAK inhibitor ruxolitinib is the current standard of care for patients with MF who are not candidates for hematopoietic stem cell transplantation, JAK inhibitors are known to be associated with limited efficacy and high dropout rates due to toxicities.

“Life after ruxolitinib results in reduced overall survival (OS). Additionally, the only factor in this retrospective study that improved OS was the introduction of new agents after ruxolitinib failure, rather than the standard conventional agents already available in your therapeutic armamentarium,” Pemmaraju said in his presentation.

This leads researchers to wonder if they can begin to modify the disease sooner than they are currently doing with new intervention studies of JAK monotherapy.

Investigative Officers

Pelabrisib (CPI-0610) is a BET inhibitor that downregulates the expression of genes that contribute to the heterogeneous features of MF pathology.

Based on preliminary data from arms 2 and 3 of the phase 1/2 MANIFEST trial4 (NCT02158858), ruxolitinib and pelabrisib demonstrated durable responses beyond week 24 in MF patients who had a suboptimal response to ruxolitinib and in those who had never received an inhibitor. Jak,

Data showed that 68% (95% CI, 57% to 78%) of JAK inhibitor naïve MF patients (n=84; arm 3) had a reduction in spleen volume of at minus 35% (SVR35) at week 24 when taking into account the combination of ruxolitinib and pelabrisib. Fifty-six percent (95% CI, 45% to 67%) of patients in this group had a 50% or greater reduction in total symptom score (TSS) from baseline at week 24, resulting in median TSS change of -59% at this time point.

Then, in arm 2 of patients with MF who previously had a suboptimal response to ruxolitinib (n=81), 20% achieved SVR35 at week 24, which was observed in 17% of those who were transfusion dependent (DT) and 26% of those who were not transfusion dependent (ATN). Thirty percent of patients achieved SVR35 at any time.

SVR of 25% or greater from baseline at week 24 was noted in 27% of patients. The median SVR was -18%. Adding pelabresib to ruxolitinib also had a positive effect on symptoms in these patients. The TSS50 at week 24 was 37%; this rate was 36% in patients with DT and 39% in patients with NTD, with a median reduction in symptom burden of -47%.

Next, LIMBER-313 (NCT04551066) is a Phase 3, randomized, double-blind, placebo-controlled study of ruxolitinib plus parsaclisib vs ruxolitinib plus placebo in patients with MF who are treatment-naïve to JAK AND P13K inhibitors. A total of An estimated 440 patients are randomized to group A (n=220) and receive ruxolitinib and parsaclisib 5 mg daily or to group B (n=220) and receive ruxolitinib plus placebo.

Looking forward

The REFINE trial (NCT03222609) examining treatment with navitoclax, a novel oral BCL-X and BCL-2 inhibitor, plus ruxolitinib has entered Phase 3 testing.5

“Preclinical studies nearly a decade ago have now shown promising activity either as a single agent or in combination with a JAK inhibitor, leading not only to improved disease burden, but also potentially overcome acquired resistance to a JAK inhibitor alone,” Pemmaraju said. .

A total of 34 patients were treated in Cohort 1a and received at least 1 dose of navitoclax starting at 50 mg/day and increasing to 300 mg daily as tolerated plus ruxolitinib at the patient’s current stable dose. Bone marrow fibrosis (BMF) was assessed locally and the reduction in the frequency of variant alleles (VAF) of the driver gene, i.e. JAK2 Where CALRwas evaluated centrally by next-generation sequencing in blood at baseline and at 24 weeks.

Investigators measured efficacy using SVR35 from baseline at week 24 as the primary endpoint. At week 24, 9 patients (27%) achieved the primary endpoint of SVR35. Throughout the study, 14 (41%) patients experienced SVR35. Median duration of SVR35 achieved was 13.8 months (95% CI 8.2 – not estimable [NE]).

Secondary endpoints were reduction in total symptom score by 50% or greater (TSS50) from baseline at week 24, improvement in hemoglobin, change in BMF grade, and safety.

At week 24, 6 of 20 patients evaluable for TSS50 (30%) achieved the desired reduction in symptoms, and 41% of patients achieved TSS50 at any time during the study. BMF had improved from baseline to Grade 1 or better in 11 of 33 patients at any time during the study. Of the 11 patients with improved BMF enrolled in the study, 7 improved by 1 grade and 4 patients by 2 grades. The remaining 22 patients (67%) had equal or worsening BMF grades, with 13 patients having grade 3 fibrosis at baseline.

All patients had at least 1 AE and 30 patients (88%) had grade 3 or higher AEs. The most common AEs of all grades were thrombocytopenia (88%), diarrhea (71%), fatigue (62%) and nausea (38%). Additionally, the most common grade 3 or higher AEs were thrombocytopenia without clinically significant bleeding (56%), anemia (32%), and pneumonia (12%).

“As we think about these trials in 2022 and beyond, I am amazed to tell you that we have 10-12 phase 3 studies underway. 2023 will be our best year yet and I end on a note of hope and optimism for our patients and for our field as we move towards the theme of disease modification and improved overall survival,” concluded Pemmaraju.

  1. Pemmaraju, Naveen. Combination of agents for the treatment of myelofibrosis. Lecture presented at the 14th Annual International Congress on Myeloproliferative Neoplasms; October 27-28, 2022; Brooklyn, NY.
  2. Incyte announces FDA approval of Pemazyre® (pemigatinib) as the first and only targeted therapy for myeloid/lymphoid neoplasms (MLNs) with FGFR1 rearrangement. Press release. Incyte. August 26, 2022. Accessed August 26, 2022.
  3. Harrison C, Kiladjian JJ, Al-Ali HK, et al. Inhibition of JAK with ruxolitinib compared with the best available treatment for myelofibrosis. N Engl J Med. 2012;366(9):787-798. doi:10.1056/NEJMoa1110556
  4. Mascarenhas J, Kremyanskaya M, Patriarca A, et al. BET inhibitor Pelabresib (CPI-0610) plus ruxolitinib in patients with myelofibrosis––JAK inhibitor naïve or with a suboptimal response to ruxolitinib––preliminary data from the MANIFEST study. Presented at: European Hematology Association Congress 2022; June 9-12, 2022; Vienna, Austria. Summary S198.
  5. Harrison CN, Garcia JS, Somervaille TCP, et al. Addition of navitoclax to ongoing ruxolitinib therapy in patients with myelofibrosis with progression or suboptimal response: Phase II safety and efficacy. Published online February 18, 2022. J Clin Oncol. 2022;JCO2102188. doi:10.1200/JCO.21.02188

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