MPN Landscape Shifts from JAKi Monotherapy to Combining Novel Agents


During a presentation at the 14th Annual International Congress on Myeloproliferative Neoplasms, Naveen Pemmaraju, MD, discussed the current agents being examined for MPNs.

Naveen Pemmaraju, MD

Naveen Pemmaraju, MD

With more than 10 active and rolling phase 3 trials around the world, novel treatments are being combined with JAK inhibitors to develop new treatment strategies for patients with myeloproliferative neoplasms (MPN).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, The University of Texas MD Anderson Cancer Center, discussed the current agents being examined for MPNs, beyond just 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. The monopegylated, long-acting interferon was approved based on findings from the phase 3 PROUD/CONTINUATION-PV clinical trial (NCT01949805; NCT02218047). Data revealed ropeginterferon alfa-2b-njft to have a high and durable hematological response in patients over 36 months, compared with hydroxyurea (Siklos).

There is also rusfertide (PTG-300), which has been investigated in several clinical trials of patients with PV and was granted breakthrough therapy designation as a treatment option for patients with PV in June 2021.

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

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

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

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


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 vs the best available therapy. Most patients in COMFORT-2 received hydroxyurea.3

Both trials revealed there to be favorable spleen response with an approximate 42% response rate in the spleen in COMFORT-I (odds ratio, 134.4; 95% CI, 18.0-1004.9; P < .001). In COMFORT-II, w97% of patients on ruxolitinib had a decrease in spleen volume compared with 56% of patients who received best available therapy.

Regarding the survival benefit, with an additional 4 months of follow-up after the primary analysis, the median OS of the pooled data from both COMFORT trials, revealed an extension of life at about a year and a half (5.3 years [4.7- not estimable] vs 3.8 years [3.2-4.6]; HR, 0.70; 95% CI, 0.54-0.91; P = .0065).

While the JAK inhibitor ruxolitinib is the current standard of care for patients with MF who are not candidates for hematopoietic stem cell transplant, it is known that, JAK inhibitors are associated with limited efficacy and high discontinuation rates due to toxicities.

“Life after ruxolitinib leads to reduced overall survival (OS). Also, the only factor in this retrospective study that improved OS was the introduction of novel agents post-ruxolitinib failure, rather than the standard conventional agents already available in your therapeutic armamentarium,” stated Pemmaraju in his presentation.

This leads investigators to wondering if they can begin to modify the disease earlier than what they are currently doing with new intervention studies of JAK monotherapy.

Investigational Agents

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

According to 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 patients with MF who experienced a suboptimal response to ruxolitinib and in those who were JAK inhibitor naïve,

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

Then in arm 2 of patients with MF who had previously experienced a suboptimal response to ruxolitinib (n = 81), 20% experienced SVR35 at week 24 which was seen in 17% of those who were transfusion dependent (TD) and 26% of those who were non–transfusion dependent (NTD). Thirty percent of patients achieved SVR35 at any time point.

A 25% or higher SVR from baseline by week 24 was noted in 27% of patients. The median SVR was –18%. The addition of pelabresib to ruxolitinib positively affected symptoms in these patients, as well. The TSS50 at week 24 was 37%; this rate was 36% in TD patients and 39% in NTD patients, with a median symptom burden reduction of –47%.

Then, 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 JAK- AND P13K-inhibitor treatment-naive.A total of 440 patients are estimated to be randomized to group A (n = 220) and given ruxolitinib and parsaclisib 5 mg every day or group B ( n = 220) and given ruxolitinib plus placebo.

Looking Forward

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

“Preclinical studies almost a decade ago now showed promising activity either as a single-agent or in combination with JAK inhibitor, leading to not only an improvement in the disease burden, but also potentially overcoming acquired resistance to a JAK inhibitor alone,” stated Pemmaraju.

A total of 34 patients were treated in cohort 1a and received at least 1 dose of navitoclax starting at 50 mg/day and escalating to 300 mg daily based on tolerability plus ruxolitinib at the patient’s current stable dose. Bone marrow fibrosis (BMF) was assessed locally, and variant allele frequency (VAF) reduction of the driver gene, either JAK2 or CALR, was assessed centrally by next-generation sequencing in the blood at baseline and 24 weeks.

Investigators measured efficacy using SVR35 from baseline at week 24 as the primary end point. At week 24, 9 patients (27%) achieved the primary end point of SVR35. Across the entire duration of the study, 14 (41%) patients met SVR35. The median duration for achieved SVR35 was 13.8 months (95% CI, 8.2- not estimable [NE]).

The secondary end points were reduction in total symptom score of 50% or higher (TSS50) from baseline at week 24, hemoglobin improvement, change in BMF grade, and safety.

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

All patients had at least 1 AE, and 30 patients (88%) experienced grade 3 or higher AEs. The most common AEs of any grade were thrombocytopenia (88%), diarrhea (71%), fatigue (62%), and nausea (38%). Further, 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'm amazed to tell you that we have 10-12 ongoing phase 3 studies. 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. Combining agents for treating myelofibrosis. Lecture presented at 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 treatment for myeloid/lymphoid neoplasms (MLNs) with FGFR1 rearrangement. News release. Incyte. August 26, 2022. Accessed August 26, 2022.
  3. Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy 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) combined with ruxolitinib in patients with myelofibrosis––JAK inhibitor-naïve or with suboptimal response to ruxolitinib––preliminary data from the MANIFEST study. Presented at: European Hematology Association 2022 Congress; June 9-12, 2022; Vienna, Austria. Abstract S198.
  5. Harrison CN, Garcia JS, Somervaille TCP, et al. Addition of navitoclax to ongoing ruxolitinib therapy for 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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