Targeted Treatment Arsenal for Myelofibrosis Set to Explode

OncologyLive, Vol. 23/No. 8, Volume 23, Issue 08

Ruben Mesa, MD, Jamile M. Shammo, MD, FASCP, FACP, Angela G. Fleischman, MD, PhD, and Stephen T. Oh, MD, PhD discuss the emerging treatment landscape in myelofibrosis.

Myelofibrosis is a highly heterogeneous disease, with patients having varying symptoms and presentations. The only cure is allogeneic stem cell transplantation; however, this treatment is not appropriate for many patients. Consequently, treatment is often aimed at controlling a variety of disease symptoms and complications while enhancing quality of life and extending survival. Over the past decade, JAK inhibitors have given an increasing number of patients with MF access to meaningful treatments that enable them to achieve these therapeutic goals.

During a recent OncLive Peer Exchange®, a panel of hematology cancer experts discussed currently approved and emerging JAK inhibitors as well as targeted agents with other mechanisms of action that are in various stages of clinical development for MF, either as monotherapies or in combination with a JAK inhibitor. They shared their insights on which patient subsets might be the best candidates for these treatments and discussed considerations for using these agents in clinical practice.

JAK Inhibitors

Three JAK inhibitors have been approved by the FDA: ruxolitinib (Jakafi), approved in November 2011; fedratinib (Inrebic), approved in August 2019; and pacritinib (Vonjo), granted accelerated approval in February 2022.1-6 Although these agents belong to the same medication class, they have distinguishing features that may help guide treatment selection (TABLE4-6). “Each patient with MF is unique; there’s not a 1-size-fits-all JAK inhibitor,” Angela Fleischman, MD, PhD, said.

Ruxolitinib: Monotherapy and Combinations

Ruxolitinib, which has now been used for more than a decade, was the first treatment to receive FDA approval for patients with MF and has been shown to be effective in reducing splenomegaly and ameliorating symptoms of MF.1 However, the agent is not appropriate for patients with very low platelet counts (< 50,000/µL). The panel noted ruxolitinib could be considered for patients with platelet counts in the 50,000/µL to 100,000/µL range; however, patients need to be able to reach a certain dosing threshold to obtain benefit. “If I can’t get above 5 mg twice a day with ruxolitinib in that kind of category, I’m not typically expecting to see a robust improvement in spleen or symptoms,” Stephen T. Oh, MD, PhD, said. “We know from the literature that, in general, you need to get to 10 mg [twice daily] of ruxolitinib to see a substantial improvement.”

An area of ongoing investigation is combining ruxolitinib with agents that have different mechanisms of action. The ongoing ADORE study (NCT04097821) is a 3-part, open-label, multicenter, phase 1/2 open-platform study assessing the safety and efficacy of ruxolitinib in combination with a variety of novel compounds for the treatment of MF, including the HDM2 inhibitor siremadlin, the P-selectin inhibitor crizanlizumab, the TIM-3 inhibitor sabatolimab, the ERK inhibitor LTT462, and the TGFβ inhibitor NIS793.7

“When I saw the design of this ADORE trial... it just goes to show you that the perfect combination isn’t known yet,” Jamile M. Shammo, MD, FASCP, FACP, said, adding that although the idea of combination therapy is intriguing, she will stick with monotherapy in the second line until there are data to support double-agent vs single-agent treatment in this setting.

“That’s my personal view, because unless you’re using a nonmyelosuppressive agent, you probably aren’t giving a full dose and you may be sacrificing some of the efficacy that had been reported initially,” she said.

Several agents have shown promise in combination with ruxolitinib. One such approach is to add the PI3Kδ inhibitor parsaclisib to ruxolitinib. In an interim analysis of a small phase 2 study (NCT02718300) that included 32 patients with a suboptimal response to ruxolitinib, the combination showed improvement in spleen volume and symptom reduction.8

According to Oh, another promising approach that may be closer to approval is combining ruxolitinib with the BCL2 inhibitor navitoclax. Investigators evaluated this combination in a small phase 2 study (NCT03222609) that included 34 adults with intermediate-risk or high-risk MF who had progressed on or had a suboptimal response to a stable ruxolitinib dose of 10 mg twice daily.

In the study, the addition of navitoclax not only led to durable, at least 35% spleen volume reductions and significant reductions in symptoms but also was associated with significant improvements in hemoglobin levels and bone marrow fibrosis grade.9

“Molecular response, and the so-called holy grail of disease modification, may be something that combination could provide,” Oh said, noting that this remains speculation and that the benefits of adding navitoclax need to be verified by phase 3 data.

Fedratinib

Fedratinib is indicated for adults with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) MF. These indications are supported by data from the phase 3 JAKARTA (NCT01437787) and phase 2 JAKARTA-2 (NCT01523171) studies.10,11 In JAKARTA, among the 96 patients who received the FDA-approved dose of 400 mg once daily, 36% achieved at least 35% spleen volume reduction and MF symptom responses (≥ 50% reduction from baseline in total symptom scores).10 In an updated analysis of the JAKARTA-2 study that used more stringent criteria for ruxolitinib failure (n = 97), 30% of patients had at least 35% spleen volume reduction and 27% of patients had MF symptom responses with fedratinib 400 mg daily.12

The road to approval for fedratinib was not easy. The FDA had placed fedratinib on hold from 2013 to 2017, after symptoms suggestive of Wernicke encephalopathy manifested in 8 of 608 study participants (1.3%) treated with this agent.13 Although fedratinib was ultimately deemed not to be directly responsible for inducing Wernicke encephalopathy, this life-threatening condition is still included as a potential complication in a boxed warning in the prescribing information. This is because clear risk factors for the condition have been identified, including thiamine deficiency and uncontrolled gastrointestinal (GI) toxicity. In JAKARTA-2, GI toxicities were the most common adverse effects (AEs), with diarrhea occurring in 62% of patients, nausea in 56%, and vomiting in 41%.14

Questions regarding fedratinib’s AE profile led investigators to initiate the phase 3b FREEDOM trial (NCT03755518), which is further evaluating the safety and efficacy of this agent in patients previously treated with ruxolitinib, including the use of strategies to prevent or mitigate thiamine deficiency and GI toxicities.14 The data indicate that GI toxicities can be reduced via early implementation of GI prophylaxis, such as use of ondansetron or loperamide, and that monitoring thiamine levels before initiating fedratinib and periodically during treatment can ensure any thiamine deficiencies are diagnosed and corrected before they become problematic.

“In terms of thiamine deficiency, I check it on every patient I have, though I’m not going to be waiting for the results. I typically would treat them accordingly but monitor the level moving forward,” Shammo said.

Ruben Mesa, MD, said he takes a more proactive approach recommending OTC thiamine as a cost-efficient option for patients. “The study would suggest that [if levels are] monitored, it’s really not as big a deal. It’s a [boxed] warning but, again, one that is relatively manageable,” he said.

Pacritinib

Prior to the approval of pacritinib, patients with cytopenic MF did not have any FDA-approved treatment options. The FDA granted the accelerated approval based on data from the phase 3 PERSIST-2 study (NCT02055781), which compared the safety and efficacy of pacritinib with best available therapy (BAT) in patients with thrombocytopenia and primary or secondary MF.3,15

Investigators randomly assigned patients with baseline platelet counts less than 100,000/µL to receive pacritinib 200 mg twice daily, pacritinib 400 mg once daily, or BAT.15 In patients with baseline platelet counts less than 50,000/ µL who received pacritinib 200 mg twice daily, 29% had at least 35% spleen volume reduction compared with 3% of patients receiving BAT, which included ruxolitinib.15

“Patients [with cytopenic MF] whose disease is JAK2 positive tend to have a lower JAK2 allele burden, or they may be triple negative for the 3 common driver mutations—JAK2, CALR, and MPL—and often other mutations that are likely contributing to the phenotype,” Oh said. “This may also dovetail with IRAK as being a target of pacritinib in the sense that IRAK signaling is involved in inflammatory cytokine production, and that may be an additional mechanism that is not entirely related or driven by JAK2 that could explain responses seen with pacritinib.”

Momelotinib

Momelotinib is an investigational JAK inhibitor targeting JAK1, JAK2, and ACVR1 that is in latestage development.16 It is being assessed in the phase 3 MOMENTUM trial (NCT04173494), in which investigators are comparing momelotinib with the steroid danazol in symptomatic and anemic patients with MF who have previously been treated with an FDA-approved JAK inhibitor. Momelotinib’s clinical development program is extensive, having already included more than 20 phase 1, 2, and 3 clinical studies that have collectively enrolled more than 820 patients with MF, with some being treated 10 or more years.

Two previously conducted phase 3 trials assessing momelotinib monotherapy are SIMPLIFY-1 (NCT01969838) and SIMPLIFY-2 (NCT02101268), results of which showed responses in symptom, spleen volume, and anemia end points.16 Investigators of MOMENTUM will assess these metrics and evaluate associations between anemia benef it, transfusion burden, and patient-reported measures of clinical benefit.16 “I’m hopeful that again we’re going to evolve to this state of [having] up to 4 JAK inhibitors [available] but with some areas of differences, differentiation, and importance between them,” Mesa said.

BET Inhibitor Pelabresib

Mesa said a range of drugs with different mechanisms of action are under evaluation for MF, with pelabresib (CPI-0610) being one of the furthest along in clinical development. Pelabresib is a potent, first-in-class, selective, oral small-molecule inhibitor of bromodomain and extraterminal (BET) proteins.17 The agent works by modifying the expression of genes involved in nuclear factor kappa B (NFκB) signaling, which is hyperactive in MF.

Pelabresib showed signals of clinical activity in the phase 1/2, open-label MANIFEST trial (NCT02158858), which investigated this agent as a monotherapy in transfusion-dependent and non–transfusion dependent patients with advanced MF who were intolerant/refractory to ruxolitinib or ineligible to receive ruxolitinib.17 “[MANIFEST investigators] measured the cytokines along [the NFκB] pathway and demonstrated that not only do you have a spleen volume reduction, reduction in total symptom score, and reduction in transfusion dependency in those who were transfusion dependent, but also you have a reduction in the cytokine signature that may be along the pathway of NFκB,” Shammo said. “This goes along with the proof of concept that the agent isn’t only effective but also works through that mechanism of action, and that presumably is why it’s effective.”

Pelabresib is being evaluated in the phase 3 MANIFEST-2 trial (NCT04603495). Approximately 400 treatment-naïve patients with MF will be randomly assigned to receive pelabresib plus ruxolitinib or placebo plus ruxolitinib.18 The study’s primary outcome measure will be splenic response at week 24 and the secondary outcome measure will be total symptom score response at week 24. Mesa said MANIFEST-2 will be the first study to examine an alternative path to monotherapy with a JAK inhibitor as up-front therapy.

References

  1. Mascarenhas J, Hoffman R. Ruxolitinib: the first FDA approved therapy for the treatment of myelofibrosis. Clin Cancer Res. 2012;18(11):30083014. doi:10.1158/1078-0432.CCR-11-3145
  2. FDA approves fedratinib for myelofibrosis. FDA. Updated August 16, 2019. Accessed March 28, 2022. bit.ly/3IFr1lK
  3. FDA approves drug for adults with rare form of bone marrow disorder. Updated March 1, 2022. Accessed March 28, 2022. bit.ly/3iFLQmq
  4. Jakafi. Prescribing information. Incyte; 2021. Accessed March 28, 2022. bit.ly/3uyiA6z
  5. Inrebic. Prescribing information. Celgene Corporation; 2021. Accessed March 28, 2022. bit.ly/35goXCW
  6. Vonjo. Prescribing information. CTI BioPharma Corp; 2022. Accessed March 28, 2022. bit.ly/3iGbEyG
  7. Ross DM, Heidel FH, Perkins AC, et al. ADORE: a randomized, open-label, phase 1/2 open-platform study evaluating safety and efficacy of novel ruxolitinib combinations in patients with myelofibrosis. Presented at: 63rd American Society of Hematology Annual Meeting and Exposition; December 10-13, 2021; Atlanta, GA. Abstract 1489. Accessed March 31, 2022. bit.ly/3JZLH9q
  8. Yacoub A, Borate U, Rampal R, et al. Add-on parsaclisib (a PI3K5 inhibitor) in patients with myelofibrosis and suboptimal response to ruxolitinib: interim analysis from a phase 2 study. Clin Lymphoma Myeloma Leuk. 2021;21(suppl 1):S354-S355. doi:10.1016/S21522650(21)01819-X
  9. 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. J Clin Oncol. Published online February 18, 2022. doi:10.1200/ JCO.21.02188
  10. Pardanani A, Harrison C, Cortes JE, et al. Safety and efficacy of fedratinib in patients with primary or secondary myelofibrosis: a randomized clinical trial. JAMA Oncol. 2015;1(5):643-651. doi:10.1001/jamaoncol.2015.1590
  11. Harrison CN, Schaap N, Vannucchi AM, et al. Janus kinase-2 inhibitor fedratinib in patients with myelofibrosis previously treated with ruxolitinib (JAKARTA-2): a single-arm, open-label, non-randomised, phase 2, multicentre study. Lancet Haematol. 2017;4(7):e317-e324. doi:10.1016/S2352-3026(17)30088-1
  12. Harrison CN, Schaap N, Vannucchi AM, et al. Fedratinib in patients with myelofibrosis previously treated with ruxolitinib: an updated analysis of the JAKARTA2 study using stringent criteria for ruxolitinib failure. Am J Hematol. 2020;95(6):594-603. doi:10.1002/ajh.25777
  13. Mullally A, Hood J, Harrison C, Mesa R. Fedratinib in myelofibrosis. Blood Adv. 2020;4(8):1792-1800. doi:10.1182/bloodadvances.2019000954
  14. Gupta V, Yacoub A, Verstovsek S, et al. Safety and tolerability of fedratinib (FEDR), an oral inhibitor of Janus kinase 2 (JAK2), in patients with intermediate- or high-risk myelofibrosis (MF) previously treated with ruxolitinib (RUX): results from the phase 3b FREEDOM trial. Blood. 2021;138(suppl 1):389. doi:10.1182/blood-2021-147607
  15. CTI BioPharma announces FDA accelerated approval of Vonjo (pacritinib) for the treatment of adult patients with myelofibrosis and thrombocytopenia. News release. CTI BioPharma Corp. February 28, 2022. Accessed March 29, 2022. bit.ly/3DGlSJ6
  16. Verstovsek S, Chen CC, Egyed M, et al. MOMENTUM: momelotinib vs danazol in patients with myelofibrosis previously treated with JAKi who are symptomatic and anemic. Future Oncol. 2021;17(12):1449-1458. doi:10.2217/fon-2020-1048
  17. Kremyanskaya M, Mascarenhas J, Palandri F, et al. Pelabresib (CPI-0610) monotherapy in patients with myelofibrosis – update of clinical and translational data from the ongoing Manifest trial. Blood. 2021;138(suppl 1):141. doi:10.1182/blood-2021-150172
  18. Phase 3 study of pelabresib (CPI-0610) in myelofibrosis (MF) (MANIFEST-2). ClinicalTrials.gov. Updated April 5, 2022. Accessed April 5, 2022. https://clinicaltrials.gov/ct2/show/NCT04603495