Novel Therapies Improve Survival and Symptoms in Myelofibrosis


Novel therapeutics have not only boosted outcomes in myelofibrosis, but paved the way for new combination treatment strategies, too.

Srdan Verstovsek, MD, PhD

Srdan Verstovsek, MD, PhD

Several novel therapeutics such as JAK inhibitors and luspatercept (Reblozyl) have been developed for the treatment of patients with myelofibrosis and its associated symptoms, paving the way for improved survival rates and new combination strategies over the last decade, according to Srdan Verstovsek, MD, PhD.1

“[Patients] appear to be living longer,” Verstovsek, a professor of medicine in the Department of Leukemia at The University of Texas MD Anderson Cancer Center, said in a presentation during the 25th Annual International Congress on Hematologic Malignancies. “The survival benefit does not appear to be tied to [high-risk] patients alone. We have new therapies [and patients are responding; that’s why they’re living longer. Even the lower-risk patients are living longer.”

During his presentation, Verstovsek highlighted several concepts under exploration in myelofibrosis that may help patients who are transfusion dependent, high risk, and who are experiencing splenic symptoms.

Everyday Management of Myelofibrosis

One retrospective, international study evaluated the efficacy of direct oral anticoagulants (DOACs) in patients with various types of myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis.2

The results from the study, which included 239 patients, indicated that 4.5% of patients who were on a DOAC, 4.7% who were on vitamin K antagonists (VKAs), and 8.9% of those who were off VKA, experienced thrombosis. Moreover, 2.3% of patients on a DOAC, 2.4% who were on VKA, and 0.7% who were off VKAs experienced bleeding events.

“I am always asked whether there is good evidence to use DOACs instead of coumadin [Warfarin] as the anticoagulation approach in [patients with] MPNs,” Verstovsek said. “DOACs are as active and safe as coumadin; there is now indirect evidence of their utility in MPNs, at least through this retrospective review.”

Survival has improved for patients with myelofibrosis over the past decade, according to Verstovsek.3 In a retrospective study, investigators followed more than 1000 patients who were diagnosed with myelofibrosis before and after 2010 to determine their outcomes. Notably, those who were diagnosed with the disease after 2010 had a superior overall survival (OS) vs those diagnosed before 2010 (HR, 0.70; 95% CI, 0.59-0.82; P <.001). The median OS had not yet been reached in patients with a low International Prognostic Scoring System (IPSS) score who were diagnosed between 2010 and 2020.

For patients with intermediate- to high-risk myelofibrosis, the FDA approval of ruxolitinib (Jakafi) in November 2011 had a significant impact on treatment.4 In a real-world survival analysis, investigators found that the risk of mortality was lowest and OS was longest in patients with myelofibrosis who were exposed to ruxolitinib.

Patients who were exposed to ruxolitinib post approval (n = 272) had a 1-year survival rate of 82.3% (95% CI, 76.7%-86.7%), while who were unexposed to the agent pre- (n = 278) and post-approval (n = 1127) experienced OS rates of 55.6% (95% CI, 49.4%-61.3%) and 72.5% (95% CI, 69.5%-75.2%), respectively.

“Our overall care has improved,” noted Verstovsek. “[Patients] are living longer, and 1 of the therapies, ruxolitinib—JAK inhibitors in general—give you that extra push….”

Concept #1: Anemia Therapy Plus JAK Inhibition

A lack of anemia drugs is an unmet need within the field of myelofibrosis; however luspatercept may represent a potential a solution. The agent is current being examined in in combination with ruxolitinib as part of an ongoing, open-label phase 2 ACE-5336-MF-001 study (NCT03194542).5

Two of the study cohorts included patients who had received a red blood cell transfusion within the last 12 weeks who were either not given ruxolitinib (cohort 2; n = 21) or received a stable dose of ruxolitinib (cohort 3b; n = 22). Results from the study examined responses based on rates of transfusion independence and decreases in transfusion burden.

“[Some patients in cohorts 2 and 3B] became transfusion independent for 3 months during the first 6 months of therapy [10% and 27%, respectively], who had no transfusion for 3 months throughout the entire treatment duration [19% and 36%], and [those who had] decreased transfusion requirements by at least 50% throughout the entire treatment duration [37% and 46%],” Verstovsek explained.

A phase 3 randomized study of luspatercept will soon be launched in an effort to obtain FDA approval of the agent for use in patients with myelofibrosis, according to Verstovsek.

Concept #2: First-Line JAK Inhibitor Combinations

In the phase 2 MANIFEST study (NCT02158858), investigators are examining the use of CPI-610 in combination with ruxolitinib in JAK inhibitor–naïve patients with myelofibrosis.6

Updated data demonstrated a sustained virologic response 35 (SVR35) rate of 67% (n = 42/63; 95% CI, 54%-78%), as well as a total symptom score 50 (TSS50) improvement rate of 57% (n = 34/60; 95% CI, 43%-69%).

“The best [use of this agent] is in the frontline setting where you combine CPI-610 and ruxolitinib together from day 1,” Verstovsek explained. “CPI-610 is a bromodomain inhibitor and epigenetic modifier, similar to histidine catalase inhibitors or hypomethylating agents; this is a different flavor of epigenetic modification.”

Concept #3: Adding Novel Agents in Suboptimal Responders to JAK Inhibition

Patients who have been exposed to JAK inhibitors such as ruxolitinib may not achieve an impressive response or they may lose their response over time. Adding navitoclax (previously ABT-263) to ruxolitinib may help to overcome this challenge, according to Verstovsek; this concept is currently being explored in a phase 2 study (NCT03222609).7

Results showed that the approach resulted in 27% of patients (n = 9/34) achieving an SVR of 35% or higher at week 24. Moreover, a TSS reduction of 50% or more at this time point was attained in 30% of evaluable patients (n = 6/20). Twenty-nine percent of patients (n = 10/34) experienced improvements in bone marrow fibrosis of at least 1 grade at any time.

“[Inhibiting the] BCL-XL [pathway] is what really matters for MPNs—not BCL-2,” Verstovsek explained. “These are important proteins that will help lead to the demise of the malignant cells. In this study, the combination of a BCL-XL inhibitor that is added onto [the JAK inhibitor] in suboptimal responders has a good result.” Verstovsek added that venetoclax (Venclexta) does not have a role in MPN management. “[The agent] has no role in chronic, accelerated, or even blastic phase MPN.”

The most notable treatment-emergent adverse effects (TEAEs) reported with the approach included thrombocytopenia (88%), diarrhea (68%), and fatigue (62%). Grade 3 or higher TEAEs were reported in 85% of patients, with thrombocytopenia (53%), anemia (32%), and pneumonia (12%), among the most frequently reported.

Concept #4: Novel Second-Line Approaches to Manage Spleen and Symptoms

Although not a new concept, Verstovsek expanded on the importance of utilizing novel second-line therapies to help manage splenic symptoms in patients with myelofibrosis. In the phase 2 JAKARTA-2 trial (NCT01523171), patients with intermediate- or high-risk myelofibrosis were administered fedratinib (Inrebic) after having progressed on ruxolitinib.8

“Expectations of fedratinib after ruxolitinib are, a 30% spleen volume reduction and a 27% reduction in symptoms,” Verstovsek said. “This is a fantastic option in the second-line setting if you are targeting splenic symptoms. Two studies are underway to get fedratinib labeled for use, [including] FREEDOM [NCT033755518] and FREEDOM2 [NCT03952039].”

Concept #5: Novel Second-Line Approaches to Manage Anemia and Symptoms

For patients with anemia, momelotinib (formerly GS-0387) is currently being examined as part of the phase 3 MOMENTUM trial (NCT04173494).9 This is important, as anemic symptoms are the reason why 40% of patients discontinue treatment with ruxolitinib; 30% discontinue due to splenic symptoms, according to Verstovsek.

“Drugs that target anemic symptoms such as momelotinib, a JAK1/2 and ACVR1 inhibitor, may have a role. You may recall that momelotinib was studied for splenic symptoms and didn’t make it,” Verstovsek said. “This study compares momelotinib with danazol in the second-line setting with the primary goal of improving symptoms and a secondary goal of transfusion independence.”

Verstovsek is optimistic that the agent will receive approval if the results of the study are positive. Increased understanding of myelofibrosis anemia has allowed for additional opportunities beyond momelotinib. By reducing hepcidin, red blood cell production can be restored, according to Verstovsek.

Aberrant activation of hepcidin transcription via hyperactivated ACVR1 signaling has been shown to result in functional iron deficiency anemia, said Verstovsek. It is also known that decreased hepcidin transcription restores iron homeostasis and increases hemoglobin, which can lead to various anemia benefits. Plasma iron elevation caused by momelotinib can result in erythropoiesis and red blood cell production.

“This concept, which appears to partially [explain] how momelotinib is working, is being explored with more specific drugs,” Verstovsek noted.

Concept #6: Using Novel Therapies to Prolong Survival in the Second-Line Setting

Intermediate 2 or high-risk patients who are relapsed or refractory to JAK inhibitors and have achieved a favorable OS with imetelstat (GRN163L) have been found to have other positive clinical benefits, according to data from the phase 2 IMbark trial (MYF2001; NCT02426086).10

Results from the trial showed that when imetelstat was given at a dose of 9.4 mg/kg, the agent resulted in a median OS of 28.1 months (95% CI, 22.8-31.6) vs 19.9 months (95% CI, 17.1-33.9) when given at a smaller dose of 4.7 mg/kg.

“The higher dose appears to be prolonging survival in [a population] where survival is somewhere between 15 to 20 months,” Verstovsek said.

Additionally, patients who achieved symptom response at week 24 had a trend of longer OS compared with those who did not achieve a response who were who had no assessment (HR, 0.79; 95% CI, 0.41-1.51). A SVR of 20% or greater was linked with a trend of better OS vs a 20% or greater reduction (HR, 0.44; 95% CI, 0.19-1.04). Even at a 10% or greater SVR cutoff, the trend was upheld (HR, 0.69; 95% CI, 0.38-1.27).

“We now have a phase 3 trial underway for prolonging the survival of patients in the second-line setting, comparing imetelstat to the best valuable therapy,” noted Verstovsek.

Concept #7: New Approach for Managing Very Low Platelet Counts

Lastly, the ongoing phase 3 PACIFICA study (NCT03165734) will be evaluating the use of the JAK2/FLT3 inhibitor pacritinib in patients with primary myelofibrosis, post polycythemia vera myelofibrosis, or post essential thrombocytopenia myelofibrosis who have a platelet count of less than 50 x 109/L.11 The primary end point of the study is SVR at 24 weeks, while the key secondary end points consist of TSS at 24 weeks, OS, and patient global impression of change at 24 weeks.

Based on data from the phase 3 PERSIST-1 (NCT01773187) and PERSIST-2 trials (NCT02055781), as well as findings from the phase 2 PAC203 trial, a rolling submission of a new drug application for pacritinib has been initiated for patients with myelofibrosis and severe thrombocytopenia defined as platelet counts of less than 50,000 μL.

“Hopefully, we will have this drug approved next year for this underserved area,” Verstovsek said.

Additionally, various phase 2 and single-agent studies are on the horizon, that are focused on helping a number of subgroups of patients with myelofibrosis, noted Verstovsek.

“Numerous phase 2 studies [are being done] for patients in the accelerated/blastic phase, those with cytopenias, or [that are evaluating approaches] to boost responses in patients with splenic symptoms,” Verstovsek concluded.


  1. Versovsek S. Concepts in the management of myelofibrosis. Presented at: 25th Annual International Congress on Hematologic Malignancies; February 25-28, 2021; Virtual. Accessed March 2, 2021.
  2. Barbui T, De Stefano V, Carobbio A, et al. Direct oral anticoagulants for myeloproliferative neoplasms (MPN-DOACs): results from an international study of 442 patients. Blood. 2020;136(suppl 1):42-43. doi:10.1182/blood-2020-1339229
  3. Masarova L, Bose P, Pemmaraju N, et al. Improved survival of patients with myelofibrosis in the last decade. Blood. 2020;136(suppl 1):50-51. doi:10.1182/blood-2020-142578
  4. Verstovsek S, Parasuraman S, Yu J, et al. Real-world survival among patients with intermediate- to high-risk myelofibrosis in the United States: impact of ruxolitinib approval. Blood. 2020;136(suppl 1):46-47. doi:10.1182/blood-2020-140820
  5. Gerds AT, Vannucchi A, Passamonti F, et al. Duration of response to luspatercept in patients (Pts) requiring red blood cell (RBC) transfusions with myelofibrosis (MF) – updated data from the phase 2 ACE-536-MF-001 study. Blood. 2020;136(suppl 1):47-48. doi:10.1182/blood-2020-137265
  6. Mascarenhas J, Harrison C, Patriarca A, et al. CPI-0610, a Bromodomain and extraterminal domain protein (BET) inhibitor, in combination with ruxolitinib, in JAK-inhibitor-naïve myelofibrosis patients: update of MANIFEST phase 2 study. Presented at: 2020 ASH Annual Meeting & Exposition; December 5-8, 2020; Virtual. Accessed March 2, 2021. Abstract 55.
  7. Garcia JS, Potluri J, Holes L, et al. The addition of navitoclax to ruxolitinib demonstrates efficacy within different high-risk populations in patients with relapsed/refractory myelofibrosis. Presented at: 2020 ASH Annual Meeting & Exposition; December 5-8, 2020; Virtual. Accessed March 2, 2021. Abstract 52.
  8. Harrison C, 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
  9. A study of momelotinib versus danazol in symptomatic and anemic myelofibrosis patients (MOMENTUM). Updated March 2, 2021. Accessed March 2, 2021.
  10. Mascarenhas J, Komrokji R, Cavo M, et al. Favorable overall survival with imetelstat treatment correlates with other clinical benefits in intermediate 2 or high risk myelofibrosis relapsed/refractory to Janus kinase inhibitor. Presented at: 2020 ASH Annual Meeting & Exposition; December 5-8, 2020; Virtual. Accessed March 2, 2021. Abstract 53.
  11. Harrison CN, Gerds AT, Kiladjian JJ, et al. Pacifica: a randomized, controlled phase 3 study of pacritinib vs. physician's choice in patients with primary myelofibrosis, post polycythemia vera myelofibrosis, or post essential thrombocytopenia myelofibrosis with severe thrombocytopenia (platelet count <50,000/mL). Blood. 2019;134(suppl 1):4175. doi:10.1182/blood-2019-129245
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