Treatment Strategies Utilizing New Agents and Existing Therapies Can Improve Outcomes in Myelofibrosis


Various phase 2 and 3 studies are currently underway utilizing both new and existing treatments in an effort to improve outcomes for patients with myelofibrosis.

Srdan Verstovsek, MD, PhD

Srdan Verstovsek, MD, PhD

Various phase 2 and 3 studies are currently underway utilizing both new and existing treatments in an effort to improve outcomes for patients with myelofibrosis, according to Srdan Verstovsek, MD, who presented on the topic during the 2021 Society of Hematologic Oncology (SOHO) Annual Meeting.1

Seven therapeutic concepts are currently in the advanced stages of research and 10 other concepts are being investigated in early-phase studies. The solutions Verstovsek mentioned use FDA-approved agents in new ways or explore novel therapies that are still being considered by the FDA.

New Treatment Concepts With Existing Therapies in MF

The first treatment concept Verstovsek highlighted during his SOHO presentation was the use of anemia therapy in combination with a JAK inhibitor. This concept is being investigated in the open-label, phase 2 ACE-536-MF-001 trial (NCT03194542) of luspatercept (Reblozyl) in patients with myeloproliferative neoplasm-associated myelofibrosis and anemia with or without red blood cell-transfusion dependence.

A total of 79 patients with MF were enrolled in the study and assessed for anemia response as it relates to hemoglobin and red blood cell transfusion independence, which are the primary end points of the study. As secondary end points, investigators evaluated time to anemia response, duration of anemia response, frequency of RBC transfusion, frequency of RBC transfusion dependence, and multiple quality-of-life outcomes.2

Luspatercept is administered to patients by subcutaneous infusion at 1.0 mg/kg with titration up to 1.75 mg/kg every 21 days for 168 days. Twenty-one patients from cohort 2 and 22 from cohort 3B received RBC transfusion within the last 12 weeks.

A 50% or higher transfusion burden reduction was seen by week 12 in 19% of patients from cohort 2 and 36% of those from cohort 3B. Verstovsek noted that “some patients had multiple episodes of response,” which shows that the concept is working. A phase 3 study is underway to confirm these phase 2 findings.

Another strategy being studied in MF clinical trials is using combination regimens in the frontline setting. A recent update to the phase 3, randomized, double-blind, active-control MANIFEST study (NCT04603495) showed that treatment with the bromodomain inhibitor pelabresib (CPI-0610) in combination with the JAK inhibitor ruxolitinib (Jakafi) may enhance efficacy and is well-tolerated in patients. Pelabresib was also found to have synergy with ruxolitinib, according to preliminary results.3

In 64 patients, SVR35 and TSS50 rates at 24 weeks were higher with pelabresib plus ruxolitinib compared with historical controls. Any-grade hematological treatment-emergent adverse events (TEAEs) were observed, including anemia (23.4%) and thrombocytopenia (20.3%), and these events were grade 3 in 17.2% and 4.7%, respectively. The most common non-hematological TEAEs were diarrhea (26.6%), respiratory tract infections (18.8%), and nausea (18.8%).

“The BET or bromodomain inhibitor pelabresib affects the expression of the genes. So, it can affect the inflammation, it can affect possibly fibrosis, the next medullary hematopoiesis by modifying the cytokines that are part of the inflammation, and it may possibly affect the function of the bone marrow by affecting the aberrant megakaryocytic differentiation. These are the cells in the bone marrow that we usually associate with amount of fibrosis. Therefore, the benefits would be through suppression of cytokine production. It would be possibly improving the red blood cell count and decrease the tumor burden overall, said Verstovsek, during his presentation.1

The final concept of using existing therapies to improve outcomes for patients with MF is adding a new medication in patients who have a suboptimal response to treatment with a JAK inhibitor. Using this strategy, an FDA-approved JAK inhibitor is still administered but its effects are enhanced with a new mechanism of action. Verstovsek explained this concept using data from the phase 2, open-label REFINE study in which the small molecule BCL-2 inhibitor navitoclax (previously ABT-263) is administered alone or in combination with ruxolitinib (NCT03222609).1,4

“This is a standard problem. We treat patients with JAK inhibitors, and we improve the condition, but not optimally. There is room for improvement,” explained Verstovsek.

Of the 34 patients with MF who were treated with navitoclax plus ruxolitinib, clinically meaningful improvement in spleen volume and total symptom score (TTS) were observed. The combination also led to a decrease in bone marrow fibrosis (BMF). Specifically, 27% of patients achieved spleen volume reduction (SVR)of at least 35% at week 24, and TSS reduction of at least 50% was observed in 30% of patients at week 24.

In terms of treatment toxicity, TEAEs were seen in all patients, with the most common being thrombocytopenia (88%), diarrhea (68%), and fatigue (62%). Eighty-five percent of patients also experienced grade 3 TEAEs with thrombocytopenia in 53%, anemia in 32%, and pneumonia in 12% being the most common. Although thrombocytopenia was prevalent with the combination, it was manageable with dose modifications.

Similar results have been achieved with the addition of the PI3K-delta inhibitor parsaclisib (INCB050465) to ruxolitinib, as tested in a phase 2 study (NCT02718300).1,5

In 32 patients with MF, the combination of parsaclisib and ruxolitinib demonstrated preliminary efficacy and was generally well-tolerated. The median percentage change in spleen volume and response at 24 weeks was -3.5% with daily and weekly dosing of parsaclisib combined with ruxolitinib and -21.8% with all daily dosing.5

New Therapies Offer New Treatment Concepts for MF

In the second-line setting of MF, new therapies may offer improvement in symptoms that patients experience in addition to improving outcomes overall, explained Verstovsek. These include improvement to splenomegaly, anemia, survival, and plantlet count.

The global randomized, controlled, open-label BOREAS study (NCT03662126) is exploring the novel MDM2 inhibitor KRT-232 in patients with TP53 wild-type relapsed or refractory MF. The study will randomize approximately 385 patients in a 2:1 fashion to received either KRT-232 240 mg once daily on day 1 through 7 of a 28-day cycle or best available therapy.6

The primary end point to be assessed in the study is the rate of SVR ≥35% at week 24, and the secondary end points include PFS, overall survival, best overall SVR ≥35%, and duration of spleen response.

Another ongoing study is the randomized, double-blind, phase 3 MOMENTUM study of momelotinib versus danazol for the treatment of symptomatic and anemic patients with MF (NCT04173494).7

“The main reason for failing JAK inhibitor in the frontline setting does not appear to be progressive splenomegaly. Maybe in a third of the patients, but the majority appears to be lowering of the blood cell count through disease process and anemia, specifically, it appears to be the leading cause for discontinuation of group selection. So, in that setting, then you need a drug that would counteract the DNA synthesis and possibly even control the spleen at the same time.”

The study will include approximately 195 patients who will be randomized 2:1 to receive momelotinib orally once daily or danazol orally twice daily.

To potentially improve survival in the second-line setting, results from the randomized, single-blind, multicenter phase 2 IMbark study (NCT02426086) imply that the use of a telomerase inhibitor in patients who failed on JAK inhibitors in the frontline setting can be promising for patients with MF.8

In 107 patients treated with imetelstat and followed for a median of 41.7 months, the median OS was 28.1 months (95% CI, 22.8-31.6) among patients treated at the highest dose of 9.4 mg/kg.

Verstovsek stated “There was a significant observation of the survival of 28 months, which is something that you will not usually expect the setting. Therefore, a phase 3 study is underway, comparing the higher dose to best available therapy in patients that fail the JAK inhibitors.”

Finally, to improve outcomes in patients with very low platelets, the phase 3 PACIFICA trial of the novel JAK inhibitor pacritinib. In about 348 patients with myeloproliferative neoplasms, pacritinib will be administered at 200 mg twice daily and compared with physician’s choice of either corticosteroids, hydroxyurea, danazol, or low-dose ruxolitinib. The primary end point of the study is spleen volume and the secondary end points include TSS, OS, safety, and quality of life.

Verstovsek concluded that many studies are underway to improve outcomes for patients with MF but the studies he highlighted appear very promising for the near future.


  1. Verstovsek S. Potential new therapeutic approaches for myelofibrosis. Presented at: t: Society of Hematologic Oncology 2021 Annual Meeting; September 8-10. Accessed September 9, 2021.
  2. Gerds AT, Vannucchi AM, 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
  3. Mascarenhas J, Harrison C, Luptakova K a, et al. MANIFEST-2, a global, phase 3, randomized, double-blind, active-control study of CPI-0610 and ruxolitinib vs. placebo and ruxolitinib in JAK-inhibitor-naive myelofibrosis patients. Blood. 2020;136(suppl 1):43. doi: blood-2020-140901
  4. Pemmaraju N, Garcia JS, Potluri J, et al. The Addition of navitoclax to ruxolitinib demonstrates efficacy within different high-risk populations in patients with relapsed/refractory myelofibrosis. Blood. 2020;136(suppl 1):49-50. doi: 10.1182/blood-2020-136938
  5. Yacoub A,, borate U, Rampal R, et al. add-on parsaclisib (a pi3k-delta inhibitor) in patients with myelofibrosis and suboptimal response to ruxolitinib: interim analysis from a phase 2 study. Presented at: 2021 European Society of Hematology Congress; June 9-17, 2021. Virtual. Accessed June 11, 2021. Abstract EP1075
  6. Verstovsek S, Al-Ali HK, Mascarenhas J, et al. BOREAS: A global phase 3 study of KRT-232, a first-in-class murine double minute 2 (MDM2) inhibitor in TP53WT relapsed/refractory (R/R) myelofibrosis (MF). J Clin Oncol. 2021;39(suppl 15). doi: 10.1200/JCO.2021.39.15_suppl.TPS7057
  7. A study of momelotinib versus danazol in symptomatic and anemic myelofibrosis patients (MOMENTUM). Accessed September 9, 2021
  8. 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: 62nd ASH Annual Meeting and Exposition; December 5-8. 2020. Abstract 53.
  9. A phase 3 study of pacritinib in patients with primary myelofibrosis, post polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis (PACIFICA). Accessed September 9, 2021.
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