“Progress lies not in enhancing what is, but in advancing toward what will be.” –Kahlil Gibran
To complement The ASCO Post’s continued comprehensive coverage of the 2020 American Society of Hematology (ASH) Annual Meeting & Exposition, here are several abstracts selected from the meeting proceedings focusing on novel targeted therapies for myelofibrosis—the LSD1 inhibitor bomedemstat; the small-molecule inhibitor of BET protein CPI-0610 in combination with the JAK inhibitor ruxolitinib; the JAK1, JAK2, and ACVR1 inhibitor momelotinib; and the BCL2 inhibitor navitoclax in combination with ruxolitinib. For full details of these study abstracts, visit ashpublications.org.
Inhibitor of the Epigenetically Active LSD1
ABSTRACT 51: Phase II multinational, open-label study of bomedemstat (IMG-7289) for the treatment of advanced (primary and secondary) myelofibrosis (ClinicalTrials.gov identifier NCT03136185)1
Background: Virtually all patients with myelofibrosis exhaust the clinical benefits of ruxolitinib, illustrating the need for therapies with distinct modes of action that can improve outcomes and the patient experience. Bomedemstat is an orally active irreversible inhibitor of the epigenetically active lysine-specific demethylase 1 (LSD1). In mouse models of myeloproliferative neoplasms (MPNs), this agent was found to improve peripheral blood cell counts, splenomegaly, inflammatory cytokines, marrow fibrosis, and mutant cell burdens.2
Syed Ali Abutalib, MD
Ruben A. Mesa, MD, FACP
Methods: Key objectives are safety and reduction of spleen volume (SVR) by MRI/CT and total symptoms scores (TSS) using the self-administered MPN–Symptom Assessment Form TSS instrument. A platelet count ≥ 100,000/μL is a key inclusion criterion. All but 1 of 40 patients were previously treated with ruxolitinib.
Results: Of all enrolled patients evaluable at 24 weeks for TSS (n = 14), 86% recorded a reduction in TSS, with ~30% reporting more than a 50% reduction. Of the phase 2b patients evaluable for SVR after 12 weeks (n = 10), 100% had a reduction in spleen volume from baseline, with 20% showing more than 35% SVR. A total of 70% of evaluable patients (n = 30) had stable or improved hemoglobin (> 1 g/dL). Serially tracking 49 distinct variant allele frequencies among 22 patients, the frequency of variant alleles was reduced in 45% and stable in 41%. Cells with JAK2 mutations were more sensitive to treatment compared with CALR and MPL; clones with ASXL1 mutations showed the greatest sensitivity to bomedemstat.
Four serious adverse events, all grade 3, each occurring once, were deemed possibly related to bomedemstat: painful splenomegaly, rectal bleeding, heart failure, and headache. There have been no safety signals, dose-limiting toxicity, deaths related to drug, or progression to acute myeloid leukemia. Of 18 of the 22 phase IIb patients, 14 have completed 12 weeks of therapy.
“With dose optimization, bomedemstat improved symptom burden and reduced spleen volume without safety signals.”— Syed Ali Abutalib, MD, and Ruben A. Mesa, MD, FACP
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Clinical Implications: This is the first clinical study of bomedemstat in patients with myelofibrosis. Once-daily bomedemstat as monotherapy was reported to be well tolerated among patients with advanced myelofibrosis. With dose optimization, bomedemstat improved symptom burden and reduced spleen volume without safety signals. Additionally, improvements in fibrosis scores, anemia, and variant allele frequencies have been observed. This validates this novel target in myeloproliferative neoplasms as relevant, and it is being studied in ongoing trials in essential -thrombocythemia.
Inhibitor of Bromodomain and Extraterminal (BET) Proteins
ABSTRACT 55: Phase II MANIFEST study—CPI-0610 in combination with ruxolitinib in JAK inhibitor–naive myelofibrosis (NCT02158858)3
Background: The BET family of proteins bind to chromatin to regulate the transcription of target genes involved in multiple profibrotic pathways and is a novel therapeutic target for reducing fibrosis in myelofibrosis. CPI-0610 is a unique, first-in-class, oral, small-molecule inhibitor of BET proteins, designed to promote disease-modifying activity. The outcomes for patients who discontinue ruxolitinib are poor, with median survival of approximately 1 year. CPI-0610 may act synergistically in combination with ruxolitinib in advanced myelofibrosis. CPI-0610 in combination with ruxolitinib is currently being studied in patients with JAK inhibitor–naive myelofibrosis in arm 3 of the MANIFEST study.4
Methods: Safety (n = 64) and efficacy (n = 30) data from arm 3 of the ongoing MANIFEST study were presented. The primary endpoint was spleen volume reduction of at least 35% (SVR35) at week 24. The median ruxolitinib dose was 10 mg twice a day; the median CPI-0610 dose was 125 mg once a day.
Efficacy: A total of 63.3% of patients (19 of 30) achieved SVR35 at week 24 (median change = –52.9%). A total of 58.6% of patients (17 of 29) achieved TSS50 (≥ 50% reduction in total symptom score) at week 24 (secondary endpoint).
Safety: The most common hematologic treatment-emergent adverse events of any grade were anemia (23.4%, ≥ grade 3: 17.2%) and thrombocytopenia (20.3%, ≥ grade 3: 4.7%). These cytopenias were generally manageable with dose modifications, including reductions or interruptions. The most common nonhematologic treatment-emergent adverse events were diarrhea (26.6%, no ≥ grade 3), respiratory tract infections (18.8%, ≥ grade 3: 4.7%), nausea (18.8%, no ≥ grade 3), abdominal pain (15.6%, no ≥ grade 3), dysgeusia (14.1%, no ≥ grade 3), fatigue (12.5%, no ≥ grade 3), and headache and back pain (10.9% each, no ≥ grade 3). In all, two patients discontinued treatment due to treatment-emergent adverse events (infections unrelated to CPI-0610).
“The addition of CPI-0610 to ruxolitinib is potentially synergistic in JAK inhibitor–naive myelofibrosis.”— Syed Ali Abutalib, MD, and Ruben A. Mesa, MD, FACP
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Clinical Implications: This abstract further confirms the relevance of BET inhibition with this compound either as monotherapy or in combination. Preliminary data demonstrate the potential for the combination treatment to provide enhanced efficacy, as evidenced by higher SVR35 and TSS50 rates at week 24 compared with historical data from pivotal phase III studies. Overall, the data suggest that the addition of CPI-0610 to ruxolitinib is potentially synergistic in JAK inhibitor–naive myelofibrosis.
Also, review Abstract 56,4 where results from arm 2 of the MANIFEST study, investigating CPI-0610 as “add-on” to ruxolitinib in patients with advanced myelofibrosis who have a suboptimal response to ruxolitinib, are discussed. Early clinical data indicate that CPI-0610 as “add-on” to ruxolitinib is generally well tolerated and provided clinical benefits in most transfusion-dependent patients with myelofibrosis. Upcoming phase III trials will seek to validate both monotherapies or combination approaches with ruxolitinib (either in JAK inhibitor–naive patients or those previously exposed). If successful, this could change the monotherapy approach to front-line therapy in myelofibrosis.
Inhibitor of JAK1, JAK2, and ACVR1
ABSTRACT 54: Phase III SIMPLIFY-1 and -2 studies—Momelotinib in JAK inhibitor–naive and previously JAK inhibitor–treated intermediate- and high-risk myelofibrosis (NCT01969838 and NCT02101268).5
Background: Momelotinib is a JAK1/2 and activin receptor type 1 (ACVR1) inhibitor with demonstrated clinical activity in all three hallmarks of myelofibrosis: anemia, constitutional symptoms, and splenomegaly.6 Aberrant cytokine-driven signaling via ACVR1, a member of the transforming growth factor-β superfamily of receptors, controls iron storage and also upregulates the production of hepcidin, an iron-regulatory hormone associated with restricted erythropoiesis.6 In a phase II study, momelotinib reversed or reduced transfusion dependency in transfusion-dependent patients with myelofibrosis as well as inhibited hepcidin.6
Methods: SIMPLIFY-1 was conducted in JAK inhibitor–naive patients with myelofibrosis (n = 432) randomly assigned 1:1 to receive momelotinib or ruxolitinib over a 6-month double-blind dosing period. SIMPLIFY-2 was conducted in patients with myelofibrosis who experienced hematologic toxicity during ruxolitinib therapy (n = 156) and were randomly assigned 2:1 to receive momelotinib or best available therapy (consisting of ruxolitinib in 88% of patients) over a 6-month open-label dosing period. Following the 6-month randomized treatment period, patients originally randomly assigned to momelotinib could continue momelotinib therapy (momelotinib → momelotinib), and those randomly assigned to ruxolitinib/best available therapy were eligible to cross over to momelotinib (ruxolitinib/best available therapy → momelotinib) for additional extended treatment.
Results: In SIMPLIFY-1, overall, 40% of patients achieved a splenic response at any time during the study.
In both trials, overall survival and leukemia-free survival were similar between groups (stratified hazard ratio for overall survival = 0.99 in SIMPLIFY-1, 0.96 in SIMPLIFY-2). Robust and consistent survival outcomes were demonstrated for patients who commenced JAK inhibitor therapy with momelotinib and those dosed initially with ruxolitinib/best available therapy followed by momelotinib.
In addition, the median overall survival in SIMPLIFY-2 (momelotinib arm of 34.3 months) compares favorably with previously reported median survival, ranging from 13 to 30 months in patients who have discontinued therapy.7
Clinical Implications: Further analyses of data from the 550 JAK inhibitor–naive and previously JAK inhibitor–treated patients with myelofibrosis who received momelotinib in randomized treatment and/or extended treatment showed robust long-term survival, sustained efficacy, and durability of dosing consistent with momelotinib’s differentiated pharmacologic profile. These data demonstrate momelotinib’s potential ability to durably address the unmet needs of patients with intermediate- and high-risk myelofibrosis. Furthermore, it continues to expand evidence that effective therapies for myelofibrosis (ruxolitinib, the telomerase inhibitor imetelstat, and now momelotinib) may have a favorable impact on survival.
Inhibitor of BCL-XL
ABSTRACT 52: Phase II REFINE study—Addition of navitoclax to ruxolitinib demonstrates efficacy within different high-risk populations in patients with relapsed or refractory myelofibrosis (NCT03222609).8
Background: Ruxolitinib and the JAK2 inhibitor fedratinib are the only U.S. Food and Drug Administration–approved pharmacotherapy for patients with myelofibrosis, with limited control of all clinical manifestations of the disease. Navitoclax is an orally bioavailable, novel small molecule that targets and binds with high affinity to multiple antiapoptotic B-cell lymphoma 2 (BCL2) family proteins, including BCL-XL, BCL2, and BCL-W. The combination of these two agents has been shown to induce clinically meaningful responses in patients with myelofibrosis who no longer benefit from ruxolitinib.9 This phase II study explored whether the presence of high molecular risk or the total number of genes mutated at study entry correlated with clinical outcomes and reductions in the frequency of driver gene variant alleles following navitoclax to ruxolitinib.
“These data demonstrate momelotinib’s potential ability to durably address the unmet needs of patients with intermediate- and high-risk myelofibrosis.”— Syed Ali Abutalib, MD, and Ruben A. Mesa, MD, FACP
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Methods: Patients with myelofibrosis who did not respond to at least 12 weeks of continuous ruxolitinib therapy and experienced persistent splenomegaly were enrolled. At baseline and 6 months, mutational analyses, including variant allele frequency measurement, were performed in peripheral blood by next-generation sequencing with the 54-gene Focus::Myeloid™ panel (3% limit of detection). At baseline, 3 months, and 6 months, levels of inflammatory cytokines were measured in plasma with the 133-analyte Explorer MAP™ panel.
Results: Study endpoints at 6 months: 27% (n = 9 of 34) achieved splenic volume reduction of at least 35% by MRI imaging, 30% (6 of 20) reached at least a 50% reduction in TSS, 21% (7 of 34) had grade 1 or 2 improvement in bone marrow fibrosis, and 46% (12 of 26) had at least 10% reductions in the frequency of driver gene variant alleles.
At 6 months, clinical responses and variant allele frequency reductions were observed independent of the presence of high–molecular-risk mutations (defined with the presence of ASXL1, SRSF2, EZH2, U2AF1, and IDH1/2) and the number of genes mutated.
Ongoing cytokine analyses suggest that the combination may play a role in modulating key cytokines implicated in TSS improvement in patients with myelofibrosis who have a suboptimal response to ruxolitinib alone.
Notably, five of nine patients who achieved splenic volume reduction of at least 35% at 6 months had high–molecular-risk mutations.
Clinical Implications: This study showed that patients with myelofibrosis previously treated with ruxolitinib who then received navitoclax in combination with ruxolitinib achieved clinically meaningful spleen volume reduction, TSS improvement, reduction in bone marrow fibrosis, and reductions in the frequency of driver gene variant alleles independent of high–molecular-risk mutations and the total number of genes mutated. Apoptotic induction with navitoclax may be a treatment option for these patients to prevent or reverse JAK2 resistance and modify variant allele frequency.8 TRANSFORM-1, a phase III study of navitoclax in combination with ruxolitinib when compared with ruxolitinib in adults with myelofibrosis, is also ongoing (NCT04472598). Similar to the discussion with BET inhibition, we now will have more than one potential candidate approach for combination therapy that might change our paradigm for front-line therapy in myelofibrosis.
Dr. Abutalib is Associate Director of the Hematology and BMT/Cellular Therapy Programs and Director of the Clinical Apheresis Program at the Cancer Treatment Centers of America, Zion, Illinois; Associate Professor at the Rosalind Franklin University of Medicine and Science; and Founder and Co-Editor of Advances in Cell and Gene Therapy. Dr. Mesa is Professor of Medicine and Executive Director of the Mays Cancer Center at UT Health San Antonio MD Anderson and the Mays Family Foundation Distinguished University Presidential Chair.
DISCLOSURE: Dr. Abutalib has served on the advisory board for AstraZeneca. Dr. Mesa has received honoraria from Geron, Genentech, Novartis, AbbVie, Blueprint, Incyte, and Sierra Oncology; has served as a consultant or advisor to Baxalta, Galena Biopharma, Incyte, and Novartis; has received institutional research funding from AbbVie, Celgene, CTI, Genentech, Gilead Sciences, Imago Pharma, Incyte, NS Pharma, Pfizer, PharmaEssentia, Promedior, and Sierra Oncology; has been reimbursed for travel, accommodations, or other expenses by Incyte, Novartis, and PharmaEssentia.
1. Yacoub A, Pettit KM, Bradley TJ, et al: A phase 2 study of the LSD1 inhibitor IMG-7289 (bomedemstat) for the treatment of advanced myelofibrosis. 2020 ASH Annual Meeting & Exposition. Abstract 51. Presented December 5, 2020.
2. Jutzi JS, Kleppe M, Dias J, et al: LSD1 inhibition prolongs survival in mouse models of MPN by selectively targeting the disease alone. Hemasphere 2:e54, 2018.
3. Mascarenhas J, Harrison C, Patriarca A, et al: CPI-0610, a bromodomain and extraterminal domain protein inhibitor, in combination with ruxolitinib, in JAK-inhibitor-naive myelofibrosis patients: Update of MANIFEST phase 2 study. 2020 ASH Annual Meeting & Exposition. Abstract 55. Presented December 5, 2020.
4. Verstovsek S, Mascarenhas J, Kremyanskaya M, et al: CPI-0610, bromodomain and extraterminal domain protein inhibitor, as ‘add-on’ to ruxolitinib, in advanced myelofibrosis patients with suboptimal response: Update of MANIFEST phase 2 study. 2020 ASH Annual Meeting & Exposition. Abstract 56. Presented December 5, 2020.
5. Verstovsek S, Egyed M, Lech-Marańda E, et al: Robust overall survival and sustained efficacy outcomes during long term exposure to momelotinib in JAK inhibitor naive and previously JAK inhibitor treated intermediate/high risk myelofibrosis patients. 2020 ASH Annual Meeting & Exposition. Abstract 54. Presented December 5, 2020.
6. Oh ST, Talpaz M, Gerds AT, et al: ACVR1/JAK1/JAK2 inhibitor momelotinib reverses transfusion dependency and suppresses hepcidin in myelofibrosis phase 2 trial. Blood Adv 4:4282-4291, 2020.
7. Tang D, Taneja A, Rajora P, et al: Overall survival in patients with myelofibrosis who have discontinued ruxolitinib: A literature review. Blood 134(suppl 1):3457, 2019.
8. 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. 2020 ASH Annual Meeting & Exposition. Abstract 52. Presented December 5, 2020.
9. Harrison C, Garcia JS, Mesa R, et al: Navitoclax in combination with ruxolitinib in patients with primary or secondary myelofibrosis: A phase 2 study. Clin Lymphoma Myeloma Leuk 20:S325-S, 2020.