ASH 2023: Coverage in MDS, Myeloproliferative Disease

COMMANDS: Updated Data for Luspatercept to Treat Anemia in ESA-Naive Patients With Lower-Risk MDS Presented at ASH

Updated results from the primary analysis of the phase 3 COMMANDS trial (NCT03682536) continue to show benefits of luspatercept-aamt (Reblozyl) compared with epoetin alfa for treatment of anemia in patients with myelodysplastic syndromes (MDS), among those not previously treated with erythropoiesis-stimulating agents (ESAs) but who may require red blood cell transfusions.¹

Guillermo Garcia-Manero, MD | Image: MD Anderson

The data were presented on December 9, 2023, during the 65th American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego, California. These results updated the interim analysis presented at the American Society of Clinical Oncology (ASCO), which led to the approval for luspatercept for this group of patients in late August.²

“These data from the COMMANDS trial, including additional patients and longer follow-up from the data shown at ASCO, confirm the positive outcome of the interim analysis with superior efficacy and durability compared [with] ESAs and exemplify how [luspatercept] may impact the treatment of anemia related to MDS,” Guillermo Garcia-Manero, MD, lead investigator and chief of the section of myelodysplastic syndromes at The University of Texas MD Anderson Cancer Center in Houston, said in a statement. “Further, beyond the intent-to-treat population, the analysis confirms that [luspatercept] demonstrated clinical benefit across subgroups.”³

The treatment is being developed and commercialized through a global collaboration with Merck as of November 2021 and awaits action from the European Commission.

Results
The analysis presented at ASH involved 363 patients randomly assigned 1:1 to receive luspatercept or epoetin alfa. Results presented were from the analysis of the intent-to-treat population, with a cutoff date of March 31, 2023, a median treatment duration of 51.3 (3-196) and 37.0 (1-202) weeks for luspatercept and epoetin alfa, and a median follow-up of 17.2 (1-46) and 16.9 (0-46) months, respectively. The treatment length was approximately 10 weeks longer at this analysis than at the ASCO presentation.⁴ Results showed the following:

• A total of 110 patients (60.4%) who received luspatercept vs 63 patients (34.8%) who received epoetin alfa achieved the primary end point of being independent from red blood cell transfusions for at least 12 weeks, alongside a mean hemoglobin increase of at least 1.5 g/dL within the first 24 weeks (P < .0001). Only 63 patients (34.8%) in the epoetin alfa group achieved this end point.
• An erythroid response increase of at least 8 weeks was achieved by 135 patients (74.2%) who received luspatercept vs 96 patients (53%) who received epoetin alfa (P < .0001).
• Red blood cell transfusion independence of at least 12 weeks was achieved by 124 patients (68.1%) in the luspatercept group vs 88 (48.6%) in the epoetin alfa group (P < .0001).
• Duration of response was 126.6 weeks (99-NE) for luspatercept in patients who achieved transfusion independence for at least 12 weeks (achieved weeks 1-24) compared with 89.7 weeks (61.9-123.9) for epoetin alfa (HR, 0.586; 95% CI, 0.380-0.904; P = .0147).
• Common treatment-emergent adverse events in at least 10% of patients were diarrhea, fatigue, COVID-19, hypertension, dyspnea, nausea, peripheral edema, asthenia, dizziness, anemia, back pain, and headache. Rates of patient-reported fatigue and asthenia decreased over time. The share of patients who progressed to acute myeloid leukemia and total deaths were similar between arms of the study.

Subanalyses confirmed patients taking luspatercept had similar or better transfusion independence than those taking epoetin alfa across a range of clinical subgroups, including mutational profile, Molecular International Prognostic Scoring System status, ring sideroblast status, transfusion burden, and serum erythropoietin level. Duration of transfusion independence also favored luspatercept across all subgroups, according to the results.

References
1. Garcia-Manero G, Platzbecker U, Santini V, et al. Efficacy and safety of luspatercept versus epoetin alfa in erythropoiesis-stimulating agent (ESA)-naive patients (Pts) with transfusion-dependent (TD) lower-risk myelodysplastic syndromes (LR-MDS): full analysis of the COMMANDS trial. Blood. 2023;142(suppl 1):193. doi:10.1182/blood-2023-178596
2. US FDA approves Bristol Myers Squibb’s Reblozyl (luspatercept-aamt) as first-line treatment of anemia in adults with lower-risk myelodysplastic syndromes (MDS) who may require transfusions. News release. Bristol Myers Squibb. August 28, 2023. Accessed December 16, 2023. https://bit.ly/3Rp0RtJ
3. Bristol Myers Squibb presents primary efficacy and safety analysis of the phase 3 COMMANDS trial of Reblozyl for treatment of anemia in erythropoiesis stimulating agent-naïve patients with lower-risk myelodysplastic syndromes at ASH 2023. News release. Bristol Myers Squibb. December 9, 2023. Accessed December 16, 2023. https://bit.ly/47Zs1P7
4. Caffrey M. ASCO 2023: myelodysplastic syndromes. Am J Manag Care. 2023;29(SP6):SP494-SP495.

Data Show Trend Toward Improved Persistence After 6 Months With Oral MDS Regimen

New results show that the oral hypomethylating agent (HMA) decitabine and cedazuridine (DEC-C), approved for treatment of myelodysplastic syndromes (MDS) in July 2020 may improve persistence beyond the 6-month mark compared with HMA agents given intravenously (IV) or subcutaneously (SC).

Real-world data presented in an abstract at the 65th American Society of Hematology Annual Meeting and Exhibition in San Diego, California, show “comparable persistence” between the different formulations in the early stages of therapy, but by the 6-month mark, a persistence advantage emerged with the oral regimen that increased in later months.

While the trend favored the oral regimen, the authors said it did not reach statistical significance.

The authors said theirs was the largest study of real-world data to date involving the oral MDS regimen. The retrospective analysis used data from the US Cerner Enviza claims database, with medical and prescription claims linked to mortality data. The time period covered patients who had an MDS diagnosis and initiated at least 1 claim between August 1, 2020, and August 31, 2022; the first claim served as the index date for the study. Patients were followed until the end of enrollment, death, or the end of the study. Investigators used propensity score matching to account for differences between the groups in age, gender, subsequent diagnosis with acute myeloid leukemia (AML), and red blood cell transfusions.

According to the authors, longitudinal persistence was measured by the number of cycles of therapy received during follow-up, with a cycle defined as either 3 to 10 days for receipt of IV/SC treatment or 1 claim for DEC-C, within each 28-day cycle.

Results. The analysis began with 1569 patients, including 160 (10.2%) who received DEC-C and 1409 (89.8%) who received IV/SC HMAs. Patients in the DEC-C group had a median age of 72.5 years and 66.9% were male. In the IV/SC group, the median age was 69 years and 58.2% were male. More than two-thirds of patients in both groups had switched from a prior IV/SC HMA treatment, and the groups were well balanced for levels of comorbidity; in the 6 months prior to their index date, 55.3% of patients in both groups received transfusions.

After matching, there were 158 patients in each treatment group. Median age was 72 years in the DEC-C group and 74 years in the IV/SC group. The groups were 66.5% and 69.6% male, respectively. Rates for comorbidities and AML diagnoses were comparable.

During the first 6 months after the index date, persistence was comparable between the 2 groups, with similar shares of each group receiving the maximum number of treatment cycles: at 2 months, it was 73.8% for DEC-C vs 71.1% for IV/SC; at 4 months, 46.5% vs 48.7%; and at 6 months, 28.6% vs 24.8%.

After that, the authors wrote, “a trend towards improved persistence with DEC-C versus IV/SC HMAs was observed,” with the oral regimen pulling away: at 8 months, 25.0% vs 17.0%; at 10 months, 18.5% vs 9.0%; at 12 months, 11.4% vs 7.6%. The number of days to discontinuation of treatment was higher for the oral regimen group compared with the IV/SC treatment group, at 87.7 days vs 82.0 days. Neither of these differences reached statistical significance.

Nonetheless, the authors concluded, “These data support the consideration of oral DEC-C as an alternative to chronic parenteral HMA therapy, with the potential for oral DEC-C to reduce the treatment burden associated with the administration of IV/SC HMAs.”

Oral decitabine and cedazuridine is marketed as Inqovi by Taiho Oncology, which provided funding for the study. 

Reference
Zeidan AM, Costantina H, Modi K, Salimi T, Washington T, Epstein RS. Real-world treatment patterns among patients with myelodysplastic syndromes initiating oral decitabine and cedazuridine or intravenous/subcutaneous hypomethylating agents. Presented at: 65th American Society of Hematology Annual Meeting and Exposition; December 9-12, 2023; San Diego, CA. Abstract 548. https://ash.confex.com/ash/2023/webprogram/Paper188638.html

Analysis Shows Momelotinib Offers Improved Maintenance of Red Blood Cell Status for Patients With Myelofibrosis Anemia

An analysis using data from recent trials involving momelotinib, approved in September 2023 as Ojjaara (GSK), finds that this treatment for anemia in patients with myelofibrosis offers them more ability to avoid red blood cell transfusions than comparator treatments. For those with prior treatment with a Janus kinase (JAK) inhibitor, momelotinib offered a higher likelihood of maintaining or even improving transfusion status.^1,2
The data for momelotinib, a JAK1/JAK2/activin A receptor type 1 inhibitor, were presented at the 65th American Society of Hematology Annual Meeting and Exposition in San Diego, California.²

Ruben Mesa, MD

Authors led by Ruben Mesa, MD, president and executive director of Atrium Health Levine Cancer and Atrium Health Wake Forest Baptist Comprehensive Cancer Center, describe anemia as “cardinal feature” of myelofibrosis, a bone marrow cancer that disrupts blood cell production. Myelofibrosis must often be managed with red blood cell transfusions, which the authors say are “a negative prognostic factor for overall survival and are associated with diminished quality of life and increased healthcare-related economic burden.”²

The authors evaluated data from the phase 3 SIMPLIFY-1 (NCT01969838) and MOMENTUM (NCT04173494) trials.^3,4 SIMPLIFY-1 compared momelotinib to ruxolitinib in patients with myelofibrosis who had not received a JAK inhibitor, while MOMENTUM compared momelotinib to danazol in patients who had received a JAK inhibitor. This analysis culled data for prespecified anemia end points, which were defined as no transfusions for at least 12 weeks before the end of week 24, with all hemoglobin levels at least 8 g/dL.

Across both trials, they found, more than 85% of patients treated with momelotinib “maintained or improved transfusion intensity.”

Results Detailed
In SIMPLIFY-1, 70% of evaluable patients (150 of 213) receiving momelotinib and 76% of those receiving ruxolitinib (163 of 216) required zero transfusions every 28 days at baseline. Among these patients, 95% (142 of 150) taking momelotinib maintained their status over 24 weeks compared with 57% (93 of 163) of patients taking ruxolitinib. The transfusion burden dropped for the momelotinib arm by 0.10 units per 28 days and increased by 0.39 units per 28 days in the ruxolitinib arm. When evaluating patients based on prior transfusion need, 87% of patients in the momelotinib arm maintained (67.6%) or improved (19.2%), compared with 54% of the ruxolitinib arm, which saw 43.5% maintain transfusion status and 10.6% improve.

In MOMENTUM, the authors reported, “most patients had some transfusion requirement at baseline.” In the momelotinib arm, 20% (26 of 130) required transfusion at baseline, compared with 17% (11 of 65) for the danazol group. During the trial, a higher share of those taking momelotinib maintained their zero-transfusion status—35% (46 of 130 patients) in the momelotinib arm vs 17% (11 of 65) in the danazol arm. In addition, patients who started the trial with zero transfusion status were more likely to maintain it in the momelotinib arm (92% vs 64%). The transfusion burden per 28 days declined 0.86 units from baseline among patients receiving momelotinib compared with 0.28 units for danazol. In evaluating how well patients did compared with their transfusion needs prior to the trial, 85% in the momelotinib arm maintained (19.2%) or improved (65.4%) their status compared with 63% who maintained (10.8%) or improved (52.3%) their status in the danazol arm.

“These data demonstrate that momelotinib was associated with better maintenance of red blood cell transfusion intensity and zero red blood cell transfusion status vs ruxolitinib in patients with myelofibrosis who were JAK inhibitor naive and showed greater reduction in red blood cell transfusion burden from baseline vs danazol in patients with myelofibrosis in patients with myelofibrosis who were JAK inhibitor experienced,” the authors concluded. 

References
1. Ojjaara (momelotinib) approved in the US as the first and only treatment indicated for myelofibrosis patients with anaemia. News release. GSK. September 15, 2023. Accessed January 2, 2024. https://bit.ly/46dFFNa
2. Mesa RA, Perkins, AC, Goh YT, et al. Longitudinal assessment of transfusion intensity in patients with JAK inhibitor-naïve or -experience myelofibrosis treated with momelotinib in phase 3 SIMPLIFY-1 and MOMENTUM trials. Presented at: 65th American Society of Hematology Annual Meeting and Exposition; December 9-12, 2023; San Diego, CA. Abstract 3182. https://ash.confex.com/ash/2023/webprogram/Paper177774.html
3. Mesa RA, Kiladjian JJ, Catalano JV, et al. SIMPLIFY-1: a phase III randomized trial of momelotinib versus ruxolitinib in Janus kinase inhibitor-naïve patients with myelofibrosis. J Clin Oncol. 2017;35(34):3844-3850. doi:10.1200/JCO.2017.73.4418
4. Verstovsek S, Gerds AT, Vannuchi AM, et al. Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis (MOMENTUM): results from an international, double-blind, randomised, controlled, phase 3 study. Lancet. 2023;401(10373):269-280. doi:10.1016/S0140-6736(22)02036-0