Recent Approvals Signal a Bright Future for Myelodysplastic Syndromes

Jamile M. Shammo, MD

Dr. Marjorie C. Barnett-Dr. Hau C.

Kwaan Professor

Professor of Medicine

Northwestern University Feinberg School of Medicine

Hematologist

Northwestern Medicine

Chicago, IL

The emergence of risk-adapted strategies in the treatment of patients with myelodysplastic syndromes (MDS) marks a significant advance for the current treatment landscape. For many years, MDS was treated with hypomethylating agents; however, as many as 50% of patients had no response to the treatment.¹

“For many years, all we could do was provide supportive care with growth factors and transfusions for patients with low-risk disease,” said Jamile M. Shammo, MD, the Dr. Marjorie C. Barnett-Dr. Hau C. Kwaan Professor and Chair, and professor of medicine at Northwestern University Feinberg School of Medicine in Chicago, Illinois, during an interview with Targeted Therapies in Oncology. “And in patients at high risk, we had hypomethylating agents that have been shown to improve survival; however, the only curative option had been stem cell transplantation, available only to a small subset of patients,” continued Shammo, who is also a hematologist at Northwestern Medicine. “We are now seeing the impact of utilizing better tools for risk stratification that include molecular data and better outcomes with therapies that target a particular molecular aberration.”

Luspatercept-aamt

New treatments such as luspatercept-aamt (Reblozyl) have been added to the treatment algorithm of patients with low-risk disease in 2020. The agent was approved by the FDA² based on findings from the phase 3 Medalist trial (NCT02631070) in transfusion-dependent lower-risk patients with MDS with ring sideroblasts (RS), which demonstrated the efficacy of luspatercept in improving anemia in patients who were either refractory or unlikely to respond to erythropoietin stimulating agents (ESAs). A more recent report described the results of the COMMANDS study (NCT03682536)3 that evaluated luspatercept in patients who were ESA-naïve, transfusion- dependent. Findings demonstrated a superior concurrent red blood cell transfusion independence (RBC-TI) and hemoglobin (Hb) increase in patients treated with luspatercept compared with epoetin alfa (Procrit). Overall, 58.5% (n = 86) of patients who received luspatercept vs 31.2% (n = 48) of those who received epoetin alfa achieved the primary end point of RBC-TI of at least 12 weeks with a mean Hb increase of at least 1.5 g/dL within the first 24 weeks (P < .0001).³

“The COMMANDS trial was a large phase 3 study that evaluated patients who were treatment-naive, transfusion-dependent lower risk and [randomly assigned] them to [receive either] erythropoiesis-stimulating agents or luspatercept,” Shammo said. “For years, erythropoiesis-stimulating agents were a cornerstone therapy for patients with anemia or lower-risk disease,” Shammo said.

It should be noted that in general, those with transfusion dependent LR- MDS have historically had a lower response rate to ESAs. Furthermore, the trial included a substantial number of patients with ring sideroblasts whose hematological responses, when treated with luspatercept, were superior to those achieved in treated patients without RS whose erythroid response was comparable to epoetin alfa.

Investigators reported a median duration of RBC-TI of 126.6 weeks in patients treated with luspatercept compared with 77.0 weeks with epoetin alfa (HR, 0.456; 95% CI, 0.260-0.798). In the trial, patients were randomly assigned to receive luspatercept (n = 178) at 1.0 mg/kg subcutaneously every 3 weeks with a dose leveling up to 1.75 mg/ kg, or epoetin alfa (n = 178) at 450 IU/kg every week with a dose leveling up to 1050 IU/kg.³

At baseline, median transfusion burden was 3 (range, 1-10) and 64% of patients had a burden of less than 4 packed RBCs. The median baseline level was 7.8 g/dL, platelet count was 230 × 10⁹/L, and the absolute neutrophil count was 2.5 × 10⁹/L. The median time to first transfusion was 168.0 days in the luspatercept arm and 42.0 days in the epoetin alfa arm. After 8 weeks or more, 74.1% of patients had a hematologic improvement in the treatment arm compared with 51.3% of patients in the epoetin alfa arm (P < .0001). Investigators reported that if the improvement was not taken into account, RBC-TI at 12 weeks was 66.7% in the luspatercept arm vs 46.1% in the epoetin-alfa arm (P = .0002).

Treatment was discontinued in 44% of patients in the treatment arm compared with 60% in the control arm, with lack of efficacy (28 vs 57 patients), death (11 in each arm), and progressive disease (7 patients in each arm) being the most common causes.

The most common treatment-emergent adverse events (TEAEs) with luspatercept were fatigue (14.6%), diarrhea (14.6%), and peripheral edema (12.9%).

The most common grade 3/4 TEAE with luspatercept was anemia (7.3%). A TEAE of any grade was experienced by 92.1% of patients in the luspatercept arm vs 85.2% in the epoetin alfa arm.

“Findings from the COMMANDS trial are confirmatory to the Medalist trial data; however, it will now make it feasible for community oncologists to treat patients with LR-MDS with ring sideroblasts or those with SF3B1 mutation in frontline setting,” Shammo said. The question regarding sequencing of therapy in patients with lower risk disease, no RS and a low endogenous erythropoietin level, remains.

Ivosidenib

In October 2023, ivosidenib (Tibsovo) was cleared by the FDA for the treatment of IDH1-mutated relapsed or refractory MDS, based on findings from the AG120-C-001 trial (NCT02074839).4 In the study, 18 adult patients with relapsed or refractory MDS with an IDH1 mutation received oral ivosidenib daily on a 28-day cycle. All responses in the trial were complete responses (CRs), and the CR rate was 38.9% (95% CI, 17.3%-64.3%). The median time to CR was 1.9 months (range, 1.0-5.6 months), and the median duration of CR was not estimable (range, 1.9-80.8+ months).⁴

In the first stage of the trial (dose escalation), patients received ascending doses of AG-120 to establish the maximum tolerated dose or the recommended phase 2 dose. The second stage of the trial (dose expansion) evaluated 4 cohorts of patients who received AG-120 to further evaluate the safety, tolerability, and clinical activity of the recommended phase 2 dose.

“Nearly 40% of patients achieved a complete response, meaning [a] blast count [of] less than 5% in the bone marrow and near normalization of hematological parameters,” Shammo said. “The median time to achieving a response was about 2 months, so this drug is a welcome addition to the limited treatment options that we have for patients who have relapsed/refractory disease,” Shammo said.

Perhaps even more importantly, it is evident that the field is moving to understanding the underlying biology of the disease even better. “It’s proof of concept that we are moving toward treating patients dependent on the biological underpinnings of the disease,” Shammo said. “We are now evaluating patients in terms of their disease biology and using targeted therapy for that specific disease molecular characteristics. I think that is how the treatment of MDS should be employed in the future,” Shammo continued. “Treating MDS in the future is going to be more dependent on disease biology.”

Classification System

Historically, several editions of the WHO Classification of Tumours of Hematopoietic and Lymphoid Tissues, in 2001, 2008, and 2016, served as the international standard for diagnosis.⁵ However, the recent updates to the classification schema include 2 systems that are substantially different. The diagnosis of MDS will now depend on which system a practitioner/pathologist uses, namely the World Health Organization (WHO) or the International Consensus Classification (ICC) system.

The emergence of these 2 systems has created a dilemma in the field and has led to controversy about which one to follow. For example, a marrow blast count of 12% is considered MDS with increased blasts (MDS-IB-2), previously designated as MDS-EB-2 in the recent rendition of the WHO classification, whereas in the ICC classification, it references the newly created MDS/AML category.

“How should we treat patients with the new MDS/AML category today? How can we interpret and apply the results of clinical trials that have utilized a different classification schema for patient selection?” asked Shammo. “It may be a worthwhile endeavor to compare and contrast the results of the clinical trials according to the new ICC classification schema, which could inform future therapeutic decisions in this patient population,” Shammo said.

Until the harmonization of the 2 systems takes place, a conundrum remains when treating patients with increased blasts. Shammo suggests utilizing risk classifications such as the International Prognostic Scoring System (IPSS) or Revised IPSS, to predict the course of disease as both prognostic systems are agnostic to the pathological designation of the disease and generally include the percentage of leukemic blast cells in the marrow, cytogenetic abnormalities, and cytopenias.⁶

High-Risk Methylating Agents

In the high-risk patient, allogeneic hematopoietic cell transplantation is the only curative approach. The majority of MDS patients, who are typically transplant- ineligible, azacitidine, and other hypomethylating agents have been the mainstay of therapy for this patient population. The addition of venetoclax (Venclexta), a selective, potent, oral BCL-2 inhibitor, was approved in combination with hypomethylating agents for the treatment of older patients with comorbidities with newly diagnosed acute myeloid leukemia.⁷ This indication is undergoing evaluation in MDS.

The VERONA trial (NCT04401748)8 is evaluating the safety and efficacy of the combination of venetoclax and azacitidine in treatment-naive patients with high-risk MDS. The primary end points are complete remission rate and overall survival (OS). Secondary objectives are RBC-TI, platelet transfusion independence, and overall response. “We’re eagerly awaiting outcomes from this trial,” Shammo said. “The results could tell us, once and for all, if that combination is better than single-agent azacitidine.”

Another trial of interest is STIMULUS- MDS1 (NCT03946670),9 a phase 2 trial evaluating 127 patients with MDS who were randomly assigned to receive sabatolimab plus a hypomethylating agent (n = 65) vs placebo plus a hypomethylating agent (n = 62).

The combination had a median progression-free survival (PFS) of 11.1 months vs 8.5 months in the control arm (P = .102). An updated CR rate at primary analysis was 23.1% vs 21.0%, respectively. The CR plus partial remission (PR) and hematologic improvement (HI) rate was 49.2% for the treatment arm vs 37.1% in the control arm. The median duration of CR was 18.0 vs 9.2 months and median duration of CR plus PR and HI was 13.4 vs 9.2 months, and OS was 19.0 vs 18.0 months (HR, 0.905; 95% CI, 0.565-1.450).

The researchers said the combination had a favorable safety profile in patients with higher- risk MDS. Despite insignificant improvements in CR and PFS, when a longer duration of response was analyzed, the data suggest a delayed-onset benefit in the sabatolimab arm.

Next steps are for research on better characterization of the disease at baseline. “We need agreement to better define the trajectory of both low- and high-risk entities in a dynamic fashion in addition to incorporating molecular characteristics,” Shammo said. Although there are a number of clinical trials in progress, she emphasized the need to expand the understanding of the disease, which in turn will lead to improved outcomes.

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2. FDA approves luspatercept-aamt for anemia in adults with MDS. FDA. Updated April 6, 2020. Accessed November 16, 2023. https://tinyurl.com/ncafpezv

3. Platzbecker U, Della Porta MG, Santini V, et al. Efficacy and safety of luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): interim analysis of a phase 3, open-label, randomised controlled trial. Lancet. 2023;402(10399):373-385. doi:10.1016/S01406736(23)00874-7

4. FDA approves ivosidenib for myelodysplastic syndromes. FDA. October 24, 2023. Accessed October 24, 2023. https:// tinyurl.com/yc562fpp

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8. Zeidan AM, Garcia JS, Fenaux P, et al. Phase 3 VERONA study of venetoclax with azacitidine to assess change in complete remission and overall survival in treatment-naive higher-risk myelodysplastic syndromes. J Clin Oncol. 2021;39(suppl 15):TPS7054. doi:10.1200/JCO.2021.39.15_suppl.TPS7054

9. Zeidan AM, Ando K, Rauzy O, et al. Primary results of Stimulus-MDS1: a randomized, double-blind, placebo-controlled phase II study of TIM-3 inhibition with sabatolimab added to hypomethylating agents (HMAs) in adult patients with higher-risk myelodysplastic syndromes (MDS). Blood. 2022;140(suppl 1):2063-2065. doi:10.1182/blood-2022-158612