Findings from several large phase 3 studies along with continued development of emerging therapies promise to alter the treatment landscape for patients with myelodysplastic syndromes.
Traditionally, the treatment backbone for patients with myelodysplastic syndromes (MDS) has been supportive care for the symptomatic cytopenias and anemia that characterize the malignancy.1 That paradigm is likely to change, however, with the development of novel drug regimens across the MDS risk spectrum, according to an international panel of experts.
Findings from several large phase 3 studies along with continued development of emerging therapies promise to alter the treatment landscape, experts said during a recent OncLive Peer Exchange® program. The panelists discussed diagnostic issues as well as data on investigational agents presented during the 64th American Society of Hematology (ASH) Annual Meeting and Exposition in December 2022.
“We don’t have a lot of drugs today, but there are drugs in development with a lot of promising [signals] in low-risk and high-risk MDS,” Thomas Cluzeau, MD, PhD, said. “We hope to have a new standard very soon to improve outcomes for our patients.”
“We are in a transition period,” Guillermo Garcia-Manero, MD, added. “We need to see [findings] from phase 3 trials. Hopefully, some of them will be positive.”
Specifically, Garcia-Manero mentioned 4 such trials: the COMMANDS study (NCT03682536) comparing luspatercept-aamt (Reblozyl) with epoetin alfa in treatment-naïve patients; the VERONA trial (NCT04401748) evaluating venetoclax (Venclexta) with or without azacitidine; the ENHANCE study (NCT04313881) testing magrolimab or placebo with azacitidine; and the IMerge trial (NCT02598661) evaluating imetelstat vs placebo. Additionally, the panelists discussed the prospects for sabatolimab, which is being studied in combination with hypomethylating agents (HMAs) in the phase 3 STIMULUS-MDS2 trial (NCT04266301). (Table)
Rami Komrokji, MD, who moderated the program, added that perceptions about MDS have changed over the years, noting that there was a time when insurance carriers would not recognize MDS as a type of cancer. “I think we’ve made progress in making people know that MDS is really a serious disease,” he said.
The term MDS describes a group of myeloid disorders marked by 1 or more peripheral blood cytopenias that carry a risk of progression to acute myeloid leukemia (AML).1,2 Most patients with MDS experience anemia and anemia- related symptoms that can negatively affect quality of life. Treatment options are limited, and relapse rates are high.2 The FDA has approved 6 therapies to treat specific types of MDS,3 but many patients are not eligible for these regimens.
“Myelodysplastic syndromes are essentially bone marrow failure syndromes,” Sanam Loghavi, MD, said. “Patients typically present with sequela cytopenias. Anemia can be shortness of breath, tiredness, or infections if they have leukopenia or neutropenia, and then thrombocytopenia can present with bleeding.”
Other potential causes for cytopenias must be ruled out before proceeding to a bone marrow biopsy, which is the gold standard for making a diagnosis of MDS, Loghavi said. “Nowadays, really, adequate diagnosis and prognostication of MDS require molecular and cytogenetic testing, which includes a conventional karyotype and FISH [fluorescence in situ hybridization]. You don’t necessarily have to do it all, but it can be a constellation. Most academic and private practice settings now have panel-based next-generation sequencing testing that covers genes that are recurrently mutated in myeloid malignancies.”
Risk stratification through tools such as the International Prognostic Scoring System (IPSS) and its revised version (IPSS-R) is essential for the initial work-up of patients with MDS and for guiding the treatment course.2 The IPSS-R system takes into account prognostic variables such as the patient’s cytogenetic profile, percentage of marrow blasts, hemoglobin level, platelet counts, and absolute neutrophil counts. Overall scores range from very low (≤ 1.5) to very high (> 6.0).3 “At the end, we are just trying to put patients into 2 major categories: higher risk, where we’re thinking of transplant immediately, and lower risk, where we could go stepwise, managing cytopenias,” Komrokji said.
One agent that is making waves in the MDS treatment space is luspatercept, a recombinant fusion protein that binds selectively to transforming growth factor β ligands, thereby decreasing SMAD2 and SMAD3 signaling. Reduction of SMAD2 and SMAD3 signaling has been shown to reduce erythroid hyperplasia, enhance erythroid maturation, and increase hemoglobin levels in mouse models of MDS.4 The therapy is categorized as an erythroid maturation agent.5
Luspatercept was evaluated for safety and efficacy among patients rated on the IPSS-R system as having very low-, low-, or intermediate-risk MDS in the phase 3 MEDALIST trial (NCT02631070). The trial enrolled adult patients with ring sideroblasts who had been receiving regular red blood cell (RBC) transfusions and were either refractory to erythropoiesis-stimulating agents (ESAs) or unlikely to respond to them. Patients were randomly assigned to receive either luspatercept at a dose ranging from 1.0 mg/kg to 1.75 mg/kg (n = 153) or placebo (n = 76), both administered subcutaneously every 3 weeks for 24 weeks.4
The median age of patients enrolled on the trial was 71 years (range, 26-95). Most patients were men (63%), had an IPSS-R risk category of low (72%), and had MDS with refractory cytopenia with multilineage dysplasia (96%). The median time since the original diagnosis of MDS was 41.8 months (range, 3-421).4
The primary end point of the study was transfusion independence (TI) for 8 weeks or longer during weeks 1 through 24.4
Results from the trial showed that at the May 8, 2018, data cutoff, 38% of patients in the luspatercept arm achieved TI for 8 weeks or longer compared with 13% of patients in the placebo arm (P < .001). During the first 24 weeks of treatment, 28% of patients who received luspatercept had TI for 12 weeks or longer compared with 8% in the placebo group (P < .001). Over weeks 1 through 48, the TI rate for at least 12 weeks was 33% vs 12%, respectively.4
Regarding safety, the most common adverse effects (AEs) of any grade in the investigational arm included fatigue (27%), diarrhea (22%), and nausea (20%). In the control arm, the most commonly occurring any-grade AEs consisted of peripheral edema (17%), cough (13%), and fatigue (13%). Seven patients who received luspatercept had a dose reduction due to AEs and 13 patients discontinued treatment with the agent due to AEs.
In light of the strong findings from the MEDALIST trial, the FDA approved luspatercept in April 2020 for the treatment of anemia failing an ESA and requiring 2 or more RBC units over 8 weeks in adult patients with very low-risk to intermediate-risk MDS with ring sideroblasts.5
Additional findings from MEDALIST presented during the 2022 American Society of Clinical Oncology Annual Meeting showed that, at a data cutoff of January 15, 2021, 31.4% (95% CI, 24.12%39.39%) of patients who received luspatercept achieved RBC TI for at least 16 weeks compared with 7.9% (95% CI, 2.95%-16.40%) in the placebo arm (odds ratio [OR], 5.90; 95% CI, 2.34-14.90; P < .0001). Additionally, patients who received luspatercept progressed to high-risk MDS or AML at a rate of 8.5% vs 6.6% for those treated with placebo. The median cumulative duration of response was 80.7 weeks (95% CI, 53.71–154.14) vs 21.0 weeks (95% CI, 10.86-not evaluable [NE]), respectively.6
The study was not powered to evaluate progression-free survival (PFS) or overall survival (OS) but showed the potential of luspatercept to enhance outcomes for patients in certain subgroups. For the intent-to-treat population, median PFS was not significantly different with luspatercept (P = .3514). Treatment with luspatercept also had a minimal impact on OS compared with placebo (P < .9604).7
However, treatment with luspatercept was associated with a higher 36-month OS rate (77.8%) for the 18 patients in the study with IPSS-R very low-risk disease (OR, 17.50; 95% CI, 1.56-196.32; P = .0088), as well as a high 36-month PFS rate (97.3%) in the 37 patients with a baseline serum erythropoietin level of 100 to less than 200 U/L (OR, 9.60; 95% CI, 0.9993.16; P = .0238). Comparatively, these rates were 16.7% and 78.9% , respectively, in the corresponding subgroups that received placebo (n = 6 and n = 19, respectively).7
“I’m wondering if data from the MEDALIST trials should push us toward considering when to stop the ESA and move to second-line therapy,” Garcia-Manero said. “For heavily transfusion-dependent patients, an ESA may not make a lot of clinical sense. Perhaps adopting drugs like luspatercept a little bit earlier in the second line [would]….This is very exciting.”
There also has been some interest in combining luspatercept with other agents for patients with lower-risk MDS, particularly ESAs. Komrokji et al examined the activity of luspatercept plus ESA in a cohort of patients off protocol at Moffitt Cancer Center in Tampa, Florida. The rationale for combining the therapies was that ESAs stimulate early stages of erythropoiesis and luspatercept improves terminal erythroid maturation.8
From February 2020 to September 2021, 28 patients with lower-risk MDS received the combination after no response to luspatercept monotherapy (n = 18), a loss of initial response to luspatercept (n = 7), or as an initial treatment (n = 3). The treating physician chose which ESA to use as well as dosing for luspatercept and the ESA.8
Participants had a median age of 72 years (range, 51-94) and 96.4% had intermediate- or lower-risk MDS by IPSS-R. Overall, the hematologic response rate following treatment with the combination was 36%; 71% of patients who originally responded to luspatercept monotherapy responded when an ESA was added, whereas 17% of patients who did not respond to luspatercept monotherapy responded when an ESA was added.8
Two of 3 patients who received the combination as their frontline regimen displayed a hematologic response. Among patients who responded, the median duration of response from time of response to luspatercept monotherapy or combination was 18.9 months (range, 5.4-27.3). Study authors said these were the first proof-ofconcept results that displayed the synergistic activity of luspatercept plus ESA.8
Luspatercept monotherapy has demonstrated “a highly statistically significant and clinically meaningful improvement” in RBC TI compared with epoetin alfa, an ESA, as first-line therapy for adults with very low-, low-, or intermediate-risk MDS who require transfusions, according to a prespecified interim analysis of findings from the COMMANDS trial. Bristol Myers Squibb, the company developing luspatercept, said in October 2022 that detailed results would be presented at a future medical meeting.9
Besides luspatercept, multiple investigational regimens have been showing promise for patients with lower-risk MDS. Imetelstat, a first-in-class telomerase inhibitor, is being compared with placebo in patients with low- or intermediate-1–risk MDS in the ongoing phase 2/3 IMerge trial (NCT02598661). Participants have MDS that is relapsed/refractory after ESA therapy.
At the 2022 ASH Annual Meeting, Uwe Platzbecker, MD, and colleagues reported findings for a subset of IMerge participants with heavily transfused non-del(5q) disease that was relapsed/refractory to ESAs who had not received lenalidomide (Revlimid) or an HMA. As part of the study, patients received imetelstat 7.5 mg/kg via 2-hour intravenous (IV) infusion every 4 weeks.10
Of the 38 patients in this cohort, 11 achieved sustained TI for more than 1 year. Moreover, among 27 patients with ring sideroblasts, 37% maintained TI for 1 year or longer. The 11 patients who experienced TI for at least 1 year had a median independence period of 92.4 weeks (95% CI, 69.6-140.9) after a median of 126.1 weeks (range, 70.1-168.1) of treatment with imetelstat. At a median follow-up of 51.5 months, the median PFS was 34.2 months (95% CI, 25.1-39.2), the median OS was 57.0 months (95% CI, 29.4-NE), and none of the patients had progressed to AML.10
AG-946 is an investigational, small molecule, allosteric activator of wild-type and mutated RBC-specific pyruvate kinase (PK) isoforms. Acquired PK deficiency has been detected in patients with MDS, and investigators believe that RBC-specific PK enzymes may be directly involved in the development of MDS-associated anemia. AG-946 may enhance RBC survival and functionality.11
Investigators are currently recruiting patients with anemia attributed to lower-risk MDS in a phase 2a/2b proof-of-concept and double-blind randomized study (NCT05490446). The primary end point of the second portion of the study is modified hematologic improvementerythroid response.11
Investigators believe the SYK inhibitor fostamatinib (Tavalisse) may help improve hematopoiesis in MDS. The FDA approved the agent in April 2018 for the treatment of thrombocytopenia in adults with chronic immune thrombocytopenia who had an insufficient response to prior therapy.12,13
Fostamatinib is being evaluated in a phase 1 trial (NCT05030675) recruiting transfusion- dependent patients with lower-risk MDS and chronic myelomonocytic leukemia (CMML) who have not responded to ESAs or HMAs.12 As of July 2022, 5 patients, including 3 with MDS and ring sideroblasts, were treated on the study. The median age was 71 years (range, 59-82) as of July 2022.12
Early findings showed that 3 patients developed treatment-emergent AEs (TEAEs), mostly grade 1 to 2 diarrhea or constipation. There were no instances of expected on-target uncontrolled hypertension or transaminitis. At a median follow-up of 2.7 months (95% CI, 0-5.6), no responses were observed, and all 5 patients remained on the study. Investigators concluded that treatment with fostamatinib was safe up to 200 mg twice daily and noted that enrollment was ongoing to further characterize the efficacy of the agent up to this dose.12
There also is interest in the potential for low-dose HMA therapy for patients with lower-risk MDS. In July 2020, the FDA approved an oral combination of decitabine and cedazuridine (Inqovi), for patients with MDS characterized by refractory anemia, including with ringed sideroblasts and excess blasts, in the IPSS intermediate-1– , intermediate-2– , and high-risk groups.14
Garcia-Manero and colleagues are evaluating whether lowering the decitabine dose will prove effective.15
At the June 17, 2022, data cutoff, a total of 47 patients with a median age of 76 years (range, 51-88) received study treatment. The cohort of patients who received 10 mg of decitabine for 10 days was closed after 4 patients were treated due to hematologic dose-limiting toxicity (DLT), leading to cohort A3 being closed before any patients were randomly assigned to that regimen.
Overall, the hematologic response rate was 29.8%. Nearly half (47%) of the patients on the study died at the data cutoff. The median OS was 929 days (95% CI, 526-NE). The median leukemia- free survival was 690 days (95% CI, 428-934).15
Study authors selected 10-mg decitabine plus 100-mg cedazuridine daily for 5 days as the recommended phase 2 dose, noting that this regimen balanced clinical efficacy with a manageable safety profile. In the ongoing phase 2 portion of the study, investigators are comparing safety and efficacy of the dose with that of 35-mg decitabine and 100-mg cedazuridine for 3 days in a 28-day cycle.15
Investigators also plan to evaluate oral combination of decitabine and cedazuridine in combination with magrolimab, an investigational anti-CD47 monoclonal antibody, for patients with higher-risk MDS. They hope to enroll approximately 100 patients in a phase 2 single-arm, open-label study that will evaluate the safety and preliminary efficacy of the combination in patients with intermediate- to very high-risk MDS by IPSS-R.16
“Magrolimab is a CD47 antibody, and CD47 [acts as] a so-called don’t-eat-me signal,” Platzbecker said. “It’s overexpressed on myeloid progenitor cells. By capturing this, macrophage monocytes can actually target leukemic cells. That’s the concept, which initially was pioneered in patients with lymphoma with the addition of rituximab [Rituxan], sensitizing lymphoma cells to rituximab again.”
Secondary objectives of the trial include determining the pharmacokinetic profiles of oral decitabine/cedazuridine and magrolimab, additional clinical efficacy of the combination, and safety and efficacy in prespecified patient subgroups, such as patients with TP53-mutant MDS. To be eligible for enrollment, patients must have an ECOG performance score of 2 or less and previously untreated MDS.16
Investigators also have hypothesized that combining HMAs with lysine-specific demethylase 1 inhibition could be synergistic and ultimately lead to enhanced antileukemic and prodifferentiation effects in MDS. The selective lysine-specific demethylase 1 inhibitor seclidemstat plus the HMA azacitidine is under study for patients with intermediate- or higher-risk MDS and chronic myelomonocytic leukemia in a phase 1/2 trial (NCT04734990).17
Patients enrolled on the study will be treated with oral seclidemstat at 1 of 6 dosing levels (150 mg, 300 mg, 450 mg, 600 mg, 900 mg, or 1200 mg twice daily) on days 1 through 28 of each 28-day cycle during the dose-escalation phase. Participants also will receive azacitidine at 75 mg/m2 daily on days 1 through 7 of each cycle.17
As of July 2022, 3 patients were treated with seclidemstat 150 mg and 3 received the agent at a dose of 300 mg. Five patients were evaluable for toxicity and efficacy; no DLTs were reported. All patients experienced TEAEs, but none were of grade 3 severity. Dose interruption occurred in 1 patient due to grade 2 creatinine elevation, but treatment was resumed following normalization of creatinine levels.17
At a median follow-up of 4.3 months (95% CI, 2.0-6.6), with a median of 3 (range, 2-4) cycles of therapy, 2 patients displayed a response. Of these respondents, 1 patient who was treated at the 150-mg dose experienced a marrow complete response with a partial cytogenetic response, and 1 patient treated at the 300-mg dose experienced a marrow complete response. Two patients, both treated at the 300-mg dose, remained on study.17
Another HMA-containing regimen is being examined for patients with intermediate- to higher-risk MDS in the phase 2 STIMULUS-MDS1 trial (NCT03946670). In this study, sabatolimab (MBG453), a novel TIM-3–targeted immunotherapy, was combined with investigator’s choice of azacitidine or decitabine. Patients received sabatolimab 400 mg or placebo in addition to either IV or subcutaneous azacitidine 75 mg/m2 or decitabine 20 mg/m2 IV.18
At a median follow-up of 24 months, patients in the sabatolimab arm (n = 65) experienced a median PFS of 11.1 months (95% CI, 7.6-17.6) compared with 8.5 months (95% CI, 6.9-11.3) in the 62-patient placebo arm (HR, 0.749; 95% CI, 0.479-1.173; P = .102). The updated complete remission rate was 23.1% (95% CI, 13.5%-35.2%) vs 21.0% (95% CI, 11.7%-33.2%), respectively.18
Although the complete response and PFS findings were not statistically significant, study authors noted that better duration of response f indings may suggest a delayed-onset benefit of adding sabatolimab to an HMA. The median duration of complete remission was 18.0 months (95% CI, 6.5-not reached) compared with 9.2 months (95% CI, 5.1-15.1) in the sabatolimab and placebo arms, respectively. A potentially preferential effect was also observed for patients with a lower disease burden. STIMULUS-MDS2 is an ongoing phase 3 trial with a primary end point of OS that investigators hope will more clearly define the efficacy of sabatolimab plus an HMA.18
Finally, investigators are seeking to add a therapeutic option for patients with relapsed/refractory MDS who have experienced treatment failure with HMAs. In a phase 1b study (NCT02936752), the investigational histone deacetylase inhibitor entinostat was added to the anti–PD-1 antibody pembrolizumab (Keytruda) for patients with MDS or oligoblastic AML.19
The overall cohort of 28 patients had a median IPSS-R of 5.5 (range, 2-10). Two DLTs were observed at the higher dose level and 4 patients died while on study. At a median follow-up of 5.9 months (range, 0.5-59.1), the median OS was 6.9 months (95% CI, 4.8-13.6). Investigators noted that the combination was well tolerated but showed limited efficacy. Additional correlative studies are planned.19