Current Methods for Prognostication and Management of Lower-Risk MDS

Uwe Platzbecker, MD

In an interview with The SOHO Daily News, Uwe Platzbecker, MD, professor of hematology and director of Medical Clinic I at the University Hospital of Leipzig in Germany, discussed findings from recent phase 3 trials and their clinical implications for daily care in patients with lower-risk myelodysplastic neoplasms (MDS).¹

The SOHO Daily News: How is lower-risk MDS differentiated from higher-risk MDS?

Platzbecker: In general, by the speed of disease progression i.e. developing secondary acute myeloid leukemia. With regard to the clear prognostication now also based on molecular abnormalities, we have a new scoring system, the Molecular International Prognostic Scoring System, which allows better prognostication of patients across all subtypes.² Based on this, we can better differentiate patients with lower-risk MDS from those with higher-risk MDS. This is important for clinical trials in the future, although not for the ones [going on] right now.

What is the current standard of care for patients with lower-risk MDS?

It is still and unfortunately rather limited for patients with lower-risk MDS. The standard in the EU is an ESA [erythropoiesis-stimulating agent] or EPO [erythropoietin] for patients [with anemia], iron chelation for patients with iron overload based on transfusions, [and] lenalidomide [Revlimid] for patients with deletion 5q, and luspatercept [Reblozyl] is approved as a second-line therapy for patients with ring sideroblastic [RS] phenotype.³ HMAs are used and approvedin the US but not in most other parts of the world.

Why did the FDA grant a priority review to the supplemental biologics license application and the European Medicines Agency (EMA) validate an applicationfor luspatercept as first-line therapy in lower-risk MDS?⁴

The novelty comes from a phase 3 study that has recently been published and presented, COMMANDS study [NCT03682536].⁵ That study investigated the head-to-head comparison of EPO/ESA-based therapy vs luspatercept in patients with lower-risk MDS [with] RS-positive or [RS]-negative disease who were ESA-näive and receiving red blood cell transfusions. The primary endpoint was transfusion independence and the concomitant increase of hemoglobin by at least 1.5 g/dL. [Findings from] the trial showed a superiority of luspatercept with regard to this primary end point but also secondary end points, including durability. These trial results can therefore be considered pivotal which may have driven [the] FDA decision.

In a subgroup analysis, all patients benefited from luspatercept with 1 [exception], where response rates were similar between the two groups, and this was in patients with the non-RS phenotype.¹ Notably, only one-third of the patients had an RS-negative phenotype in the study. But there were some signals from the trial [findings] showing that the durability was better in the luspatercept-treated patients [with] RS-negative [disease] compared with the ESA-treated patients, suggesting the benefit may come [with] a little delay in this patient cohort, but again, further studies are needed to investigate this issue. This was filed with the FDA and EMA for extension of the label of luspatercept, and [we are waiting to see] what the decision will be.

Blood cells | Image Credit: © Катерина Євтехова - www.stock.adobe.com

What other data are relevant in the lower-risk MDS space?

We have another trial, the IMerge trial [NCT02598661]; [findings have] been presented at the European Hematology Association 2023 Hybrid Congress, and is now in press with The Lancet, and the 2023 American Society of Clinical Oncology Annual Meeting.^6,7 The trial is a different study [from COMMANDS] because only patients who [had] ESA-relapsed or [ESA]-refractory [disease] were included. It’s an ESA-exposed cohort of patients with lower-risk MDS [and] with a high transfusion burden, meaning that patients had to have at least 4 units of red blood cells within 8 weeks compared with COMMANDS, where the threshold was at least 2 units of red blood cells within 8 weeks. The majority, basically two-thirds of the patients, had the RS phenotype, and the others [had the] non-RS [phenotype]. This trial investigated [patients] in a placebo-controlled way, with a 2:1 randomization to imetelstat, a first-in-class telomerase inhibitor, given every 4 weeks as an infusion as outpatient [care] vs placebo, with the primary end point of 8-week transfusion independence rate.

The study met its primary end point, [with findings] showing a superiority of transfusion independence rate in patients receiving imetelstat, which is very good news as well. There was a 40% response rate vs 15% for the primary end point. But interestingly, a substantial amount of patients, [approximately] 18%, also achieved a 1-year transfusion independence rate. So the durability was meaningful, especially given that many of these patients had a high transfusion burden, and transfusion independence is hardly achieved with currently available conventional therapies in the second line. Also important to note is that quality of life was improved, specifically fatigue.

Last but not least, we need to talk about safety. There were no new signals detected; hematologic toxicity [such as] neutropenia and thrombocytopenia occurred in the majority of the patients but was also reversible in short term in the majority of the patients, so it can be easily managed by an experienced hematologist. The new drug application was also submitted to the FDA [and accepted] on August 21, 2023.⁸ We don’t know what the future will bring, but it’s expected and hoped that the drug will be approved as a second-line therapy for all eligible patients with lower-risk MDS.

How may these trials affect sequencing therapies in this population?

This will open the avenue for new thinking with regard to sequencing. It depends very much, though, on the approval and the way the drugs will be approved in North America but also in the European Union. Luspatercept may become the new first-line option for a still to be defined large portion of LR-MDS patients. However, imetelstat could be the preferred second-line therapy, especially for patients with a high transfusion burden.

Do you have any advice for community oncologists who treat these patients?

Community oncologists have experience already with luspatercept. It’s an easy and injectable every-3-weeks agent that has a good safety profile. Based on [findings from] the COMMANDS trial, responses occurred in the majority of patients during the first 6 months, so you should not give up after 2 injections—continue and dose escalate.

For imetelstat, it’s an easy to use every-4-week intravenous infusion over 2 hours. It can be nicely done also in the outpatient setting. Cytopenias occur mainly after 2 weeks in these patients but, at least in the clinical trials, were not harmful with regard to a higher mortality rate. But still, especially in the first cycles, I would recommend very close surveillance with regard to these patients, including granulocyte colony-stimulating factor use [and] transfusion support. And depending on the nadir and what happens after the first and second cycle, the dose may be adjusted [or] reduced or the distance between the cycles could be extended. In the early phase, the first 2 cycles, patients need to be watched carefully. But longer term, patients can stay on imetelstat very safely. The neutropenia and thrombocytopenia [can be] mitigated after the first 2 or 3 cycles, so I think that practical perspective [is] quite important. As hematologic oncologists, we give cytotoxic agents to most of our patients, so this is something we can definitely handle.

_References

_{1. Platzbecker U. Update on treatment of lower risk MDS. Presented at: Society of Hematologic Oncology Annual Meeting; September 6-9, 2023; Houston, TX.}

_{2. Bernard E, Tuechler H, Greenberg PL, et al. Molecular International Prognostic Scoring System for myelodysplastic syndromes. NEJM Evid. 2022;1(7).doi:10.1056/EVIDoa2200008}

_{3. FDA approves luspatercept-aamt for anemia in adults with MDS. FDA. April 6, 2020. Accessed August 14, 2023. https://bit.ly/448xoZx}

_{4. U.S. FDA accepts for priority review supplemental biologics license application and EMA validates application for Reblozyl (luspatercept-aamt) as first-line treatment of anemia in adults with lower-risk myelodysplastic syndromes (MDS). News release. Bristol Myers Squibb. May 1, 2023. Accessed August 14, 2023. https://bit.ly/3HuiOTI}

_{5. 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/S0140-6736(23)00874-7}

_{6. Santini V, Platzbecker U, Fenaux P, et al. S164: disease modifying activity of imetelstat in patients with heavily transfused non-del(5q) lower-risk myelodysplastic syndromes relapsed/refractory to erythropoiesis stimulating agents in IMerge phase 3. Hemasphere. 2023;7(suppl):e5257893. doi:10.1097/01.HS9.0000967568.52578.93}

_{7. Zeidan AM, Platzbecker U, Santini V, et al. IMerge: results from a phase 3, randomized, double-blind, placebo-controlled study of imetelstat in patients (pts) with heavily transfusion dependent (TD) non-del(5q) lower-risk myelodysplastic syndromes (LR-MDS) relapsed/refractory (R/R) to erythropoiesis stimulating agents (ESA). J Clin Oncol. 2023;41(suppl 16):7004. doi:10.1200/JCO.2023.41.16_suppl.7004}

_{8. Geron announces FDA acceptance of new drug application for imetelstat for the treatment of lower risk MDS. News release. Geron. August 21, 2023. Accessed August 21, 2023. https://bit.ly/3QNWJ81}