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Senior Member, Vice Chair
Leukemia and MDS
H. Lee Moffitt Cancer Center & Research Institute
Department of Oncologic Sciences
University of South Florida
Rami S. Komrokji, MD, has disclosed that he has received consulting fees from Acceleron, AbbVie, Agios, Bristol-Myers Squibb, Celgene, Geron, Incyte, Jazz, Novartis, and Pfizer.
Myelodysplastic syndromes (MDS) are a very heterogeneous group of neoplastic stem cell disorders, making proper diagnosis and risk stratification essential. For a proper diagnosis, obtaining a bone marrow aspirate biopsy, cytogenetic testing, and a next-generation sequencing (NGS) molecular profile to detect somatic mutations are standard. Although obtaining these results can be very challenging, they are crucial for appropriate treatment of the patient. For example, the discordance in assessing MDS bone marrow biopsies between experienced and inexperienced hematopathologists can result in up to a 20% discrepancy for this important diagnostic test.
Data from the National Institutes of Health MDS observational study and the MDS Connect Disease Registry showed that in community practices, fewer than 50% of patients had cytogenetic and molecular studies assessed, yet these studies are crucial for establishing proper diagnosis and risk assessment. Currently, risk stratification involves using the revised International Prognostic Scoring System clinical tool, integrating molecular data, and accounting for any patient-related factors. With this information we categorize patients into two broad categories: either lower-risk or higher-risk MDS groups.
Challenges and Emerging Strategies for Patients With Higher-Risk MDS
As allogeneic stem cell transplant is the only cure for patients in the higher risk group, these patients should be referred as soon as possible. The decision to transplant patients depends on the disease state and patients’ functional status and comorbidities. The challenge in the higher-risk MDS group is that with standard therapy of hypomethylating agents (HMAs) azacitidine or decitabine, fewer than 50% of patients respond, and only 20% achieve complete responses, with an average duration of 1 year. Real-life data show that the average survival for patients with higher-risk MDS is approximately 1.0-1.5 years with this standard therapy. This shows an unmet need to raise the bar for responses, particularly prior to transplant, as well as for patients who are not candidates for transplant due to coexisting comorbidities or poor functional status.
In the higher-risk group, after HMA failure there is no current standard of care, and the outcome is typically very poor. I recommend always reviewing the next-generation sequencing profile for any identifiable somatic mutations, such as IDH1 or IDH2, and considering clinical trials. If patients transformed to acute myeloid leukemia, consider intensive chemotherapy, including CPX-351 (liposomal cytarabine and daunorubicin), indicated for patients with secondary acute myeloid leukemia (AML) from MDS. Data also suggest that using the BCL2 inhibitor venetoclax as an “add-back” strategy after HMA failure may yield responses and may be a bridge to take patients to transplant. This is definitely an open area for research.
Current studies are addressing other unmet needs in these patients. APR-246 is a first-in-class small molecule that that can reactivate mutant p53, restoring its functionality and triggering apoptosis in cancer cells. In a phase II trial in combination with azacitidine, it showed efficacy in patients with TP53-mutant MDS. Final data collection from the phase III trial in similar patient groups is currently underway (NCT03745716). This is a very challenging MDS subtype associated with very poor outcome, with an average OS of less than 6 months, which makes this agent exciting.
Magrolimab, an anti-CD47 antibody, is the first drug enabling macrophages to phagocytose MDS or leukemia cells. Results from a phase Ib study suggested promising safety and efficacy in untreated patients with MDS and AML, and the drug received breakthrough therapy status from the FDA. Patient recruitment is ongoing for the phase III ENHANCE trial in treatment-naive patients with higher-risk MDS (NCT04313881).
Pevonedistat is a first-in-class small molecule inhibitor of NEDD8-activating enzyme that blocks cell-cycle progression and survival. Event-free survival (EFS) benefit with a median EFS of 21.0 vs 16.6 months (HR: 0.665; P = .076) was obtained in a phase II trial comparing pevonedistat plus azacitidine vs azacitidine. The phase III PANTHER trial in frontline MDS, AML, and chronic myelomonocytic leukemia is ongoing (NCT03268954).
Challenges and New Strategies for Patients With Lower-Risk MDS
There are several unmet challenges with lower-risk MDS. In the majority of these patients, when we treat, we are treating for cytopenias and the resultant complications. Patients are anemic, and the majority of them become blood cell transfusion-dependent over time. In a way, we treat for the cytopenias, but I think that when we achieve hematological improvement or restoration of effective erythropoiesis, we may also improve the quality of life for patients and improve the survival for patients even indirectly because of the interaction of MDS with other comorbidities.
Anemia is the major indication for treatment in the lower-risk MDS group. Historically, we start treatment with erythroid-stimulating agents (ESAs), to which almost 50% of patients will respond, with an average duration of 1-2 years before they lose response. Park and colleagues showed in a multicenter, retrospective cohort of patients (N = 1698) that the outcomes of patients after ESA failure is poor. In reality, fewer than 50% of patients with MDS after ESA failure receive subsequent treatment other than supportive blood transfusions.
Subsequent treatment options after ESA failure include lenalidomide for patients with deletion 5q, and sometimes for patients who are non–deletion 5q and who are purely anemic. Immunosuppressive therapy may help a very small subset of patients, who tend to be younger or have hypoplastic MDS. HMAs are also an option for lower-risk MDS, particularly if there is concomitant thrombocytopenia or neutropenia.
However, many of these options have a 30% response rate on average and a duration of 1-2 years, so patients are always in need of novel therapies. That is why clinical trials remain essential. For example, the FDA recently approved luspatercept, the first new drug approved for MDS in 10 years, for patients with very low to intermediate-risk MDS with ring sideroblasts who are transfusion dependent after ESA failure or with MDS/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis-associated anemia. Luspatercept is a monoclonal antibody that binds to ligands that activate transforming growth factor beta (TGF‑β) signaling in the bone marrow. TGF‑β signaling regulates erythropoiesis, which is dysfunctional in patients with MDS. Luspatercept inhibits ligand binding to TGF‑β, with the hypothesis that this will help restore erythropoiesis and improve anemia by releasing the blocking of terminal erythroid differentiation. It shows clinically meaningful benefit for those patients becoming transfusion independent or with hemoglobin increase or reduction of transfusions. Luspatercept is becoming the standard of care for patients after ESA failure in that patient subset. The ongoing, open-label, randomized, phase III COMMANDS study is currently evaluating the role of luspatercept in RBC transfusion-dependent, ESA-naive patients (NCT03682536).
In addition, there are intriguing data for imetelstat, a telomerase inhibitor that, in the phase II portion of the IMerge trial in patients with RBC transfusion-dependent MDS, showed 30% to 40% transfusion independency rates, which were durable. IMerge phase III (NCT02598661) is now recruiting patients. In the phase II study there was some suggestion that imetelstat may have disease-modifying features, as indicated by the cytogenetic and mutational malignant clone decrease observed in some patients.
Finally, oral hypomethylating agents are becoming an option for MDS patients, “oral decitabine” (decitabine and cedazuridine) was recently approved by FDA for intermediate to higher risk MDS patients with similar pharmacokinetics and pharmacodynamics to intravenous decitabine. Oral azacitidine approved recently for maintenance in acute myeloid leukemia is trying to find its role in MDS management through clinical trials.
In summary, the challenges in treating patients with MDS begin with making the correct diagnosis and risk stratification, and getting appropriate testing; then optimizing the use of current, available therapies; knowing which patients will benefit the most from each therapy, and thinking of the sequence of those treatments. We can move the therapeutic bar for patients with MDS through the clinical trials we are conducting and by incorporating doublets or even triplets into the backbone of hypomethylating agents in the higher-risk group to improve responses or the durability of responses. We hope that the landscape for MDS treatment will change dramatically in the coming years, and that all of these new agents will help clinicians provide their patients with better outcomes.
What are your most pressing questions about the care of your patients with MDS? Please let us know in the discussion box below so that we can consider them for our upcoming virtual symposium on MDS.
Be sure to join my colleagues Guillermo Garcia-Manero, MD; Jamile Shammo, MD; and me for our upcoming virtual satellite symposium at ASH 2020 on Friday, December 4, to learn more about optimizing the care of patients with MDS.