Garcia-Manero Calls for New Combination Approaches in MDS

Guillermo Garcia-Manero, MD

Current standard treatments for myelodysplastic syndromes (MDS) are limited by less than optimal success rates because of genetic and clinical variability of the disease. Emerging research is currently focused on improving response rates, delaying transformation to acute myeloid leukemia (AML), and improving overall survival,¹ according to Guillermo Garcia-Manero, MD, professor in the Department of Leukemia in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston. Garcia-Manero will deliver the Plenary Session I lecture at 2:11 pm, “A Total Approach to MDS,” during the 10th Annual Meeting of the Society of Hematologic Oncology (SOHO 2022), September 28-October 1, 2022, in Houston, Texas.

“There are major new updates on the progress of managing this very complex disease,” Garcia-Manero said during an interview with The SOHO Daily News prior to the conference start. “[Approximately] 20 years ago, we developed 3 compounds for this disease—azacitidine [Vidaza], decitabine [Dacogen], lenalidomide [Revlimid]—but then there were no other FDA medication approvals until 2020,” Garcia-Manero said, who is also chief of the Section of Myelodysplastic Syndromes in the Department of Leukemia at The University of Texas MD Anderson Cancer Center.

During the plenary session, Garcia-Manero will provide an overview of the single-cell level in early stage disease and describe new molecular classifications of MDS. The gold standard for the diagnosis of MDS relies on morphologic alterations that are subject to significant subjectivity, particularly in patients with low-risk disease.^2,3 In a 2020 study (NCT01688011), Garcia-Manero et al reported that diagnostic discrepancy can occur in approximately 20% of patients at the time of initial presentation, which has significant implications for therapeutic decision-making and patient counseling.²

In addition to an update on molecular classification, Garcia-Manero will overview the emerging data on new initiatives in lower-risk disease, such as oral hypomethylating agents (HMAs) and new pathways to intervene in anemia. Currently, hematopoietic growth factors may be used to treat low-risk patients with mild pancytopenia. Treatment is dependent on erythropoietin levels. For levels less than 500 mU/mL, erythropoiesis-stimulating agents, such as recombinant human erythropoietin, may be given with or without granulocyte colony-stimulating factors (G-CSFs). Although G-CSF does not affect survival, it does appear to have a synergistic effect to improve anemia in 40% to 60% of patients.⁴

Another noteworthy development for MDS involves the addition of venetoclax (Venclexta) and magrolimab to oral azacitidine or decitabine. Magrolimab is a first-in-class anti-CD47 monoclonal antibody that was granted breakthrough therapy approval by the FDA in 2020 for the treatment of newly diagnosed higher-risk MDS in combination with azacitidine.⁵ The breakthrough therapy designation was granted based on positive preliminary results observed in a phase 1b trial, which evaluated magrolimab in patients previously diagnosed with intermediate, high, and very high-risk MDS.5 Magrolimab works synergistically with azacitidine to enhance tumor phagocytosis in AML with CD47 blockade.⁶ The pivotal phase 1b trial (NCT03248479) aims to evaluate the efficacy and safety of magrolimab monotherapy and in combination with azacitidine in MDS and relapsed and refractory AML.⁷ The study reported preliminary results of 43 patients (18 with MDS and 25 with AML), with a median age of 73 years. The expansion cohort of the trial reported data on 29 evaluable patients, with objective response in 13 (100%) of 13 patients with untreated MDS, including 54% who achieved a complete response (CR), with 39% with marrow CR. In patients with AML, 11 (69%) of 16 had an objective response, with 50% with CR. The median time to initial response was more rapid than azacitidine alone at 1.9 months.6 The success of the phase 1b trial supported the currently recruiting ENHANCE trial (NCT04313881), a phase 3, randomized, double-blind, placebo-controlled, international multicenter trial seeking to evaluate the efficacy of magrolimab in previously untreated patients with higher-risk MDS.⁸

On July 21, 2021, venetoclax, a selective BCL-2 inhibitor, also received FDA breakthrough therapy designation for the treatment of newly diagnosed higher-risk MDS.⁹ Bell et al¹⁰ reviewed medical records of 44 patients with MDS who received venetoclax in combination with HMAs across 5 institutions and reported an overall response of 59%, including 14% CR. With a median follow-up of 7.6 months, the median overall survival was 19.5%.¹⁰ Currently, there is an active phase 1b, open-label, multicenter, dose-finding study (NCT02942290) to evaluate venetoclax in combination with azacitidine in patients with newly diagnosed higher-risk MDS.¹¹ Thus far, the combination therapy has demonstrated a tolerable safety profile, with promising efficacy for patients with higher-risk MDS.

Myelodysplastic Syndromes

MDS are a heterogenous group of hematologic malignancies characterized by clonal hematopoiesis, peripheral blood cytopenia, abnormal cellular maturation, and possess the potential to transform to AML.¹² MDS is considered among the 10 most frequently diagnosed neoplasms in adults.¹³ The incidence of MDS in the United States is estimated to be approximately 4.9 per 100,000 persons, according to the Surveillance, Epidemiology, and End Results database. However, the incidence of MDS increases with age, with most cases occurring after the age of 65.⁴ Age is a major prognostic parameter on overall survival, with increased age associated with decreased survival.14 Fewer than 5% of patients with MDS are candidates for curative therapy with allogeneic hematopoietic stem cell transplantation (HSCT) because of advanced age and comorbid conditions.¹²

Clinical manifestations of MDS are variable and dependent on the severity of cytopenia. Patients with MDS may present with symptomatic anemia, infection, bleeding, or other bloodline-related complications, whereas others can be asymptomatic, with abnormalities found on a routine complete blood count.⁴ MDS may be clinically asymptomatic for many years, with gradual symptoms that progress over time.^4,12

As such, MDS treatment involves individual assessment of symptoms and risk of morbidity for each patient. As the median age at diagnosis is approximately 70 years, many patients have comorbid conditions that may affect therapy approaches. For example, patients with chronic cardiovascular or pulmonary disease may have a low tolerance to anemia.⁴

The Revised International Prognostic Scoring System has been used to guide the course of treatment, which includes supportive measures, systemic agents, or HSCT. Patients who are asymptomatic can be monitored and treated with supportive care as needed, such as transfusions or hematopoietic growth factors.¹⁴ However, patients who are lower risk are expected to survive more than 5 years without therapy, whereas very high-risk patients are expected to survive less than 1 year without therapy. Progression to AML can occur rapidly in untreated patients with higher-risk MDS.¹⁴

Azacitidine and decitabine are pyrimidine analogues, which are classified as DNA HMAs. Response to azacitidine was seen in 90% of responders by 6 cycles, thus improving survival in patients with high-risk MDS.15 Decitabine has demonstrated similar results. Current studies show HMA responses are limited and short-lived, especially in patients with poor-risk abnormalities. Efforts to identify factors to predict treatment response with molecular markers are crucially needed.¹⁶

HMA therapy remains the only option for patients who are not transplant candidates. A randomized trial with 358 higher-risk patients with MDS reported that azacitidine treatment was associated with a median survival of 24 months compared with only 15 months in patients treated with intensive chemotherapy or supportive care. However, some real-world studies with azacitidine were unable to reproduce the survival outcomes observed in randomized trials, thus HMA therapy may be even less beneficial for patients in high-risk groups than commonly presented. Furthermore, the median survival is less than 6 months for patients who fail HMA therapy, and there is no approved second-line therapy available.¹²

Lenalidomide, a thalidomide derivative, was approved by the FDA for the treatment of patients with low-risk, transfusion-dependent MDS who have a deletion 5q (del[5q]) cytogenetic abnormality in 2005.¹³ In a phase 3 randomized study (NCT00179621) that included low-risk patients with MDS and del(5q), lenalidomide induced transfusion independence in 43% to 52% of patients, with responses lasting longer than 6 months.¹⁷ Notably, lenalidomide has limited activity in low-risk, transfusion-dependent patients without the del(5q) lesion. A phase 2 study (NCT00071799) with similar design observed that only 26% of patients achieved transfusion independence, with a median response duration of 41 weeks (range, 8-136 weeks).¹⁸ As the median overall survival is less than 6 months following HMA failure, optimizing response to first-line treatment is critical.¹²

Standard treatments for MDS have been available with modest success. “It’s time we develop some new combinations that could really improve response and survival of our patients that have not been achieved for the past 14 to 15 years,” Garcia-Manero said.

_References

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_{9. FDA grants breakthrough therapy designation for Venclexta in combination with azacitidine for the treatment of patients with myelodysplastic syndromes. News release. Genentech; July 20, 2021. Accessed August 18, 2022. https://www.gene.com/media/press-releases/14921/2021-07-20/fda-grants-breakthrough-therapy-designat}

_{10. Ball BJ, Famulare CA, Stein EM, et al. Venetoclax and hypomethylating agents (HMAs) induce high response rates in MDS, including patients after HMA therapy failure. Blood Adv. 2020;4(13):2866-2870. doi:10.1182/bloodadvances.2020001482}

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