Treatment Options Continue to Increase in Low-Risk MDS

Nov 3, 2021

Azanucleosides, such as azacitidine, remain the backbone of disease-modifying therapy for patients with myelodysplastic syndromes, however, new adjuncts are leading to longer remissions and disease-free survival in patients with low-risk disease.

Michael R. Savona, MD

Michael R. Savona, MD

Azanucleosides, such as azacitidine (Onureg), remain the backbone of disease-modifying therapy for patients with myelodysplastic syndromes (MDS). However, new adjuncts are leading to longer remissions and disease-free survival in patients with low-risk disease, according to Michael R. Savona, MD.

“Lower-risk MDS is a bit of a complicated term to unpack,” said Savona, head of Hematology, Cellular Therapy, and Stem Cell Transplant at Vanderbilt University Medical Center in Nashville, Tennessee, during a presentation at the 39th Annual CFS®. “Except for the patients with very low risk, patients less than 60 [years can] expect a median survival of anywhere from 5 to 10 years. For patients over 60 [years], low-risk disease has a mean survival of 5 years or less. It’s important to note that the majority of patients with MDS are older than 60 [years]. The median [age of] diagnosis is between 70 and 73 years.”

The Role of Clonal Hematopoiesis

Unexplained cytopenias, such as clonal cytopenias of undetermined significance (CCUS) are an active area of investigation in MDS.

Clonal hematopoiesis (CH) refers to the clones present in a significant number of cells, with a variant allele frequency approximately 2% or higher in myeloid-mutation-associated genes. CH repeatedly occurs in genes associated with epigenetic function, splicing, and DNA damage repair.2

A majority of patients with clonal hematopoiesis of indeterminate potential (CHIP) do not develop MDS; however, a significant number of patients develop CCUS and ultimately go on to develop MDS. A third of these patients will eventually develop acute myeloid leukemia (AML).2 CCUS is determined if 1 or more somatic mutations associated with myeloid neoplasms are detected in peripheral blood cells or bone marrow with an allele burden or 2% or higher; cytopenia lasting longer than 4 months in 1 or more peripheral blood cell lineages; diagnostic criteria are not met for myeloid neoplasms; and all other causes of cytopenia are excluded.2

“We are looking at new therapies for CCUS, as CCUS is evolving to an interventional state,” Savona explained. “It’s moving very quickly with the discovery in the laboratory of new clinical interventions. We are taking a couple of different approaches to try and slow down the evolution from CCUS to MDS, including targeted therapies and anti-inflammatory approaches.”

Agents Looking to Transform MDS Treatment Landscape

Luspatercept-aamt (Reblozyl), a fusion protein containing a modified activin receptor type IIB that acts as a TGF-β ligand trap, blocking the inhibitory signals of late-stage erythropoiesis, was approved in 2020 for the treatment of patients with MDS. Specifically, the agent is indicated for the treatment of anemia failing an erythropoiesis stimulating agent and requiring 2 or more red blood cell units over 8 weeks in adult patients with very low- to intermediate-risk MDS with ring sideroblasts or with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis.3

The agent acts on late-stage erythropoiesis, ultimately increasing the number of mature red blood cells in circulation. In the phase 3 MEDALIST study (NCT02631070), investigators compared luspatercept with placebo in patients with ring sideroblast-positive, low-risk MDS.

A total of 229 patients were randomized 2:1 to receive either luspatercept or placebo. The median age of the trial population was 71 years (range, 26-95). The median time since original diagnosis of MDS was 41.8 months (range, 3-421) and the median serum erythropoietin level was 153.2 U/L (range, 12-2760).

At the prespecified checkpoints (8 weeks, 12 weeks, and 16 weeks), patients in the luspatercept group (n = 153) had a greater response rate compared with patients receiving placebo (n = 76). At week 8, the overall response rate (ORR) in the luspatercept group was 38% (95% CI, 30%-46%) compared with 13% (95% CI, 6%-23%) in the placebo group. For the totality of the trial (weeks 1-48), the ORR for patients treated with luspatercept was 28% (95% CI, 21%-36%) vs 7% (95% CI, 2%-15%) for patients in the placebo cohort.4

In terms of safety, luspatercept was found to be very-well tolerated. Adverse events (AEs) of any grade in the luspatercept group included fatigue (27%), diarrhea (22%), and dizziness (20%). Grade 3 AEs were rare and included fatigue (5%) and asthenia (3%).4

“Luspatercept is not clearly disease modifying, but certainly improves anemia and likely quality of life,” Sovona said. “ASTX 727 is a bit of a practical development, but certainly an improvement in quality of life in the disease-modifying area of treatment for MDS.”

ASTX 727 is oral decitabine plus cedzauridine, a novel cytidine deaminase (CDA) inhibitor. The administration of oral decitabine with a CDA inhibitor facilitates enhanced bioavailability of decitabine at low doses. ASTX 727 has the potential for improved efficacy due to the increased systemic exposure caused by systemic CDA inhibition and more convenient chronic administration.1,5

Oral ASTX 727 was evaluated against intravenous (IV) decitabine monotherapy in the phase 3 ASCERTAIN trial (NCT03306264). The trial enrolled 133 patients with intermediate/high-risk MDS, chronic myelomonocytic leukemia, and AML. Patients were randomized 1:1 to sequence A or sequence B. In sequence A, patients received 1 tablet of ASTX 727 daily for 5 days in cycle 1, then 1 hour of IV decitabine daily for 5 days in cycle 2, and 1 tablet of ASTX 727 daily for 5 days in subsequent cycles. Sequence B followed the same dosing schedule but administered IV decitabine in cycle 1 and ASTX 727 in cycle 2.

The median age in the trial population was 71 (range, 44-88). Most patients (59%) had an ECOG performance score of 1 and were intermediate risk (68%).

The study met its primary endpoint of total 5-day decitabine area under the curve (AUC) equivalence, defined as oral/IV 90% with a CI ranging from 80%-125%, with high confidence. The oral/IV 5-day decitabine AUC was 98.9% (90% CI, 92.7%-105.6%).5

The ORR in the study was 61.7% (95% CI, 52.8%-69.9%) and 22% of patients achieved a complete response (CR). The median duration of CR was 14.0 months, and the median duration of best response was 12.7 months. At a median follow-up of 32 months, the median overall survival was 31.7 months (95% CI, 28-not evaluable).5

“After some experience in mice that we conducted indicating that cedzauridine is necessary for azacitidine to actually be beneficial if given orally, there is a phase 1 study of ASTX 030 [oral azacitidine plus cedzauridine],” Sovona said. “This is a similar combination [to ASTX 727].”

Oral azacitidine was found to be safe and clinically active in patients with AML in a phase 1 dose-finding study (NCT00528983). Patients were treated with 200 or 300 mg of CC-486 daily or twice daily for 14 or 21 days. Investigators noted that extending oral azacitidine administration beyond 7 days could lead to an increase in the number of leukemic cells exposed to azacitidine over the course of the cycle, and result in improved response.

“[Oral azacitidine] has a place in MDS, we just can’t quite figure out what it is,” Sovona concluded. “Luspatercept is the hottest ‘new toy’ we have to treat patients with MDS. It’s been very useful in patients with lower-risk, and we are still trying to figure out all the different places we can use this therapy in myeloid disease.”

References

  1. Savona MR. Treatment strategies for lower risk myelodysplasia. Presented at: 39th Annual Chemotherapy Foundation Symposium®. November 3-5, 2021; New York, New York and Virtual.
  2. DeZern AE, Malcovati, Ebert BL. CHIP, CCUS, and other acronyms: definition, implications, and impact on practice. Am Soc Clin Oncol Educ Book. 2019;39:400-410. doi:10.1200/EDBK_239083
  3. FDA approves luspatercept-aamt for anemia in adults with MDS. FDA. Updated April 6 2021. Accessed November 3, 2021. bit.ly/391vXSy
  4. Fenaux P, Platzbecker U, Mufti G, et al. Luspatercept in patients with lower-risk myelodysplastic syndromes. N Engl J Med. 2020;382(2):140-151. doi:10.1056/NEJMoa1908892
  5. Savona MR, McCloskey JK, Griffiths EA, et al. Prolonged survival observed in 133 MDS patients treated with oral decitabine/cedazuridine. Presented at: 16th International Congress on Myelodysplastic Syndromes; September 23-26, 2021; Virtual. Abstract P48. Accessed November 3, 2021. bit.ly/3ENe1cV
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