Azacitidine Still Standard of Care in High-Risk MDS

Alexander M. Castellino, PhD

August 22, 2017

Azacitidine (Vidaza, Celgene) is standard treatment for patients with myelodysplastic syndrome (MDS) and will remain the treatment of choice — at least for now.

A new study that tested two different combinations —  azacitidine with lenalidomide (Revlimid, Celgene) and with vorinostat (Zolinza, Merck & Co) — found that the additional agents did not offer significant improvement over azacitidine used alone.

These negative results come from the North American Intergroup  Study SWOG S1117 study, published August 20 in the Journal of Clinical Oncology.  Mikkael A. Sekeres, MD, from the Cleveland Clinic Taussig Cancer Institute, Ohio, is the corresponding author of the study.

Conducted in 277  patients with high-risk MDS, the study showed that overall response rates (ORRs) with the two combinations were not significantly different from that seen with azacitidine alone. The ORR was 49% for azacitidine and lenalidomide, 27% for azacitidine and vorinostat, and 38% for azacitidine alone.

In addition, rates of complete remission, partial remission, and hematologic improvement were similar across the three treatment groups.

However, a subset of patients, including those with chronic myelomonocytic leukemia (CMML), those with normal cytogenetics, and those with MDS with chromosome 5 abnormalities, benefited from the combinations.

With respect to subgroup analysis, the ORR was significantly higher for patients with CMML treated with azacitidine plus lenalidomide (68% vs 28% for azacitidine; P = .02). The ORR was also higher for patients with chromosome 5 abnormality (vs those without; odds ratio, 2.17; P = .008).  In addition, ORR was significantly higher for patients with mutations in DNMT3A, numerically higher for those with mutations in BCOR and NRAS, and numerically lower for those with mutations in SRSF2 and ASXL1.

Although azacitidine-based combinations were beneficial for certain patient subtypes, these observations should be confirmed in studies focused on these subgroups, the authors emphasize.   

They also note that significantly more patients in the combination groups stopped therapy because of toxicities or complications (8% for azacitidine, 20% for azacitidine plus lenalidomide, and 21% for azacitidine plus vorinostat). Nonprotocol dose modifications were also significantly higher for patients receiving the combinations (24% for azacitidine, 43% for azacitidine plus lenalidomide, and 42% for azacitidine plus vorinostat).

In an accompanying editorial, Charles Craddock, MD, from the Queen Elizabeth Hospital in Birmingham, United Kingdom, suggests two reasons why "this meticulously conducted trial" did not work: selection bias inherent in early-phase studies and underdosing of azacitidine or premature cessation of combination therapy due to the additional toxicities with combination azacitidine.

"This possibility is supported by the trend toward improved survival in the vorinostat arm despite increased toxicity," he notes.

In evolving therapeutic options to manage MDS, it is important to proceed expeditiously but prudently, he writes.

The definition of insanity is doing the same thing over and over again and expecting different results. Dr Charles Craddock

"On the assumption that therapeutic decision making should be informed by Einstein's apocryphal observation that the definition of insanity is doing the same thing over and over again and expecting different results, it is perhaps important now to consider what alternative strategies might improve the clinical activity of AZA [azacitidine]," he says.

Azacitidine, a DNA methyltransferase inhibitor, represents "the first pharmacologic agent to alter the natural history of high-risk MDS," Dr Craddock notes.

Most elderly patients are not candidates for transplantation — the only curative option for MDS. But they are candidates for azacitidine or the related drug, decitabine (Dacogen, Otsuka), two agents that have been approved for the treatment of MDS. In addition, lenalidomide, an immunomodulatory agent, has been approved for the treatment of transfusion-dependent anemia in 5q deletion MDS.

Evolving MDS Management

MDS, which is typically diagnosed in patients 70 to 75 years of age,  comprises a spectrum of bone marrow disorders characterized by "ineffective hematopoiesis," which is associated with cytopenias (associated with risk for bleeding and infections) and a significant risk for transformation to acute myeloid leukemia in patients with higher-risk disease — determined from degree of cytopenia, blast percentage, and cytogenetics at presentation.

In addition to supportive care, which includes blood transfusions for symptomatic anemia and platelet transfusions for bleeding, the National Comprehensive Cancer Network (NCCN) recommends the use of azacitidine or decitabine for patients with progressive or higher-risk MDS.

According to the NCCN, patients who should be considered for these agents include those with high-risk disease and who are not candidates for high-intensive therapy; patients receiving bridge therapy as they wait for transplantation; and patients who may not respond to agents for symptomatic anemia or immunosuppressive therapy.

The NCCN panel recommends continuous treatment with these agents if there are an ongoing response and no toxicity. Treatment failure is considered after four courses of decitabine or six courses of azacitidine therapy.

Strategies for the Future

Looking ahead, Dr Craddock hopes that in the future it may be possible to identify subclones associated with resistance that develop with azacitidine treatment. These are apparent at relapse but present at a low frequency at diagnosis, he points out.  A clonal analysis suggests a sequential approach with azacitidine plus inhibitors that target FLT3ITD, IDH1, or IDH2. He also notes that immunophenotyping stem/progenitor compartments during therapy allows for a quantitation of resistant clones, which informs novel drug development.

Next-generation sequencing may also identify patients who are likely to respond to azacitidine, Dr Craddock suggests. He pointed out that the SOG S1117 study used this approach prospectively to correlate response in 40 candidate myeloid genes. "This prospective evaluation provides a template for integrating mutational profiling into future trials," he said.

"Integration of next-generation sequencing, studies of measurable residual disease and candidate biomarkers, where possible in real time, must be ensured so that both discovery science and trial delivery have the opportunity to impact clinical care as swiftly as possible," Dr Craddock notes.

Molecular stratification of disease such as MDS — once considered homogeneous — along with a plethora of emerging therapies "poses profound questions," according to Dr Craddock. These pertain to "the scale and capacity of the translational infrastructure that will be required if we are to rapidly assess an exponentially increasing number of promising novel drug, antibody, and cellular therapies in ever-decreasing genetically defined disease populations."

Trial designs and translational infrastructures need to change, he suggests. "At the heart of accelerated trial delivery is the establishment of resourced trial networks with a sufficient density of patients to allow the rapid assessment of a range of novel therapies as developed so effectively in stem-cell transplantation and planned for antibiotic trials," he writes. He calls for resourced networks that are incentivized to reward rapid clinical development.

Several authors on the publication have disclosed their ties to pharmaceutical and biotech companies. Corresponding author Dr Sekeres consults with and/or has an advisory role with Celgene and Millenium. Dr Craddock reports receiving honoraria from Celgene, Janssen Oncology, Novartis, Merck Sharp & Dohme; consults with Celgene, Janssen Oncology, and Merck Sharp & Dohme; and is on the speakers' bureau of Celgene and Janssen Oncology. He also receives research funding from Celgene.

J Clin Oncol. Published August 20, 2017. Abstract, Editorial   

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