David P. Steensma, MD, associate professor of medicine, Harvard Medical School, clinical director, Center for Prevention of Progression, Edward P. Evans Chair in Myelodysplastic Syndromes Research, and institute physician, Dana-Farber Cancer Institute, discusses the potential utility of venetoclax (Venclexta) in myelodysplastic syndrome (MDS).

While venetoclax is not approved in MDS, it has off-label usage, explains Steensma. Venetoclax in combination with hypomethylating agents may elicit more durable responses for patients with high-risk, 

-mutant MDS who do not achieve deep remissions with hypomethylating agents alone.

At the 2019 ASH Annual Meeting, two phase Ib studies (NCT02942290; NCT02966782) evaluating the safety and efficacy of venetoclax in combination with azacitidine (Vidaza) in patients with MDS were presented.

Among 57 evaluable treatment-naïve patients with high-risk disease, 18 experienced an objective response with the combination of venetoclax plus azacitidine. Additionally, 11 patients had stable disease.

Among 24 evaluable patients with relapsed/refractory disease in the second trial, 12 experienced an objective response with the combination. Additionally, 31% of patients experienced stable disease with the combination versus 75% with venetoclax alone.

Both studies reported treatment-related deaths resulting from infections. More patients appeared to tolerate the combination as upfront therapy after the dosing schedule was revised and prophylactic antibiotics were implemented, concludes Steensma.

Videos

David P. Steensma, MD, discusses the potential utility of venetoclax in myelodysplastic syndrome.

Dr. Steensma on the Utility of Venetoclax in MDS

David P. Steensma, MD, Senior Physician, Associate Professor of Medicine, Harvard Medical School, Dana Farber Cancer Institute discusses myelodysplastic syndromes.

Myelodysplastic syndromes are increasingly recognized, with 30,000-35,000 new cases per year in the United States. These are both marrow failure syndromes and bone marrow cancers, as the majority of patients have either a chromosome abnormality or systemic genetic mutation or both, explains Steensma. There is a risk that myelodysplastic syndromes will progress to acute leukemia.

Individualized therapy is currently based on risk stratification and clinical pathological disease features, said Steensma. However, in the future molecular genetic profiling will play an increasing role.

Dr. David Steensma on Myelodysplastic Syndrome

David P. Steensma, MD, senior physician, associate professor of Medicine, Harvard Medical School, Dana-Farber Cancer Institute, discusses a phase III study comparing midostaurin with placebo in combination with daunorubicin cytarabine induction, high-dose cytarabine consolidation, and as maintenance therapy in newly diagnosed patients with acute myeloid leukemia (AML) with 

This randomized, double-blind, placebo-controlled study examined midostaurin in patients aged 18 to 60. Patients were randomized to midostaurin plus daunorubicin cytarabine induction or placebo plus cytarabine induction. Patients who received midostaurin had an overall survival (OS) of 74.7 months versus 26.0 months with placebo (HR, 0.77). Median OS data that were censored for stem cell transplant were not available; however, the hazard ratio for the censored group was the same as the uncensored data (HR, 0.77). It is rare to observe an OS benefit in AML, Steensma adds.

Several patients followed the therapy with stem cell transplantation, he explains. Adverse events were fairly similar between the two arms, suggesting that this could potentially be a new treatment regimen for patients with AML. 

View more from the 2015 ASH Annual Meeting

David P. Steensma, MD, senior physician,  associate professor of Medicine, Harvard Medical School, Dana-Farber Cancer Institute, discusses a phase III study comparing midostaurin with placebo in combination with daunorubicin cytarabine induction, high-dose cytarabine consolidation, and as maintenance therapy in newly diagnosed patients with acute myeloid leukemia (AML) with FLT3 mutations.


Dr. Steensma on Midostaurin for Patients With AML

David P. Steensma, MD, a member of the FDA’s Oncologic Drugs Advisory Committee (ODAC), an associate professor of medicine at Harvard Medical School, and a faculty member of the Adult Leukemia Program at the Dana-Farber Cancer Institute, provides insight into the ODAC decision to recommend approval for a neoadjuvant pertuzumab-containing regimen for patients with HER2-positive breast cancer.

The discussion at the ODAC meeting made it clear that a company that submits an agent for approval based on a single neoadjuvant trial will face an uphill battle, Steensma believes. However, for pertuzumab, this was a special situation, as the agent has been approved in the metastatic setting.

It is exciting that the FDA may approve pertuzumab as part of the first-ever approved neoadjuvant regimen, Steensma states. However, he feels this decision does not set a strong precedent for utilizing pathological complete response (pCR) as a surrogate endpoint for new drug development. At this point, disease-free survival and overall survival should remain the gold standard for clinical trial endpoints, Steensma believes. The recommendation from the ODAC panel to approve this regimen based on pCR is a special situation that may not apply to other treatments.

David P. Steensma, MD, from the Dana-Farber Cancer Institute, provides insight into the ODAC decision to recommend approval for a neoadjuvant pertuzumab-containing regimen for patients with HER2-positive breast cancer. 

Dr. Steensma on ODAC's Pertuzumab Decision

David P. Steensma, MD, attending physician, hematologic oncology, Dana-Farber Cancer Institute, Boston, MA, discusses the arguments against the use of iron chelation in patients with myelodysplastic syndrome (MDS).

One of the reasons some hematologic oncologists do not use chelation is because the 2 largest prospective studies that investigated it in MDS patients experienced dropout rates close to 50%. This high of a dropout rate is unusual, and was related to adverse events, disease progression, and unrelated deaths.

Steensma notes that despite the avid promotion of using iron chelation for MDS patients there is currently no prospective data showing morbidity or mortality benefits. An ongoing prospective trial, labeled TELESTO, plans to investigate the event free survival of MDS patients when treated with iron chelation; however, due to the strong opinions of physicians the trial has had a difficult time recruiting participants. Some retrospective studies support the use of iron chelation but Steensma explains that retrospective studies are inherently biased because the cause of a decision may have been due to an unrelated factor.

There is generally a low occurrence of side effects to chelation treatment when it is given correctly. The most common adverse events are diarrhea and an upset stomach, or more seriously, kidney failure. The overall safety and efficacy of iron chelation for patients with MDS remains greatly unknown. Without further prospective data it is difficult to address the concerns regarding the true risk and benefit balance of this treatment.

Dr. David Steensma, from Dana-Farber Cancer Institute, Discusses Iron Chelation Therapy for MDS

David P. Steensma, MD

Articles

Dr. Steensma on the Utility of Venetoclax in MDS

Dr. David Steensma on Myelodysplastic Syndrome

Dr. Steensma on Midostaurin for Patients With AML

Dr. Steensma on ODAC's Pertuzumab Decision

Dr. Steensma Discusses Iron Chelation Therapy for MDS