ASCO: Developing effective combination therapies for leukemia

Findings from three studies led by researchers at MD Anderson suggest that new combination therapies are safe and effective against various types of leukemia. The investigators believe that the promising data about the use of these therapeutic regimens may lead to new standards of care and more leukemia treatment options. Results from the clinical trials were presented at the 2020 American Society of Clinical Oncology (ASCO) Annual Meeting.

Combination of targeted therapy and chemotherapy is effective in patients with newly diagnosed acute myeloid leukemia (abstract 7501)

When used as single agents, the oral targeted IDH2 inhibitor enasidenib (ENA) and the chemotherapy azacitidine (AZA) are effective therapies for newly diagnosed patients with acute myeloid leukemia (AML) with response rates of 31% and 28%, respectively. Following promising laboratory results from studies combining the two therapies, MD Anderson researchers are leading a randomized Phase II clinical trial to evaluate the overall response rate of the combination.

This presentation provides a data update on the clinical trial, which evaluates azacitidine with or without enasidenib in newly diagnosed, older patients with IDH2-mutated acute myeloid leukemia, who are ineligible for intensive chemotherapy strategies.  In this older and higher risk patient population, the findings demonstrate that enasidenib + azacitidine results in improved response rates and duration of response, when compared to treatment with azacitidine alone, and the combination was generally well-tolerated.

In this study of 101 patients, combination therapy led to an improved response rate (71%) and event-free survival (17.2 months) when compared to azacitidine treatment alone (42% and 10.8 months, respectively). The complete remission rate was 53% with the combination as compared to 12% with azacitidine alone. Grade 3-4 adverse events related to the combination therapy included thrombocytopenia (37%), neutropenia (35%), anemia (19%), and febrile neutropenia (15%), with IDH2-related differentiation syndrome occurring in 10%. 

“This study confirms that the combination of azacitidine with enasidenib is a well-tolerated lower intensity combination, which leads to improved rates of complete remissions and overall responses as compared to azacitidine alone in our older acute myeloid leukemia patients with IDH2 mutations,” says lead author Courtney DiNardo, M.D., associate professor of Leukemia. “This study aims to build upon the standard of care and improve upon our historical expectations for our patients.”

New data regarding the co-occurring mutation profile of enrolled patients and the effect of subsequent treatments is being presented at the conference. The study has been fully enrolled, and follow-up with active patients is ongoing.  See the abstract and co-authors here.

Venetoclax and decitabine combination is safe and effective against acute myeloid leukemia and high-risk MDS (abstract 7519)

The targeted therapy drug venetoclax is FDA-approved for combination treatments with low-intensity regimens for acute myeloid leukemia patients older than age 75, or those who are unfit for intensive therapies; and the chemotherapy drug decitabine is FDA-approved for treatment of myelodysplastic syndromes (MDS), which is a group of conditions in which a patient’s bone marrow does not produce enough healthy blood cells.

An MD Anderson research team hypothesized that the combination of 10-day decitabine with venetoclax may be effective against subgroups of both acute myeloid leukmeia and myelodysplastic syndromes. Their Phase II clinical trial found that the combination is safe and effective in patients with acute myeloid leukemia and high-risk MDS. Further, the combination has promise as a bridge therapy before stem cell transplant in patients who have received previous treatments for AML. Data were presented by lead author Abhishek Maiti, M.D., fellow in the division of cancer medicine, who was mentored by DiNardo and Marina Konopleva, M.D.

The clinical trial enrolled patients with newly diagnosed acute myeloid leukemia (older than age 60), treated/untreated secondary acute myeloid leukemia, relapsed/refractory AML or high-risk MDS. Of the 184 patients on the trial, 25 (14%) proceeded to receive a stem cell transplant. The overall response rate was 89% for newly diagnosed acute myeloid leukemia patients and was 80% for previously untreated secondary acute myeloid leukemia patients.

“These results are promising because of high complete remission, composite complete remission and minimal residual disease negativity rates in newly diagnosed patients with AML,” says Maiti. “We hope this treatment combination will be a new option for patients with relapsed or refractory AML who can potentially be bridged to a stem cell transplantation.”

At the conference, the research team is presenting additional analyses of the molecular subgroups. Trial accrual is continuing, and the abstract and co-authors can be found here.

Monoclonal antibody and targeted therapy combination is a promising treatment option for subtypes of acute lymphoblastic leukemia and chronic myeloid leukemia (abstract 7512)

In response to typical poor outcomes for patients with relapsed or refractory Philadelphia chromosome-positive (Ph+) acute lymphocytic leukemia and chronic myeloid leukemia in the lymphoid blast phase (CML LBP), this study finds that a combination of inotuzumab ozogamicin, a CD22-targeted monoclonal antibody, and bosutinib, a kinase inhibitor, was well-tolerated and showed promising activity against these cancers.

This Phase I/II clinical trial sought to evaluate the safety and the maximum tolerated dose of the combination therapy, and its secondary objective was to establish efficacy. Eighteen relapsed/refractory patients – 16 patients with Ph+ acute lymphocytic leukemia and two patients with CML LBP – received increasing dose levels of daily bosutinib and weekly doses of inotuzumab ozogamicin. Bosutinib is a second-generation BCR-ABL tyrosine kinase inhibitor that is FDA-approved to treat chronic myeloid leukemia, and inotuzumab ozogamicin is an anti-CD22 antibody drug conjugate approved for relapsed/refractory acute lymphocytic leukemia.

The overall response rate (complete response/complete response with incomplete blood count recovery) was 83%, and 56% of patients achieved complete molecular response. No patient experienced veno-occlusive disease. 

After a median follow-up of 36.7 months, the median overall survival was 15.4 months. At the time of data collection, nine of the enrolled patients were alive, six patients underwent stem cell transplant in remission, nine patients had morphologic disease relapse, and two patients continued receiving therapy.

“This study shows that the combination of inotuzumab and bosutinib, a non-chemotherapy regimen, is a safe and effective treatment strategy in patients with R/R Ph+ ALL,” says Nitin Jain, M.D., lead author of the study and associate professor of Leukemia.

The study continues recruiting participants, and the abstract and co-authors can be found here.