Targeted therapies and new drug combinations hold promise for treating more leukaemias

Researchers at the University of Texas MD Anderson Cancer Center are presenting compelling results from three clinical trials at the 2022 American Society of Hematology (ASH) Annual Meeting. These oral presentations highlight encouraging results to advance the use of therapeutics targeted and novel combinations in multiple types of leukemia, including high-risk and newly diagnosed acute myeloid leukemia (AML) in elderly and young patients and Philadelphia chromosome acute lymphoblastic leukemia (ALL ). Learn more about all of MD Anderson’s ASH Annual Meeting content at MDAnderson.org/ASH.

Elderly or high-risk patients with newly diagnosed AML respond well to triplet therapy (Abstract 61)

Researchers observed encouraging response rates in elderly or high-risk patients with newly diagnosed acute myeloid leukemia (AML) who were treated with the triplet combination therapy of azacitidine, venetoclax and magrolimab in a phase Ib/II study. The newly diagnosed cohort had an overall response rate (ORR) of 80%, and median overall survival (OS) had not yet been reached at a median follow-up of 9.2 months. Naval Daver, MD, an associate professor of leukemia, presented the study results Dec. 10.

“We are encouraged by the promising evidence of this triplet therapy as a treatment option for elderly or ineligible patients with AML,” Daver said. “We will continue to expand the study to include more patients and have initiated an international randomized phase III trial evaluating triplet therapy versus azacitidine-venetoclax doublet. If the study is positive, it could set a new standard of first-line care for these patients”.

Approximately 50-55% of patients with AML are considered elderly or unsuitable for intensive chemotherapy. First-line treatment with azacitidine and venetoclax achieves response rates of 65-70% in newly diagnosed patients, but most patients will relapse and those with TP53 mutations continue to have poor outcomes, with a median OS of less than six months. Magrolimab is an anti-CD47 antibody that works to block the “don’t eat me signal” on leukemia cells. In a previous study, demonstrated efficacy with azacitidine in newly diagnosed AML, with a particularly encouraging first-line response and survival rate TP53-AML mutated.

The current study enrolled 74 patients in two cohorts. The first cohort enrolled 45 first-line patients aged 75 years and older with documented comorbidities that made them unfit for intensive care or with adverse risk factors and/or a TP53 mutation, regardless of age. This cohort included 27 patients with a TP53 mutation and 14 without. The second cohort enrolled 29 patients with relapsed/refractory (R/R) disease.

All patients who received at least one dose of any of the three study drugs were included for response and adverse events. Eighteen patients experienced anemia greater than grade 3, and the most common nonhematologic side effects were febrile neutropenia, pneumonia, hyperbilirubinemia, transaminitis, increased creatine, and hypokalemia.

In the newly diagnosed cohort, ORR in patients with and without TP53 mutations was 74% and 93%, respectively. Median OS has not yet been reached for either patient group. Responses in patients with R/R disease with prior venetoclax treatment were modest, and the cohort was closed for futility. Patients with R/R disease without venetoclax exposure are still being enrolled.

The study was funded by Gilead. Daver has served in a consulting role for Gilead.

Ponatinib plus blinatumomab chemotherapy-free regimen effective in patients with newly diagnosed Ph+ ALL (Abstract 213)

Chemotherapy-free regimen of ponatinib and blinatumomab achieved high response rates and reduced the need for allogeneic stem cell transplantation for patients with newly diagnosed Philadelphia chromosome (Ph+) positive acute lymphoblastic leukemia (ALL), according to findings of a Phase II study. One of the principal investigators, Nicholas Short, MD, an assistant professor of leukemia, presented the findings on Dec. 10.

“Traditionally, Ph+ ALL responds poorly to standard chemotherapy and is at high risk of relapse, so these survival results and the reduced need for a stem cell transplant are very encouraging,” said Short. “Not only does this regimen appear to be a safe and effective option without chemotherapy, it also appears to overcome the historic need for transplantation in these patients.”

Patients with Ph+ ALL have historically had low long-term survival rates. Researchers have found that adding tyrosine kinase inhibitors (TKIs), such as ponatinib, to chemotherapy can dramatically improve survival. Ponatinib is a third-generation TKI that targets BCR-ABL1 and has traditionally been used to treat certain types of chronic myeloid leukemia. Blinatumomab is a CD3-CD19 bispecific antibody effective as a single agent in relapsed or refractory Ph+ ALL.

The study enrolled 40 patients with newly diagnosed Ph+ ALL. Patients with uncontrolled cardiovascular disease or clinically significant central nervous system comorbidities were excluded from the study. The mean age of the participants was 56 years.

Of patients evaluable for hematologic response, 96% had complete remission or complete remission with incomplete count recovery. Among 38 patients evaluable for complete molecular response (CMR), 68% achieved CMR after one course of treatment and 87% achieved CMR during the trial period. Molecular responses were rapid, with most patients achieving peripheral blood CMR within two weeks of therapy. Only one patient underwent stem cell transplantation in first remission.

At a median follow-up of 15 months, the estimated overall and event-free survival was 95%. These encouraging results were seen despite the very low rate of transplants in the study. The treatment was well tolerated, and most toxicities were grade 1-2 and consistent with the known side effects of the two agents.

The study was funded by Amgen and Takeda Oncology. Short held an advisory or consultancy role for Takeda Oncology.

Venetoclax with highly effective CLIA in younger patients with newly diagnosed AML, high-risk MDS (Abstract 709)

Latest results from a phase II study evaluating the addition of venetoclax to intensive cladribine, idarubicin, and cytarabine chemotherapy (CLIA) treatment as first-line therapy have demonstrated high rates of disease control and remissions in younger patients with AML newly diagnosed and high-risk myelodysplastic syndrome (MDS). In the study, 96% of patients responded to treatment and 90% found no measurable disease in a bone marrow sample. Patrick Reville, MD, instructor in leukemia, presented the updated results and long-term follow-up data on Dec. 12.

“Venetoclax was a breakthrough for AML patients who are ineligible for intensive care. These data continue to demonstrate the benefit of including venetoclax in the CLIA induction regimen,” said Reville. “This regimen is leading to unprecedented response and measurable residual disease negativity rates. As we continue to follow the participants, we are encouraged by their long-term results and survival.”

The single-arm, single-center study enrolled 67 patients with a mean age of 48 years. Sixty patients had AML and four patients had high-risk MDS. In addition, three patients had mixed phenotype acute leukemia (MPAL).

The composite complete response rate was 96% in all patients and 100% for MDS and MPAL patients with a myeloid-dominant clone. Most patients received subsequent allogeneic stem cell transplantation (alloSCT), including 70% of those who responded to treatment.

Encouragingly, with a median follow-up of just over two years, the median duration of response, event-free survival, and overall survival have not yet been reached. At 12 months, the estimated event-free survival rate is 70% and the estimated overall survival rate is 86%. An estimated 74% of responding patients have a continuous response at 12 months.

The most common nonhematologic adverse event experienced by participants was febrile neutropenia, which was managed. Researchers continue to follow patients and investigate this regimen as a safe and effective induction treatment strategy for this patient population.

The study was funded by the Joe Moakley Leukemia SPORE and institutional support from MD Anderson.

Source:

University of Texas MD Anderson Cancer Center

Add a Comment

Your email address will not be published. Required fields are marked *