Targeted therapies and novel drug combinations show promise for the treatment of multiple leukemias
Researchers from The University of Texas MD Anderson Cancer Center are presenting compelling findings 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 targeted therapies and novel combinations in multiple types of leukemia, including high-risk and newly diagnosed acute myeloid leukemia (AML) in older and younger patients and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL). More information on all ASH Annual Meeting content from MD Anderson can be found at MDAnderson.org/ASH.
Older or high-risk patients with newly diagnosed AML respond well to triplet therapy (Abstract 61)
Researchers observed encouraging response rates in older or high-risk patients with newly diagnosed acute myeloid leukemia (AML) who were treated with the triplet combination therapy of azacitidine, venetoclax and magrolimab on a Phase Ib/II trial. The newly diagnosed cohort had an 80% overall response rate (ORR), and the median overall survival (OS) was not yet reached at a median follow-up of 9.2 months. Naval Daver, M.D., associate professor of Leukemia, presented study results Dec. 10.
"We are encouraged by the promising evidence of this triplet therapy as a treatment option for older or unfit patients with AML," Daver said. "We will continue to expand the trial to include more patients, and we have initiated an international Phase III randomized study evaluating the triplet therapy versus the doublet azacitidine-venetoclax. If the study is positive, it could establish a new frontline standard of care for these patients."
About 50-55% of patients with AML are considered older or unfit for intensive chemotherapy. Frontline 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 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 trial, it demonstrated efficacy with azacitidine in newly diagnosed AML, with an especially encouraging signal of response and survival in frontline TP53-mutated AML.
The current trial enrolled 74 patients across two cohorts. The first cohort enrolled 45 frontline patients aged 75 or older with documented comorbidities that made them ineligible for intensive therapy 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 greater than grade 3 anemia, and the most common non-hematologic side effects were febrile neutropenia, pneumonia, hyperbilirubinemia, transaminitis, creatine elevation and hypokalemia.
In the newly diagnosed cohort, the ORR in patients with and without TP53 mutations was 74% and 93%, respectively. Median OS was not yet reached for either group of patients. 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 still are being enrolled.
The study was funded by Gilead. Daver has served in an advisory role for Gilead.
Chemotherapy-free regimen ponatinib plus blinatumomab effective in patients with newly diagnosed Ph+ ALL (Abstract 213)
The chemotherapy-free regimen of ponatinib and blinatumomab achieved high response rates and reduced the need for an allogeneic stem cell transplant for patients with recently diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), according to results from a Phase II trial. One of the lead investigators, Nicholas Short, M.D., assistant professor of Leukemia, presented the findings Dec. 10.
"Traditionally, Ph+ ALL responds poorly to standard chemotherapy and is high-risk for relapse, so these survival results and reduced need for a stem cell transplant are very encouraging," Short said. "Not only does this regimen appear to be a safe and effective chemotherapy-free option, but it also seems to overcome the historical need for transplant in these patients."
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Patients with Ph+ ALL have historically had poor long-term survival rates. Researchers have found adding tyrosine kinase inhibitors (TKIs), such as ponatinib, to chemotherapy can drastically improve survival. Ponatinib is a third-generation TKI that targets BCR-ABL1 and is traditionally used to treat certain types of chronic myeloid leukemia. Blinatumomab is a CD3-CD19 bispecific antibody that is effective as a single agent in relapsed or refractory Ph+ ALL.
The trial 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 average age of participants was 56 years old.
Of the patients that were evaluable for a hematologic response, 96% had a complete remission or complete remission with incomplete count recovery. Among the 38 patients who were evaluable for complete molecular response (CMR), 68% achieved CMR after one treatment cycle and 87% achieved CMR during the trial period. Molecular responses were rapid, with a majority of patients achieving CMR in the peripheral blood within two weeks of therapy. Only one patient underwent stem cell transplant in first remission.
At a median follow-up of 15 months, event-free and estimated overall survival was 95%. These encouraging outcomes were observed despite the very low rate of transplant in the study. The treatment was well tolerated, and most toxicities were grade 1-2 and consistent with known side effects of the two agents.
The study was funded by Amgen and Takeda Oncology. Short has served in a consulting or advisory role for Takeda Oncology.
Venetoclax with CLIA highly effective in younger patients with newly diagnosed AML, high-risk MDS (Abstract 709)
The latest results of a Phase II study evaluating the addition of venetoclax to the intensive chemotherapy treatment of cladribine, idarubicin and cytarabine (CLIA) as a frontline therapy demonstrated high rates of disease control and remissions in younger patients with newly diagnosed AML and high-risk myelodysplastic syndrome (MDS). In the study, 96% of patients responded to treatment and 90% had no measurable disease detected in a bone marrow sample. Patrick Reville, M.D., instructor of Leukemia, presented updated results and longer-term follow-up data Dec. 12.
"Venetoclax has been a breakthrough for AML patients that are ineligible for intensive therapy. This data continues to demonstrate the benefit of including venetoclax with the CLIA induction regimen," Reville said. "This regimen is leading to unprecedented response and measurable residual disease-negativity rates. As we continue to follow participants, we are encouraged by their long-term outcomes and survival."
The single-center, single-arm trial enrolled 67 patients with a median age of 48. Sixty patients had AML and four patients had high-risk MDS. In addition, three patients had a mixed-phenotype acute leukemia (MPAL).
The composite complete response rate was 96% across all patients and 100% for patients with both MDS and MPAL with a myeloid predominant clone. Most patients went on to receive a subsequent allogeneic stem cell transplant (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%. Seventy-four percent of responding patients are estimated to have an ongoing response at 12 months.
The most common non-hematologic adverse event that participants experienced was febrile neutropenia, which was managed. Researchers continue to follow patients and study this treatment regimen as a safe and effective induction treatment strategy for this patient population.
The study was funded by the Joe Moakley Leukemia SPORE and MD Anderson institutional support.
University of Texas M. D. Anderson Cancer Center
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Tags: Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Anemia, Antibody, Bispecific antibody, Blood, Bone, Bone Marrow, Cancer, Cardiovascular Disease, CD3, Cell, Central Nervous System, Chemotherapy, Chromosome, Chronic, Chronic Myeloid Leukemia, Cladribine, Creatine, Drugs, Efficacy, Hematology, Hyperbilirubinemia, Hypokalemia, Kinase, Leukemia, Mutation, Myeloid Leukemia, Nervous System, Neutropenia, Oncology, pH, Phenotype, Pneumonia, Research, Syndrome, Transplant, Tyrosine
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