Summary
In patients with newly diagnosed acute myeloid leukemia (AML), one cycle of therapy with glasdegib plus low-dose cytarabine (LDAC) improved overall survival (OS) associated with various blood count thresholds. An anti-leukemic effect of glasdegib that spares normal hematopoiesis is a novel characteristic that could improve the risk-benefit ratio of AML therapy.
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Original Article
Glasdegib + LDAC Improves Survival in Newly Diagnosed AML
Oncology Times
By Mark L. Fuerst
In patients with newly diagnosed acute myeloid leukemia (AML), one cycle of therapy with glasdegib plus low-dose cytarabine (LDAC) improved overall survival (OS) associated with various blood count thresholds. An anti-leukemic effect of glasdegib that spares normal hematopoiesis is a novel characteristic that could improve the risk-benefit ratio of AML therapy.
“For AML patients unsuitable for intensive therapies, the clinical benefit may be associated with early peripheral count recovery, even in patients with baseline cytopenias or those who do not achieve optimal bone marrow blast reduction,” said lead author Eunice Wang, MD, of the Roswell Park Comprehensive Cancer Center in Buffalo, N.Y., at the 2020 ASCO Annual Meeting.
In patients with newly diagnosed AML, recovery of blood counts during initial treatment could improve quality of life and reduce mortality, she noted.
BRIGHT AML 1003 Trial
Glasdegib is a small-molecule selective inhibitor of Hedgehog signaling, a pathway not involved in normal adult hematopoiesis. Instead, it is thought to act by reducing survival of leukemic cells.
In the randomized, phase II BRIGHT AML 1003 trial, glasdegib plus LDAC prolonged OS as compared to LDAC alone. Further analysis showed glasdegib plus LDAC reduced the transfusion requirements by minimizing cytopenias, with blood count recovery as early as the first treatment cycle for a meaningful proportion of patients.
Glasdegib is approved in the U.S. and Canada for treatment of AML when used in combination with LDAC when intensive therapy is precluded, and is also being investigated in combination with intensive chemotherapy in patients able to tolerate such regimens.
All patients in the Bright AML 1003 trial had newly diagnosed AML or MDS, and had preset criteria that indicated intensive chemotherapy was unsuitable for them. As a result, the trial recruited a very high-risk population, with about two-thirds of patients having a history of prior cardiovascular disease.
The primary study results reported in 2018 demonstrated a prolonged OS in patients randomized to glasdegib plus LDAC over LDAC alone. Individuals randomized to glasdegib/LDAC had median OS of 8.8 months, as opposed to 4.9 months for the control group. The final results of the study were also presented at ASCO (Abstract 7509).
Post Hoc Analysis
In this post hoc analysis of BRIGHT AML 1003 (Abstract 7525), researchers looked at early blood counts in patients with AML. They used blood counts taken at cycle 2, day 1. As each treatment cycle was 28 days, these blood counts were measured 4 weeks after initiation of therapy. They divided patients into subgroups above and below defined thresholds, defining two thresholds each for neutrophils, hemoglobin, and platelets.
The researchers looked at absolute neutrophil count (ANC) of 500 or 1,000 per microliter, hemoglobin of 9 or 10 grams per deciliter, for a platelet count of 50 or 100,000 per microliter.
“First, we looked at OS in all of the patients with an available measurement at cycle 2, day 1, regardless of their baseline values. For patients who met thresholds, the glasdegib plus LDAC combination was associated with prolonged overall survival versus LDAC alone for all thresholds measured,” said Wang. These were highly statistically significant, with P values less than 0.01.
“Interestingly, in subgroups that did not meet the threshold, the glasdegib combination therapy was also associated with longer OS versus LDAC alone. This was seen for all thresholds, with P value 0.05 or less,” she said.
The researchers also included only the patients whose baseline values were below the threshold. For these subgroups, some of the patient numbers were very low, she noted.
“For example, only one of the patients treated with LDAC alone had an ANC under 500 at baseline and recovered to at least 500,” said Wang. “While this obviously limits the analysis, we did note that subgroups of baseline anemia or thrombocytopenia who met hemoglobin or platelet thresholds showed longer OS with the glasdegib plus LDAC combination.” The relationship was not significant for patients with baseline ANC below either threshold.
Patients below thresholds at baseline and still below threshold at 4 weeks also demonstrated improved OS with glasdegib plus LDAC for all subgroups, except those with platelets below 50,000 per microliter at the baseline.
In conclusion, Wang noted: “Our results appear to show that AML patients treated with glasdegib plus LDAC who met cycle 2, day 1 recovery thresholds were found to have prolonged OS. Correlation of rapid blood cell count recovery with OS might be expected, given that complete remission obviously is associated with OS benefit.
“However, more intriguing was the observation that combination therapy was also associated with OS in patient subgroups who did not meet these thresholds, albeit the effect was more modest,” Wang added. “This may suggest a potential survival benefit with glasdegib whether or not patients achieve a complete remission.”
Although this differs from how clinicians tend to think about AML therapy, “it is, however, consistent with the underlying mechanism of action of glasdegib, which targets leukemic stem cells,” said Wang. She noted that the results must be considered exploratory, and the researchers hope to undertake future studies in larger data sets to address these intriguing observations.
Mark L. Fuerst is a contributing writer.