Glasdegib in combination with cytarabine and daunorubicin in patients with AML or high‐risk MDS: Phase 2 study results

Abstract

Glasdegib is a Hedgehog pathway inhibitor. This ongoing, open‐label, phase 2 study (NCT01546038) evaluated glasdegib plus cytarabine/daunorubicin in patients with untreated acute myeloid leukemia (AML) or high‐risk myelodysplastic syndromes (MDS). Patients received glasdegib 100 mg orally, once daily in continuous 28‐day cycles from day −3, with intravenous cytarabine 100 mg/m2 on days 1‐7 and daunorubicin 60 mg/m2 on days 1‐3. Patients in remission then received consolidation therapy (2‐4 cycles of cytarabine 1 g/m2 twice daily on days 1, 3, 5 of each cycle), followed by maintenance glasdegib (maximum 6 cycles). Primary endpoint was complete remission (CR) in patients aged ≥55 years. Secondary endpoints included overall survival (OS), safety and outcome by mutational status. Patients had a median (range) age of 64.0 (27‐75) years, 60.0% were male, and 84.5% were white. In 69 evaluable patients, 46.4% (80% confidence interval [CI]: 38.7‐54.1) achieved investigator‐reported CR. Among patients ≥55 years old (n = 60), 40.0% (80% CI 31.9‐48.1) achieved CR. Among all 69 patients, median OS was 14.9 (80% CI 13.4‐19.3) months, with 12‐month survival probability 66.6% (80% CI 58.5‐73.4). The most common treatment‐related adverse events (≥50% patients) were diarrhea and nausea. There were no significant associations between mutational status (12 genes) and clinical response, suggesting potential benefit across diverse molecular profiles. Glasdegib plus cytarabine/daunorubicin was well tolerated and associated with clinical activity in patients with untreated AML or high‐risk MDS. A randomized phase 3 trial of glasdegib in combination with chemotherapy (7 + 3 schedule) is ongoing.

Temporal patterns and predictors of receiving no active treatment among older patients with acute myeloid leukemia in the United States: A population‐level analysis

“…This trend may be due to the introduction of less toxic regimens such as HMAs and improved supportive care measures . It remains to be seen how the recent approvals of effective and generally well‐tolerated novel oral agents for unfit older patients and those with comorbidities, such as venetoclax, ivosidenib, and glasdegib, will impact treatment patterns and outcomes in this patient population . In addition, the oral administration of these agents may decrease the logistic burden for patients associated with travel to and from treatment centers and the inconvenience of HMA injections, potentially leading to increased therapy adherence.…”

“…Although high‐intensity treatment with curative intent might not be feasible for older patients with AML, several treatment options to alleviate symptoms, improve quality of life (QOL), reduce the need for transfusion, and possibly prolong survival are available . These include hypomethylating agents (HMAs) such as azacitidine and decitabine, low‐dose cytarabine, and, more recently, targeted therapies such as the hedgehog signaling pathway inhibitor glasdegib and the BCL‐2 inhibitor venetoclax, which have been approved in the United States for older, unfit patients with AML …”

“…[2][3][4] These include hypomethylating agents (HMAs) such as azacitidine and decitabine, lowdose cytarabine, and, more recently, targeted therapies such as the hedgehog signaling pathway inhibitor glasdegib and the BCL-2 inhibitor venetoclax, which have been approved in the United States for older, unfit patients with AML. [7][8][9][10][11] Although in the United States HMAs are not specifically labeled for use in patients with AML, they are the de facto standard of care among older unfit patients with AML since their approval for the management of the closely related myelodysplastic syndromes in 2004 (azacitidine) and 2006 (decitabine). Large registry and real-life data in Cancer December 1, 2019 the United States have demonstrated that a significant percentage of older patients with AML are managed with no active therapy (NAT), which includes transfusions of blood products, growth factor support, and antibiotics.…”

Targeting cancer stem cell pathways for cancer therapy

“…613 In a phase II trial, glasdegib combined with cytarabine/daunorubicin had a significant efficacy in patients with AML, chronic myeloid leukemia (CML) or high-risk myelodysplastic syndromes. 614 Glasdegib combined with lowdose cytarabine (LDAC) is a potential option for AML patients who are not suitable for intensive chemotherapy. 615 Other selective SMO inhibitors, including taladegib (LY2940680) and saridegib (IPI-926), have also entered clinical trials for other cancers.…”

Transcriptional Silencing of MCL-1 Through Cyclin-Dependent Kinase Inhibition in Acute Myeloid Leukemia

“…Thus, there is a clear need for improved therapeutic options in AML. Since 2013, 65 drugs have been granted orphan designation specifically for the treatment of AML (9); however, there were only four US FDA approvals for new treatments in AML in 2017 (6,(10)(11)(12)(13)(14)(15)(16) and another four in 2018 (17)(18)(19)(20)(21)(22)(23)(24)(25)(26).…”