CLINICAL BENEFIT OF GLASDEGIB PLUS LOW-DOSE CYTARABINE IN PATIENTS WITH DE NOVO AND SECONDARY ACUTE MYELOID LEUKEMIA: LONG-TERM ANALYSIS OF A PHASE 2 RANDOMIZED TRIAL
Author(s): ,
Michael Heuser
Affiliations:
Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School,Hannover,Germany
,
Walter Fiedler
Affiliations:
Department of Hematology and Oncology, University Hospital Hamburg-Eppendorf,Hamburg,Germany
,
Mikkael A Sekeres
Affiliations:
Leukemia Program, Cleveland Clinic,Cleveland, OH,United States
,
Pau Montesinos
Affiliations:
Hospital Universitari i Politècnic La Fe, Valencia, Spain, and CIBERONC, Instituto Carlos III,Madrid,Spain
,
Brian Leber
Affiliations:
Juravinski Hospital at Hamilton Health Sciences,Hamilton,Canada
,
Akil Merchant
Affiliations:
Department of Medicine,Keck School of Medicine, University of Southern California,Los Angeles, CA,United States
,
Cristina Papayannidis
Affiliations:
Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna,Bologna,Italy
,
José A Pérez-Simón
Affiliations:
Hospital Universitario Virgen del Rocío-Virgen Macarena, Instituto de Biomedicina (IbiS)/Universidad de Sevilla,Seville,Spain
,
Caroline J Hoang
Affiliations:
Pfizer Inc,New York, NY,United States
,
Weidong Wendy Ma
Affiliations:
Pfizer Inc,New York, NY,United States
,
Mirjana Zeremski
Affiliations:
Pfizer Inc,New York, NY,United States
,
Ashleigh O’Connell
Affiliations:
Pfizer Inc,New York, NY,United States
,
Geoffrey Chan
Affiliations:
Pfizer Inc,New York, NY,United States
Jorge E Cortes
Affiliations:
University of Texas, MD Anderson Cancer Center,Houston, TX,United States
EHA Library. Fiedler W. Jun 15, 2019; 266646; PS1029
Prof. Dr. Walter Fiedler
Prof. Dr. Walter Fiedler
Contributions
Abstract

Abstract: PS1029

Type: Poster Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 17:30 - 19:00

Location: Poster area

Background
Secondary acute myeloid leukemia (AML) is known for its treatment resistance and confers a poorer prognosis vs de novo AML. The incidence of secondary AML increases with age, with ~25% of patients (pts) aged 70 or older being diagnosed with secondary AML. Glasdegib is a potent, selective, oral inhibitor of the Hedgehog signaling pathway that is approved in the US in combination with low-dose cytarabine (LDAC) for the treatment of newly diagnosed AML in pts unable to receive intensive chemotherapy due to comorbidities or age. The treatment combination showed superior overall survival (OS) vs LDAC alone in a phase 2 randomized study that included pts with newly diagnosed de novo or secondary AML who were ineligible for intensive chemotherapy.

Aims
To evaluate the clinical benefit and safety of glasdegib + LDAC in the AML subgroups of de novo or secondary disease.

Methods
In the phase 2 BRIGHT AML trial (NCT01546038), pts were randomized 2:1 to glasdegib + LDAC or LDAC alone (design of the main study reported previously: Cortes et al., Leukemia 2018). The current post hoc subgroup analysis evaluated efficacy and safety after ~20 additional months of follow-up in pts categorized by diagnosis as determined by the investigator: de novo AML or secondary AML (defined as AML evolving from myelodysplastic syndrome or other antecedent hematologic disease, and AML after previous cytotoxic therapy or radiation).

Results
As of 11 October, 2018, 116 pts were assigned to treatment with glasdegib + LDAC (de novo, n=38; secondary AML, n=40) or LDAC alone (de novo, n=18; secondary AML, n=20). In the overall population (de novo + secondary AML), the median follow-up time for glasdegib + LDAC and LDAC alone was 43.4 and 42.0 months, respectively, and glasdegib + LDAC significantly prolonged OS vs LDAC alone (median: 8.3 vs 4.3 months; hazard ratio (95% CI): 0.495 (0.325–0.752); P = 0.0004). In the de novo subgroup, the median follow-up time for glasdegib + LDAC and LDAC alone was 39.7 and 42.0 months, respectively; for the secondary AML subgroup, the median follow-up for glasdegib was 44.2 months (and all pts except one for LDAC alone died). The median OS was generally higher with glasdegib + LDAC vs LDAC alone, for both de novo and secondary AML subgroups, and improvement was consistent across most groups stratified by cytogenetic risk (Table). The improvement in OS was statistically significant in pts with secondary AML (Table). The main cause of death in both groups of pts, in both treatment arms, was disease progression. With glasdegib + LDAC in pts with de novo AML, the most common adverse events in the short term (during the first 90 days) and long term (after 90 days) were anemia/nausea and muscle spasms/decreased appetite, respectively; in pts with secondary AML, these were anemia/febrile neutropenia and anemia/diarrhea, respectively. There were no discontinuations due to myalgia or dysgeusia.

Conclusion
Addition of glasdegib to LDAC vs LDAC alone demonstrated improved OS both in pts with de novo AML and secondary AML. In this exploratory analysis, the clinical benefit with glasdegib + LDAC was most pronounced in pts with secondary AML. Furthermore, improvement was consistent across groups stratified by cytogenetic risk, except in de novo AML with poor risk cytogenetics in which the small sample size precludes meaningful comparisons. Long-term follow-up confirmed that treatment with glasdegib was associated with an acceptable safety profile.

 

Session topic: 4. Acute myeloid leukemia - Clinical

Keyword(s): Acute myeloid leukemia, AML, Clinical outcome

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