scholarly journals Clinical benefit of glasdegib plus low-dose cytarabine in patients with de novo and secondary acute myeloid leukemia: long-term analysis of a phase II randomized trial

2021 ◽  
Author(s):  
Michael Heuser ◽  
B. Douglas Smith ◽  
Walter Fiedler ◽  
Mikkael A. Sekeres ◽  
Pau Montesinos ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Phase Ii ◽  
Clinical Benefit ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
De Novo ◽  
Secondary Acute Myeloid Leukemia ◽  
Low Dose Cytarabine ◽  
Acute Myeloid

AbstractThis analysis from the phase II BRIGHT AML 1003 trial reports the long-term efficacy and safety of glasdegib + low-dose cytarabine (LDAC) in patients with acute myeloid leukemia ineligible for intensive chemotherapy. The multicenter, open-label study randomized (2:1) patients to receive glasdegib + LDAC (de novo, n = 38; secondary acute myeloid leukemia, n = 40) or LDAC alone (de novo, n = 18; secondary acute myeloid leukemia, n = 20). At the time of analysis, 90% of patients had died, with the longest follow-up since randomization 36 months. The combination of glasdegib and LDAC conferred superior overall survival (OS) versus LDAC alone; hazard ratio (HR) 0.495; (95% confidence interval [CI] 0.325–0.752); p = 0.0004; median OS was 8.3 versus 4.3 months. Improvement in OS was consistent across cytogenetic risk groups. In a post-hoc subgroup analysis, a survival trend with glasdegib + LDAC was observed in patients with de novo acute myeloid leukemia (HR 0.720; 95% CI 0.395–1.312; p = 0.14; median OS 6.6 vs 4.3 months) and secondary acute myeloid leukemia (HR 0.287; 95% CI 0.151–0.548; p < 0.0001; median OS 9.1 vs 4.1 months). The incidence of adverse events in the glasdegib + LDAC arm decreased after 90 days’ therapy: 83.7% versus 98.7% during the first 90 days. Glasdegib + LDAC versus LDAC alone continued to demonstrate superior OS in patients with acute myeloid leukemia; the clinical benefit with glasdegib + LDAC was particularly prominent in patients with secondary acute myeloid leukemia. ClinicalTrials.gov identifier: NCT01546038.

Low-Dose Lenalidomide Plus Low Dose Cytarabine Induce Complete Remission That Can Be Predicted By Genetic Profiling In Very Elderly Acute Myeloid Leukemia Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 496-496
Author(s):  
Giuseppe Visani ◽  
Francesco Di Raimondo ◽  
Felicetto Ferrara ◽  
Federica Loscocco ◽  
Pier Paolo Piccaluga ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Treatment Response ◽  
Phase Ii ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Phase Ii Study ◽  
Expression Profiles ◽  
Low Dose Cytarabine ◽  
Acute Myeloid

Abstract Outcome for older patients with acute myeloid leukemia (AML) is extremely poor. Intensive induction chemotherapy is often unsuitable. In this phase II study we tested, for the first time, the efficacy of a novel combination therapy with low-dose lenalidomide plus low-dose cytarabine. Further, based on the hypothesis that genetic features might influence treatment response, we aimed at identifying a possible biomarker by studying the global gene expression profiles (GEP). We designed a prospective phase II study to assess the efficacy of the concomitant administration of low-dose lenalidomide and low-dose cytarabine in patients with acute myeloid leukemia (AML) aged more than 70 years. Forty-five patients (median age 76 years, range: 70-85) ineligible for standard therapy, were consecutively treated with low-dose lenalidomide (10 mg/day orally, days 1-21) plus low-dose cytarabine (10mg/m2 twice daily, subcutaneously, days 1-15) every six weeks, up to 6 cycles. Median white blood cell count at diagnosis was 3.2x109/l (range: 0,4-46,8x109/l), whereas median hemoglobin was 8,9 g/dl and median platelet count was 31x109/l. Twenty-three out of 45 patients had an intermediate karyotype (18/23 normal), 18/45 an unfavorable karyotype and 4/45 were not evaluable. Nineteen patients had a de novo AML, whereas 26 patients had a secondary AML (18 after MDS, 3 after a CMPD, 2 after myelofibrosis, 3 after chemo-radiotherapy for a breast cancer). To identify possible biomarkers associated to sensitivity/resistance, global gene and miRNA expression profiling (Affymetrix Transciptome 2.0) was performed on purified AML cells. Induction-period mortality was 17%, with 8 deaths occurring during cycle 1. Thirty-seven patients completed at least one cycle of therapy and are evaluable for response. Overall CR rate was 43% among evaluable patients. Nine out of 16 responding patients are still in CR after a median follow-up of 12 months (range: 2-39). Statistical analysis showed that responding patients had a longer median overall survival than non-responders (428 vs. 74 days, P = .000). Conversely, by studying the global miRNA and gene expression profile we identified a molecular signature, including 114 genes and 18 miRNA associated with the clinical response (CR vs. no CR). Of note, the involved genes belonged to relevant functional categories such as angiogenesis, cell cycle regulation and immune response. Of note, based on the expression of 5 genes, we developed an algorithm to predict treatment response that was successfully validated by showing an 87% overall accuracy. In conclusion, low-dose lenalidomide plus low-dose cytarabine has high clinical activity, predictable by GEP, in elderly AML patients with poor prognosis. The study was registered at EMA (EUDRA-CT 2008-006790-33). Acknowledgments Celgene is acknowledged for providing Lenalidomide for the patients. The study was supported in part by AIL Pesaro Onlus. Disclosures: No relevant conflicts of interest to declare.

Phase II trial to assess the safety and efficacy of clofarabine in combination with low-dose cytarabine in elderly patients with acute myeloid leukemia

2013 ◽  
Vol 93 (1) ◽  
pp. 43-46 ◽  
Author(s):  
David Martínez-Cuadrón ◽  
Pau Montesinos ◽  
Albert Oriol ◽  
Olga Salamero ◽  
Belén Vidriales ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Elderly Patients ◽  
Phase Ii ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Phase Ii Trial ◽  
Safety And Efficacy ◽  
Low Dose Cytarabine ◽  
Acute Myeloid

Low-Dose Cytarabine With or Without Glasdegib in Newly Diagnosed Patients with Acute Myeloid Leukemia: Long-Term Analysis of a Phase 2 Randomized Trial

2019 ◽  
Vol 19 ◽  
pp. S228-S229 ◽  
Author(s):  
Cristina Papayannidis ◽  
B. Douglas Smith ◽  
Michael Heuser ◽  
Pau Montesinos ◽  
Mikkael A. Sekeres ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Randomized Trial ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Term Analysis ◽  
Low Dose Cytarabine ◽  
Acute Myeloid
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