Randomized phase II study of clofarabine versus clofarabine plus low-dose cytarabine (ara-C) for patients (pts) ≥ 60 years (yrs) with newly diagnosed acute myeloid leukemia (AML)

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.

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LOW-DOSE LENALIDOMIDE COUPLED with LOW-DOSE Cytarabine INDUCES COMPLETE REMISSION of Elderly ACUTE Myeloid LEUKEMIA PATIENTS with Unfavorable Citogenetics: PRELIMINARY RESULTS of A PHASE II STUDY,

Blood ◽

10.1182/blood.v118.21.3627.3627 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3627-3627

Author(s):

Giuseppe Visani ◽

Felicetto Ferrara ◽

Francesco Di Raimondo ◽

Maria Rita Caraci ◽

Tiziana Izzo ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Phase Ii ◽

Myeloid Leukemia ◽

Low Dose ◽

Phase Ii Study ◽

High Dose ◽

Combination Regimen ◽

Blast Count ◽

Low Dose Cytarabine ◽

Acute Myeloid

Abstract Abstract 3627 We designed a phase II study to assess the antitumor efficacy of the combination regimen with low-dose lenalidomide and low-dose cytarabine in patients with acute myeloid leukemia (AML) aged >70 years. Twenty-one patients (median age 76 years, range: 70–80) were consecutively enrolled in the study. Median white blood cell count at diagnosis was 11.920 x109/l (range: 0.59–46.8×109/l), whereas median haemoglobin was 8.9 g/dl and median platelet count was 30×109/l. Four out of 21 patients had a normal karyotype, whereas 17/21 presented with an intermediate or unfavourable karyotype. Twelve patients had a de novo AML, whereas 9 patients had a secondary AML (5 after MDS, 1 after a CMPD, 1 after myelofibrosis, 2 after chemo-radiotherapy for a breast cancer). All patients received low-dose lenalidomide (10 mg/day orally, days 1–21) and low-dose cytarabine (20mg twice day subcutaneously, days 1–15). Therapy was repeated every 6 weeks, up to 6 cycles. Six out of 21 patients died in aplasia while receiving the first induction cycle of therapy, and are not evaluable for response. One patients is still completing the first cycle. Fourteen patients completed at least one cycle of therapy and are evaluable for response. Among these patients, 8/14 (57%) cleared peripheral blood blasts at the end of the second week of the first cycle, with recovery of normal WBC, hemoglobin and platelets values after a median of 31 days (range: 27–42) from the start of chemotherapy. Six out of 8 responding patients are still in morphologic, cytogenetic and FISH CR after 14, 12, 10, 7, 3 and 3 months from the start of therapy, respectively. Two patient died while in CR after receiving, respectively, the second and the third cycle of therapy due to a multi organ failure after an infectious complication. The other 6 patients who completed at least one cycle of therapy did not respond at all and rapidly died due to progressive disease. At present, out of 8/14 (57%) patients evaluable for response that obtained CR, 6/14 (42%) are alive in continuous CR and two died in CR. Notably, all responding patients presented with low blast count and unfavorable cytogenetics at diagnosis. In conclusion, low-dose lenalidomide has clinical activity, when coupled with low-dose cytarabine, in an extremely poor-prognosis subset of AML. Considering the scarce compliance of elderly, frail AML patients to high-dose therapy, the low dose schedule could be particularly profitable, specially for patients with low blast count and unfavorable cytogenetics. The study was registered at EMA with the EUDRACT no 2008–006790–33. Acknowledgments: Celgene is acknowledged for providing Lenalidomide for the patients. The study was supported in part by AIL Pesaro Onlus. Conflict-of-interest disclosure: The Authors declare no competing financial interests. Disclosures: Di Raimondo: celgene: Honoraria.

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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

Annals of Hematology ◽

10.1007/s00277-021-04465-4 ◽

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.

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