International Randomized Phase III Study of Elacytarabine Versus Investigator Choice in Patients With Relapsed/Refractory Acute Myeloid Leukemia

Roboz, Gail J.; Rosenblat, Todd L.; Arellano, Martha; Gobbi, Marco; Altman, Jessica K.; Montesinos, Pau; O’Connell, Casey L.; Solomon, Scott R.; Pigneux, Arnaud; Vey, Norbert; Hills, Robert Kerrin; Jacobsen, Tove Flem; Gianella‐Borradori, Athos; Foss, Oivind; Vetrhusand, Sylvia; Giles, Francis J.

doi:10.1200/jco.2013.52.8562

Cited by 177 publications

(147 citation statements)

References 16 publications

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“…Although the 10‐day regimen was associated with a higher incidence of grade 3 or higher adverse events, there was no increase in all‐cause mortality at 30 and 60 days. Overall, early mortality was lower than that observed in other studies of AML salvage therapy 3, 16…”

Section: Discussioncontrasting

confidence: 55%

“…Trials in AML have failed to date to show a survival benefit in the salvage setting 3, 16, 17. We report here the first results of different doses and schedules of guadecitabine, a next‐generation HMA, in a multicenter study of 103 patients.…”

Section: Discussionmentioning

confidence: 96%

“…The CRc rate of 30%, the median overall survival of 7.1 months, and the 30‐day mortality rate of 1.9% for patients treated with the 10‐day regimen compare favorably with published data. In a study by Roboz et al3 comparing elacytarabine with physician choice in a very similar patient population, the control group had a 21% CRc rate, a median overall survival of 3.3 months, and a 30‐day mortality rate of 14.8%. The increased efficacy observed with the 10‐day regimen (Table 2) is further supported by increased response rates in poor‐prognosis patients, such as those with poor cytogenetics, those with prior HCT, and those refractory to induction.…”

Section: Discussionmentioning

confidence: 99%

“…Unless they achieve a second remission followed by allogeneic hematopoietic cell transplantation (HCT), their prognosis is poor 1, 2, 3…”

Section: Introductionmentioning

confidence: 99%

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Dose, schedule, safety, and efficacy of guadecitabine in relapsed or refractory acute myeloid leukemia

Roboz

Kantarjian

Yee

et al. 2017

Cancer

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BACKGROUNDOutcomes for patients with relapsed or refractory acute myeloid leukemia (AML) are poor. Guadecitabine, a next‐generation hypomethylating agent, could be useful in treating such patients.METHODSIn this multicenter, open‐label, phase 2 dose‐expansion study, AML patients from 10 North American medical centers were first randomized (1:1) to receive subcutaneous guadecitabine at 60 or 90 mg/m2 on 5 consecutive days in each 28‐day cycle (5‐day regimen). Subsequently, another cohort was treated for 10 days with 60 mg/m2 (10‐day regimen).RESULTSBetween June 15, 2012, and August 19, 2013, 108 patients with previously treated AML consented to enroll in the study, and 103 of these patients were treated; 5 patients did not receive the study treatment. A total of 103 patients were included in the safety and efficacy analyses (24 and 26 patients who were randomly assigned to 60 and 90 mg/m2/d, respectively [5‐day regimen] and 53 patients who were assigned to 60 mg/m2/d [10‐day regimen]). The 90 mg/m2 dose showed no benefit in clinical outcomes in comparison with 60 mg/m2 in the randomized cohort. Composite complete response (CRc) and complete response (CR) rates were higher with the 10‐day regimen versus the 5‐day regimen (CRc, 30.2% vs 16.0%; P = .1061; CR, 18.9% vs 8%; P = .15). Adverse events (grade ≥ 3) were mainly hematologic, with a higher incidence on the 10‐day regimen. Early all‐cause mortality was low and similar between regimens. Twenty patients (8 on the 5‐day regimen and 12 on the 10‐day regimen) were bridged to hematopoietic cell transplantation.CONCLUSIONSGuadecitabine has promising clinical activity and an acceptable safety profile and thus warrants further development in this population. Cancer 2018;124:325‐34. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

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Section: Discussioncontrasting

confidence: 55%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

“…Unless they achieve a second remission followed by allogeneic hematopoietic cell transplantation (HCT), their prognosis is poor 1, 2, 3…”

Section: Introductionmentioning

confidence: 99%

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Dose, schedule, safety, and efficacy of guadecitabine in relapsed or refractory acute myeloid leukemia

Roboz

Kantarjian

Yee

et al. 2017

Cancer

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“…Elacytarabine is the elaidic acid ester derivative of cytarabine, designed to enter cells independently of nucleoside transporters. Phase I/II trials were encouraging although subsequent clinical studies did not confirm superiority of elacytarabine as monotherapy in relapsed/refractory AML, compared with standard of care (27). Perhaps, elacytarabine should be further tested in earlier stage of disease and in combination with fludarabine or other conventional AML drugs.…”

Section: Discussionmentioning

confidence: 99%

Intesive fludarabine-high dose cytarabine-idarubicin combination as induction therapy with risk-adapted consolidation may improve treatment efficacy in younger Acute Myeloid Leukemia (AML) patients: Rationales, evidences and future perspectives

Guolo

Minetto

Clavio

et al. 2017

BST

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Acute myeloid leukemia (AML) has an incidence of 3-4 cases per 100,000 people/year and is the commonest form of acute leukemia in the adults (1,2).T h e d e v e l o p m e n t o f A M L i s a m u l t i -s t e p process linked to the progressive accumulation of mutations in a multipotent stem cell. According to a hierarchical model, different mutations occur during leukemogenesis, with founder mutations usually affecting genes involved in the epigenetic machinery (1,2).Intensive induction chemotherapy followed by a consolidation treatment for patients achieving hematological complete remission represents the backbone of AML treatment (3).In the last three decades no effective new drugs have been introduced for AML treatment, with the exception of gemtuzumab-ozogamicin, whose potential benefit for AML patients has not been completely elucidated (1).Standard induction therapy for younger AML patients is still based on a combination of daunorubicin and cytarabine. The rational for testing alternative SummaryAcute Myeloid Leukemia (AML) is the commonest form of leukemia in the adults, with an incidence of 3-4 cases per 100,000 people/year. After the first description of the effective cytarabine + antracycline (3+7) induction regimen, in the last 3 decades, no effective targeted drug has been included in the standard treatment of AML. Many efforts of modifying 3+7 adding a third drug or increasing the dose of anthracycline, cytarabine or both did not lead to substantial improvements, mainly due to increased toxicity. Many in vitro and in vivo evidences suggested that fludarabine may increase efficacy of cytarabine through a synergistic effect. Considering the continuous improvements in supportive care and management of infectious complications the feasibility of more intensive induction strategies have increased and a renewed interest in fludarabine-containing induction strategies arose. The recent MRC AML 15 trial has shown that a fludarabine-containing induction, FLAG-Ida, resulted superior to conventional 3+7 in terms of complete remission rates, relapse incidence and survival, although only a minority of patients could complete the whole planned consolidation program due to an excessive hematological toxicity. Our group recently published a 10-year experience with a fludarabine-containing induction that slightly differed from the MRC one and resulted in good efficacy and higher feasibility. In this commentary we review the major evidences supporting the employ of a fludarabine-containing induction in AML, and discuss the future perspectives.

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Myeloid Malignancies

Zeidner

Roy²,

Perl

et al. 2018

The American Cancer Society's Oncology in Practice

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International Randomized Phase III Study of Elacytarabine Versus Investigator Choice in Patients With Relapsed/Refractory Acute Myeloid Leukemia

Cited by 177 publications

References 16 publications

Dose, schedule, safety, and efficacy of guadecitabine in relapsed or refractory acute myeloid leukemia

Dose, schedule, safety, and efficacy of guadecitabine in relapsed or refractory acute myeloid leukemia

Intesive fludarabine-high dose cytarabine-idarubicin combination as induction therapy with risk-adapted consolidation may improve treatment efficacy in younger Acute Myeloid Leukemia (AML) patients: Rationales, evidences and future perspectives

Myeloid Malignancies

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