Clofarabine Plus Cytarabine Compared With Cytarabine Alone in Older Patients With Relapsed or Refractory Acute Myelogenous Leukemia: Results From the CLASSIC I Trial

Faderl, Stefan; Wetzler, Meir; Rizzieri, David A.; Schiller, Gary J.; Jagasia, Madan; Stuart, Robert K.; Ganguly, Siddhartha; Avigan, David; Craig, Michael; Collins, Robert H.; Maris, Michael B.; Kovacsovics, Tibor; Goldberg, Stuart L.; Seiter, Karen; Hari, Parameswaran; Greiner, Jochen; Vey, Norbert; Récher, Christian; Ravandi, Farhad; Wang, Eunice S.; Vasconcelles, Michael J.; Huebner, Dirk; Kantarjian, Hagop M.

doi:10.1200/jco.2011.37.9743

Cited by 162 publications

(139 citation statements)

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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: Discussionmentioning

confidence: 65%

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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: Discussionmentioning

confidence: 65%

“…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: 97%

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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“…Several randomized trials have not found that this nucleoside analog more effective than standard therapy. The CLASSIC1 trial [35] involved 326 patients aged > 50 and approximately equally divided between relapsed and primary refractory assigned to "high-dose" ara-C (HiDAC: 1g/m2 days 1-5) 1/2 clofarabine 40mg/m2 days 1-5. While CR rate was superior with clofarabine (35% vs. 23%) RFS was not and together with a higher TRM rate (16% vs. 5%) resulted in similar OS (medians 6.6 and 6.3 months).…”

Section: Worse Prognosis Patientsmentioning

confidence: 99%

Acute myeloid leukemia: 2013 update on risk‐stratification and management

2013

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Disease overviewAcute myeloid leukemia (AML) results from accumulation of abnormal blasts in the marrow. These cells interfere with normal hematopoiesis, can escape into the peripheral blood, and infiltrate CSF and lung. It is likely that many different mutations, epigenetic aberrations, or abnormalities in micro RNA expression can produce the same morphologic disease with these differences responsible for the very variable response to therapy, which is AMLs principal feature.DiagnosisThis rests on demonstration that the marrow or blood has > 20% blasts of myeloid lineage. Blast lineage is assessed by multiparameter flow cytometry, with CD33 and CD13 being surface markers typically expressed by myeloid blasts. It should be realized that clinical/prognostic considerations, not the blast % per se, should be the main factor determining how a patient is treated.Risk StratificationTwo features determine risk: the probability of treatment‐related mortality (TRM) and, more important, even in patients aged >75 with Zubrod performance status 1, the probability of resistance to standard therapy despite not incurring TRM. The chief predictor of resistance is cytogenetics, with a monosomal karyotype (MK) denoting the disease is essentially incurable with standard therapy even if followed by a standard allogeneic transplant (HCT). The most common cytogentic finding is a normal karyotype(NK) and those of such patients with an NPM1 mutation but no FLT3 internal tandem duplication (ITD), or with a CEBPA mutation, have a prognosis similar to that of patients with the most favorable cytogenetics (inv 16 or t[8;21]) (60–70% cure rate). In contrast, NK patients with a FLT3 ITD have only a 30–40% chance of cure even after HCT. Accordingly analyses of NPM1, FLT3, and CEBPA should be part of routine evaluation, much as is cytogenetics. Risk is best assessed considering several variables simultaneously rather than, for example, only age. Increasing evidence indicates that other mutations and abnormalities in microRNA (miRNA) expression also affect resistance as do post treatment factors, in particular the presence of minimal residual disease. These newer mutations and MRD are discussed in this update.Risk‐adapted therapyPatients with inv (16) or t(8;21) or who are NPM1+/FLT3ITD—can receive standard therapy (daunorubicin + cytarabine) and should not receive HCT in first CR. It seems likely that use of a daily daunorubicin dose of 90 mg/m2 will further improve outcome in these patients. There appears no reason to use doses of cytarabine > 1 g/m2 (for example bid X 6 days), as opposed to the more commonly used 3 g/m2. Patients with an unfavorable karyotype (particularly MK) are unlikely to benefit from standard therapy (even with dose escalation) and are thus prime candidates for clinical trials of new drugs or new approaches to HCT; the latter should be done in first CR. Patients with intermediate prognoses (for example NK and NPM and FLT3ITD negative) should also receive HCT in first CR and can plausibly receive either investigational or standard induction therapy, with the same prognostic information about standard therapy leading one patient to choose the standard and another an investigational option. This update discusses results with newer agents: quizartinib and crenolanib, gemtuzumab ozogamicin, clofarabine and cladribine, azacitidine and decitabine, volasertib, and means to prevent relapse after allogeneic transplant.The diagnosis of AML essentially is made as it was in 2012. Thus this review will emphasize new developments in risk stratification and treatment using as references many papers published in 2012. Am. J. Hematol. 88:318–327, 2013. © 2013 Wiley Periodicals, Inc.

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“…Several studies have demonstrated similar survival rates with improved safety outcomes using IDAC-containing regimes (in comparison with high-dose cytarabine (HiDAC)) [63][64][65][66][67] and it has long been known that cytarabine-activating enzyme deoxycytidine kinase is fully saturated at cytarabine doses (0.5 --1 g/m 2 ) [68]. The Phase III randomized controlled trial looking at clofarabine [69] with Ara-C (CLASSIC-1) has also used IDAC rather than HiDAC, establishing the former as an acceptable comparator for combination trials.…”

Section: Resultsmentioning

confidence: 99%

Vosaroxin: a new valuable tool with the potential to replace anthracyclines in the treatment of AML?

Freeman¹,

Keane²,

Swords³

et al. 2013

Expert Opinion on Pharmacotherapy

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Clofarabine Plus Cytarabine Compared With Cytarabine Alone in Older Patients With Relapsed or Refractory Acute Myelogenous Leukemia: Results From the CLASSIC I Trial

Cited by 162 publications

References 22 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

Acute myeloid leukemia: 2013 update on risk‐stratification and management

Vosaroxin: a new valuable tool with the potential to replace anthracyclines in the treatment of AML?

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