Epigenetic therapy is associated with similar survival compared with intensive chemotherapy in older patients with newly diagnosed acute myeloid leukemia

Quintás‐Cardama, Alfonso; Ravandi, Farhad; Liu-Dumlao, Theresa; Brandt, Mark; Faderl, Stefan; Pierce, Sherry; Borthakur, Gautam; Garcia‐Manero, Guillermo; Cortes, Jorge; Kantarjian, Hagop M.

doi:10.1182/blood-2012-06-436055

Cited by 205 publications

(173 citation statements)

References 26 publications

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“…Although patients receiving either Aza or Dec induction were included in both studies, patients at MDACC received a 5-day Dec regimen in contrast to our patients, the majority of whom (63 of 83) received a 10-day decitabine (Dec10) induction. Despite these differences, Quintas-Cardama et al [44] reported similar results as ours with higher response rates following IC but no statistically significant differences in OS following either IC or Epi induction in older patients.…”

Section: Discussionsupporting

confidence: 80%

“…In the univariate analysis, IC was associated with higher ORR (50% vs. 28%, P 5 0.001), CRR (43% vs. 20%, P 5 0.004), and median OS (10.7 vs. 9.1 months, P 5 0.012) as compared with Epi therapy [7,21,43,44]. However, when we performed a Cox proportional hazards regression model controlling for the baseline differences in patient characteristics and accounting for HSCT as a timedependent factor, we found no statistically significant difference in OS outcome based on induction choice (IC vs. Epi).…”

Section: Discussionmentioning

confidence: 96%

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Comparison of epigenetic versus standard induction chemotherapy for newly diagnosed acute myeloid leukemia patients ≥60 years old

et al. 2015

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Older patients with acute myeloid leukemia (AML) have poor outcomes with standard induction chemotherapy. We retrospectively reviewed our institute's experience with epigenetic (Epi) versus cytarabine-and anthracycline-based intensive chemotherapy (IC) as induction in newly diagnosed AML patients aged 60 years and older. One hundred sixty-seven patients (n 5 84, IC; n 5 83, Epi) were assessed; 69 patients received decitabine and 14 azacitidine. Baseline characteristics between the IC and Epi patient cohorts were not statistically different except for age, initial white blood cell count, and comorbidity index. Overall response rate (ORR, 50% vs. 28%, respectively, P < 0.01) and complete response rate (CRR, 43% vs. 20%, respectively, P < 0.01) were superior following IC vs. Epi. Although univariate analysis demonstrated longer overall survival after IC (10.7 vs. 9.1 months, P 5 0.012), multivariate analysis showed no independent impact of induction treatment. Treatment-related mortality was not statistically different in the two groups. Outcomes of patients with secondary, poor cytogenetic risk, FLT-3 mutated AML, or relapsed/refractory disease after IC or Epi were not significantly different. Outcomes of patients receiving IC versus a 10-day decitabine regimen (n 5 63) also were not significantly different. Our results suggest that IC and Epi therapy are clinically equivalent approaches for upfront treatment of older patients with AML and that other factors (feasibility, toxicity, cost, etc.) should drive treatment decisions. Prospective randomized trials to determine the optimal induction approach for specific patient subsets are needed.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 96%

Comparison of epigenetic versus standard induction chemotherapy for newly diagnosed acute myeloid leukemia patients ≥60 years old

et al. 2015

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“…While the median OS in our study appears short in comparison with that reported by Fenaux et al from the comparison of azacitidine and BSC only (median, 19.1 vs 13.4 months), the studies are not directly comparable due to differences in the patient cohorts, as displayed by the OS of patients in the BSC arms [6]. The few retrospective studies that compared decitabine and azacitidine did not specifically assess the survival among patients with RAEBt and/or 20-30 % blasts [18][19][20][21][22]. Importantly, we also observed that the favorable impact of decitabine on the outcome of RAEBt patients was similar among various patient subgroups and significantly differed from that among RAEB patients.…”

Section: Survival In Subgroups Of Raebt Patientscontrasting

confidence: 65%

Decitabine versus best supportive care in older patients with refractory anemia with excess blasts in transformation (RAEBt) - results of a subgroup analysis of the randomized phase III study 06011 of the EORTC Leukemia Cooperative Group and German MDS Study Group (GMDSSG)

et al. 2015

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In the European Organisation for Research and Treatment of Cancer (EORTC)/GMDSSG phase III trial 06011, we compared decitabine (15 mg/m 2 every 8 h for 3 days) with best supportive care (BSC) in patients ≥60 years with myelodysplastic syndromes (MDS) by FrenchAmerican-British (FAB) criteria. Here, we reinvestigate trial 06011 for the activity and efficacy specifically in patients with refractory anemia with excess blasts in transformation (RAEBt). Response rates in the decitabine arm (N=40) were as follows: complete or partial remission, 15 %; hematologic improvement, 15 %; resistant disease, 30 %. RAEBt patients in the decitabine arm had longer progression-free survival (PFS; hazard ratio (HR) 0.30, 95 % confidence interval (CI) 0.18-0.51; median, 6.2 vs 2.8 months) and overall survival (OS; HR 0.68, 95 % CI 0.42-1.11; median, 8.0 vs 6.0 months) than in the BSC arm (N=35). Censoring at allogeneic hematopoietic stem cell transplantation, the OS difference between the treatment groups increased, particularly among patients Electronic supplementary material The online version of this article (doi:10.1007/s00277-015-2489-6) contains supplementary material, which is available to authorized users.

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“…For example Quintas-Cardama et al found similar OS among 557 patients aged 65 given regimens generally containing ara-C at 1-2 g/m 2 daily 1 idarubicin or fludarabine 6 other agents and 114 patients given decitabine (n 5 67) or azacitidine (n 5 47) despite higher CR rates with the more intense therapies [40] (Fig. 7), thus again, as in the AML16 clofarabine trial [37] questioning the role of CR.…”

Section: Azacitidine and Decitabinementioning

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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Epigenetic therapy is associated with similar survival compared with intensive chemotherapy in older patients with newly diagnosed acute myeloid leukemia

Cited by 205 publications

References 26 publications

Comparison of epigenetic versus standard induction chemotherapy for newly diagnosed acute myeloid leukemia patients ≥60 years old

Comparison of epigenetic versus standard induction chemotherapy for newly diagnosed acute myeloid leukemia patients ≥60 years old

Decitabine versus best supportive care in older patients with refractory anemia with excess blasts in transformation (RAEBt) - results of a subgroup analysis of the randomized phase III study 06011 of the EORTC Leukemia Cooperative Group and German MDS Study Group (GMDSSG)

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

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