Cladribine, But Not Fludarabine, Added to Daunorubicin and Cytarabine During Induction Prolongs Survival of Patients With Acute Myeloid Leukemia: A Multicenter, Randomized Phase III Study

Hołowiecki, Jerzy; Grosicki, Sebastian; Giebel, Sebastian; Robak, Tadeusz; Kyrcz‐Krzemień, Sławomira; Kuliczkowski, Kazimierz; Skotnicki, Aleksander B.; Hellmann, Andrzej; Sułek, K; Dmoszyńska, Anna; Kłoczko, Janusz; Jędrzejczak, Wiesław Wiktor; Zdziarska, Barbara; Warzocha, Krzysztof; Zawilska, Krystyna; Komarnicki, Mieczysław; Kiełbiński, Marek; Piątkowska−Jakubas, Beata; Wierzbowska, Agnieszka; Wach, Małgorzata; Haus, Olga

doi:10.1200/jco.2011.37.1286

Cited by 217 publications

(178 citation statements)

References 39 publications

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“…In the subsequent study, they compared 3 arms, 2 of them adding cladribine or fludarabine. In this study, they again showed the addition of cladribine (but not fludarabine) to be associated with significantly higher CR (67.5% versus 56%; p 5 0.001) and 3-year survival rates (45% versus 33%; p 5 0.02) [88].…”

Section: Younger Patients With Amlsupporting

confidence: 55%

Acute myeloid leukemia—Major progress over four decades and glimpses into the future

2015

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Section: Younger Patients With Amlsupporting

confidence: 55%

Acute myeloid leukemia—Major progress over four decades and glimpses into the future

2015

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“…CR was more common with DAC than DA (68% vs. 56%) as was CR after the first course (62% vs. 51%), reflecting less resistance and translating into improved survival despite similar CR duration (Fig. 6) [38]. The effect of cladribine was most obvious in patients age 50-60 with "unfavorable" cytogenetics and seemed independent of HCT.…”

Section: Worse Prognosis Patientsmentioning

confidence: 97%

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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“…6 The safety and efficacy of modified induction chemotherapy or preparative regimen for elderly patients need to be validated. [18][19][20][21][22][23][24][25] We found that decreases in GVHD-related and infection-related mortality contributed to the reduced risk of NRM. These findings are consistent with prior reports.…”

Section: Discussionmentioning

confidence: 75%

Recent decrease in non-relapse mortality due to GVHD and infection after allogeneic hematopoietic cell transplantation in non-remission acute leukemia

Kurosawa¹,

Yakushijin

Yamaguchi

et al. 2013

Bone Marrow Transplant

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Although recent improvements have been indicated in the outcome after allogeneic hematopoietic cell transplantation (allo-HCT), little information is available on how changes in transplant modalities have affected the outcomes after allo-HCT in non-remission, based on patient age, donor source and disease type. We compared the incidence and causes of non-relapse mortality (NRM) after allo-HCT in non-remission among three consecutive four-year periods using a nationwide transplant outcome registry database. A total of 3308 patients with acute leukemia in non-remission were analyzed. The risk of NRM decreased over the three periods, and the hazard ratios We found that a decrease in the incidences of death due to GVHD and infection contributed to the reduction in NRM, to which high-resolution donor-recipient HLA matching and other improvements may have contributed. As none of the subgroups showed improved survival without a reduction in NRM, the effective prevention of transplant-related complications appears to be necessary for improving outcomes after allo-HCT in non-remission.

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Cladribine, But Not Fludarabine, Added to Daunorubicin and Cytarabine During Induction Prolongs Survival of Patients With Acute Myeloid Leukemia: A Multicenter, Randomized Phase III Study

Abstract: The addition of cladribine to the standard induction regimen is associated with increased rate of complete remission and improved survival of adult patients with AML.

Cited by 217 publications

References 39 publications

Acute myeloid leukemia—Major progress over four decades and glimpses into the future

Acute myeloid leukemia—Major progress over four decades and glimpses into the future

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

Recent decrease in non-relapse mortality due to GVHD and infection after allogeneic hematopoietic cell transplantation in non-remission acute leukemia

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