Addition of Gemtuzumab Ozogamicin to Induction Chemotherapy Improves Survival in Older Patients With Acute Myeloid Leukemia

Burnett, Alan Kenneth; Russell, Nigel H.; Hills, Robert Kerrin; Kell, Jonathan; Freeman, Sylvie; Kjeldsen, Lars; Hunter, Ann; Yin, John; Craddock, Charles; Dufva, Inge Høgh; Wheatley, Keith; Milligan, Donald

doi:10.1200/jco.2012.42.2964

Cited by 366 publications

(274 citation statements)

References 21 publications

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“…The effect of induction GO was similar regardless of chemotherapy regimen, suggesting that the drug was not a non-specific means of dose intensification and regardless of randomization to GO post-remission. Randomizing 1115 newly-diagnosed older patients (median age 67, 98% age > 60) considered "fit for intensive chemotherapy" to one of two induction chemotherapy regimens each1/2 GO the MRC/ NCRI AML16 trial found similar CR rates but lower cumulative incidence of relapse (CIR) and superior RFS and OS with GO again regardless of induction chemotherapy received and again with intermediate cytogenetics deriving more OS benefit than adverse cytogenetics (17% and 5% reductions in risk of death respectively) [24]. Figure 3 depicts a meta-analysis of the MRC/NCRI AML 15 (younger patients) and 16 (older patients) trials The third randomized trial assigned 280 patients aged 50-70 (median 62) to receive three courses (the 1 st to induce remission, the 2 nd and 3 rd to "consolidate" it) of daunorubicin 1 cytarabine 1/2 GO (3 mg/m2 day 1,4,7 induction, d1 consolidation).…”

Section: Treatmentmentioning

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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Section: Treatmentmentioning

confidence: 99%

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

2013

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“…The dose of daunorubicin was also suboptimal in the GO arm, a fact confirmed today by several studies (mentioned above). In the meantime, 4 other randomized trials matured, all demonstrating the benefit of adding GO, either overall or in subsets of patients [15,[102][103][104]. This led to a meta-analysis of the 5 randomized trials involving 3,325 patients, which showed that the addition of GO did not increase the CR rate, but reduced significantly the risk of relapse (p 5 0.0001) and improved the 5-year survival rate (p 5 0.01), particularly in patients with favorable cytogenetics (p 5 0.0006) and intermediate cytogenetics (p 5 0.005).…”

Section: Younger Patients With Amlmentioning

confidence: 99%

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

Kantarjian

2015

American J Hematol

107

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“…Nombre d'entre eux s'attaquent, soit directement aux cellules tumorales en neutralisant des récepteurs impliqués dans les mécanismes de prolifé-ration et de survie cellulaires, soit à la vascularisation tumorale, ou encore visent à (ré)activer la surveillance de la tumeur par le système immunitaire 1, 2. Comme l'efficacité clinique globale des anticorps nus reste limitée, notamment en monothérapie et dans le traitement de tumeurs solides 3, 4, ces molécules sont clas-un bénéfice clinique chez certaines sous-populations de patients atteints de LAM [8,9]. Ces résultats, bien qu'associés à l'amélioration du profil de toxicité grâce à l'optimisation du schéma d'administration, sont largement débattus au sein de la communauté des héma-tologues et avec les agences réglementaires [10].…”

Section: Un Développement Clinique Riche En Rebondissements…unclassified