Second induction with high-dose cytarabine and mitoxantrone: different impact on pediatric AML patients with t(8;21) and with inv(16)

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Key Points• AML induction with liposomal daunorubicin (80 mg/m 2 per day for 3 days) shows antileukemic activity comparable to idarubicin (12 mg/m 2 per day for 3 days).• Liposomal daunorubicin promises to be more active in the t(8;21) subgroup and causes less treatment-related toxicity.Outcomes of patients with acute myeloid leukemia (AML) improve significantly by intensification of induction. To further intensify anthracycline dosage without increasing cardiotoxicity, we compared potentially less cardiotoxic liposomal daunorubicin (L-DNR) to idarubicin at a higher-than-equivalent dose (80 vs 12 mg/m 2 per day for 3 days) during induction. In the multicenter therapy-optimization trial AML-BFM 2004, 521 of 611 pediatric patients (85%) were randomly assigned to L-DNR or idarubicin induction. Five-year results in both treatment arms were similar (overall survival 76% 6 3% [L-DNR] vs 75% 6 3% [idarubicin], P logrank 5 .65; event-free survival [EFS] 59% 6 3% vs 53% 6 3%, P logrank 5 .25; cumulative incidence of relapse 29% 6 3% vs 31% 6 3%, P (Gray) 5 .75), as were EFS results for standard (72% 6 5% vs 68% 6 5%, P logrank 5 .47) and high-risk (51% 6 4% vs 46% 6 4%, P logrank 5 .45) patients. L-DNR resulted in significantly better probability of EFS in patients with t(8;21). Overall, treatment-related mortality was lower with L-DNR than idarubicin (2/257 vs 10/264 patients, P 5 .04). Grade 3/4 cardiotoxicity was rare after induction (4 L-DNR vs 5 idarubicin). Only 1 L-DNR and 3 idarubicin patients presented with subclinical or mild cardiomyopathy during follow-up. In conclusion, at the given dose, L-DNR has overall antileukemic activity comparable to idarubicin, promises to be more active in subgroups, and causes less treatment-related mortality. This trial was registered at www.clinicaltrials.gov as #NCT00111345. (Blood. 2013;122(1):37-43)

Section: Discussionmentioning

confidence: 80%

Randomized trial comparing liposomal daunorubicin with idarubicin as induction for pediatric acute myeloid leukemia: results from Study AML-BFM 2004

Creutzig

Zimmermann

Bourquin

et al. 2013

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“…31 The outcome of our SR patients was inferior to that reported by other groups. 3,[6][7][8]10,32 There is no obvious explanation for this result. Considering compliance with dose intensity as a possible reason for the outcome of our SR patients being worse than expected, the median treatment duration for SR patients was 170 days (range 135-210 days); the estimated median duration of treatment of SR patients was 140 days.…”

Section: Discussionmentioning

confidence: 90%

“…This delay could have partly contributed to the unsatisfactory outcome of SR children. The new AIEOP study will address the question of whether the use of flow-cytometry-based minimal residual disease detection, which is certainly much more sensitive than morphologic evaluation for monitoring early leukemia clearance 7 and/or early/repeated courses of mitoxantrone, 32 can improve the EFS of SR children. The worse outcome observed in patients with monosomal karyotype has been reported in adult patients, 33 but it is a relatively novel observation for childhood AML, since only the negative impact of monosomy 7 has been previously described.…”

Section: Discussionmentioning

confidence: 99%

Results of the AIEOP AML 2002/01 multicenter prospective trial for the treatment of children with acute myeloid leukemia

Pession

Masetti

Rizzari

et al. 2013

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Key Points• Risk-adapted therapy and broad use of HSCT resulted in a significant improvement in outcome.• AUTO-or ALLO-HSCT in high-risk patients resulted in a cumulative incidence of leukemia relapse superimposable to that of SR.We evaluated the outcome of 482 children with acute myeloid leukemia (AML) enrolled in the Associazione Italiana di Ematologia e Oncologia Pediatrica AML 2002/01 trial. Treatment was stratified according to risk group; hematopoietic stem cell transplantation (HSCT) was used in high-risk (HR) children. Patients with core binding factor leukemia achieving complete remission (CR) after the first induction course were considered standard risk (SR; 99 patients), whereas the others (n 5 383) were assigned to the HR group. Allogeneic (ALLO) or autologous (AUTO) HSCT was employed, respectively, in 141 and 102 HR patients after consolidation therapy. CR, early death, and induction failure rates were 87%, 3%, and 10%, respectively. Relapse occurred in 24% of patients achieving CR. The 8-year overall survival (OS), event-free survival (EFS), and disease-free survival (DFS) were 68%, 55%, and 63%, respectively. OS, EFS, and DFS for SR and HR patients were 83%, 63%, and 66% and 64%, 53%, and 62%. DFS was 63% and 73% for HR patients given AUTO-HSCT and ALLO-HSCT, respectively. In multivariate analysis, risk group, white blood cell >100 3 10 9 /L at diagnosis, and monosomal karyotype predicted poorer EFS. Risk-oriented treatment and broad use of HSCT result in a long-term EFS comparing favorably with previously published studies on childhood AML. (Blood. 2013; 122(2):170-178)

“…The results of the AML-BFM 98 and 2004 trials in patients with t(8;21) AML demonstrated a significant favorable impact of HiDAC plus mitoxantrone in second induction. 87 Additional agents. Other drugs that have been used during induction include aclarubicin, amsacrine (adults), mitoxantrone (children and adults), and 2-chlorodeoxyadenosine (children).…”

Section: Recommendationmentioning

confidence: 99%

Diagnosis and management of acute myeloid leukemia in children and adolescents: recommendations from an international expert panel

Creutzig

Heuvel‐Eibrink

Gibson

et al. 2012

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526

IntroductionChildhood acute myeloid leukemia (AML) is a rare and heterogeneous disease, with an incidence of 7 cases per million children younger than 15 years. In high-income countries, intensive therapy in conjunction with effective supportive care has increased survival rates to ϳ 70%. In 1990 and 2003, expert working groups made recommendations for diagnosis, outcomes, standardization of response criteria, and reporting standards for AML. 1,2 Recent improvements in identifying the molecular genetics and pathogenesis of AML have been implemented in the new World Health Organization (WHO) classification of AML. 3 These changes, and the definition of new diagnostic and prognostic markers and their associated targeted therapies, have prompted the update of earlier recommendations by an international group, on behalf of the European LeukemiaNet for AML in adults in 2010. 4 Despite broad overlap in the diagnostic and treatment recommendations for AML for children and adults, there are important differences in both the diagnostic criteria and disease management, which merit age-specific recommendations. The absence of published recommendations specific for pediatric AML motivated an international group of pediatric hematologists and oncologists (panel and participating groups see "Appendix") to develop evidence-and expert opinionbased consensus recommendations for the diagnosis and management of AML in children, incorporating emerging information on the biology of the disease. The scope of the review is presented in the "Appendix." Recommendations for specific subgroups are also included. This article discusses diagnostic procedures and initial workup, prognostic factors, response criteria, and management, and in particular focuses on differences between adults and children with AML. For personal use only. on May 12, 2018. by guest www.bloodjournal.org From WHO classification and pediatric AMLThe recent WHO 2008 classification is applicable to both adult and pediatric AML 3,5 and has been summarized by Döhner et al. 4 The classification contains most, but not all, cytogenetic subgroups specific to children. Differences in genetic background between children and adults are given in Table 1 and discussed further in "Cytogenetics."Compared with previous classifications (European Group of Immunologic Characterization of Leukemias [EGIL], WHO 2001), 6 the new WHO classification introduced a stringently defined subclass of acute leukemias of ambiguous lineage (mixed phenotype acute leukemias [MPALs]), mainly on the basis of detailed immunophenotypic criteria (Table 2) or presence of t(9;22)(q34; q11.2)/BCR-ABL1 or t(v;11q23)/MLL rearrangement. 3,5,6 The new classification aims to create uniform subgroups defined by unifying molecular targets, which allow selection of specific treatment. Diagnostic procedures and initial workupThe minimal diagnostic requirements in childhood AML are morphology with cytochemistry, immunophenotyping, karyotyping, FISH, and specific molecular genetics in the bone marrow, which is comparable ...