Presence of FLT3-ITD and high BAALC expression are independent prognostic markers in childhood acute myeloid leukemia

Rondelli

et al. 2014

Bone Marrow Transplant

on behalf of AIEOP BMT Working GroupWe analyzed the outcome of 243 children with high-risk (HR) AML in first CR1 enrolled in the AIEOP-2002/01 protocol, who were given either allogeneic (ALLO; n = 141) or autologous (AUTO; n = 102) hematopoietic SCT (HSCT), depending on the availability of a HLA-compatible sibling. Infants, patients with AML-M7, or complex karyotype or those with FLT3-ITD, were eligible to be transplanted also from alternative donors. All patients received a myeloablative regimen combining BU, Cyclophosphamide and Melphalan; AUTO-HSCT patients received BM cells in most cases, while in children given ALLO-HSCT stem cell source was BM in 96, peripheral blood in 19 and cord blood in 26. With a median follow-up of 57 months (range 12-130), the probability of disease-free survival (DFS) was 73% and 63% in patients given either ALLO-or AUTO-HSCT, respectively (P = NS). Although the cumulative incidence (CI) of relapse was lower in ALLO-than in AUTO-HSCT recipients (17% vs 28%, respectively; P = 0.043), the CI of TRM was 7% in both groups. Patients transplanted with unrelated donor cord blood had a remarkable 92.3% 8-year DFS probability. Altogether, these data confirm that HSCT is a suitable option for preventing leukemia recurrence in HR children with CR1 AML.

Section: Discussionsupporting

confidence: 83%

“…27,28 In particular, Meshinchi et al 27 reported that children with FLT3-ITD had a 4-year progression-free survival and a CI of leukemia recurrence of 31% and 65%, respectively. The probability of OS in children with FLT3-ITD given an allograft from a matched family donor increased to 64%, thanks to reduced risk of leukemia recurrence.…”

Section: Discussionmentioning

confidence: 99%

Outcome of children with high-risk acute myeloid leukemia given autologous or allogeneic hematopoietic cell transplantation in the aieop AML-2002/01 study.

Locatelli

Rondelli

et al. 2014

Bone Marrow Transplant

“…3,7 FLT3-ITD has been reported to be an adverse prognostic factor in both adults and children with AML. [36][37][38] The observation that our 42 patients with FLT3-ITD, 20 of them given ALLO-HSCT, had an outcome not statistically different from that of HR patients without this molecular abnormality can be explained considering that these children, after 2006, were offered, if in CR and with an available HLA-matched donor, ALLO-HSCT, a treatment associated with an immune-mediated graft-versus-leukemia effect. Indeed, the DFS of our children given ALLO-HSCT was 75% 1/2 15%.…”

mentioning

confidence: 92%

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

Pession

Rizzari

et al. 2013

Blood

176

166

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)

“…1 Many genetic abnormalities have been identified in AML with normal karyotype, with the most frequent affecting genes such as NPM1, FLT3, CEBPA, and WT1. [1][2][3][4][5] Genome-wide analyses have been used with the aim of determining the full array of genetic lesions of CN-AML. Recent studies have provided new insight into the molecular genetics and biology of AML, confirming both the complexity and the heterogeneity of this disease.…”

Section: Introductionmentioning

confidence: 99%

CBFA2T3-GLIS2 fusion transcript is a novel common feature in pediatric, cytogenetically normal AML, not restricted to FAB M7 subtype

Pigazzi

Togni

et al. 2013

Blood

128

136

• The CBFA2T3-GLIS2 fusion transcript is common in pediatric cytogenetically normal AML and not restricted to FAB M7 subtype.• The CBFA2T3-GLIS2 fusion transcript is associated with poor prognosis in pediatric patients with AML.Pediatric cytogenetically normal acute myeloid leukemia (CN-AML) is a heterogeneous subgroup of myeloid clonal disorders that do not harbor known mutations. To investigate the mutation spectrum of pediatric CN-AML, we performed whole-transcriptome massively parallel sequencing on blasts from 7 CN-AML pediatric patients. In 3 patients we identified a recurrent cryptic inversion of chromosome 16, encoding a CBFA2T3-GLIS2 fusion transcript. In a validation cohort of 230 pediatric CN-AML samples we identified 17 new cases. Among a total of 20 patients with CBFA2T3-GLIS2 fusion transcript out of 237 investigated (8.4%), 10 patients (50%) did not belong to the French-American-British (FAB) M7 subgroup. The 5-year event-free survival for these 20 children was worse than that for the other CN-AML patients (27.4% vs 59.6%; P 5 .01). These data suggest that the presence of CBFA2T3-GLIS2 fusion transcript is a novel common feature of pediatric CN-AML, not restricted to the FAB M7 subtype, predicting poorer outcome. (Blood. 2013;121(17):3469-3472) IntroductionPediatric acute myeloid leukemia (AML) is a molecularly heterogeneous disease that arises from genetic alterations of pathways that regulate self-renewal and myeloid differentiation. While the majority of patients carry recurrent chromosomal translocations, almost 20% of childhood AMLs do not show any recognizable cytogenetic alteration and are defined as cytogenetically normal AML (CN-AML). 1Many genetic abnormalities have been identified in AML with normal karyotype, with the most frequent affecting genes such as NPM1, FLT3, CEBPA, and WT1. 1-5Genome-wide analyses have been used with the aim of determining the full array of genetic lesions of CN-AML. Recent studies have provided new insight into the molecular genetics and biology of AML, confirming both the complexity and the heterogeneity of this disease.6 Novel lesions such as mutations in IDH1 and DNMT3A have been identified. 7,8 However, these alterations are rare in pediatric AML, with IDH1/IDH2 accounting for 2% to 4% of cases 9,10 and DNMT3A not even being found mutated in childhood AML.11 Recently, 2 studies identified a novel recurrent translocation involving CBFA2T3 and GLIS2 in about 30% of children with non-Down syndrome acute megakaryoblastic leukemia (non-DS AMKL, AML French-American-British [FAB] M7).12,13 Nevertheless, there are many children with CN-AML in whom no genetic abnormality has been detected. The identification of the different genetic profiles characterizing this subgroup is a primary objective to be pursued. To this end, we performed whole-transcriptome massively parallel sequencing of 7 cases of pediatric CN-AML with the aim of identifying recurrent somatic mutations or genomic rearrangements. Subsequently, we validated our findings in a larger cohort of 230 pedi...