© F e r r a t a S t o r t i F o u n d a t i o nations are most likely required for ETV6/RUNX1-positive leukemogenesis and might be important for the differences in clinical outcome. More than 80% of initial ETV6/RUNX1-positive ALL display additional genetic alterations of the ETV6 and RUNX1 gene loci in fluorescence in situ hybridization (FISH) analyses. These include deletions of the untranslocated ETV6 gene (70%), an extra copy of RUNX1 (23%) and duplication of the derivative chromosome der(21) t(12;21) (10%). 18 At relapse, additional alterations of chromosomes 12 and 21 are often detected in leukemic cells as well (85%). 19 Current genome wide high resolution analyses of DNA copy number alterations (CNA) have identified numerous genetic alterations in childhood ALL. [20][21][22][23] In initial ETV6/RUNX1-positive ALL, genes related to B-lymphocyte development and differentiation, cell cycle regulation, tumor suppression and apoptosis are recurrently affected. 20,21,[24][25][26][27] Recent DNA copy number analyses on matched initial diagnosis and relapse ALL samples revealed that CNA acquired at relapse primarily affect genes implicated in cell cycle regulation, B-cell development, drug metabolism and drug response. 25,28,29 In the present study, leukemic cell DNA from 51 patients with a first relapse of ETV6/RUNX1-positive ALL enrolled in and treated according to the ALL-REZ BFM relapse trials were examined by whole genome array comparative genomic hybridization (CGH) for cooperating genetic lesions. This cohort represents the largest number of patients analyzed so far, enabling the investigation of an association between identified CNA and relapse-specific clinical and prognostic parameters for the first time. Methods Patients and samplesLeukemic bone marrow samples from 51 patients with first relapse of an ETV6/RUNX1-positive BCP-ALL were collected at relapse diagnosis after written informed consent was obtained from the patients, their parents or guardians in accordance with the ethical committee of the Charité and the declaration of Helsinki. All patients were enrolled in and treated according to ALL-REZ relapse trials 90, 95/96, and 2002 of the BFM study group, which were approved by the Institutional Review Boards of the Charité and the FU-Berlin, Germany. Diagnostic bone marrow samples were selected to contain >60% leukemic cells prior to further enrichment by Ficoll-density gradient separation of mononuclear cells. The presence of the ETV6/RUNX1 fusion was detected by reverse transcriptase polymerase chain reaction analysis as described previously. 9 DNA isolationLeukemic cell samples were prepared and DNA isolated from bone marrow or peripheral blood mononuclear cells of all patients and of 20 healthy controls, serving as gender-specific control DNA, as described previously. 30 All DNA samples were amplified using the GenomePlex Whole Genome Amplification Kit (SigmaAldrich Chemie GmbH, Munich, Germany) following the manufacturer's directions. Array comparative genomic hybridizationArray CGH...
SummaryChildren with Down syndrome (DS) have a greater risk for developing both acute lymphoblastic leukaemia (ALL) and significant adverse effects of chemotherapy. We investigated their outcome with, and tolerance of, treatment protocols for relapsed ALL optimized in the paediatric population without DS. Probability of survival and causes of treatment failure were determined for 49 children with DS and a matched cohort of 98 children without DS among 2160 children treated for relapsed ALL in clinical trials conducted by the Berlin-Frankfurt-M€ unster ALL Relapse Study Group between 1983 and 2012. Despite more favourable ALL relapse characteristics, children with DS experienced lower event-free (EFS) and overall survival (OS) than the control group without DS (EFS 17 AE 08% vs. non-DS 41 AE 06%, P = 0Á006; OS 17 AE 09% vs. non-DS 51 AE 06%, P < 0Á001). Children with DS developed more frequently fatal complications of treatment (34 AE 07% vs. non-DS 10 AE 04%, P < 0Á001). During the last decade, EFS and OS were no longer significantly different in children with and without DS (EFS 31 AE 09% vs. 36 AE 09%, P = 0Á399; OS 31 AE 12% vs. 53 AE 09%, P = 0Á151). DS proved an independent prognostic factor of outcome after ALL relapse. Induction deaths and treatment-related mortality but not subsequent relapse were the main barrier to successful outcomes of relapse therapy in children with DS.
669 Background. Children with Down syndrome (DS) have a higher risk for developing not only acute lymphoblastic leukemia (ALL) but also significant adverse effects of chemotherapy compared to the overall pediatric population. Currently, it is unknown how children with DS, who develop a relapse of ALL, respond to treatment protocols that were optimized in the pediatric population without DS. We hypothesized that a concomitant diagnosis of DS is an independent prognostic factor of survival after treatment for relapsed ALL and that decreased tolerance of therapy impairs the success of relapse treatment in children with DS. Patients and Methods. The probability of event-free (EFS) and overall survival (OS) and the causes of treatment failure were determined for 51 children with DS and a matched cohort of 102 children without DS among 2736 children and young adults (up to 22 years of age) who were treated for relapsed ALL on a series of clinical trials conducted by the ALL-REZ-BFM Study Group between 1983 and 2012. Results. Among children with DS, who were enrolled on clinical trials of the ALL-REZ-BFM Study Group, ALL relapse more frequently exhibited favorable prognostic characteristics compared to the unmatched population of 2579 patients without DS. High risk forms of relapse were less frequent among children with DS (risk group S4, 10 vs. 28%, p<0.001) including relapse at a very early and early time point (35 vs. 56%, p<0.001). A higher proportion of relapse in DS involved the bone marrow (94 vs. 83% p<0.001). Transcripts of ETV6-RUNX1 or BCR-ABL1 were detected in none of the cases of relapsed ALL in DS compared to 20% (231/895, p<0.001) and 6% (83/1379, p=0.02) of cases in the population without DS. Treatment for relapsed ALL in children with DS less frequently included irradiation (of the central nervous system or total body) and hematopoietic stem cell transplantation compared to the matched non-DS group (28 vs. 70%, p<0.001, and 15 vs. 40%, p=0.002), respectively. Despite the apparent favorable risk profile, EFS and OS were lower in children with DS than the matched control group without DS (EFS 16 ± 08% vs. 39 ± 06%, p=0.005; OS 17 ± 08% vs. 48 ± 06%, p<0.001). Fatal adverse events of treatment developed more frequently in children with DS than the control group (36 ± 07% vs. 9 ± 03%, p<0.001). In contrast, the cumulative incidence of a subsequent relapse was similar in both groups (32 ± 07%, DS vs. 36 ± 05%, non-DS, p=0.373). The proportion of children with DS registered on clinical trials for relapsed ALL after frontline treatment on ALL-BFM trials showed an increase over time (from 1 registered vs. 1 non registered patient in ALL-BFM 81 to 18 registered vs. 8 non registered patients in ALL-BFM 2000). Furthermore, the proportion of patients with high risk relapse features (S4 group) and DS increased from 5 to 15%. During the more recent study period (2000–2012) EFS and OS were no longer significantly different in children with and without DS (EFS 30 ± 09% vs. 35 ± 09%, p=0.403; OS 30 ± 11% vs. 51 ± 08%, p=0.158). DS was an independent prognostic factor of outcome after relapse of ALL in multivariate analysis. Conclusion. A higher rate of induction deaths and treatment-related mortality was the main barrier to successful outcomes of relapse therapy in children with DS whereas relapse rates were not different from patients without DS. An increased representation of children with DS including those with high risk features in recent time suggests that access to clinical trials for relapsed ALL has been successfully broadened for children with DS. Specific optimization of treatment modifications and supportive care have improved survival in children with DS and are suggested to further decrease the number of fatal treatment-related events during relapse therapy in this group. Disclosures: No relevant conflicts of interest to declare.
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