Outcome of Treatment for Relapsed Acute Lymphoblastic Leukemia in Children with Down Syndrome

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 669-669
Author(s):  
Franziska Meyr ◽  
Fabian Baumann ◽  
Gabriele Escherich ◽  
Georg Mann ◽  
Thomas Klingebiel ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Down Syndrome ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Pediatric Population ◽  
Lymphoblastic Leukemia ◽  
Control Group ◽  
Study Group ◽  
Children With Down Syndrome ◽  
Relapse Therapy

Abstract Abstract 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.

Mutation Analysis of JAK-1, 2 and 3 in Children with Down Syndrome and Acute Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 5035-5035
Author(s):  
Marjolein Blink ◽  
Trudy Buitenkamp ◽  
Astrid A Danen-van Oorschot ◽  
Valerie de Haas ◽  
Dirk Reinhardt ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Janus Kinase ◽  
Children With Down Syndrome ◽  
Activating Mutations ◽  
Increased Risk ◽  
Frequent Event

Abstract Abstract 5035 Children with Down Syndrome (DS) have an increased risk of developing leukemia, including both acute myeloid (ML-DS), as well as acute lymphoblastic leukemia (DS-ALL). ML-DS can be preceded by a pre-leukemic clone in newborns (transient leukemia-TL), which in most cases resolves spontaneously. Janus Kinase (JAK) 1-3 belongs to a family of intracellular non-receptor protein tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. JAK plays an important role in regulating the processes of cell proliferation, differentiation and apoptosis in response to cytokines and growth factors. Mullighan et al. described JAK 1-3 mutations in non-DS high-risk childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL; PNAS, 2009). In T-ALL, JAK-1 mutations are a frequent event (∼25%) as reported among others by Jeong et al (Clinical Cancer Research, 2008). Mutations in JAK-2 and JAK-3 have been described in TL and ML-DS. Bercovich et al. recently reported mutations within the pseudokinase domain of JAK-2 in DS-ALL patients (Lancet 2008). This activating JAK-2 mutation differs from the V617F exon 14 mutation found in myeloproliferative diseases. However, JAK-1 has never been investigated in Down syndrome leukemias. Therefore we performed mutational analysis of the pseudokinase and kinase domains of JAK-1, 2 and 3 by direct sequencing in 8 TL, 16 ML-DS and 35 DS-ALL samples taken at initial diagnosis. The TL and ML-DS samples were unpaired. In the ML-DS group, 12 patients were classified as FAB M7, 3 as FAB M0 and 1 as FAB M6; all 35 DS-ALL patients were classified as BCP-ALL. Mutations in JAK-1 were found in 1 ML-DS patient (D625R) and in 1 DS-ALL patient (V651M). These mutations were localised in the same region of the pseudokinase domain, but not identical to the activating mutations in JAK1 described in high-risk ALL (Mullighan et al., PNAS 2009). The JAK-1 mutated ML-DS patient had a complex karyogram, and the DS ALL patient a normal karyotype. No events occurred in either of the patients with a follow-up of 2.4 and 3.1 years, respectively. JAK-2 activating mutations at position R683 were found in 5/35 (14.3%) of the DS-ALL patients. These patients had diverse cytogenetic aberrations, and had no events at a median follow up of 4.4 years. In the TL and ML-DS patients no mutations were identified in JAK-2. For JAK-3, 1 TL-patient (13%) and 1 ML-DS patient (6.3%) harboured the A573V-mutation. This activating mutation is previously described in ML-DS patients and the megakaroyblastic cell line CMY ((Kiyoi et al, Leukemia 2007). Because the mutations occur in both TL and ML-DS, this suggests that they do not play a role in the clonal progression model from TL to ML-DS. A mutation at JAK3 R1092C, which to our knowledge has never been reported before, was found in 1 DS-ALL patient. This patient had a deletion on chromosome 12 (p11p13), and was in CCR with a follow up of 5 years. In conclusion, JAK-mutations are rare in DS-leukemias, except for JAK-2 mutations in DS-ALL, which occur in approximately 15% of cases. The rarity of JAK-1 mutations in DS is in accordance with the rarity of T-ALL in DS. Of interest, none of the DS ALL cases with a JAK-2 mutation relapsed so far, which differs from the patients with JAK-2 mutations that were recently in high-risk BCP-ALL. Hence, JAK-2 may be an interesting novel therapeutic target. Disclosures No relevant conflicts of interest to declare.

scholarly journals Acute lymphoblastic leukemia in children with Down syndrome: a retrospective analysis from the Ponte di Legno study group

Blood ◽  
2014 ◽  
Vol 123 (1) ◽  
pp. 70-77 ◽  
Author(s):  
Trudy D. Buitenkamp ◽  
Shai Izraeli ◽  
Martin Zimmermann ◽  
Erik Forestier ◽  
Nyla A. Heerema ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Good Prognosis ◽  
Study Group ◽  
Children With Down Syndrome ◽  
Key Points ◽  
Leukemia In Children ◽  
Treatment Related Mortality ◽  
Related Mortality

Key Points Although the risk of ALL relapse is significantly higher in children with DS, good-prognosis subgroups have been identified. Patients with DS-ALL have higher treatment-related mortality throughout the treatment period independent of the therapeutic regimen.

Pentoxifylline During Steroid Window At Induction To Remission Increases Apoptosis In Childhood Acute Lymphoblastic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2623-2623
Author(s):  
Oscar Gonzalez-Ramella ◽  
Jimenez-Lopez Xochiquetzatl ◽  
Sergio Gallegos-Castorena ◽  
Pablo Ortiz-Lazareno ◽  
Jose Manuel Lerma-Diaz ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Complete Remission ◽  
Cancer Cells ◽  
Lymphoblastic Leukemia ◽  
Remission Induction ◽  
Control Group ◽  
Induction Phase ◽  
Study Group ◽  
Significant Difference

Abstract Introduction Acute lymphoblastic leukemia (ALL) is the most common cancer diagnostic in children, and it represents the second death cause in this population. Despite advances in the treatment of childhood ALL, there are small portion of patients whom still succumb to this disease. A reduced apoptosis in cells plays an important role in carcinogenesis. This phenomenon is an important component in the cytotoxicity induced by anticancer drugs. A currently challenge is the chemotherapy resistance of tumor cells, inhibiting the apoptosis induced by chemotherapy. Pentoxifylline, (PTX) has been studied for its role on increase of apoptosis on cancer cells by different pathways. Our group has reported its efficacy in vitro and ex vivo in increasing apoptosis induced by chemotherapy drugs such as adriamycin and cisplatin in fresh leukemic human cells, lymphoma murine models and cervical cancer cells. We conducted a phase 1 controlled randomized trial to evaluate the efficacy of adding PTX to the steroid window during the remission induction phase in new diagnosed children with ALL. Methods We included all children from both sexes from 9 months to 17 years old during October 2011 to December 2012. Patients were divided into 3 groups, the first one as a non-malignant control group (NL group) included children with a non-hematology disease in which bone marrow aspiration (BMA) was mandatory in order to reach the diagnosis. The second one, the ALL control group whom received prednisone (PRD group) for the steroid window at 40mg/m2/day PO from day -7 to day 0; and then the third one (PTX group), the study group which included children receiving the steroid phase with PRD as early described, plus PTX at 10mg/kg/day IV divided in 3 doses, at the same days as recommended in our treatment protocol (Total Therapy XV). For all 3 groups a BMA was performed at diagnosis, for PRD group as well as PTX group, a second BMA was also collected at day 0. Apoptosis was evaluated by means of Annexin V Apoptosis Detection Kit FITC/PI (eBioscience¨, San Diego, CA, USA) in 1×106 bone marrow mononuclear cells. We measured minimal residual disease (MRD) by flow cytometry at day 14 to demonstrate complete remission in leukemic patients. Statically analysis was performed by U Man Whitney. Results We enrolled 32 patients: 10 in NL group; 11 in PRD group; and 11 in PTX group. The median age of all groups was 6 years (range 9 months-17 years). In PRD group, patient 1 abandoned treatment after administration of day 0, nevertheless the second BMA sample was collected. Patient number 7 died at day 4 due to complications from tumor lysis syndrome. Consequently, in these patients we were not able to measure MRD and BM aspiration at day 14. Except one patient in PRD group, all achieved complete remission at day 14. We did not find any significant difference between NL group and PRD and PTX groups before intervention (U=32 p=0.7; U=28.5 p=0.48 respectively). There was no significant difference between treatment groups before intervention (U= 37 p=0.79). However, after treatment we found an important difference between PRD and PTX groups, we observed an increase in apoptosis in PTX group in comparison with PRD group (U=17.5 p=0.04). There were no adverse effects during treatment. Conclusions The present study is the first one that shows the efficacy of PTX in increasing apoptosis induced by PRD in new ALL diagnosed children, whom have not received any treatment yet. This might be helpful, not only in patients with relapse, but to increase the overall cure rate in ALL. Further studies are needed to prove this hypothesis. With this objective, our study group is already planning a second trial were PTX will be given during all remission induction phase. Experimental reports strongly suggest that PTX induces inhibition of the transcription factor NF-ĸB, by inhibiting survival gens and facilitating apoptosis. To prove it, we are currently processing these patients' samples to know their genetic expression. Disclosures: No relevant conflicts of interest to declare.

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