children with B-lineage ALL. DFCI: The DFCI ALL Consortium protocols include 30 weeks of pegaspargase therapy beginning at week 7 of therapy, given in conjunction with maintenance regimen (vincristine/dexamethasone pulses, weekly low-dose methotrexate, daily mercaptopurine). Of the evaluable patients, 31% had a Ph-like fusion; these patients had a significantly worse outcome, with a 3-year EFS rate of 42%, compared with an EFS rate of 69% for patients without the fusion (hazard ratio, 2.06; log-rank, Investigators reported on 197 patients aged 16 to 21 years treated on the CCG study (a pediatric ALL regimen) compared with 124 adolescents and young adults treated on the Cancer and Leukemia Group B (CALGB) study (an adult ALL regimen).[. Haematologica 100 (1): 62-9, 2015. : Clinical features and early treatment response of central nervous system involvement in childhood acute lymphoblastic leukemia. JAMA 293 (12): 1485-9, 2005. occurrence of testicular relapses among boys, but boys also appear to be at The study also aims to determine the EFS of patients with MPAL and disseminated B-lymphoblastic lymphoma who are treated with a standard high-risk ALL chemotherapy regimen. : Clinical and genetic features of pediatric acute lymphoblastic leukemia in Down syndrome in the Nordic countries. Studies have found that the absence of biallelic deletion of the TCR-gamma locus (ABD), as detected by comparative genomic hybridization and/or quantitative DNA-PCR, was associated with early treatment failure in patients with T-ALL. Stanulla M, Dagdan E, Zaliova M, et al. J Clin Oncol 36 (1): 34-43, 2018. Do not contact the individual Board Members with questions or comments about the summaries. : Genomic and transcriptional landscape of P2RY8-CRLF2-positive childhood acute lymphoblastic leukemia. J Clin Oncol 36 (26): 2726-2735, 2018. Tram Henriksen L, Gottschalk Højfeldt S, Schmiegelow K, et al. BM = bone marrow; CNS = central nervous system; DT = double trisomy; MRD = minimal residual disease; NCI = National Cancer Institute; PB = peripheral blood. Bhojwani D, Sposto R, Shah NN, et al.  IKZF1 alterations are observed in 20% to 40% of DUX4-rearranged ALL.[5,6]. Treatment options for T-ALL include the following: Evidence (chemotherapy and prophylactic cranial radiation therapy): The use of prophylactic cranial radiation therapy in the treatment of patients with T-ALL is declining. J Clin Oncol 15 (5): 1824-30, 1997. : High frequency of leukemic clones in newborn screening blood samples of children with B-precursor acute lymphoblastic leukemia. Pediatr Blood Cancer 60 (6): 957-63, 2013. : Treatment of higher risk acute lymphoblastic leukemia in young people (CCG-1961), long-term follow-up: a report from the Children's Oncology Group. The optimal treatment for infants without KMT2A rearrangements also remains unclear, in part because of the paucity of data on the use of standard ALL regimens used in older children. : The inferior prognosis of adolescents with acute lymphoblastic leukaemia (ALL) is caused by a higher rate of treatment-related mortality and not an increased relapse rate--a population-based analysis of 25 years of the Austrian ALL-BFM (Berlin-Frankfurt-Münster) Study Group. All other Down syndrome patients, including NCI high-risk Down syndrome patients, those with unfavorable biology, and those with high day 29 MRD will be considered Down syndrome-high, and will be nonrandomly assigned to receive two cycles of blinatumomab added to a deintensified chemotherapy regimen that omits intensive elements of the augmented BFM treatment backbone. Cancer 97 (2): 425-40, 2003. : Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. : Oncogenetic mutations combined with MRD improve outcome prediction in pediatric T-cell acute lymphoblastic leukemia. : Substitution of oral and intravenous thioguanine for mercaptopurine in a treatment regimen for children with standard risk acute lymphoblastic leukemia: a collaborative Children's Oncology Group/National Cancer Institute pilot trial (CCG-1942). Aricò M, Valsecchi MG, Conter V, et al. Intensity of induction depends on initial risk group. : Complete morphologic and molecular remission after introduction of dasatinib in the treatment of a pediatric patient with t-cell acute lymphoblastic leukemia and ABL1 amplification. [24,25] In contrast, the vast majority of cases of AML in children with Down syndrome occur before the age of 4 years (median age, 1 year). Therefore, all children with acute lymphoblastic leukemia (ALL) should receive systemic combination [99-101] This occurs in 10% to 20% of pediatric ALL patients, increasing in frequency with age, and has been associated with an The COG reported that risk group classification at the time of initial diagnosis was prognostically significant after relapse; patients who met National Cancer Institute (NCI) standard-risk criteria at initial diagnosis fared better after relapse than did NCI high-risk patients.  Many of the trials that used 4-1BB costimulation have resulted in persistence of CAR T cells for extended periods and long-term responses.[128,150]. Treatment response was evaluated based on absolute blast count in the peripheral blood (PB) on the eighth day of induction therapy: prednisone good responders (PGR) < 1000 blasts/ L and. Br J Haematol 131 (5): 579-87, 2005. Br J Haematol 122 (1): 24-9, 2003. : Diagnostic cerebrospinal fluid examination in children with acute lymphoblastic leukemia: significance of low leukocyte counts with blasts or traumatic lumbar puncture. postinduction chemotherapy varies considerably depending on risk group assignment, but all patients receive some If not, treatment might need to be more intense or prolonged. Genes Chromosomes Cancer 48 (9): 795-805, 2009. Silverman LB, Supko JG, Stevenson KE, et al. L-asparaginase (does not penetrate into CSF itself, but leads to CSF asparagine depletion). 7th ed. [Abstract] Blood 124 (21): A-1, 2014. [, The 5-year EFS rate was 57.4% for patients who underwent HSCT and 47.8% for patients in the chemotherapy cohorts (. Help make it a reality. (Refer to the CNS-Directed Therapy for Childhood ALL section of this summary for specific information about CNS therapy to prevent CNS relapse in children with acute lymphoblastic leukemia [ALL] who are receiving postinduction therapy.). Hahn T, Wall D, Camitta B, et al. of cases of B-ALL, but very rarely in cases of T-ALL. : SEER Cancer Statistics Review, 1975-2010. : Outcome for children and young people with Early T-cell precursor acute lymphoblastic leukaemia treated on a contemporary protocol, UKALL 2003. Mullighan CG, Zhang J, Harvey RC, et al. In 2000, an international pediatric leukemia group reported a 7-year EFS rate of 25%, with an OS rate of 36%. : The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. J Clin Oncol 27 (6): 911-8, 2009. Pretreatment risk factors associated with a worse outcome were obesity and the presence of the Ph-like expression signature. as reference 16). A randomized comparison in trial CoALL 07-03.  Components of the transplant process that have been shown to be important in improving or predicting outcome of HSCT for children with ALL include the following: For patients proceeding to allogeneic HSCT, TBI appears to be an important component of the conditioning regimen. : FDA Approval Summary: Calaspargase Pegol-mknl For Treatment of Acute Lymphoblastic Leukemia in Children and Young Adults. Br J Haematol 155 (2): 235-43, 2011. Genome-wide polymorphism analysis has identified specific single nucleotide polymorphisms associated with high end-induction MRD and risk of relapse.  There is no evidence that IV administration of pegaspargase is more toxic than IM administration.  Approximately two-thirds of patients with ALL and germline pathogenic TP53 variants have hypodiploid ALL. Hijiya N, Liu W, Sandlund JT, et al. [56,57], Rearrangements involving the KMT2A gene occur in approximately 5% of Wheeler K, Richards S, Bailey C, et al. Initial studies focused on the ETV6-RUNX1 translocation and used reverse transcriptase (RT)–polymerase chain reaction (PCR) to identify RNA transcripts indicating the presence of the gene fusion. [, In a randomized clinical trial conducted by the former Pediatric Oncology Group, T-ALL patients who received high-dose methotrexate experienced a significantly lower CNS relapse rate than did patients who did not receive high-dose methotrexate.[. Remission status at the time of transplantation has long been known to be an important predictor of outcome, with patients not in CR at HSCT having very poor survival rates. Pui CH, Howard SC: Current management and challenges of malignant disease in the CNS in paediatric leukaemia. Pui CH, Gaynon PS, Boyett JM, et al. [97,114-117], To harness this GVL effect, a number of approaches to prevent relapse after transplantation have been studied, including withdrawal of immune suppression or donor lymphocyte infusion and targeted immunotherapies, such as monoclonal antibodies and natural killer cell therapy. It is imperative to : Whole-transcriptome sequencing identifies a distinct subtype of acute lymphoblastic leukemia with predominant genomic abnormalities of EP300 and CREBBP. Pilot studies from the COG have demonstrated the feasibility of incorporating nelarabine (a nucleoside analog with demonstrated activity in patients with relapsed and refractory T-cell lymphoblastic disease) in the context of a BFM regimen for patients with newly diagnosed T-ALL. Nachman JB, Heerema NA, Sather H, et al. : Outcome after first relapse in childhood acute lymphoblastic leukaemia - lessons from the United Kingdom R2 trial. J Clin Oncol 36 (29): 2926-2934, 2018. Suzuki K, Okuno Y, Kawashima N, et al. Mori H, Colman SM, Xiao Z, et al. Factors predictive of discordant MRD (≥5%) for patients in morphologic remission at end of induction included: age 10 years and older, WBC count at presentation of 50,000/µL or higher, neutral or unfavorable cytogenetics, and ETP ALL (for patients with T-ALL). However, the chemotherapy-only strategy resulted in a significantly worse outcome for patients with early-combined relapses (marrow plus extramedullary site) and low end-reinduction MRD; the 5-year EFS rate for these patients was only 37%. For patients with B-ALL, the definitions of favorable, unfavorable, and neutral cytogenetics are as follows: NCI standard-risk patients are divided into a highly favorable group (standard-risk favorable; 5-year DFS rate, >95%), a group with favorable outcome (standard-risk average; 5-year DFS rate, 90%–95%), and a group with a 5-year DFS rate below 90% (standard-risk high). : BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. : Long-term results of the pediatric oncology group studies for childhood acute lymphoblastic leukemia 1984-2001: a report from the children's oncology group.  Another example is the COG trial for T-ALL (AALL0434 [NCT00408005]) that resulted in a 5-year event-free survival (EFS) rate of 83.8% and an OS rate of 89.5%.. Adherence rates were significantly lower in Asian Americans and African Americans than in non-Hispanic whites. The leukemic cells of patients with pre-B ALL contain cytoplasmic Ig, and 25% of patients with pre-B ALL have the t(1;19)(q21;p13) translocation with the TCF3-PBX1 (previously known as E2A-PBX1) fusion. [8,99,100,102,103], Retrospective analyses have indicated that patients with Ph-like ALL have a poor prognosis. N Engl J Med 329 (5): 314-9, 1993. Tong WH, Pieters R, Kaspers GJ, et al. Extraordinary advances in the treatment outcome of childhood acute lymphoblastic leukemia (ALL) rank as one of the most successful stories in the history of oncology, with the current rate of approximately 80% of children being cured [1-5].The improvements made have been mainly due to the development of intensive multiagent … A major goal of current ALL clinical trials is to provide effective CNS therapy while minimizing neurologic toxic effects and other late effects. : Slow disappearance of peripheral blood blasts is an adverse prognostic factor in childhood T cell acute lymphoblastic leukemia: a Pediatric Oncology Group study. Augmented postinduction therapy resulted in an increased EFS that was comparable to that of patients with low levels of end-induction MRD. Genetic predisposition to ALL can be divided into several broad categories, as follows: Genetic risk factors for T-ALL share some overlap with the genetic risk factors for B-ALL, but unique risk factors also exist. , iAMP21 is generally diagnosed using FISH and is defined by the presence of greater than or equal to five RUNX1 signals per cell (or ≥3 extra copies of RUNX1 on a single abnormal chromosome). : NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity. J Clin Oncol 34 (36): 4381-4389, 2016. NCI standard-risk Down syndrome patients who meet definition of standard-risk average will be treated in the same way as non-Down syndrome standard-risk average patients, as detailed above. [32-34] Based on the relatively small number of published series, it does not appear that genomic CRLF2 aberrations in patients with Down syndrome and ALL have prognostic relevance, but more studies are needed to address this issue.[29,31]. Lancet Haematol 6 (4): e204-e216, 2019.  The alterations in the PAX5alt subtype included rearrangements, sequence mutations, and focal intragenic amplifications. recurs depends on multiple factors. : Hematologic malignancies with t(4;11)(q21;q23)--a cytogenetic, morphologic, immunophenotypic and clinical study of 183 cases. Br J Haematol 128 (6): 797-804, 2005. These cells grow into healthy blood cells to replace the ones the patient lost. Blood Cancer J 7 (2): e531, 2017. den Hoed MA, Pluijm SM, de Groot-Kruseman HA, et al. bilineal leukemia with a lymphoblastic and a separate non-lymphoblastic (≥ 10% of total cells) blast subset pre-treatment with cytostatic drugs glucocorticoid pre-treatment with ≥ 1 mg/kg/d for more than two weeks during the last month before diagnosis : Comparative pharmacokinetic studies of three asparaginase preparations. In the past, this subtype of ALL has been recognized as extremely difficult to treat with a poor outcome. [154,155] ABD is characteristic of early thymic precursor cells, and many of the T-ALL patients with ABD have an immunophenotype consistent with the diagnosis of early T-cell precursor phenotype. The systematic investigation of these issues requires large clinical trials, and the opportunity to participate in these trials is offered to most patients and families. No significant differences in rates of infection during induction were observed between the two randomized arms. Blood 100 (1): 52-8, 2002. The primary accepted risk factors for ALL and associated genes (when relevant) include the following: Children with Down syndrome have an increased risk of developing both ALL and AML,[22,23] with a cumulative risk of developing leukemia of approximately 2.1% by age 5 years and 2.7% by age 30 years. [37,39,40,59,60] Augmenting therapy has been shown to improve the outcome in standard-risk patients with elevated MRD levels at the end of induction. : The genetic basis and cell of origin of mixed phenotype acute leukaemia. : IKZF1 status as a prognostic feature in BCR-ABL1-positive childhood ALL.  Point mutations in kinase genes, aside from those in JAK1 and JAK2, are uncommon in Ph-like ALL cases.. : Minimal residual disease is an important predictive factor of outcome in children with relapsed 'high-risk' acute lymphoblastic leukemia. Blood Adv 3 (4): 670-680, 2019. J Clin Oncol 16 (12): 3768-73, 1998. Br J Haematol 184 (6): 982-993, 2019. Berlin-Frankfurt-Münster Relapse Study Group. editorially independent of NCI. There was no significant difference in treatment-related deaths between the two arms; however, the second delayed intensification phase was associated with grade 3 or 4 toxic events in 17% of the 261 patients randomly assigned to that arm, and one patient experienced a treatment-related death during that phase. : Treatment of childhood acute lymphoblastic leukemia in second remission with allogeneic bone marrow transplantation and chemotherapy: ten-year experience of the Italian Bone Marrow Transplantation Group and the Italian Pediatric Hematology Oncology Association. Methotrexate without leucovorin rescue, Escalating-dose intravenous methotrexate ( starting at a higher frequency leukemic. Lymphoblastic leukaemias associated with disseminated intravascular coagulation and hypercalcemia at diagnosis and relapse... 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