Ph-like acute lymphoblastic leukemia: a high-risk subtype in adults

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In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993).

Anthony H Goldstone, Susan M Richards, Hillard M Lazarus … (2008)

An international collaboration was set up to prospectively evaluate the role of allogeneic transplantation for adults with acute lymphoblastic leukemia (ALL) and compare autologous transplantation with standard chemotherapy. Patients received 2 phases of induction and, if in remission, were assigned to allogeneic transplantation if they had a compatible sibling donor. Other patients were randomized to chemotherapy for 2.5 years versus an autologous transplantation. A donor versus no-donor analysis showed that Philadelphia chromosome-negative patients with a donor had a 5-year improved overall survival (OS), 53% versus 45% (P = .01), and the relapse rate was significantly lower (P < or = .001). The survival difference was significant in standard-risk patients, but not in high-risk patients with a high nonrelapse mortality rate in the high-risk donor group. Patients randomized to chemotherapy had a higher 5-year OS (46%) than those randomized to autologous transplantation (37%; P = .03). Matched related allogeneic transplantations for ALL in first complete remission provide the most potent antileukemic therapy and considerable survival benefit for standard-risk patients. However, the transplantation-related mortality for high-risk older patients was unacceptably high and abrogated the reduction in relapse risk. There is no evidence that a single autologous transplantation can replace consolidation/maintenance in any risk group. This study is registered at http://clinicaltrials.gov as NCT00002514.

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Racial and ethnic differences in survival of children with acute lymphoblastic leukemia.

Smita Bhatia, Leslie Robison, Harland Sather … (2002)

Black children with acute lymphoblastic leukemia (ALL) have poor outcomes, but limited information is available for children from other racial and ethnic backgrounds, such as Hispanic and Asian. We undertook a retrospective cohort study of children with ALL treated on Children's Cancer Group therapeutic protocols to determine outcomes by racial and ethnic backgrounds of patients treated with contemporary risk-based therapy. In total, 8447 children (white, n = 6703; Hispanic, n = 1071; black, n = 506; and Asian, n = 167) with newly diagnosed ALL between 1983 and 1995 were observed for a median of 6.5 years. Analysis of disease outcome was measured as overall survival (OS) and event-free survival (EFS) and was adjusted for known predictors of outcome including clinical features, disease biology, socioeconomic status, and treatment era (1983-1989 vs 1989-1995). There was a statistically significant difference in survival by ethnicity (P <.001). Five-year EFS rates were: Asian, 75.1% +/- 3.5%; white, 72.8% +/- 0.6%; Hispanic, 65.9% +/- 1.5%; and black, 61.5% +/- 2.2%. Multivariate analysis revealed that when compared with white children, black and Hispanic children had worse outcomes and Asian children had better outcomes after adjusting for known risk factors. The poorer outcomes among black children were most apparent among patients with standard-risk features (relative risk [RR], 2.0; 95% confidence interval [CI], 1.6-2.5), whereas poorer outcomes in Hispanic children (RR, 1.4; 95% CI, 1.2-1.6) were most evident among patients with high-risk features. Asian children had better outcomes than all racial and ethnic groups among high-risk patients, particularly in the recent era (5-year EFS, 90.9% +/- 6.1%). Racial and ethnic differences in OS and EFS persist among children with ALL who receive contemporary risk-based therapy. Future studies should focus on reasons-perhaps compliance or pharmacogenetics-for those differences.

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Truncating Erythropoietin Receptor Rearrangements in Acute Lymphoblastic Leukemia.

Ilaria Iacobucci, Yongjin Li, Kathryn Roberts … (2016)

Chromosomal rearrangements are a hallmark of acute lymphoblastic leukemia (ALL) and are important ALL initiating events. We describe four different rearrangements of the erythropoietin receptor gene EPOR in Philadelphia chromosome-like (Ph-like) ALL. All of these rearrangements result in truncation of the cytoplasmic tail of EPOR at residues similar to those mutated in primary familial congenital polycythemia, with preservation of the proximal tyrosine essential for receptor activation and loss of distal regulatory residues. This resulted in deregulated EPOR expression, hypersensitivity to erythropoietin stimulation, and heightened JAK-STAT activation. Expression of truncated EPOR in mouse B cell progenitors induced ALL in vivo. Human leukemic cells with EPOR rearrangements were sensitive to JAK-STAT inhibition, suggesting a therapeutic option in high-risk ALL.