T-cell acute lymphoblastic leukemia in patients 1–45 years treated with the pediatric NOPHO ALL2008 protocol

Quist‐Paulsen, Petter; Toft, Nina; Heyman, Mats; Abrahamsson, Jonas; Griškevičius, Laimonas; Hallböök, Heléne; Jónsson, Òlafur G.; Palk, Katrin; Vaitkevičienė, Goda; Vettenranta, Kim; Åsberg, Arne; Frandsen, Thomas Leth; Opdahl, Signe; Marquart, Hanne Vibeke; Siitonen, Sanna; Osnes, Liv; Hultdin, Magnus; Overgaard, Ulrik Malthe; Wartiovaara‐Kautto, Ulla; Schmiegelow, Kjeld

doi:10.1038/s41375-019-0598-2

Cited by 40 publications

(39 citation statements)

References 38 publications

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“…Fifty-five years was set as the age-related prognostic cut-off, and HCT-related mortality was taken into account, thereby increasing the cumulative TRM in our study from 8 and 13% in patients aged ≤55 years who did not undergo and underwent HCT, respectively, to 52% in those older than 55 years. The Group for Research in Adult ALL (GRAALL) reported in two consecutive trials a cumulative incidence of induction and CR mortality of 41.5 and 29% above 45 and 55 years of age, respectively 38,39 , and even in AYAs aged 18-45 years, this risk was estimated to be between 6.7 and 12% 34,40 . Because induction mortality was a major drawback in patients aged >55 years (P < 0.0001), the cyclophosphamide and anthracycline doses were attenuated in the successor trial, improving both CR and early survival figures (CR 87.1% and 1-year OS 73.2%, P = 0.08) 41 .…”

Section: Discussionmentioning

confidence: 99%

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Updated risk-oriented strategy for acute lymphoblastic leukemia in adult patients 18–65 years: NILG ALL 10/07

et al. 2020

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An updated strategy combining pediatric-based chemotherapy with risk-oriented allogeneic hematopoietic cell transplantation (HCT) was evaluated in Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph− ALL) and compared with a published control series. Following induction–consolidation chemotherapy, responsive patients were assigned to receive maintenance chemotherapy or undergo early HCT according to the risk stratification criteria and minimal residual disease (MRD) status. Of the 203 study patients (median age 41 years, range 17–67), 140/161 with Ph− ALL achieved complete remission (86.9%; 91.6% ≤55 years, P = 0.0002), with complete MRD clearing in 68/109; 55 patients were assigned to maintenance chemotherapy, and 85 to HCT due to very high-risk characteristics (hyperleukocytosis, adverse genetics, early/mature T-precursor ALL, and MRD persistence). The 5-year relapse incidence was 36%, and the treatment-related mortality rate was 18%. Median overall and relapse-free survival were 7.4 and 6.2 years, with rates of 54 and 53% at 5 years, respectively, which were significantly better than those obtained with the historical protocol (P = 0.001 and P = 0.005, respectively), without significant differences between maintenance and HCT cohorts. In prognostic analysis, MRD negativity and age ≤55 years were the most favorable independent prognostic factors. A reduction in treatment toxicity and further improvements in the risk definitions and risk-oriented design are the focuses of this ongoing research.

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Section: Discussionmentioning

confidence: 99%

“…In the multivariable analysis, age >55 years and the MRD pos status retained a strongly negative prognostic effect on OS (HR 3. 40…”

Section: Prognostic Analysismentioning

confidence: 99%

Updated risk-oriented strategy for acute lymphoblastic leukemia in adult patients 18–65 years: NILG ALL 10/07

et al. 2020

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“…13 14 A recent study by the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL Group confirmed the importance of asparaginase in T-ALL and the outcome in patients aged 18-45 years was excellent. 15 Taken together, as PEG asparaginase is increasingly being used in the treatment of adult ALL including T-ALL, it is important to understand how to manage its toxicities in adults properly. 16 An expert group met in November 2019 in London to discuss recent data of paediatric as well as adult studies using paediatric regimens with regard to the best management of several key toxicities that can occur in adults treated with asparaginase including hepatotoxicity, pancreatitis, hypertriglyceridaemia, thrombosis and hypersensitivity.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Managing toxicities with asparaginase-based therapies in adult ALL: summary of an ESMO Open–Cancer Horizons roundtable discussion

Burke

Hoelzer²,

Park

et al. 2020

ESMO Open

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With recent prospective clinical trials that used paediatric regimens with multiple doses of pegylated form of asparaginase (PEG asparaginase) in adults reporting significantly improved survival compared with historical data with regimens that used less asparaginase, PEG asparaginase is increasingly being used in the treatment of adult acute lymphoblastic leukaemia (ALL). However, administering asparaginase still comes with its challenges, especially in adult patients. Therefore, it is important to understand how to manage its toxicities properly. An expert group met in November 2019 in London to discuss recent data of paediatric as well as adult studies using paediatric regimens with regard to the best management of several key toxicities that can occur in adults treated with asparaginase including hepatotoxicity, pancreatitis, hypertriglyceridaemia, thrombosis and hypersensitivity. Several recommendations were made for each one of these toxicities, with the goal of safe administration of the drug and to educate clinicians when the drug can be continued despite side effects.

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“…Increasing intensity of chemotherapy has improved prognosis of T-ALL from 50% to 75% between 1970 and 2000 ( 24 ). However, the last 20 y have seen only marginal improvements in outcome, with survival rates for relapsed T-ALL remaining just 10% to 25% ( 25 ). In addition, the long and intensive course of chemotherapy employed in T-ALL frequently results in serious, often fatal, side effects ( 26 ).…”

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confidence: 99%

TET2 as a tumor suppressor and therapeutic target in T-cell acute lymphoblastic leukemia

Bensberg

Rundquist

Selimović

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Significance Pediatric T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy in need of novel targeted therapies to prevent relapse and lessen treatment toxicity. We reveal frequent (∼88%) transcriptional silencing or repression of the tumor suppressor TET2 in T-ALL. We show that loss of TET2 in T-ALL is correlated with hypermethylation of the TET2 promoter and that TET2 expression can be rescued by treatment with the DNA demethylating agent, 5-azacytidine (5-aza). We further reveal that the TET2 cofactor vitamin C exerts a strong synergistic effect on global transcriptional changes when added to 5-aza treatment. Importantly, 5-aza treatment results in increased cell death, specifically in T-ALL cells lacking TET2. Thus, we clearly identify 5-aza as a potentially targeted therapy for TET2 -silenced T-ALL.

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T-cell acute lymphoblastic leukemia in patients 1–45 years treated with the pediatric NOPHO ALL2008 protocol

Cited by 40 publications

References 38 publications

Updated risk-oriented strategy for acute lymphoblastic leukemia in adult patients 18–65 years: NILG ALL 10/07

Updated risk-oriented strategy for acute lymphoblastic leukemia in adult patients 18–65 years: NILG ALL 10/07

Managing toxicities with asparaginase-based therapies in adult ALL: summary of an ESMO Open–Cancer Horizons roundtable discussion

TET2 as a tumor suppressor and therapeutic target in T-cell acute lymphoblastic leukemia

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