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

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Abstract

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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Results of NOPHO ALL2008 treatment for patients aged 1–45 years with acute lymphoblastic leukemia

K Palk, N. Toft, H Birgens … (2017)

Adults with acute lymphoblastic leukemia (ALL) do worse than children. From 7/2008 to 12/2014, Nordic and Baltic centers treated 1509 consecutive patients aged 1-45 years with Philadelphia chromosome-negative ALL according to the NOPHO ALL2008 without cranial irradiation. Overall, 1022 patients were of age 1-9 years (A), 266 were 10-17 years (B) and 221 were 18-45 years (C). Sixteen patients (three adults) died during induction. All others achieved remission after induction or 1-3 intensive blocks. Subsequently, 45 patients (12 adults) died, 122 patients relapsed (32 adults) with a median time to relapse of 1.6 years and 13 (no adult) developed a second malignancy. Median follow-up time was 4.6 years. Among the three age groups, older patients more often had higher risk ALL due to T-ALL (32%/25%/9%, P<0.001), KMT2A rearrangements (6%/5%/3%, P<0.001) and higher day 29 residual leukemia for B-lineage (P<0.001), but not T-ALL (P=0.53). Event-free survival rates (pEFS5y) were 89±1% (A), 80±3% (B) and 74±4% (C) with significant differences only for non-high risk groups. Except for thrombosis, pancreatitis and osteonecrosis, the risk of 19 specified toxicities was not enhanced by age above 10 years. In conclusion, a pediatric-based protocol is tolerable and effective for young adults, despite their increased frequency of higher risk features.

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A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403

Wendy Stock, Selina M Luger, Anjali Advani … (2019)

Publisher's Note: There is a Blood Commentary on this article in this issue. Using an intensive pediatric regimen for AYAs with ALL is feasible. High rates of EFS and OS were seen compared with historical controls. Retrospective studies have suggested that older adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) have better survival rates when treated using a pediatric ALL regimen administered by pediatric treatment teams. To address the feasibility and efficacy of using a pediatric treatment regimen for AYA patients with newly diagnosed ALL administered by adult treatment teams, we performed a prospective study, CALGB 10403, with doses and schedule identical to those in the Children’s Oncology Group study AALL0232. From 2007 to 2012, 318 patients were enrolled; 295 were eligible and evaluable for response. Median age was 24 years (range, 17-39 years). Use of the pediatric regimen was safe; overall treatment-related mortality was 3%, and there were only 2 postremission deaths. Median event-free survival (EFS) was 78.1 months (95% confidence interval [CI], 41.8 to not reached), more than double the historical control of 30 months (95% CI, 22-38 months); 3-year EFS was 59% (95% CI, 54%-65%). Median overall survival (OS) was not reached. Estimated 3-year OS was 73% (95% CI, 68%-78%). Pretreatment risk factors associated with worse treatment outcomes included obesity and presence of the Philadelphia-like gene expression signature. Use of a pediatric regimen for AYAs with ALL up to age 40 years was feasible and effective, resulting in improved survival rates compared with historical controls. CALGB 10403 can be considered a new treatment standard upon which to build for improving survival for AYAs with ALL. This trial was registered at www.clinicaltrials.gov as #NCT00558519.

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Adult patients with acute lymphoblastic leukemia and molecular failure display a poor prognosis and are candidates for stem cell transplantation and targeted therapies.

Nicola Gökbuget, Renate Arnold, Arnold Ganser … (2012)

Quantification of minimal residual disease (MRD) by real-time PCR directed to TCR and Ig gene rearrangements allows a refined evaluation of response in acute lymphoblastic leukemia (ALL). The German Multicenter Study Group for Adult ALL prospectively evaluated molecular response after induction/consolidation chemotherapy according to standardized methods and terminology in patients with Philadelphia chromosome-negative ALL. The cytologic complete response (CR) rate was 89% after induction phases 1 and 2. At this time point the molecular CR rate was 70% in 580 patients with cytologic CR and evaluable MRD. Patients with molecular CR after consolidation had a significantly higher probability of continuous complete remission (CCR; 74% vs 35%; P < .0001) and of overall survival (80% vs 42%; P = .0001) compared with patients with molecular failure. Patients with molecular failure without stem cell transplantation (SCT) in first CR relapsed after a median time of 7.6 months; CCR and survival at 5 years only reached 12% and 33%, respectively. Quantitative MRD assessment identified patients with molecular failure as a new high-risk group. These patients display resistance to conventional drugs and are candidates for treatment with targeted, experimental drugs and allogeneic SCT. Molecular response was shown to be highly predictive for outcome and therefore constitutes a relevant study end point. The studies are registered at www.clinicaltrials.gov as NCT00199056 and NCT00198991.

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Author and article information

Journal

Journal ID (nlm-ta): ESMO Open

Journal ID (iso-abbrev): ESMO Open

Journal ID (hwp): esmoopen

Journal ID (publisher-id): esmoopen

Title: ESMO Open

Publisher: BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )

ISSN (Electronic): 2059-7029

Publication date Collection: 2020

Publication date (Electronic): 9 October 2020

Volume: 5

Issue: 5

Electronic Location Identifier: e000858

Affiliations

[1 ]departmentDivision of Hematology/Oncology, Department of Internal Medicine , University of Michigan , Ann Arbor, Michigan, USA

[2 ]departmentInternal Medicine , Onkologikum Frankfurt , Frankfurt, Germany

[3 ]departmentLeukemia Service, Department of Medicine , Memorial Sloan Kettering Cancer Center , New York City, New York, USA

[4 ]departmentDepartment of Pediatrics and Adolescent Medicine , Juliane Marie Center, Rigshospitalet University Hospital, and Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen, Denmark

[5 ]departmentJane Anne Nohle Division of Hematology , University of Southern California , Los Angeles, California, USA

Author notes

[Correspondence to ] Professor Patrick W Burke; pwburke@ 123456med.umich.edu

Article

Publisher ID: esmoopen-2020-000858

DOI: 10.1136/esmoopen-2020-000858

PMC ID: 7549445

PubMed ID: 33037033

SO-VID: 24f9bfb7-77dc-458a-9f3b-f8686ed445fe

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This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, any changes made are indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

History

Date received : 06 June 2020

Date revision received : 18 August 2020

Date accepted : 19 August 2020

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100011725, Servier;

Award ID: Unrestricted educational grant

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Keywords: asparaginase,acute lymphoblastic leukaemia,toxicities,hypersensitivity,therapeutic drug monitoring,pancreatitis,thrombosis

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Keywords: asparaginase, acute lymphoblastic leukaemia, toxicities, hypersensitivity, therapeutic drug monitoring, pancreatitis, thrombosis

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

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Most cited references 71

Results of NOPHO ALL2008 treatment for patients aged 1–45 years with acute lymphoblastic leukemia

A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403

Adult patients with acute lymphoblastic leukemia and molecular failure display a poor prognosis and are candidates for stem cell transplantation and targeted therapies.

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