Reduced intensity of early intensification does not increase the risk of relapse in children with standard risk acute lymphoblastic leukemia - a multi-centric clinical study of GD-2008-ALL protocol

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Abstract

Background

The prognosis of childhood acute lymphoblastic leukemia (ALL) is optimistic with a 5-year event-free survival (EFS) rate of 70–85%. However, the major causes of mortality are chemotherapy toxicity, infection and relapse. The Guangdong (GD)-2008-ALL collaborative protocol was carried out to study the effect of reduced intensity on treatment related mortality (TRM) based on Berlin-Frankfurt-Münster (BFM) 2002 backbone treatment. The study was designed to elucidate whether the reduced intensity is effective and safe for children with ALL.

Methods

The clinical data were obtained from February 28, 2008 to June 30, 2016. A total of 1765 childhood ALL cases from 9 medical centers were collected and data were retrospectively analyzed. Patients were stratified into 3 groups according to bone marrow morphology, prednisone response, age, genotype, and karyotype information: standard risk (SR), intermediate risk (IR) and high risk (HR). For SR group, daunorubicin was decreased in induction IA while duration was reduced in Induction Ib (2 weeks in place of 4 weeks). Doses for CAM were same in all risk groups - SR patients received one CAM, others got two CAMs.

Results

The 5-year and 8-year overall survival (OS), event-free survival (EFS) and cumulative incidence of relapse (CIR) were 83.5±0.9% and 83.1±1.0%, 71.9±1.1% and 70.9±1.2%, and 19.5±1.0% and 20.5±1.1%, respectively. The 2-year treatment-related mortality (TRM) was 5.2±0.5%. The 5-year and 8-year OS were 90.7±1.4% and 89.6±1.6% in the SR group, while the 5-year and 8-year EFS were 81.5±1.8% and 80.0±2.0%. In the SR group, 74 (15.2%) patients measured minimal residual disease (MRD) on Day 15 and Day 33 of induction therapy. Among them, 7 patients (9.46%) were MRD positive (≥ 0.01%) on Day 33. The incidence of relapse in the MRD Day 33 positive group ( n=7) was 28.6%, while in the MRD Day 33 negative group ( n=67) was 7.5% ( p=0.129).

Conclusions

The results of GD-2008-ALL protocol are outstanding for reducing TRM in childhood ALL in China with excellent long term EFS. This protocol provided the evidence for further reducing intensity of induction therapy in the SR group according to the risk stratification. MRD levels on Day 15 and Day 33 are appropriate indexes for stratification.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12885-020-07752-x.

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Most cited references 29

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The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes.

James W Vardiman, Juergen Thiele, Daniel Arber … (2009)

Recently the World Health Organization (WHO), in collaboration with the European Association for Haematopathology and the Society for Hematopathology, published a revised and updated edition of the WHO Classification of Tumors of the Hematopoietic and Lymphoid Tissues. The 4th edition of the WHO classification incorporates new information that has emerged from scientific and clinical studies in the interval since the publication of the 3rd edition in 2001, and includes new criteria for the recognition of some previously described neoplasms as well as clarification and refinement of the defining criteria for others. It also adds entities-some defined principally by genetic features-that have only recently been characterized. In this paper, the classification of myeloid neoplasms and acute leukemia is highlighted with the aim of familiarizing hematologists, clinical scientists, and hematopathologists not only with the major changes in the classification but also with the rationale for those changes.

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Treating childhood acute lymphoblastic leukemia without cranial irradiation.

Ching-Hon Pui, Dario Campana, Deqing Pei … (2009)

Prophylactic cranial irradiation has been a standard treatment in children with acute lymphoblastic leukemia (ALL) who are at high risk for central nervous system (CNS) relapse. We conducted a clinical trial to test whether prophylactic cranial irradiation could be omitted from treatment in all children with newly diagnosed ALL. A total of 498 patients who could be evaluated were enrolled. Treatment intensity was based on presenting features and the level of minimal residual disease after remission-induction treatment. The duration of continuous complete remission in the 71 patients who previously would have received prophylactic cranial irradiation was compared with that of 56 historical controls who received it. The 5-year event-free and overall survival probabilities for all 498 patients were 85.6% (95% confidence interval [CI], 79.9 to 91.3) and 93.5% (95% CI, 89.8 to 97.2), respectively. The 5-year cumulative risk of isolated CNS relapse was 2.7% (95% CI, 1.1 to 4.3), and that of any CNS relapse (including isolated relapse and combined relapse) was 3.9% (95% CI, 1.9 to 5.9). The 71 patients had significantly longer continuous complete remission than the 56 historical controls (P=0.04). All 11 patients with isolated CNS relapse remained in second remission for 0.4 to 5.5 years. CNS leukemia (CNS-3 status) or a traumatic lumbar puncture with blast cells at diagnosis and a high level of minimal residual disease (> or = 1%) after 6 weeks of remission induction were significantly associated with poorer event-free survival. Risk factors for CNS relapse included the genetic abnormality t(1;19)(TCF3-PBX1), any CNS involvement at diagnosis, and T-cell immunophenotype. Common adverse effects included allergic reactions to asparaginase, osteonecrosis, thrombosis, and disseminated fungal infection. With effective risk-adjusted chemotherapy, prophylactic cranial irradiation can be safely omitted from the treatment of childhood ALL. (ClinicalTrials.gov number, NCT00137111.) 2009 Massachusetts Medical Society

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Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: a report from the children's oncology group.

Stephen P. Hunger, Xiaomin Lu, Meenakshi Devidas … (2012)

To examine population-based improvements in survival and the impact of clinical covariates on outcome among children and adolescents with acute lymphoblastic leukemia (ALL) enrolled onto Children's Oncology Group (COG) clinical trials between 1990 and 2005. In total, 21,626 persons age 0 to 22 years were enrolled onto COG ALL clinical trials from 1990 to 2005, representing 55.8% of ALL cases estimated to occur among US persons younger than age 20 years during this period. This period was divided into three eras (1990-1994, 1995-1999, and 2000-2005) that included similar patient numbers to examine changes in 5- and 10-year survival over time and the relationship of those changes in survival to clinical covariates, with additional analyses of cause of death. Five-year survival rates increased from 83.7% in 1990-1994 to 90.4% in 2000-2005 (P < .001). Survival improved significantly in all subgroups (except for infants age ≤ 1 year), including males and females; those age 1 to 9 years, 10+ years, or 15+ years; in whites, blacks, and other races; in Hispanics, non-Hispanics, and patients of unknown ethnicity; in those with B-cell or T-cell immunophenotype; and in those with National Cancer Institute (NCI) standard- or high-risk clinical features. Survival rates for infants changed little, but death following relapse/disease progression decreased and death related to toxicity increased. This study documents ongoing survival improvements for children and adolescents with ALL. Thirty-six percent of deaths occurred among children with NCI standard-risk features emphasizing that efforts to further improve survival must be directed at both high-risk subsets and at those children predicted to have an excellent chance for cure.

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Author and article information

Contributors

Jian-Pei Fang: fangjpei@mail.sysu.edu.cn

Journal

Journal ID (nlm-ta): BMC Cancer

Journal ID (iso-abbrev): BMC Cancer

Title: BMC Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2407

Publication date (Electronic): 13 January 2021

Publication date PMC-release: 13 January 2021

Publication date Collection: 2021

Volume: 21

Electronic Location Identifier: 59

Affiliations

[1 ]GRID grid.12981.33, ISNI 0000 0001 2360 039X, Department of Pediatrics, Sun Yat-sen Memorial Hospital, , Sun Yat-sen University, ; Guangzhou, 510120 China

[2 ]GRID grid.12981.33, ISNI 0000 0001 2360 039X, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, , Sun Yat-sen University, ; Guangzhou, 510120 China

[3 ]GRID grid.12981.33, ISNI 0000 0001 2360 039X, The First Affiliated Hospital, , Sun Yat-sen University, ; Guangzhou, 510080 China

[4 ]GRID grid.284723.8, ISNI 0000 0000 8877 7471, Nanfang Hospital, , Southern Medical University, ; Guangzhou, 510515 China

[5 ]GRID grid.413428.8, ISNI 0000 0004 1757 8466, Guangzhou Women and Children’s Medical Center, ; Guangzhou, 510623 China

[6 ]GRID grid.452787.b, ISNI 0000 0004 1806 5224, Shenzhen Children’s Hospital, ; Shenzhen, 518038 China

[7 ]Huizhou Municipal Central People’s Hospital, Huizhou, 516001 China

[8 ]GRID grid.488530.2, ISNI 0000 0004 1803 6191, Sun Yat-sen University Cancer Center, ; Guangzhou, 510060 China

[9 ]GRID grid.12981.33, ISNI 0000 0001 2360 039X, The Third Affiliated Hospital, , Sun Yat-sen University, ; Guangzhou, 510630 China

[10 ]GRID grid.413352.2, ISNI 0000 0004 1760 3705, Guangdong General Hospital, ; Guangzhou, 510080 China

[11 ]GRID grid.10784.3a, ISNI 0000 0004 1937 0482, Hong Kong Children Hospital and Prince of Wales Hospital, , The Chinese University of Hong Kong, ; Hong Kong, 999077 China

Article

Publisher ID: 7752

DOI: 10.1186/s12885-020-07752-x

PMC ID: 7805214

PubMed ID: 33435902

SO-VID: 998f1f92-1f98-4f58-bb19-2ae3e53c65fc

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 27 April 2020

Date accepted : 20 December 2020

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: acute lymphoblastic leukemia,children,chemotherapy,reduced intensity multi-centric clinical study

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: acute lymphoblastic leukemia, children, chemotherapy, reduced intensity multi-centric clinical study

Reduced intensity of early intensification does not increase the risk of relapse in children with standard risk acute lymphoblastic leukemia - a multi-centric clinical study of GD-2008-ALL protocol

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Abstract

Background

Methods

Results

Conclusions

Supplementary Information

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Karger: Oncology

Most cited references 29

The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes.

Treating childhood acute lymphoblastic leukemia without cranial irradiation.

Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: a report from the children's oncology group.

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