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Doing less, accomplishing more for childhood acute lymphoblastic leukaemia (ALL)

Yeoh AEJ, Oh BL, Ariffin H

Br J Haematol, 2021 08;194(4):661-662.
PMID: 34231199 DOI: 10.1111/bjh.17556
Ethnic differences in the frequency of subtypes of childhood acute lymphoblastic leukemia: results of the Malaysia-Singapore Leukemia Study Group

Ariffin H, Chen SP, Kwok CS, Quah TC, Lin HP, Yeoh AE

J Pediatr Hematol Oncol, 2007 Jan;29(1):27-31.
PMID: 17230064

Childhood acute lymphoblastic leukemia (ALL) is clinically heterogeneous with prognostically and biologically distinct subtypes. Although racial differences in frequency of different types of childhood ALL have been reported, many are confounded by selected or limited population samples. The Malaysia-Singapore (MA-SPORE) Leukemia Study Group provided a unique platform for the study of the frequency of major subgroups of childhood ALL in a large cohort of unselected multiethnic Asian children. Screening for the prognostically important chromosome abnormalities (TEL-AML1, BCR-ABL, E2A-PBX1, and MLL) using multiplex reverse-transcription polymerase chain reaction was performed on 299 consecutive patients with ALL at 3 study centers (236 de novo, 63 at relapse), with the ethnic composition predominantly Chinese (51.8%) and Malay (34.8%). Reverse-transcription polymerase chain reaction was successful in 278 (93%) of cases screened. The commonest fusion transcript was TEL-AML1 (19.1%) followed by BCR-ABL (7.8%), MLL rearrangements (4.2%), and E2A-PBX1 (3.1%). Chinese have a significantly lower frequency of TEL-AML1 (13.3% in de novo patients) compared with Malays (22.2%) and Indians (21.7%) (P=0.04). Malays have a lower frequency of T-ALL (6.2%) compared with the Chinese and Indians (9.8%). Both Malays (7.4%) and Chinese (5.0%) have significantly higher frequency of BCR-ABL compared with the Indian population (P<0.05) despite a similar median age at presentation. Our study suggests that there are indeed significant and important racial differences in the frequency of subtypes of childhood ALL. Comprehensive subgrouping of childhood ALL may reveal interesting population frequency differences of the various subtypes, their risk factors and hopefully, its etiology.
Rapid detection of prognostically important childhood acute lymphoblastic leukemia chimeric transcripts using multiplex SYBR green real-time reverse transcription PCR

Ibrahim K, Daud SS, Seah YL, Yeoh AE, Ariffin H, Malaysia-Singapore Leukemia Study Group

Ann Clin Lab Sci, 2008;38(4):338-43.
PMID: 18988926

Childhood acute lymphoblastic leukaemia (ALL) is a heterogenous disease in which oncogene fusion transcripts are known to influence the biological behaviour of the different ALL subtypes. Screening for prognostically important transcripts is an important diagnostic step in treatment stratification and prognostication of affected patients. We describe a SYBR-Green real-time multiplex PCR assay to screen for transcripts TEL-AML1, E2A-PBX1, MLL-AF4, and the two breakpoints of BCR-ABL (p190 and p210). Validation of the assay was based on conventional karyotyping results. This new assay provides a rapid, sensitive, and accurate detection method for prognostically important transcripts in childhood ALL.
Effective Response Metric: a novel tool to predict relapse in childhood acute lymphoblastic leukaemia using time-series gene expression profiling

Yeoh AE, Li Z, Dong D, Lu Y, Jiang N, Trka J, et al.

Br J Haematol, 2018 Jun;181(5):653-663.
PMID: 29808917 DOI: 10.1111/bjh.15252

Accurate risk assignment in childhood acute lymphoblastic leukaemia is essential to avoid under- or over-treatment. We hypothesized that time-series gene expression profiles (GEPs) of bone marrow samples during remission-induction therapy can measure the response and be used for relapse prediction. We computed the time-series changes from diagnosis to Day 8 of remission-induction, termed Effective Response Metric (ERM-D8) and tested its ability to predict relapse against contemporary risk assignment methods, including National Cancer Institutes (NCI) criteria, genetics and minimal residual disease (MRD). ERM-D8 was trained on a set of 131 patients and validated on an independent set of 79 patients. In the independent blinded test set, unfavourable ERM-D8 patients had >3-fold increased risk of relapse compared to favourable ERM-D8 (5-year cumulative incidence of relapse 38·1% vs. 10·6%; P = 2·5 × 10-3 ). ERM-D8 remained predictive of relapse [P = 0·05; Hazard ratio 4·09, 95% confidence interval (CI) 1·03-16·23] after adjusting for NCI criteria, genetics, Day 8 peripheral response and Day 33 MRD. ERM-D8 improved risk stratification in favourable genetics subgroups (P = 0·01) and Day 33 MRD positive patients (P = 1·7 × 10-3 ). We conclude that our novel metric - ERM-D8 - based on time-series GEP after 8 days of remission-induction therapy can independently predict relapse even after adjusting for NCI risk, genetics, Day 8 peripheral blood response and MRD.
The VolREthics initiative to protect the well-being of healthy volunteers in biomedical research

Bompart F, Fisher JA, Allen E, Sevene E, Kumar N, Chew CK, et al.

Nat Med, 2023 Oct;29(10):2393-2394.
PMID: 37580535 DOI: 10.1038/s41591-023-02490-6
Successful toxicity reduction during delayed intensification in the non-high-risk arm of Malaysia-Singapore Acute Lymphoblastic Leukaemia 2010 study

Oh BLZ, Lee SHR, Foo KM, Chiew KH, Seeto ZZL, Chen ZW, et al.

Eur J Cancer, 2021 01;142:92-101.
PMID: 33246161 DOI: 10.1016/j.ejca.2020.10.010

In non-high-risk (non-HR) patients, the Malaysia-Singapore Acute Lymphoblastic Leukaemia 2003 (MS2003) study achieved good outcomes. However, its delayed-intensification (DI) phase, comprising repeated blocks of protocol III (2003-PIII), was toxic and caused significant treatment delays. The successor MS2010 study attempted to lower DI toxicity by replacing myelosuppressive drugs (doxorubicin, cytarabine) with vincristine and asparaginase.
PATIENTS AND METHODS: We analysed 1748 admissions for fever in 315 Singapore children with non-HR acute lymphoblastic leukaemia (ALL) (MS2003, n = 183; MS2010, n = 132), comprising 76% of the total cohort (n = 413), to study the impact of these changes.
RESULTS: The new 2010-PVa which has no doxorubicin, was associated with significantly fewer hospitalisations due to fever (0.08 versus 0.30 admissions per block [A/blk], p
Life-threatening infections during treatment for acute lymphoblastic leukemia on the Malaysia-Singapore 2003 and 2010 clinical trials: A risk prediction model

Oh BLZ, Fan L, Lee SHR, Foo KM, Chiew KH, Seeto ZZL, et al.

Asia Pac J Clin Oncol, 2022 Feb 08.
PMID: 35134276 DOI: 10.1111/ajco.13756

AIM: Life-threatening infections significantly impact the care of children undergoing therapy for acute lymphoblastic leukemia (ALL) who are at risk of severe sepsis due to both host and treatment factors. Our aim was to develop a life-threatening infection risk prediction model that would allow remote rapid triage of patients to reduce time to first dose of antibiotics and sepsis-related mortality.
METHODS: A retrospective analysis of 2068 fever episodes during ALL therapy was used for model building and subsequent internal validation.
RESULTS: Three hundred and seventy-seven patients were treated for ALL in two institutions with comparable critical and supportive care resources. A total of 55 patients accounted for 71 admissions to the critical care unit for sepsis that led to eight septic deaths during a 16-year study period. A retrospective analysis of risk factors for sepsis enabled us to build a model focused on 13 variables that discriminated admissions requiring critical care well: area under the receiver operating characteristic curve of .82; 95% CI .76-.87, p
Fulltext Association of Genetic Ancestry With the Molecular Subtypes and Prognosis of Childhood Acute Lymphoblastic Leukemia

Lee SHR, Antillon-Klussmann F, Pei D, Yang W, Roberts KG, Li Z, et al.

JAMA Oncol, 2022 Mar 01;8(3):354-363.
PMID: 35084434 DOI: 10.1001/jamaoncol.2021.6826

IMPORTANCE: Racial and ethnic disparities persist in the incidence and treatment outcomes of childhood acute lymphoblastic leukemia (ALL). However, there is a paucity of data describing the genetic basis of these disparities, especially in association with modern ALL molecular taxonomy and in the context of contemporary treatment regimens.
OBJECTIVE: To evaluate the association of genetic ancestry with childhood ALL molecular subtypes and outcomes of modern ALL therapy.
DESIGN, SETTING, AND PARTICIPANTS: This multinational, multicenter genetic association study was conducted from March 1, 2000, to November 20, 2020, among 2428 children and adolescents with ALL enrolled in frontline trials from the United States, South East Asia (Singapore and Malaysia), and Latin America (Guatemala), representing diverse populations of European, African, Native American, East Asian, and South Asian descent. Statistical analysis was conducted from February 3, 2020, to April 19, 2021.
MAIN OUTCOMES AND MEASURES: Molecular subtypes of ALL and genetic ancestry were comprehensively characterized by performing RNA sequencing. Associations of genetic ancestries with ALL molecular subtypes and treatment outcomes were then evaluated.
RESULTS: Among the participants in the study, 1340 of 2318 (57.8%) were male, and the mean (SD) age was 7.8 (5.3) years. Of 21 ALL subtypes identified, 8 were associated with ancestry. East Asian ancestry was positively associated with the frequency of somatic DUX4 (odds ratio [OR], 1.30 [95% CI, 1.16-1.45]; P
Fulltext Flash survey on severe acute respiratory syndrome coronavirus-2 infections in paediatric patients on anticancer treatment

Hrusak O, Kalina T, Wolf J, Balduzzi A, Provenzi M, Rizzari C, et al.

Eur J Cancer, 2020 Jun;132:11-16.
PMID: 32305831 DOI: 10.1016/j.ejca.2020.03.021

INTRODUCTION: Since the beginning of COVID-19 pandemic, it is known that the severe course of the disease occurs mostly among the elderly, whereas it is rare among children and young adults. Comorbidities, in particular, diabetes and hypertension, clearly associated with age, besides obesity and smoke, are strongly associated with the need for intensive treatment and a dismal outcome. A weaker immunity of the elderly has been proposed as a possible explanation of this uneven age distribution. Thus, there is concern that children treated for cancer may allso be at risk for an unfavourable course of infection. Along the same line, anecdotal information from Wuhan, China, mentioned a severe course of COVID-19 in a child treated for leukaemia.
AIM AND METHODS: We made a flash survey on COVID-19 incidence and severity among children on anticancer treatment. Respondents were asked by email to fill in a short Web-based survey.
RESULTS: We received reports from 25 countries, where approximately 10,000 patients at risk are followed up. At the time of the survey, more than 200 of these children were tested, nine of whom were positive for COVID-19. Eight of the nine cases had asymptomatic to mild disease, and one was just diagnosed with COVID-19. We also discuss preventive measures that are in place or should be taken and treatment options in immunocompromised children with COVID-19.
CONCLUSION: Thus, even children receiving anticancer chemotherapy may have a mild or asymptomatic course of COVID-19. While we should not underestimate the risk of developing a more severe course of COVID-19 than that observed here, the intensity of preventive measures should not cause delays or obstructions in oncological treatment.