Clinical characteristics of cytomegalovirus‐positive pediatric acute lymphoblastic leukemia at diagnosis

Gallant, Rachel; Arroyo, Katti; Bracci, Paige M.; Li, Shaobo; Metayer, Catherine; Kogan, Scott C.; Wendt, George A.; Francis, Stephen; Smith, Adam J. de

doi:10.1002/ajh.26528

Cited by 6 publications

(14 citation statements)

References 9 publications

(12 reference statements)

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“…In prior studies, we found that approximately half of ALL cases have CMV DNA present in the bone marrow at diagnosis further suggesting that CMV could contribute to ALL development 4,22 . Congenital CMV infection occurs in 0.5% to 1.3% of children in the United States 23 . Severe sequelae such as neurologic deficits, hearing loss and liver dysfunction are features of a congenital CMV infection, but <10% of children with congenital CMV will exhibit these signs and symptoms, and the majority of children are asymptomatic at birth 23 .…”

Section: Introductionmentioning

confidence: 92%

Associations between early‐life and in utero infections and cytomegalovirus‐positive acute lymphoblastic leukemia in children

Gallant

Arroyo

Metayer

et al. 2022

Intl Journal of Cancer

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Childhood infections and cytomegalovirus (CMV) are associated with pediatric acute lymphoblastic leukemia (ALL). CMV dysregulates the host immune system and alters the immune response to subsequent antigenic exposures. We suspect that this immune dysregulation contributes to increased numbers of symptomatic infections in childhood allowing for expansion of pre‐leukemic clones. We explored the association between childhood infections, maternal infections during pregnancy and CMV‐positive ALL. Using a droplet digital PCR assay, we screened diagnostic ALL bone marrow samples from the California Childhood Leukemia Study (1995‐2015) for the presence of CMV DNA identifying CMV‐positive and CMV‐negative cases. We performed a case‐only analysis (n = 524) comparing the number and types of childhood infections and maternal infections during pregnancy between CMV‐positive and CMV‐negative ALL cases using logistic regression. With increasing numbers of infections in the first 12 months of life, children were more likely to classify to the highest tertile of CMV DNA in the bone marrow at diagnosis (OR: 1.04, 95% CI: 1.01‐1.08). Specifically, those reporting cough or flu in the first 12 months were more likely to be CMV‐positive at ALL diagnosis (OR: 2.15, 95% CI: 1.06‐4.37 and OR: 2.06, 95% CI: 1.17‐3.63 respectively). Furthermore, those with a history of maternal infection during pregnancy were more likely to be CMV‐positive (OR: 2.12, 95% CI: 1.24‐3.62). We hypothesize that children with underlying immune dysregulation develop more symptomatic infections in childhood and ultimately CMV‐positive ALL; this underlying immune dysregulation may be due to early immune system alterations via CMV exposure (in utero or early infancy) proposing a potential link between CMV and ALL etiology.

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Section: Introductionmentioning

confidence: 92%

Associations between early‐life and in utero infections and cytomegalovirus‐positive acute lymphoblastic leukemia in children

Gallant

Arroyo

Metayer

et al. 2022

Intl Journal of Cancer

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“…7 Instead, the immunophenotypically similar ALL subtype characterized by the ETV6-RUNX1 translocation commonly displays the APOBEC signature, 7 despite its comparatively lower prevalence of CMV. 5 This mutational signature being a broad feature of other virally induced cancers suggests the potential for other viral involvement (apart from CMV) in the cause of the ETV6-RUNX1 subtype;…”

Section: Openmentioning

confidence: 99%

“…4 Although the original neonatal results (Francis et al 3 ) were not replicated overall, the data are compatible with a recent observation that the frequency of CMV in ALL blasts at diagnosis is enhanced specifically in the HeH subtype when compared with other subtypes. 5 Additional supportive clinical evidence for the CMV-ALL association was provided from Swedish registries where CMV infection diagnosed during pregnancy in the mother of children who contracted hematologic malignant neoplasms, or at birth in the newborn, was observed at a more than 10-fold higher frequency when compared with the remainder of the age-matched population. 6 In sum, the evidence supporting an association between CMV and ALL is tantalizing and mounting rapidly, but much additional research attention is required to mechanistically describe pathways by which CMV may influence leukemia before the virus could be considered a potential target for prevention or clinical management of ALL.…”

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confidence: 97%

Does Cytomegalovirus Play a Role in Pediatric Lymphoblastic Leukemogenesis?

Wiemels

2023

JAMA Netw Open

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Acute lymphoblastic leukemia (ALL) is the most common cancer affecting children, and incidence rates have increased 2-fold over the past 70 years. 1 Epidemiologists have long investigated patterns of infectious exposure and response in early life as causal factors, 2 but no specific infectious agent was discovered until recently when cytomegalovirus (CMV) was found within childhood ALL blasts at diagnosis. 3 Moreover, evaluation of neonatal blood spot-derived DNA in California patients revealed

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“…Our findings suggest a CMV-ALL association may be specific to hyperdiploid ALL, consistent with recent reports from diagnostic specimens. 29…”

Section: Jama Network Open | Hematologymentioning

confidence: 99%

Evaluation of the Association Between Congenital Cytomegalovirus Infection and Pediatric Acute Lymphoblastic Leukemia

et al. 2023

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ImportanceAcute lymphoblastic leukemia (ALL) is the most common form of pediatric cancer, and a leading cause of death in children. Understanding the causes of pediatric ALL is necessary to enable early detection and prevention; congenital cytomegalovirus (cCMV) has recently been identified as a potential moderate-to-strong factor associated with risk for ALL.ObjectiveTo compare the prevalence of cCMV infection between ALL cases and matched controls.Design, Setting, and ParticipantsIn this population-based case-control study of ALL cases and matched controls, cases consisted of children aged 0 to 14 years between 1987 and 2014 with an ALL diagnosis identified through the Michigan Cancer Surveillance Program and born in Michigan on or after October 1, 1987. Cancer-free controls were identified by the Michigan BioTrust for Health and matched on age, sex, and mother’s race and ethnicity. Data were analyzed from November to May 2022.ExposurescCMV infection measured by quantitative polymerase chain reaction in newborn dried blood spots.Main Outcomes and MeasuresALL diagnosed in children aged 0 to 14 years.ResultsA total of 1189 ALL cases and 4756 matched controls were included in the study. Bloodspots were collected from participants at birth, and 3425 (57.6%) participants were male. cCMV was detected in 6 ALL cases (0.5%) and 21 controls (0.4%). There was no difference in the odds of cCMV infection comparing ALL cases with controls (odds ratio, 1.30; 95% CI, 0.52-3.24). Immunophenotype was available for 536 cases (45.1%) and cytogenetic data for 127 (27%). When stratified by subtype characteristics, hyperdiploid ALL (74 cases) was associated with 6.26 times greater odds of cCMV infection compared with unmatched controls (95% CI, 1.44-27.19).Conclusions and RelevanceIn this case-control study of cCMV and pediatric ALL, cCMV was associated with increased risk of hyperdiploid ALL. These findings encourage continued research.

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Clinical characteristics of cytomegalovirus‐positive pediatric acute lymphoblastic leukemia at diagnosis

Abstract: Double vs single autologous stem cell transplantation for newly diagnosed multiple myeloma: long-term follow-up (10-years) analysis of randomized phase 3 studies.

Cited by 6 publications

References 9 publications

Associations between early‐life and in utero infections and cytomegalovirus‐positive acute lymphoblastic leukemia in children

Associations between early‐life and in utero infections and cytomegalovirus‐positive acute lymphoblastic leukemia in children

Does Cytomegalovirus Play a Role in Pediatric Lymphoblastic Leukemogenesis?

Evaluation of the Association Between Congenital Cytomegalovirus Infection and Pediatric Acute Lymphoblastic Leukemia

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