There is increasing evidence for a strong inherited genetic basis of susceptibility to acute lymphoblastic leukaemia (ALL) in children. To identify new risk variants for B-cell ALL (B-ALL) we conducted a meta-analysis with four GWAS (genome-wide association studies), totalling 5321 cases and 16,666 controls of European descent. We herein describe novel risk loci for B-ALL at 9q21.31 (rs76925697, P = 2.11 × 10⁻⁸), for high-hyperdiploid ALL at 5q31.1 (rs886285, P = 1.56 × 10⁻⁸) and 6p21.31 (rs210143 in BAK1, P = 2.21 × 10⁻⁸), and ETV6-RUNX1 ALL at 17q21.32 (rs10853104 in IGF2BP1, P = 1.82 × 10⁻⁸). Particularly notable are the pleiotropic effects of the BAK1 variant on multiple haematological malignancies and specific effects of IGF2BP1 on ETV6-RUNX1 ALL evidenced by both germline and somatic genomic analyses. Integration of GWAS signals with transcriptomic/epigenomic profiling and 3D chromatin interaction data for these leukaemia risk loci suggests deregulation of B-cell development and the cell cycle as central mechanisms governing genetic susceptibility to ALL.

Jayaram Vijayakrishnan;Maoxiang Qian;James B. Studd;Wenjian Yang;Ben Kinnersley;Philip J. Law;Peter Broderick;Elizabeth A. Raetz;James Allan;Chinghon Pui;Ajay Vora;William E. Evans;Anthony Moorman;Allen Yeoh;Wentao Yang;Chunliang Li;Claus R. Bartram;Charles G. Mullighan;Martin Zimmerman;Stephen P. Hunger;Martin Schrappe;Mary V. Relling;Martin Stanulla;Mignon L. Loh;Richard S. Houlston;Jun J. Yang

Nature Communications

2019-12-1

Background: Comprehensive studies on neutropenia and infection-related complications in patients with acute lymphoblastic leukemia (ALL) are lacking. Patients and methods: We evaluated infection-related complications that were grade≥3 on National Cancer Institute's Common Terminology Criteria for Adverse Events (version 3.0) and their risk factors in 409 children with newly diagnosed ALL throughout the treatment period. Results: Of the 2420 infection episodes, febrile neutropenia and clinically or microbiologically documented infection were seen in 1107 and 1313 episodes, respectively. Among documented infection episodes, upper respiratory tract was the most common site (n=389), followed by ear (n=151), bloodstream (n=147), and gastrointestinal tract (n=145) infections. These episodes were more common during intensified therapy phases such as remission induction and reinduction, but respiratory and ear infections, presumably viral in origin, also occurred during continuation phases. The 3-year cumulative incidence of infection-related death was low (1.0±0.9%, n=4), including 2 from Bacillus cereus bacteremia. There was no fungal infectionrelated mortality. Age 1-9.9 years at diagnosis was associated with febrile neutropenia (P=0.002) during induction and febrile neutropenia and documented infection (both P < 0.001) during later continuation. White race was associated with documented infection (P=0.034) during induction. Compared with low-risk patients, standard- and high-risk patients received more intensive therapy during early continuation and had higher incidences of febrile neutropenia (P < 0.001) and documented infections (P=0.043). Furthermore, poor neutrophil surge after dexamethasone pulses during continuation, which can reflect the poor bone marrow reserve, was associated with infections (P < 0.001). Conclusions: The incidence of infection-related death was low. However, young age, white race, intensive chemotherapy, and lack of neutrophil surge after dexamethasone treatment were associated with infection-related complications. Close monitoring for prompt administration of antibiotics andmodification of chemotherapy should be considered in these patients.

Hiroto Inaba;D. Pei;J. Wolf;S. C. Howard;R. T. Hayden;M. Go;O. Varechtchouk;T. Hahn;J. Buaboonnam;M. L. Metzger;J. E. Rubnitz;R. C. Ribeiro;J. T. Sandlund;S. Jeha;C. Cheng;W. E. Evans;M. V. Relling;Chinghon Pui

Annals of Oncology

2017-2

Somatic genetic alterations of IKZF1, which encodes the lymphoid transcription factor IKAROS, are common in high-risk B-progenitor acute lymphoblastic leukemia (ALL) and are associated with poor prognosis. Such alterations result in the acquisition of stem cell-like features, overexpression of adhesion molecules causing aberrant cell-cell and cell-stroma interaction, and decreased sensitivity to tyrosine kinase inhibitors. Here we report coding germline IKZF1 variation in familial childhood ALL and 0.9% of presumed sporadic B-ALL, identifying 28 unique variants in 45 children. The majority of variants adversely affected IKZF1 function and drug responsiveness of leukemic cells. These results identify IKZF1 as a leukemia predisposition gene, and emphasize the importance of germline genetic variation in the development of both familial and sporadic ALL. Churchman et al. identify 28 unique germline IKZF1 coding variants in 45 children with acute lymphoblastic leukemia. Many of these variants are not predicted to be damaging using in silico prediction tools, but functional tests reveal that the majority of them have deleterious effects on IKAROS function.

Michelle L. Churchman;Maoxiang Qian;Geertruy te Kronnie;Ranran Zhang;Wenjian Yang;Hui Zhang;Tobia Lana;Paige Tedrick;Rebekah Baskin;Katherine Verbist;Jennifer L. Peters;Meenakshi Devidas;Eric Larsen;Ian M. Moore;Zhaohui Gu;Chunxu Qu;Hiroki Yoshihara;Shaina N. Porter;Shondra M. Pruett-Miller;Gang Wu;Elizabeth Raetz;Paul L. Martin;W. Paul Bowman;Naomi Winick;Elaine Mardis;Robert Fulton;Martin Stanulla;William E. Evans;Mary V. Relling;Chinghon Pui;Stephen P. Hunger;Mignon L. Loh;Rupert Handgretinger;Kim E. Nichols;Jun J. Yang;Charles G. Mullighan

Cancer Cell

2018-5-14

BACKGROUND A better understanding of when cure can be declared in childhood acute myeloid leukemia (AML) would reduce anxiety and improve quality of life of AML survivors. The authors determined the likelihood that patients with AML would maintain long-term remission after the completion of therapy. METHODS The cumulative risk of relapse, the time to relapse, event-free survival, and overall survival were analyzed for 604 patients with AML who were enrolled in 7 successive clinical trials divided into 3 treatment eras (1976-1991, 1991-1997, and 2002-2008). RESULTS The median time to relapse did not change over time (0.93 years vs 0.76 years vs 0.8 years, respectively, for each consecutive era; P = .22), but the risk of relapse decreased significantly (5-year cumulative incidence of relapse: 52.6% ± 3.1% vs 31.5% ± 3.9% vs 22% ± 3%, respectively, for each consecutive era; P < .001). Among patients who were in remission 4 years from diagnosis, the probabilities of relapse were 1.7%, 2.9%, and 0.9%, respectively, for each consecutive era. In the most recent era, all but 1 of 44 relapses occurred within 4 years of diagnosis. CONCLUSIONS Children with AML who receive treatment with contemporary therapy and remain in remission 4 years from diagnosis probably are cured. Although late relapses and late deaths from other causes are rare, long-term follow-up of survivors is necessary for the timely management of late adverse effects.

Jeffrey E. Rubnitz;Hiroto Inaba;Wing H. Leung;Stanley Pounds;Xueyuan Cao;Dario Campana;Raul C. Ribeiro;Chinghon Pui

Cancer

2014-8-15

Long-term survivors of childhood acute lymphoblastic leukemia (ALL) are at risk for neurocognitive impairment, as well as compromised hypothalamic-pituitary-adrenal (HPA) function. Dehydroepiandrosterone-sulfate (DHEAS) is an adrenal androgen commonly used as a marker of HPA function. In the general population, a low level of DHEAS has been associated with poorer cognition. At ≥2 years post-treatment, we examined the association of DHEAS with attention outcomes in 35 male and 34 female long-term survivors of childhood ALL (mean[standard deviation] age at evaluation 14.5[4.7] years; 7.5[1.9] years post-diagnosis) who were treated with only chemotherapy and without prophylactic cranial irradiation. Male survivors with low-normal levels of DHEAS had worse performance than male survivors with high levels of DHEAS on multiple measures of attention (all P's < 0.05). However, association between DHEAS and attention measures were not found in female survivors. Our results suggest that survivors of ALL who suffer from partial but persistent adrenal insufficiency may be at risk for neurocognitive deficits. This finding should be validated in a larger prospective study, with attention to sex differences in the potential impact of adrenal insufficiency on neurocognitive outcomes.

Yin Ting Cheung;Wassim Chemaitilly;Daniel A. Mulrooney;Tara M. Brinkman;Wei Liu;Pia Banerjee;Deokumar Srivastava;Chinghon Pui;Leslie L. Robison;Melissa M. Hudson;Kevin R. Krull

Psychoneuroendocrinology

2017-2-1

Background: We investigated the effects of demographic, lifestyle (self-reported smoking status and physical activity levels), cancer-related treatment factors (radiation and chemotherapy), and diet (calcium and vitamin D intake) on bone turnover and the relationship of bone turnover to lumbar spine bone mineral density (BMD) Z-scores (LS-BMD Z-scores) determined by quantitative computed tomography (QCT) in 418 ≥5-year survivors of childhood acute lymphoblastic leukemia (ALL). Procedure: Bone turnover was assessed by biomarkers including serum bone-specific alkaline phosphatase (BALP), osteocalcin (OC), and urinary N-telopeptide of type I collagen indexed to creatinine (NTX/Cr). The 215 males ranged in age from 9 to 36 years (median age 17 years). Results: Age and tanner score were inversely associated with all biomarkers (BALP, OC, NTX/Cr) (P<0.001). Males had higher BALP and OC than females (P<0.001). Body mass index (BMI) was inversely associated with OC and NTX/Cr (P<0.001). There was no significant association of biomarkers with lifestyle related factors, ALL treatment-related factors, dietary calcium, vitamin D, or LS-BMD Z-score. Conclusions: In this population of long-term survivors of ALL, bone turnover was significantly associated with age, gender, tanner stage, and BMI. ALL-related treatments did not influence bone turnover and bone turnover was not predictive of volumetric LS-BMD Z-score.

Mitchell A. Watsky;Laura D. Carbone;Qi An;Cheng Cheng;Elizabeth A. Lovorn;Melissa M. Hudson;Chinghon Pui;Sue C. Kaste

Pediatric Blood and Cancer

2014

Background: Outcomes for children with relapsed or refractory acute myeloid leukaemia remain poor. The BCL-2 inhibitor, venetoclax, has shown promising activity in combination with hypomethylating agents and low-dose cytarabine in older adults for whom chemotherapy is not suitable with newly diagnosed acute myeloid leukaemia. We aimed to determine the safety and explore the activity of venetoclax in combination with standard and high-dose chemotherapy in paediatric patients with relapsed or refractory acute myeloid leukaemia. Methods: We did a phase 1, dose-escalation study at three research hospitals in the USA. Eligible patients were aged 2–22 years with relapsed or refractory acute myeloid leukaemia or acute leukaemia of ambiguous lineage with adequate organ function and performance status. During dose escalation, participants received venetoclax orally once per day in continuous 28-day cycles at either 240 mg/m² or 360 mg/m², in combination with cytarabine received intravenously every 12 h at either 100 mg/m² for 20 doses or 1000 mg/m² for eight doses, with or without intravenous idarubicin (12 mg/m²) as a single dose, using a rolling-6 accrual strategy. The primary endpoint was the recommended phase 2 dose of venetoclax plus chemotherapy and the secondary endpoint was the proportion of patients treated at the recommended phase 2 dose who achieved complete remission or complete remission with incomplete haematological recovery. Analyses were done on patients who received combination therapy. The study is registered with ClinicalTrials.gov (NCT03194932) and is now enrolling to address secondary and exploratory objectives. Findings: Between July 1, 2017, and July 2, 2019, 38 patients were enrolled (aged 3–22 years; median 10 [IQR 7–13]), 36 of whom received combination therapy with dose escalation, with a median follow-up of 7·1 months (IQR 5·1–11·2). The recommended phase 2 dose of venetoclax was found to be 360 mg/m² (maximum 600 mg) combined with cytarabine (1000 mg/m² per dose for eight doses), with or without idarubicin (12 mg/m² as a single dose). Overall responses were observed in 24 (69%) of the 35 patients who were evaluable after cycle 1. Among the 20 patients treated at the recommended phase 2 dose, 14 (70%, 95% CI 46–88) showed complete response with or without complete haematological recovery, and two (10%) showed partial response. The most common grade 3–4 adverse events were febrile neutropenia (22 [66%]), bloodstream infections (six [16%]), and invasive fungal infections (six [16%]). Treatment-related death occurred in one patient due to colitis and sepsis. Interpretation: The safety and activity of venetoclax plus chemotherapy in paediatric patients with heavily relapsed and refractory acute myeloid leukaemia suggests that this combination should be tested in newly diagnosed paediatric patients with high-risk acute myeloid leukaemia. Funding: US National Institutes of Health, American Lebanese Syrian Associated Charities, AbbVie, and Gateway for Cancer Research.

Seth E. Karol;Thomas B. Alexander;Amit Budhraja;Stanley B. Pounds;Kristin Canavera;Lei Wang;Joshua Wolf;Jeffery M. Klco;Paul E. Mead;Soumyasri Das Gupta;Su Y. Kim;Ahmed Hamed Salem;Tammy Palenski;Norman J. Lacayo;Chinghon Pui;Joseph T. Opferman;Jeffrey E. Rubnitz

The Lancet Oncology

2020-4

BACKGROUND Intensive chemotherapy for pediatric acute myeloid leukemia incurs the risk of infectious complications, but the benefits of antibiotic prophylaxis remain unclear. METHODS In the current study, among 103 children treated on the AML02 protocol between October 2002 and October 2008 at St. Jude Children's Research Hospital, the authors retrospectively assessed the effect of antibiotic prophylaxis on the frequency of febrile neutropenia, clinically or microbiologically confirmed infections (including bacteremia), and antibiotic resistance, as well as on the results of nasal and rectal surveillance cultures. Initially, patients received no prophylaxis or oral cephalosporin (group A). The protocol was then amended to administer intravenous cefepime alone or intravenous vancomycin plus either oral cephalosporin, oral ciprofloxacin, or intravenous cefepime (group B). RESULTS There were 334 infectious episodes. Patients in group A had a significantly greater frequency of documented infections and bacteremia (both P<.0001) (including gram-positive and gram-negative bacteremia; P=.0003 and.001, respectively) compared with patients in group B, especially viridans streptococcal bacteremia (P=.001). The incidence of febrile neutropenia without documented infection was not found to be different between the 2 groups. Five cases of bacteremia with vancomycin-resistant enterococci (VRE) occurred in group B (vs none in group A), without related mortality. Two of these cases were preceded by positive VRE rectal surveillance cultures. CONCLUSIONS Outpatient intravenous antibiotic prophylaxis is feasible in children with acute myeloid leukemia and reduces the frequency of documented infection but not of febrile neutropenia. Despite the emergence of VRE bacteremia, the benefits favor antibiotic prophylaxis. Creative approaches to shorten the duration of prophylaxis and thereby minimize resistance should be explored. Cancer 2014;120:1985-1992.

Hiroto Inaba;Aditya H. Gaur;Xueyuan Cao;Patricia M. Flynn;Stanley B. Pounds;Viswatej Avutu;Lindsay N. Marszal;Scott C. Howard;Chinghon Pui;Raul C. Ribeiro;Randall T. Hayden;Jeffrey E. Rubnitz

Cancer

2014-7-1

Background: Treatment of the central nervous system is crucial to the successful treatment of acute lymphoblastic leukemia in children. The intensity and timing of the therapy are based on the presence or predicted risk of central nervous system leukemia as assessed according to criteria that remain controversial. Methods: The clinical importance of leukemic blast cells detected in cerebrospinal fluid at the time of diagnosis was evaluated in 351 children with acute lymphoblastic leukemia in a randomized trial of intensive chemotherapy. All patients received intrathecal chemotherapy during the first year. Patients considered to be at high risk of relapse because of their clinical and cytogenetic features also received cranial irradiation and intrathecal chemotherapy one year after remission. Patients were considered to have central nervous system leukemia at diagnosis if they had at least 5 leukocytes per microliter of cerebrospinal fluid, with leukemic blast cells apparent in cytocentrifuged preparations, or cranial-nerve palsy; they received additional intrathecal injections of chemotherapeutic agents and cranial irradiation. Patients were retrospectively classified on the basis of cerebrospinal fluid findings: 291 patients had no detectable blast cells, 42 had fewer than 5 leukocytes per microliter and blast cells, and 18 had central nervous system leukemia as defined above. The clinical characteristics and outcomes of treatment in these groups were analyzed. Results: The five-year probability of survival free of relapses confined to the central nervous system in patients with detectable blast cells and fewer than 5 leukocytes per microliter of cerebrospinal fluid was lower than in patients without blast cells (mean [±SE], 87 ±13 vs. 96 ±2 percent), but was not different from the probability in patients with central nervous system leukemia at diagnosis. All such isolated relapses of leukemia in patients with detectable blast cells occurred during the first year of treatment, before scheduled cranial irradiation. In a multivariate analysis, the presence of cerebrospinal fluid blast cells with fewer than 5 leukocytes per microliter was independently related to the risk of relapse confined to the central nervous system. Conclusions: Patients with leukemic blast cells in their cerebrospinal fluid are at increased risk for central nervous system relapse when cranial irradiation is delayed. Such patients require intensified central nervous system treatment early in the course of therapy., Although the incidence of acute lymphoblastic leukemia recurring in the central nervous system in children has decreased markedly since the introduction of effective therapy directed at the central nervous system, more than half the patients who have such early relapse die of their disease despite aggressive attempts at salvage¹,². Treatment regimens designed to prevent overt central nervous system disease have varied from cranial irradiation combined with intrathecal chemotherapy to intrathecal chemotherapy alone or combined with high-dose intravenous methotrexate³–⁸. For patients with central nervous system leukemia at diagnosis, intensified therapy (e.g., additional intrathecal injections of chemotherapeutic agents…

Hazem H. Mahmoud;Gaston K. Rivera;Michael L. Hancock;Robert A. Krance;Larry E. Kun;Frederick G. Behm;Raul C. Ribeiro;John T. Sandlund;William M. Crist;Chinghon Pui

New England Journal of Medicine

1993-7-29

Chinghon Pui

Oncology

2011-4-15