Search

Data on outcome for patients in different body mass index (BMI) categories in young adults with acute lymphoblastic leukemia (ALL) are scarce. We explored survival and toxicities in different BMI categories in young adults with ALL. Patients aged 18–45 years, diagnosed with ALL between July 2008 and June 2022 in the Nordic countries, Estonia, or Lithuania, and treated according to the NOPHO ALL2008 protocol, were retrospectively enrolled and classified into different BMI categories. Endpoints were overall survival (OS), event-free survival (EFS) and cumulative incidence of relapse as well as incidence rate ratio (IRR) of severe predefined toxic events, and treatment delays. The group comprised 416 patients, of whom 234 (56%) were stratified to non-high-risk (non-HR) treatment. In the non-HR group, patients with severe obesity, BMI ≥35 kg/m2 had worse EFS due to relapses but there was no effect on toxicity or treatment delays compared with the healthy-weight patients. There was no association between BMI category and OS, overall toxicity, or treatment delays in the patients with high-risk treatment. Severe obesity is associated with worse EFS in young adults treated according to the non-HR arms of the NOPHO ALL2008 protocol. Poorer outcome is explained with a higher risk of relapse, possibly due to under treatment, and not caused by excess therapy-related mortality. [ABSTRACT FROM AUTHOR]

Objectives: High body mass index (BMI) is associated with poorer survival in childhood acute lymphoblastic leukemia (ALL), but the actual impact on the risk of relapse still needs to be clarified. We evaluated the impact of BMI at diagnosis on the risk of relapse in children with ALL treated according to Nordic Society of Paediatric Haematology and Oncology (NOPHO) protocols. Method: In a multicenter study, we collected data on BMI at diagnosis and outcome of 2558 children aged 2.0‐17.9 years diagnosed between 1992 and 2016. Patients were divided into four groups according to International Obesity Task Force (IOTF) childhood BMI cut‐offs: underweight, <17; healthy weight, 17‐25; overweight, 25‐30; and obese, ≥30 kg/m2. Results: In Cox multivariate regression analyses, an increased risk of relapse was observed in children aged 10‐17.9 years with unhealthy BMI at diagnosis (underweight hazard ratio HR: 2.90 [95% confidence interval: 1.24‐6.78], P =.01; overweight, HR: 1.95 [1.11‐3.43], P =.02, and obese HR: 4.32 [95% 2.08‐8.97], P <.001), compared to children with healthy weight. BMI had no impact on relapse in children under 10 years of age. Conclusion: High BMI, and especially obesity at diagnosis, is an independent adverse prognostic factor for relapse in older children with ALL. [ABSTRACT FROM AUTHOR]

Intrachromosomal amplification of chromosome 21 (iAMP21) is a cytogenetic subtype associated with relapse and poor prognosis in pediatric B-cell precursor acute lymphoblastic leukemia (BCP ALL). The biology behind the high relapse risk is unknown and the aim of this study was to further characterize the genomic and transcriptional landscape of iAMP21. Using DNA arrays and sequencing, we could identify rearrangements and aberrations characteristic for iAMP21. RNA sequencing revealed that only half of the genes in the minimal region of amplification (20/45) were differentially expressed in iAMP21. Among them were the top overexpressed genes (p < 0.001) in iAMP21 vs. BCP ALL without iAMP21 and three candidate genes could be identified, the tyrosine kinase gene DYRK1A and chromatin remodeling genes CHAF1B and SON. While overexpression of DYRK1A and CHAF1B is associated with poor prognosis in malignant diseases including myeloid leukemia, this is the first study to show significant correlation with iAMP21-positive ALL. [ABSTRACT FROM AUTHOR]

Objectives This randomized controlled trial tested the hypothesis that children with non-high-risk acute lymphoblastic leukemia could benefit from individualized 6-mercaptopurine increments during consolidation therapy (NCT00816049). Primary and secondary end points were end of consolidation minimal residual disease (MRD) positivity and event-free survival. Methods 392 patients were randomized to experimental and 396 to standard therapy. Patients allocated to standard therapy received oral 6-mercaptopurine (25 mg/m2/day) from days 30 to 85, while the experimental arm received stepwise increments of additional 25 mg/m2/day beginning on days 50 and/or 71 unless dose-limiting myelosuppression had occurred. Results In the experimental arm, 166 patients (42%) received one dose increment, and 62 (16%) received two. Fifty-seven of 387 (15%) patients in the experimental arm were MRD positive at end of consolidation vs 77 of 389 (20%) in the control arm ( P = .08). Five-year probability of event-free survival was 0.89 (95% CI: 0.85-0.93) in the experimental arm vs 0.93 (0.90-0.96) in the control arm ( P = .13). The median accumulated length of 6-mercaptopurine treatment interruptions was 7 (IQR 2-12) in the experimental arm vs 4 (IQR 0-10) in the control arm ( P = .002). Conclusion This study found no benefit from individualized 6-mercaptopurine increments compared to standard therapy. [ABSTRACT FROM AUTHOR]

Objectives Cure rates improve when adolescents and young adults with acute lymphoblastic leukemia ( ALL) are treated according to pediatric protocols. Assumed risks of toxicities and associated delays in treatment have played a role in setting upper age limits. The aim of this study was to examine the toxicity profile and treatment delays in NOPHO ALL2008 comparing children and adults. Methods We collected information on 19 treatment-related toxicities, systematically captured at 3-month intervals throughout therapy, and time intervals between 12 consecutive treatment phases for 1076 patients aged 1-45 yrs treated according to the Nordic/Baltic ALL2008 protocol. Results No adults died during induction. The duration of induction therapy and postinduction treatment phases did not differ between children and adults, except for patients 18-45 yrs being significantly delayed during two of nine high-risk blocks (median number of days for patients 1-9, 10-17, and 18-45 yrs; the glucocorticosteroid/antimetabolite-based block B1: 24, 26, and 29 d, respectively, P = 0.001, and Block 5 (in most cases also a B block): 29, 29, and 37 d, respectively, P = 0.02). A higher incidence of thrombosis with increasing age was found; highest odds ratio 5.4 (95% CI: (2.6;11.0)) for patients 15-17 yrs compared with children 1-9 yrs ( P < 0.0001). Risk of avascular osteonecrosis was related to age with the highest OR for patients 10-14 yrs ( OR = 10.4 (95% CI: (4.4;24.9)), P < 0.0001). Conclusion Adults followed and tolerated the NOPHO ALL2008 protocol virtually as well as children, although thrombosis and avascular osteonecrosis was most common among adolescents. [ABSTRACT FROM AUTHOR]

ABSTRACT Genomic characterization of pediatric acute lymphoblastic leukemia ( ALL) has identified distinct patterns of genes and pathways altered in patients with well-defined genetic aberrations. To extend the spectrum of known somatic variants in ALL, we performed whole genome and transcriptome sequencing of three B-cell precursor patients, of which one carried the t(12;21) ETV6-RUNX1 translocation and two lacked a known primary genetic aberration, and one T- ALL patient. We found that each patient had a unique genome, with a combination of well-known and previously undetected genomic aberrations. By targeted sequencing in 168 patients, we identified KMT2D and KIF1B as novel putative driver genes. We also identified a putative regulatory non-coding variant that coincided with overexpression of the growth factor MDK. Our results contribute to an increased understanding of the biological mechanisms that lead to ALL and suggest that regulatory variants may be more important for cancer development than recognized to date. The heterogeneity of the genetic aberrations in ALL renders whole genome sequencing particularly well suited for analysis of somatic variants in both research and diagnostic applications. [ABSTRACT FROM AUTHOR]

Background The prognosis of acute lymphoblastic leukemia is poorer in adults than in children. Studies have indicated that young adults benefit from pediatric treatment, although no upper age limit has been defined. Design and methods We analyzed 749 patients aged 1-45 yr treated by the NOPHO ALL-2008 protocol. Minimal residual disease (MRD) on days 29 and 79, immunophenotype, white blood cell count (WBC), and cytogenetics were used to stratify patients to standard-, intermediate-, or high-risk treatment with or without hematopoietic stem cell transplantation. Results Adults aged 18-45 had significantly lower WBCs at diagnosis compared with children aged 1-9 and 10-17 yr, but significantly more adults were stratified to high-risk chemotherapy (8%, 14%, 17%; P < 0.0001) or high-risk chemotherapy with transplantation (4%, 13%, 19%; P < 0.0001). This age-dependent skewing of risk grouping reflected more T-ALL (11%, 27%, 33%, P < 0.0001), poorer MRD response day 29 (MRD < 0.1%: 75%, 61%, 52%; P < 0.0001), and more MLL gene rearrangements (3%, 3%, 10%; P = 0.005) in older patients. Conclusions Even if identical diagnostics, treatment, and risk stratification are implemented, more adults will be stratified to high-risk therapy, which should be considered when comparing pediatric and adult outcomes. [ABSTRACT FROM AUTHOR]

Vincristine is a key drug in the treatment of childhood and adult acute lymphoblastic leukemia (ALL), and many other childhood malignancies. Despite decades of wide clinical use, no data on the correlation between vincristine pharmacokinetics and long-term clinical outcome have been published. We here report clinical data (median follow-up time 10·5 years, range 7·3–12 years) for 86 children with B-cell precursor ALL, in whom vincristine kinetics were studied on treatment day 1. The median total plasma clearance was 429 and 331 ml/min per m2 and the area under the plasma concentration-time curve (AUC) was 4·49 and 5·40 mg/l × min in relapse and non-relapse patients, respectively (not significant). In standard risk patients, where treatment depends more heavily on vincristine than in other subgroups, the relative risk (RR) of relapse was significantly increased for patients with clearance values above median (RR 5·2; P = 0·036), or AUC values below median (RR 5·8; P = 0·025). Our data suggest a relationship between the antileukemic effect and the systemic exposure of the drug, which warrants further studies. [ABSTRACT FROM AUTHOR]

Abstract: Leukemic cells from 230 children with newly diagnosed B-cell precursor ALL were tested for in vitro drug resistance to a panel of anti-cancer drugs. Minimal residual disease (MRD) was measured by RQ-PCR. During follow-up, 24 relapses occurred in the 159 children with MRD <0.1% day 29. The risk of any relapse was correlated to vincristine and doxorubicin resistance, with a relative risk of 3.7 (95% CI 1.3–10.5; p=0.016) for patients resistant to both drugs. There was a significant correlation also for the subgroup with extra-medullary relapses. Our findings indicate that analysis of drug resistance can add prognostic information to other known risk-factors including MRD. [Copyright &y& Elsevier]