To review the impact of collaborative studies on advances in the biology and treatment of acute lymphoblastic leukemia (ALL) in children and adolescents.
A review of English literature on childhood ...ALL focusing on collaborative studies was performed. The resulting article was reviewed and revised by the committee chairs of the major ALL study groups.
With long-term survival rates for ALL approaching 90% and the advent of high-resolution genome-wide analyses, several international study groups or consortia were established to conduct collaborative research to further improve outcome. As a result, treatment strategies have been improved for several subtypes of ALL, such as infant, MLL-rearranged, Philadelphia chromosome-positive, and Philadelphia chromosome-like ALL. Many recurrent genetic abnormalities that respond to tyrosine kinase inhibitors and multiple genetic determinants of drug resistance and toxicities have been identified to help develop targeted therapy. Several genetic polymorphisms have been recognized that show susceptibility to developing ALL and that help explain the racial/ethnic differences in the incidence of ALL.
The information gained from collaborative studies has helped decipher the heterogeneity of ALL to help improve personalized treatment, which will further advance the current high cure rate and the quality of life for children and adolescents with ALL.
Pharmacogenetics is frequently cited as an area for initial focus of the clinical implementation of genomics. Through the PG4KDS protocol, St. Jude Children's Research Hospital pre-emptively ...genotypes patients for 230 genes using the Affymetrix Drug Metabolizing Enzymes and Transporters (DMET) Plus array supplemented with a CYP2D6 copy number assay. The PG4KDS protocol provides a rational, stepwise process for implementing gene/drug pairs, organizing data, and obtaining consent from patients and families. Through August 2013, 1,559 patients have been enrolled, and four gene tests have been released into the electronic health record (EHR) for clinical implementation: TPMT, CYP2D6, SLCO1B1, and CYP2C19. These genes are coupled to 12 high-risk drugs. Of the 1,016 patients with genotype test results available, 78% of them had at least one high-risk (i.e., actionable) genotype result placed in their EHR. Each diplotype result released to the EHR is coupled with an interpretive consult that is created in a concise, standardized format. To support-gene based prescribing at the point of care, 55 interruptive clinical decision support (CDS) alerts were developed. Patients are informed of their genotyping result and its relevance to their medication use through a letter. Key elements necessary for our successful implementation have included strong institutional support, a knowledgeable clinical laboratory, a process to manage any incidental findings, a strategy to educate clinicians and patients, a process to return results, and extensive use of informatics, especially CDS. Our approach to pre-emptive clinical pharmacogenetics has proven feasible, clinically useful, and scalable.
The persistence of minimal residual disease (MRD) during therapy is the strongest adverse prognostic factor in acute lymphoblastic leukemia (ALL). We developed a high-throughput sequencing method ...that universally amplifies antigen-receptor gene segments and identifies all clonal gene rearrangements (ie, leukemia-specific sequences) at diagnosis, allowing monitoring of disease progression and clonal evolution during therapy. In the present study, the assay specifically detected 1 leukemic cell among greater than 1 million leukocytes in spike-in experiments. We compared this method with the gold-standard MRD assays multiparameter flow cytometry and allele-specific oligonucleotide polymerase chain reaction (ASO-PCR) using diagnostic and follow-up samples from 106 patients with ALL. Sequencing detected MRD in all 28 samples shown to be positive by flow cytometry and in 35 of the 36 shown to be positive by ASO-PCR and revealed MRD in 10 and 3 additional samples that were negative by flow cytometry and ASO-PCR, respectively. We conclude that this new method allows monitoring of treatment response in ALL and other lymphoid malignancies with great sensitivity and precision. The www.clinicaltrials.gov identifier number for the Total XV study is NCT00137111.
Despite contemporary treatment, up to 10% of children with acute lymphoblastic leukemia still experience relapse. We evaluated whether a higher dosage of PEG-asparaginase and early intensification of ...triple intrathecal therapy would improve systemic and CNS control.
Between 2007 and 2017, 598 consecutive patients age 0 to 18 years received risk-directed chemotherapy without prophylactic cranial irradiation in the St Jude Total Therapy Study 16. Patients were randomly assigned to receive PEG-asparaginase 3,500 U/m
versus the conventional 2,500 U/m
. Patients presenting features that were associated with increased risk of CNS relapse received two extra doses of intrathecal therapy during the first 2 weeks of remission induction.
The 5-year event-free survival and overall survival rates for the 598 patients were 88.2% (95% CI, 84.9% to 91.5%) and 94.1% (95% CI, 91.7% to 96.5%), respectively. Cumulative risk of any-isolated or combined-CNS relapse was 1.5% (95% CI, 0.5% to 2.5%). Higher doses of PEG-asparaginase did not affect treatment outcome. T-cell phenotype was the only independent risk factor for any CNS relapse (hazard ratio, 5.15; 95% CI, 1.3 to 20.6;
= . 021). Among 359 patients with features that were associated with increased risk for CNS relapse, the 5-year rate of any CNS relapse was significantly lower than that among 248 patients with the same features treated in the previous Total Therapy Study 15 (1.8% 95% CI, 0.4% to 3.3%
5.7% 95% CI, 2.8% to 8.6%;
= .008). There were no significant differences in the cumulative risk of seizure or infection during induction between patients who did or did not receive the two extra doses of intrathecal treatment.
Higher doses of PEG-asparaginase failed to improve outcome, but additional intrathecal therapy during early induction seemed to contribute to improved CNS control without excessive toxicity for high-risk patients.
Background
Children with acute lymphoblastic leukemia (ALL) have an increased risk of obesity and short stature. To the authors’ knowledge, data regarding patients treated on contemporary protocols ...without cranial irradiation are limited.
Methods
Changes in z scores for body mass index (BMI), height, and weight from the time of diagnosis to 5 years off therapy were evaluated using multivariable analysis in 372 children with ALL who were aged 2 to 18 years at the time of diagnosis and were enrolled on the St. Jude Children’s Research Hospital Total XV protocol from 2000 through 2007.
Results
The percentage of overweight/obese patients increased from 25.5% at the time of diagnosis to approximately 50% during the off‐therapy period. Median BMI z scores increased significantly during glucocorticoid therapy (induction: ∆0.56; 95% confidence interval 95% CI, 0.29‐0.64 P<.001; and reinduction II: ∆0.22; 95% CI, 0.13‐0.49 P=.001) and during the first year after therapy (∆0.18; 95% CI, 0.08‐0.46 P=.006). Among patients who were of healthy weight/underweight at the time of diagnosis, those aged 2 to <10 years at diagnosis had a significantly higher risk of becoming overweight/obese during or after therapy compared with those aged ≥10 years (P=.001). Height z scores declined during treatment and improved after therapy. Being aged 2 to <10 years at the time of diagnosis, being of low‐risk status, having a white blood cell count < 50×109/L at the time of diagnosis, and having negative central nervous system disease were associated with significantly better improvements in z scores for height during the off‐therapy period compared with being aged ≥10 years, being of standard‐risk/high‐risk status, having a white blood cell count ≥ 50×109/L, and having positive central nervous system disease, respectively.
Conclusions
The results of the current study demonstrate that obesity is prevalent, and height growth, especially in patients with identified risk factors, appears compromised. Multidisciplinary intervention should begin during induction therapy and continue during the off‐therapy period.
The results of the current study demonstrate that body mass index z scores increase during induction therapy and remain elevated even after the completion of therapy. Therefore, multidisciplinary intervention for obesity should begin during induction therapy and continue during the off‐therapy period. Although z scores for height appear to decline during therapy and improve after therapy completion, they remain low in patients aged ≥10 years at the time of diagnosis, in those with standard‐risk/high‐risk status, in those with a white blood cell count of ≥50×109/L at the time of diagnosis, and in those with positive central nervous system disease.
Background
Survivors of childhood acute lymphoblastic leukemia (ALL) are at increased risk for both treatment‐related exercise intolerance and neurocognitive deficits. This analysis aimed to identify ...the association between exercise intolerance and neurocognitive impairments in ALL survivors.
Methods
Cardiopulmonary exercise testing, results from a 2‐hour standardized neuropsychological assessment, and self‐report questionnaires were obtained for 341 adult survivors of childhood ALL and 288 controls. Multivariable modeling was used to test associations between oxygen uptake at 85% estimated heart rate (rpkVO2) and neuropsychological test and self‐reported questionnaire domains, adjusted for sex, age at diagnosis, cranial radiation, anthracycline, and methotrexate exposure and tobacco smoking status.
Results
Compared with controls, survivors had worse rpkVO2 and performance on verbal intelligence, focused attention, verbal fluency, working memory, dominant/nondominant motor speed, visual‐motor speed, memory span, and reading and math measures (all P < .001). In adjusted models, exercise intolerance was associated with decreases in performance of verbal ability, focused attention, verbal fluency, working memory, dominant motor speed, nondominant motor speed, visual‐motor speed, memory span, reading academics, and math academics in survivors.
Conclusion
This study demonstrates an association between exercise intolerance and neurocognitive outcomes. Research is needed to determine whether interventions that improve exercise tolerance impact neurocognitive function in ALL survivors.
Previous studies in noncancer populations of children and older adults have shown that physical fitness interventions can have a positive impact on executive function and academic performance. The present study provides evidence that even with the neurotoxic effects of anticancer therapy, improving the physical fitness of pediatric cancer patients may have a similar long‐term impact on the neurocognitive outcomes of survivors.
Background
Hyperleukocytosis in patients with acute myeloid leukemia (AML) has been associated with worse outcomes. For cytoreduction, leukapheresis has been used but its clinical utility is unknown, ...and low‐dose cytarabine (LD‐cytarabine) is used as an alternative method.
Methods
Children with newly diagnosed AML treated between 1997 and 2017 in institutional protocols were studied. Hyperleukocytosis was defined as a leukocyte count of ≥100 × 109/L at diagnosis. Clinical characteristics, early complications, survival data, and effects of cytoreductive methods were reviewed. Among 324 children with newly diagnosed AML, 49 (15.1%) presented with hyperleukocytosis. Initial management of hyperleukocytosis included leukapheresis or exchange transfusion (n = 16, considered as one group), LD‐cytarabine (n = 18), hydroxyurea (n = 1), and no leukoreduction (n = 14).
Results
Compared with patients who received leukapheresis, the percentage decrease in leukocyte counts following intervention was greater among those who received LD‐cytarabine (48% vs. 75%; p = .02), with longer median time from diagnosis to initiation of protocol therapy (28.1 vs. 95.2 hours; p < .001). The incidence of infection was higher in patients (38%) who had leukapheresis than those who receive LD‐cytarabine (0%) or leukoreduction with protocol therapy (14%) (p = .008). No differences were noted in the outcomes among the intervention groups. Although patients with hyperleukocytosis had higher incidences of pulmonary and metabolic complications than did those without, no early deaths occurred, and the complete remission, event‐free survival, overall survival rates, and outcomes of both groups were similar.
Conclusion
LD‐cytarabine treatment appears to be a safe and effective means of cytoreduction for children with AML and hyperleukocytosis.
Among 324 children with newly diagnosed acute myeloid leukemia (AML), 49 (15.1%) presented with hyperleukocytosis and were managed with leukapheresis or exchange transfusion (n = 16), low‐dose (LD)‐cytarabine (n = 18), hydroxyurea (n = 1), or no leukoreduction (n = 14). No early deaths were observed and LD‐cytarabine treatment appears to be a safe and effective means of cytoreduction for children with AML and hyperleukocytosis.
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