scholarly journals Does Body Mass Index (BMI) during Maintenance Influence Relapse Risk in Children with Acute Lymphoblastic Leukemia (ALL)? Results from COG-AALL03N1

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 213-213
Author(s):  
Aman Wadhwa ◽  
Yanjun Chen ◽  
Lindsey Hageman ◽  
Anna Hoppmann ◽  
Anne L Angiolillo ◽  
...  
Keyword(s):  
Morbid Obesity ◽  
Maintenance Therapy ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Morbidly Obese ◽  
Red Cell ◽  
Childhood All ◽  
Relapse Risk ◽  
Increased Risk ◽  
Race Ethnicity

Abstract Introduction: Higher BMI at ALL diagnosis is associated with an increased risk of post-induction residual leukemia (Orgel, Blood 2014) and relapse (Butturini, JCO 2007). However, children may experience significant changes in BMI during the pre-maintenance phases of ALL treatment (Withycombe, Pediatr Blood Cancer 2009), necessitating an examination of the association between BMI during maintenance and relapse risk. We hypothesized that higher BMI during maintenance would be associated with a greater risk of relapse. We also explored the association between BMI and red cell thioguanine (TGN) levels to understand whether BMI-associated variations in TGN biodistribution explained the BMI-relapse association. Methods: We used data from COG-AALL03N1 (primary aim was 6MP adherence) to examine the association between BMI during maintenance and relapse risk. Eligibility for enrollment on AALL03N1 included age ≤21y at ALL diagnosis and receiving maintenance therapy in first remission. The current analysis was limited to patients with wild-type thiopurine methyltransferase genotype. BMI (exposure variable) was calculated as sex- and age-based percentile per CDC normative data, and operationalized as normal/underweight [<85%ile], overweight/obese [85-98%ile] and morbidly obese [≥99%ile]). Hazard of relapse (any site) was estimated using multivariable proportional subdistributional hazards regression after adjusting for age at study enrollment, sex, race/ethnicity, NCI risk group, cytogenetics, 6MP dose intensity (6MPDI), and time from initiation of maintenance. We compared fitted means of red cell TGN levels by BMI groups after adjusting for age at enrollment, sex, race/ethnicity, 6MPDI and time from initiation of maintenance using generalized estimated equations. The association between BMI and relapse risk, as well as between BMI and TGN levels, was also examined in a sub-cohort of patients with available 6MP adherence. Results: The sociodemographic and disease characteristics of the 676 study participants are summarized in the Table. Median BMI%ile was 88.5 (range, 0-100); normal/underweight: 43%, overweight/obese: 45%, and morbidly obese: 12%. As shown in the Figure, cumulative incidence of relapse at 2y from start of maintenance therapy was significantly greater among patients with morbid obesity (11.9±4.3%) when compared to those who were overweight/obese (5.4±1.6%) and underweight/normal weight (4.1±1.4%). After adjusting for the variables listed above, we found that patients with morbid obesity had a 3.2-fold greater hazard of relapse (95%CI=1.4-7.5, P=0.008) when compared to patients who were normal/underweight. After adjusting for age at enrollment, sex, race/ethnicity, 6MPDI, and time from initiation of maintenance, patients with morbid obesity had lower mean red cell TGN levels compared to normal/underweight patients (mean difference: -27.2±7.4 pmol/8 x 10 8 erythrocytes, P=0.0002). However, inclusion of TGN in the model did not alter the association between BMI and hazard of relapse (HR=3.8, 95%CI, 1.6-9.0, P=0.003). These findings did not change after adjusting for 6MP adherence in the sub-cohort with available adherence data (n=435). Conclusion: Morbid obesity during maintenance for childhood ALL is associated with relapse as well as lower systemic exposure to 6MP. However, lower TGN levels do not explain the relation between BMI and relapse risk. Therefore, there is a need to understand the mechanism of the relation between morbid obesity during maintenance and relapse risk in children with ALL. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Acute Lymphocytic Leukemia and Down Syndrome

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. SCI-8-SCI-8
Author(s):  
Shai Izraeli
Keyword(s):  
Down Syndrome ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Mtor Inhibitors ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Aberrant Expression ◽  
Childhood All ◽  
Increased Risk ◽  
The Common

Abstract SCI-8 Children with Down syndrome are at a markedly increased risk for acute lymphoblastic leukemia (DS-ALL). These leukemias are exclusively of the B lymphoid precursor phenotype and occur in a similar age to “common” sporadic ALLs with the striking absence of infant ALL. Recent studies reveal that DS-ALLs are heterogeneous and differ from sporadic ALLs. Only about a fifth of DS-ALLs carry the common cytogenetic aberrations typical to childhood ALL. Genomic rearrangements leading to the expression of a cytokine receptor, CRLF2, are detected in 60% of DS-ALL in comparison with up to 10% of sporadic ALLs. CRLF2 heterodimerizes with Interleukin 7 receptor-α (IL7R) to form the receptor to thymic stromal lymphopoietin (TSLP). This receptor is usually present in macrophages, dendritic cells, and some T lymphocytes and participates in allergic and inflammatory processes. The aberrant expression of the TSLP receptor is DS-ALL (and sporadic ALL) is often associated with additional mutations that cause constitutive activation of the downstream JAK-STAT and mTOR growth signaling pathways. These are either lymphoid specific activating mutations of JAK2 or JAK1 or mutations in CRLF2 or IL7R that cause ligand-independent receptor dimerization. The role of the trisomy in selecting these somatic abnormalities is presently unknown. Clinically, the prognosis of DS-ALL is inferior to sporadic ALL mainly because of increased treatment toxicity. However, recent data suggest that the inferior outcome may also be related to the genetic properties of the leukemic cells and that excessive chemotherapy dose reduction may not be appropriate for these patients. Therefore increased vigilance for infectious complications and optimal supportive care are required during periods of intensive chemotherapy. The common activation of the TSLP signaling pathway in DS-ALLs suggests a future for targeted therapy with JAK and/or mTOR inhibitors. Importantly, research of DS-ALL has proven relevant for the general patient population with ALL, as somatic mutations in the TSLP pathway have been discovered in children and adults with sporadic ALL. A major research challenge is the elucidation of the roles of constitutional and somatic trisomy 21 in leukemogenesis. Disclosures: No relevant conflicts of interest to declare.

scholarly journals NUDT15 Variants Confer High Incidence of Secondary Malignancies of ALL in Children

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2751-2751
Author(s):  
Masanori Yoshida ◽  
Kazuhiko Nakabayashi ◽  
Aiko Sato-Otsubo ◽  
Shinichi Tsujimoto ◽  
Kaoru Yoshida ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
High Sensitivity ◽  
Late Complications ◽  
Buccal Swab ◽  
Malignant Neoplasms ◽  
Childhood All ◽  
Increased Risk ◽  
Functional Alleles

Background: Secondary or subsequent malignant neoplasms (SMNs) are one of the most serious late complications in children and adolescents after treatment for acute lymphoblastic leukemia (ALL). Several studies have reported that excess dosing of 6-mercaptopurine (6-MP) therapy and polymorphisms of 6-MP metabolizing enzyme coding gene might influence the risk of SMNs. Recently, nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) variants have been identified as a cause of high sensitivity to 6-MP, which reflects a high sensitivity to 6MP in East Asians. Therefore, we investigated an association between NUDT15 genotype and incidence of SMNs in pediatric ALL. Methods: Germline samples including bone marrow samples, peripheral blood samples and buccal swab samples during remission were obtained from 13 cases who suffered from SMN after childhood ALL. The prevalence of major NUDT15 non-functional alleles (*2 and *3), which is categorized intermediate or poor metabolizer of 6-MP in Clinical Pharmacogenetics Implementation Consortium Guideline (Relling M et al. Clin Pharmacol Ther 2019), was evaluated by using Sanger sequencing and/or whole exome sequencing. The NUDT15 variants prevalence in SMN patients with primary ALL was compared to those without SMN, who were registered in the TCCSG L04-16 study, which was conducted by the Tokyo Children's Cancer Study Group (TCCSG). Results: Patients' profiles and NUDT15 genotypes were summarized in table 1. Median ages at diagnoses of ALL and SMNs were 4 (1-15) and 13 (5-44) years, respectively. Median duration between ALL and SMNs was 8 (1-30) years. SMNs included acute myeloblastic leukemia (AML) / myelodysplastic syndrome (MDS) (n = 8), brain tumor (n = 1), basal cell carcinoma (n = 1), bladder cancer (n = 1), Ewing sarcoma (n = 1) and osteosarcoma (n = 1). Among the 13 SMN cases, six patients (46.2%) possessed NUDT15 non-functional alleles. The SMNs of these cases included AML / MDS (n = 4), bladder cancer (n = 1) and osteosarcoma (n = 1). Among them, 3 patients, whose SMNs were AML, bladder cancer and osteosarcoma, were treated with radiation therapy against primary ALL. All NUDT15 genotypes were heterozygous variants (3 were *1/*2 and 3 were *1/*3) and seemed to be intermediate metabolizers. In patients without known SMNs in TCCSG ALL L04-16 cohort study, 73 of 437 (16.7%) possessed NUDT15 non-functional alleles. Three of them had bi-allelic variants (2 cases were *3/*3, 1 case was *2/*3), and the others were all heterozygous. The prevalence of NUDT15 non-functional alleles was significantly higher in SMNs compared to that of non-SMN cases (P = 0.012). Conclusion: Our study indicated the NUDT15 hypomorphic variant alleles could be a risk of SMNs after ALL treatment with 6-MP. NUDT15 heterozygotic variants carriers are generally tolerable of 6-MP, and are usually treated with normal or slightly low-dose of 6-MP. However, our results suggested that standard adjustment of 6-MP in maintenance therapy might cause potential overdose of 6-MP for cases with NUDT15 variants, leading to increased risk of SMNs. To certify it, a higher number of study samples and somatic samples analysis of 6-MP induced SMNs are required. To obtain the best long-term event-free survival probability, it might be necessary to reduce the risk of SMNs development without compromising therapeutic effect by further optimal adjustment of 6-MP dose (or alternative agents). Disclosures No relevant conflicts of interest to declare.

scholarly journals Dissecting the Outcome Difference Between Children and Adolescents and Young Adults (AYAs) with Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1601-1601
Author(s):  
Julie A. Wolfson ◽  
Joshua Richman ◽  
Canlan Sun ◽  
Wendy Landier ◽  
Karen Leung ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Lymphoblastic Leukemia ◽  
Comprehensive Cancer Center ◽  
Late Relapse ◽  
Duration Of Treatment ◽  
Early Relapse ◽  
Relapse Risk ◽  
Race Ethnicity ◽  
Time Varying Covariates ◽  
Risk Of Relapse

Abstract BACKGROUND: AYAs (15-39y) with ALL have poor survival compared to children (1-14y). Placement on pediatric vs. adult clinical trials has been implicated in these differences, but a more comprehensive approach (sociodemographics, clinical prognostic factors, treatment provider/ intensity) is lacking and needs to be examined in the real world environment. We address this gap by evaluating factors contributing to the inferior outcome in AYA at a granular level. METHODS: The study included242 patients diagnosed with ALL between 1990 and 2010 at age 1-39y and treated at a comprehensive cancer center (irrespective of enrollment on clinical trial). Medical record abstraction yielded the following: Sociodemographics: payor, race/ethnicity, socioeconomic status (SES); Clinical Prognosticators: WBC at diagnosis (<100k vs. ≥100k), time between diagnosis and first clinical remission (1st CR: <5% blasts in marrow); wide temporal span precluded use of contemporary prognosticators across entire cohort; Treatment Approach: combinations of pediatric/adult oncologist and pediatric/adult therapeutic protocol (pediatric MD + pediatric protocol vs. adult MD + adult protocol vs. other); duration of treatment phases (induction, post-induction, maintenance); gaps between phases (>15d); early cessation of therapy. Using Cox regression analyses, time to relapse was evaluated from achievement of 1st CR, and censored at relapse, death, and hematopoietic cell transplantation in 1st CR or date of last contact. Five patients did not enter remission and were excluded from the analysis. We analyzed patients for two patterns of relapse: [1] Early Relapse: From 1st CR (n=237) through planned completion of therapy, with phases of therapy as time-varying covariates; [2] Late Relapse: Patients who completed treatment (n=121) were evaluated from date of last treatment until event/ follow-up. RESULTS: Clinical and demographic characteristics were similar between AYAs (n=142) and children (n=95) [non-white race/ethnicity: 67% vs. 66%, p=0.9; public insurance: 39% vs. 34%, p=0.4; WBC>100K 27% vs. 20%, p=0.2; median time to remission: 31d vs. 31d, p=0.91). However, AYAs received fewer months of maintenance therapy than children (median=14.9m vs 24.8m, p<0.001). AYAs experienced poorer relapse-free survival (5y RFS: 46%, 95%CI 38-55%) vs. children (72%, 95%CI 63-80%; p<0.001) (Figure) Early Relapse: Compared with children, AYAs had a 6-fold higher risk of relapse (HR=6.0, 95%CI 3.2-11.3, p<0.001). In a multivariable model (adjusting for gender, race/ ethnicity, payor, WBC, time to 1st CR, gaps in treatment, early cessation of therapy and physician/ therapy), the risk of relapse was partially mitigated, (HR=3.8, 95%CI 1.6-9.4, p=0.003). Other variables independently associated with relapse included months to 1st CR (HR=2.1, 95%CI 1.4-3.0, p<0.001); treatment gap (HR=5.8, 95%CI 2.4-14.3, p<0.001); early cessation of therapy (HR=3.6, 95%CI 1.2-11.4, p=0.03); and high WBC (HR=2.0, 95%CI 1.2-3.5, p=0.01). Late Relapse: In patients who completed therapy (n=121), multivariable analysis revealed a higher risk of relapse (HR=2.9, 95%CI 0.9-9.1, p=0.07) for AYAs, adjusting for gender, race/ ethnicity, payor, SES, duration of treatment phases, high WBC, time to achieve remission and physician/ therapy. The only other variable associated with relapse risk was duration of maintenance in months; longer duration of maintenance was protective (HR=0.9, 95%CI 0.8-0.95, p<0.001). CONCLUSIONS: Several factors explain, in part, the poor early outcome among AYAs, including longer time to remission, longer gaps between phases and early cessation of therapy. Among those who complete all phases of therapy, AYAs continue to have inferior outcomes, but the magnitude of difference is reduced, and duration of maintenance therapy remains the critical independent predictor of relapse risk. These findings highlight the need to elucidate the remaining factors that could explain the difference in outcome between AYAs and children, such as host and disease biology, and adherence to prescribed therapy; these are currently under investigation. Disclosures No relevant conflicts of interest to declare.

scholarly journals Variants in ARID5B Gene Are Associated with the Development of Acute Lymphoblastic Leukemia in Mexican Children

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1556-1556
Author(s):  
Adriana Reyes-León ◽  
Diana Fernández-García ◽  
Maribel Ramírez-Martínez ◽  
David Amaro-Muñoz ◽  
José Antonio Velázquez-Aragón ◽  
...  
Keyword(s):  
Native American ◽  
Acute Lymphoblastic Leukemia ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
European Ancestry ◽  
Taqman Assay ◽  
Childhood All ◽  
Risk Alleles ◽  
Mexican Children ◽  
Increased Risk

Abstract Introduction: Acute lymphoblastic leukemia (ALL) is the most common subtype of leukemia diagnosed in children under 18 years. According to the statistics of the Popular Medical Insurance Program in Mexico, the ALL incidence is 79.8 cases per million per year, and it is significantly increasing. Recently, several SNPs of ARID5B gene have been associated with ALL susceptibility and are more strongly related with ALL risk in Hispanics. However, these observations are not necessarily representative of the situation in Mexico, since the proportion of Mexican patients included in these studies is unknown. It is essential for us to know if the genetic variants of ARID5B confer susceptibility to the development of the disease in our population and if these variants contribute to the higher incidence of childhood ALL in Mexico. Aim: The purpose of this study was to determine the association between the SNPs rs10821936, rs10994982, rs7089424, rs2393732, rs2393782, rs2893881, and rs4948488 of ARID5B gene with the susceptibility to develop ALL in Mexican children. Methods: The study included 384 controls and 298 children with ALL recruited at Instituto Nacional de Pediatria in Mexico city and Hospital de Especialidades Pediatricas de Tuxtla Gutierrez, Chiapas, Mexico. This study was reviewed and approved by the Institutional Research and Ethics Committees from both participant Institutions in accordance to the ethical principles of the Declaration of Helsinki. Volunteers, parents, or legal tutors of patients were previously informed about the study, and before the biological samples were collected, they provided a signed, written informed consent letter to participate. Genomic DNA was extracted from peripheral blood and saliva samples. Genotyping analysis was performed by real-time polymerase chain reaction (RT-PCR) using a pre-designed TaqMan assay for 7 SNPs (rs10821936, rs10994982, rs7089424, rs2393732, rs2393782, rs2893881, and rs4948488) of ARID5B. Genotypic and allelic frequencies were calculated to compare the differences between controls and patients (Fisher's exact test). The odds ratio (OR) was calculated to determine the association between SNPs and ALL susceptibility. Ancestry analysis was conducted for controls and patients (STRUCTURE program), and Haplotype analysis (Haploview program). Results: The estimated proportion of Native American and European ancestry was not statistically different between controls and patients; all SNPs in ARID5B were in Hardy-Weinberg equilibrium. The frequency of the risk alleles was higher in patients than in controls, but only 3 SNPs showed statistically significant differences (p<0.05). The SNPs rs10821936, rs10994982, and rs7089424 were associated with ALL and pre-B ALL susceptibility, and rs2393732 was specifically associated with pre-B ALL. No association betwwen SNPs of ARID5B gene and T-ALL was found. The CAG haplotype (rs10821936, rs10994982, and rs7089424) was strongly associated with ALL risk in our population. The SNPs rs10821936, rs10994982, rs7089424, and rs2393732 were significantly associated with an increased risk for developing childhood ALL, specifically pre-B ALL. Conslusions: The frequency of the risk alleles was higher than in Hispanic children with ALL. Each SNP of ARID5B confers an individual effect on the risk for developing the disease, and the CAG haplotype was strongly associated with ALL susceptibility. The genetic background of our population could be positively influencing the susceptibility to ALL development, specifically pre-B ALL. The SNPs rs10821936, rs10994982, rs7089424 and rs2393732 of ARID5B gene are significantly associated with an increased risk to develop childhood ALL and this could also explain in part the high incidence of childhood ALL in Mexico. Acknowledgments: This work was supported by the grants from Fondos del Presupuesto Federal para la Investigación (project 085/2012), Consejo Nacional de Ciencia y Tecnologia (CONACyT) - Desarrollo Cientifico para Atender Problemas Nacionales (project 216163), and in part by the Intramural Program of the National Cancer Institute. Conflict-of-interest disclosure: The authors state that there are no conflicts of interest. Disclosures No relevant conflicts of interest to declare.

scholarly journals Mercaptopurine Ingestion Habits, Red Cell Thioguanine Nucleotide Levels, and Relapse Risk in Children With Acute Lymphoblastic Leukemia: A Report From the Children’s Oncology Group Study AALL03N1

2017 ◽  
Vol 35 (15) ◽  
pp. 1730-1736 ◽  
Author(s):  
Wendy Landier ◽  
Lindsey Hageman ◽  
Yanjun Chen ◽  
Nancy Kornegay ◽  
William E. Evans ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Dairy Products ◽  
Lymphoblastic Leukemia ◽  
Adherence Rate ◽  
Red Cell ◽  
Wild Type ◽  
Event Monitoring ◽  
Childhood All ◽  
Relapse Risk ◽  
Thioguanine Nucleotide

Purpose Children with acute lymphoblastic leukemia (ALL) are generally instructed to take mercaptopurine (6-MP) in the evening and without food or dairy products. This study examines the association between 6-MP ingestion habits and 6-MP adherence, red cell thioguanine nucleotide (TGN) levels, and risk of relapse in children with TMPT wild-type genotype. Methods Participants included 441 children with ALL receiving oral 6-MP for maintenance. Adherence was monitored over 48,086 patient-days using the Medication Event Monitoring System; nonadherence was defined as adherence rate < 95%. 6-MP ingestion habits examined included: takes 6-MP with versus never with food, takes 6-MP with versus never with dairy, and takes 6-MP in the evening versus morning versus varying times. Results Median age at study was 6 years (range, 2 to 20 years); 43.8% were nonadherent. Certain 6-MP ingestion habits were associated with nonadherence (taking 6-MP with dairy [odds ratio (OR), 1.9; 95% CI, 1.3 to 2.9; P = .003] and at varying times [OR, 3.4; 95% CI, 1.8 to 6.3; P = .0001]). After adjusting for adherence and other prognosticators, there was no association between 6-MP ingestion habits and relapse risk (6-MP with food: hazard ratio [HR], 0.7; 95% CI, 0.3 to 1.9; P = .5; with dairy: HR, 0.3; 95% CI, 0.07 to 1.5; P = .2; taken in evening/night: HR, 1.1; 95% CI, 0.2 to 7.8; P = .9; at varying times: HR, 0.3; 95% CI, 0.04 to 2.7; P = .3). Among adherent patients, there was no association between red cell TGN levels and taking 6-MP with food versus without (206.1 ± 107.1 v 220.6 ± 121.6; P = .5), with dairy versus without (220.1 ± 87.8 v 216.3 ± 121.3; P =.7), or in the evening/night versus morning/midday versus varying times (218.8 ± 119.7 v 195.5 ± 82.3 v 174.8 ± 93.4; P = .6). Conclusion Commonly practiced restrictions surrounding 6-MP ingestion might not influence outcome but may hinder adherence. Future recommendations regarding 6-MP intake during maintenance therapy for childhood ALL should aim to simplify administration.

scholarly journals Methotrexate/6-mercaptopurine maintenance therapy influences the risk of a second malignant neoplasm after childhood acute lymphoblastic leukemia: results from the NOPHO ALL-92 study

Blood ◽  
2009 ◽  
Vol 113 (24) ◽  
pp. 6077-6084 ◽  
Author(s):  
Kjeld Schmiegelow ◽  
Ibrahim Al-Modhwahi ◽  
Mette Klarskov Andersen ◽  
Mikael Behrendtz ◽  
Erik Forestier ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Maintenance Therapy ◽  
Lymphoblastic Leukemia ◽  
Cumulative Risk ◽  
Malignant Neoplasm ◽  
Tpmt Activity ◽  
Second Malignant Neoplasm ◽  
Childhood All ◽  
Monosomy 7 ◽  
Increased Risk

Abstract Among 1614 children with acute lymphoblastic leukemia (ALL) treated with the Nordic Society for Paediatric Haematology and Oncology (NOPHO) ALL-92 protocol, 20 patients developed a second malignant neoplasm (SMN) with a cumulative risk of 1.6% at 12 years from the diagnosis of ALL. Nine of the 16 acute myeloid leukemias or myelodysplastic syndromes had monosomy 7 (n = 7) or 7q deletions (n = 2). In Cox multivariate analysis, longer duration of oral 6-mercaptopurine (6MP)/methotrexate (MTX) maintenance therapy (P = .02; longest for standard-risk patients) and presence of high hyperdiploidy (P = .07) were related to increased risk of SMN. Thiopurine methyltransferase (TPMT) methylates 6MP and its metabolites, and thus reduces cellular levels of cytotoxic 6-thioguanine nucleotides. Of 524 patients who had erythrocyte TPMT activity measured, the median TPMT activity in 9 patients developing an SMN was significantly lower than in the 515 that did not develop an SMN (median, 12.1 vs 18.1 IU/mL; P = .02). Among 427 TPMT wild-type patients for whom the 6MP dose was registered, those who developed SMN received higher average 6MP doses than the remaining patients (69.7 vs 60.4 mg/m2; P = .03). This study indicates that the duration and intensity of 6MP/MTX maintenance therapy of childhood ALL may influence the risk of SMNs in childhood ALL.

Mercaptopurine Tolerance In Early Treatment and Correlation With Dose Modifications In Maintenance Therapy For Pediatric ALL Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3872-3872
Author(s):  
Elizabeth D. Alva ◽  
Matthew A. Kutny
Keyword(s):  
Maintenance Therapy ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Oral Chemotherapy ◽  
Tpmt Activity ◽  
Close Monitoring ◽  
Myelosuppressive Chemotherapy ◽  
Increased Risk ◽  
Mean Time ◽  
Standard Risk

Abstract Multiple studies have demonstrated the importance of oral chemotherapy dosing to outcome in the treatment of pediatric acute lymphoblastic leukemia. Dosing of oral mercaptopurine is adjusted by clinical tolerance using dose escalations or reductions depending on the patient’s neutrophil and platelet counts. Current regimens use guidelines to attempt to maximize anti-leukemic effect but minimize risk of infection or bleeding from extreme cytopenias. A recent approach to help predict patient tolerance involves testing of drug metabolites or TPMT activity phenotype or genotype, but these tests remain a send-out test for most centers and have not been universally adopted as standard of care. As a potential additional clinical tool, we sought to determine whether tolerance of mercaptopurine during an early consolidation course could help predict tolerance of mercaptopurine during maintenance. We performed a retrospective chart review of all standard risk ALL patients treated at our center in the last 10 years. Patients qualified for the study if they received standard consolidation using treatment regimens based on Children’s Oncology Group (COG) studies AALL0331 or AALL0932 which include mercaptopurine for 28 days without other myelosuppressive chemotherapy (only other chemotherapy includes a single vincristine dose on day 1 and intrathecal treatments on days 1, 8, and 15). Patients receiving consolidation including other myelosuppressive chemotherapy (such as arm LRAsp-IV on AALL0331 which included PEG-asparaginase in consolidation or arm IS-IV on AALL0331 with intensified consolidation for slow early responder patients) were excluded from the study. We hypothesized that patients who had delay in the start of their interim maintenance course following standard consolidation due to cytopenias demonstrate a clinical sensitivity to mercaptopurine that could result in increased risk of interruptions in oral chemotherapy early in maintenance therapy. Thus we correlated delays in start of interim maintenance with interruptions in dosing of mercaptopurine due to cytopenias during the first 2 cycles of maintenance. Data was analyzed using JMP® Statistical Discovery software. A total of 55 patients met our eligibility requirements (standard risk ALL, treated with standard consolidation per the regimens noted above, and completed at least 2 cycles of maintenance chemotherapy). Of these 55 patients, 11% (N=6) had a delay in the start of their interim maintenance course due to cytopenias following standard consolidation. The average duration of this delay was 12.5 days with a range of 7-21 days. Among the 6 patients who had delayed interim maintenance, 5 (83%) had mercaptopurine held during the first 2 cycles because of cytopenias. This was higher than the 61% (30 out of 49) of patients requiring dose interruptions for cytopenias in maintenance among those patients who started interim maintenance without delay. (P=0.28) The interval from start of maintenance until time of first dose interruption and number of interruptions in the first two cycles of maintenance therapy were also examined. Patients who had delays in start of interim maintenance had a mean time to first dose interruption of 51 days which was not different than the mean time of 55 days to first interruption in all other patients. (P=0.76) Both groups had a median of 43 days to time of first interruption. The number of dose interruptions ranged from 0-3. There was not a difference in the number of dose interruptions among patients who did and did not have a delay in interim maintenance. (P=0.28) Our analysis demonstrated that 65% of all patients in our cohort required dose interruptions of mercaptopurine in the first 2 cycles of maintenance therapy, suggesting this is a very common complication. A higher proportion of patients with delays in starting interim maintenance experienced such interruptions compared to those without delays. Although this was not statistically significant it should be evaluated in larger cooperative group studies. Our data does suggest that the time period between day 29 and day 57 of maintenance therapy is a high risk period for cytopenias. This data supports close monitoring of counts early in maintenance (every 2 weeks rather than every 4 weeks with vincristine visits) to minimize risks of infection or bleeding associated with prolonged cytopenias. Disclosures: No relevant conflicts of interest to declare.

Tobacco Use Is Associated with More Severe Adverse Outcomes Than Morbid Obesity after Aseptic Revision TKA

2021 ◽  
Author(s):  
Michael P. Hagerty ◽  
Rafael Walker-Santiago ◽  
Jason D. Tegethoff ◽  
Benjamin M. Stronach ◽  
James A. Keeney
Keyword(s):  
Risk Factors ◽  
Morbid Obesity ◽  
Tobacco Use ◽  
Adverse Outcomes ◽  
Smoking History ◽  
Morbidly Obese ◽  
Knee Amputation ◽  
Increased Risk ◽  
Aseptic Revision ◽  
Component Revision

AbstractThe association of morbid obesity with increased revision total knee arthroplasty (rTKA) complications is potentially confounded by concurrent risk factors. This study was performed to evaluate whether morbid obesity was more strongly associated with adverse aseptic rTKA outcomes than diabetes or tobacco use history—when present as a solitary major risk factor. Demographic characteristics, surgical indications, and adverse outcomes (reoperation, revision, infection, and amputation) were compared between 270 index aseptic rTKA performed for patients with morbid obesity (n = 73), diabetes (n = 72), or tobacco use (n = 125) and 239 “healthy” controls without these risk factors at a mean 75.7 (range: 24–111) months. There was no difference in 2-year reoperation rate (17.8 vs. 17.6%, p = 1.0) or component revision rate (8.2 vs. 8.4%) between morbidly obese and healthy patients. However, higher reoperation rates were noted in patients with diabetes (p = 0.02) and tobacco use history (p < 0.01), including higher infection (p < 0.05) and above knee amputation (p < 0.01) rates in patients with tobacco use history. Multivariate analysis retained an independent association between smoking history and amputation risk (odds ratio: 7.4, 95% confidence interval: 1.7–55.2, p < 0.01). Morbid obesity was not associated with an increased risk of reoperation or component revision compared with healthy patients undergoing aseptic revision. Tobacco use was associated with increased reoperation and above knee amputation. Additional study will be beneficial to determine whether risk reduction efforts are effective in mitigating postoperative complication risks.

scholarly journals Nutritional status and physical activity of childhood leukemia survivors

2014 ◽  
Vol 54 (2) ◽  
pp. 67
Author(s):  
Conny Tanjung ◽  
Johannes Bondan Lukito ◽  
Prima Dyarti Meylani
Keyword(s):  
Physical Activity ◽  
Nutritional Status ◽  
Childhood Leukemia ◽  
Lymphoblastic Leukemia ◽  
Induction Phase ◽  
Childhood All ◽  
Increased Risk ◽  
Long Term Survivors ◽  
First Time

Background Acute lymphoblastic leukemia (ALL), the mostcommon malignancy of childhood, has an overall cure rate ofapproximately 80%. Long-term survivors of childhood ALL areat increased risk for obesity and physical inactivity that may leadto the development of diabetes, dyslipidemia, metabolic syndrome,as well as cardiovascular dis eases, and related mortality in theyears following treatment.Objective To evaluate the physical activity and the propensityfor developing obesity longer term in ALL survivors.Methods This retrospective cohort study included all ALLsurvivors from Pantai Indah Kapuk (PIK) Hospital. We assessedtheir physical activity and nutritional status at the first time ofALL diagnosis an d at the time of interview.Results Subjects were 15 ALL survivors aged 7 to 24 years. Themedian fo llow up time was 6.4 years (range 3 to 10 years). Only2 out of 15 survivors were overweight and n one were obese.All survivors led a sedentary lifestyle. Most female subjectshad increased BMI, though most were not overweight/obese.Steroid therapy in the induction phase did not increase the riskof developing obesity in ALL survivors.Conclusion Lon g-term survivors of childh ood ALL do not meetphysical activity recommendations according to the CDC (Centersfor Disease Control). Howevei; steroid therapy do not seem tolead to overweight/obesity in ALL survivors.

scholarly journals Ripk3 Signaling Regulates Hematopoietic Stem Cell Number and Function during Stress

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3714-3714
Author(s):  
Lei Zhang ◽  
Huacheng Luo ◽  
Jing Li ◽  
Hong-Min Ni ◽  
Mark Sellin ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Low Dose ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
High Dose ◽  
Low Doses ◽  
Hematopoietic Stem ◽  
Increased Risk ◽  
Leukemia Development ◽  
Serial Transplantation

Background: Among all tissues, bone marrow (BM) is the most sensitive tissue to ionizing radiation (IR)-induced acute tissue damage (ATD) and chronic long-term residual damage (LT-RD). BM failure and a significant reduction in blood cells (pancytopenia) often occurs within days after exposure to IR due to the massive death of proliferative hematopoietic progenitor cells (HPCs). However, due to their quiescent cell cycle status and reduced fidelity of DNA repair feature, many hematopoietic stem cells (HSCs) cannot fully eliminate such damage and enter senescence; this results in LT-RD. Abnormal dysplastic hematopoiesis is the most common LT-RD in most victims of IR, followed by an increased risk of leukemia/lymphoma development. Thus IR exposure is an established cause of BM failure and leukemia. A significant increase in the production of inflammatory cytokines is induced by IR which contributes to the pathogenesis of both ATD and LT-RD. Such inflammatory cytokines induce the activation of Ripk3-Mlkl-mediated necroptotic signaling in HSCs. However, the role of Ripk3-Mlkl signaling in IR-induced damage has not studied. Experimental procedures: The self-renewal capacity of HSCs among Ripk3-/-, Mlkl-/- and WT mice were examined and compared by serial transplantation assay. The phenotypes of ATD and LT-RD induced by different dosages of IR were compared among Ripk3-/-, Mlkl-/- and WT mice. The mechanism by which Ripk3 signaling prevents IR-induced leukemia development was studied. Results: Ripk3-Mlkl signaling is not required for hematopoiesis during homeostatic condition. However, during serial transplantation, inactivation of such signaling prevents stress-induced loss of HSCs. Interestingly, Ripk3 signaling also induces an Mlkl-independent ROS-p38-p16-mediated senescence in HSCs. Thus Ripk3-/- HSCs showed better competitive hematopoietic ability compared to Mlkl-/- and WT HSCs during serial transplantation. A sub-lethal dosage of IR (6Gy) induces Ripk3-dependent NF-κB activation and pro-survival gene expression in HSCs, which is necessary for the survival of damaged HSCs. After 6Gy IR, although DNA damage is repaired in most HSCs within 2 days, a proportion of HSCs in WT and Mlkl-/- mice fail to fully repair the damage and undergo p53-p21-dependent senescence. However such cells in Ripk3-/- mice die from apoptosis. Thus the remaining HSCs in Ripk3-/- mice should be functionally normal, while a proportion of the remaining HSCs in Mlkl-/- and WT mice remain damaged but senescent, all as demonstrated by competitive hematopoietic reconstitution assay. Multiple low-doses of IR (1.75Gy once week × 4) induce HSC exhaustion in WT mice but not in Ripk3-/- and Mlkl-/- mice. Interestingly, almost all Ripk3-/- mice develop acute lymphoblastic leukemia within 200 days after such low dose IR, while 45% of WT and 60% of Mlkl-/- mice develop thymomas within 360 days (see Figure). Mechanistically, such low-dose IR stimulates chronic inflammatory cytokine production. Such cytokines induce Ripk3-Mlkl-mediated necroptosis in response to HSC exhaustion observed in WT mice. These cytokines also induce Ripk3-ROS-p38-p16-mediated senescence in response to impaired HSC functioning observed in both WT and Mlkl-/- mice. In Ripk3-/- mice, due to the lack of both necroptotic and senescent signaling, mutant HSCs accumulate and leukemia development is accelerated. Conclusion: Ripk3 signaling plays distinct roles in HSCs in response to different doses of IR. High-dose IR induces Ripk3-dependent NF-κB/survival signaling, which is required for the survival of HSCs which fail to repair the damage. Thus temporal inhibition of Ripk3-NF-κB signaling might help to remove the damaged HSCs thus preventing the occurrence of LT-RD. However multiple low-doses of IR induces Ripk3 activation in HSCs which represses leukemia development by inducing both ROS-p38-p16-mediated senescence and Ripk3-Mlkl-mediated necroptosis. Induced activation of Mlkl-necroptosis might help to repress leukemia development by removing damaged HSCs. Disclosures No relevant conflicts of interest to declare.

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