Maintenance Therapy For Acute Lymphoblastic Leukemia Research Articles

Methotrexate polyglutamate levels and co-distributions in childhood acute lymphoblastic leukemia maintenance therapy

Methotrexate polyglutamates (MTXpg) facilitate incorporation of thioguanine nucleotides into DNA (DNA-TG, the primary cytotoxic thiopurine metabolite and outcome determinant in MTX/6-mercaptopurine treatment of childhood ALL). We hypothesized that mapping erythrocyte levels of MTXpg with 1-6 glutamates and their associations with DNA-TG formation would facilitate future guidelines for maintenance therapy dosing. Summed MTX with 1-6 glutamates resolved by LCMS [median (interquartile): 5.47 (3.58-7.69) nmol/mmol hemoglobin] was in agreement with total MTX by radio ligand assay. In 16,389 blood samples from 1426 ALL maintenance therapy patients, MTXpg3 21.0 (15.2-27.4)% was the predominant metabolite, and MTXpg1 (the maternal drug) constituted 38.6 (27.2-50.2)% of MTXpg1-6. All subsets correlated; the strongest associations were between metabolites with similar polyglutamate lengths. Correlations of MTXpg1 with MTXpg2 and MTXpg3,4,5,6 were rs = 0.68 and rs = 0.25-0.42, respectively. Intercorrelations of MTXpg3,4,5,6 were all rs ≥ 0.51. MTXpg4 accounted for 29.8 (24.7-33.3)% of MTXpg3-6, yet explained 96% of the summed MTXpg3-6 variation. MTXpg1-4, MTXpg1-6, MTXpg2-6 and MTXpg3 were all associated with DNA-TG levels (p < 0.00001), but collinearity precluded identification of the most informative subset. Measuring erythrocyte MTXpg4 simplifies and can replace longer chain MTXpg monitoring. Resolving individual MTXpg identifies samples that are unsuitable for dose guidance due to high levels of MTXpg1 remaining in the plasma fraction because of recent MTX intake. All tested MTXpg subsets correlated with DNA-TG and may be used for ALL maintenance therapy dose adjustments, but the most informative subset remains to be identified.

Type 2 Diabetes Mellitus, the Metabolic Syndrome, and Its Components in Adult Survivors of Acute Lymphoblastic Leukemia and Hematopoietic Stem Cell Transplantations.

A growing number of pediatric acute lymphoblastic leukemia (ALL) and hematopoietic stem cell transplantation (HSCT) survivors reach adulthood and face long-term health-related problems. We review risk factors and the prevalence of the metabolic syndrome (MetS), a cluster of obesity-related comorbidities, including abdominal obesity, atherogenic dyslipidemia, elevated blood pressure, impaired glucose metabolism, and type 2 diabetes in ALL and HSCT survivors. Components of the MetS are already detected during the first year of ALL maintenance therapy and significantly worsen over time. The prevalence of MetS increases at a faster rate in this setting than in the general population. Factors found to be of the greatest potential risk to the development of the MetS are central obesity, increased BMI, irradiation therapy, older age, poor diet, and low level of physical activity. The early onset of MetS and its components among ALL and HSCT survivors calls for early and continuous screening to identify those at risk and to implement preventive measures.

Early Nutrition Intervention Attenuates Weight Gain for Pediatric Acute Lymphoblastic Leukemia Patients in Maintenance Therapy.

Obesity following treatment of pediatric acute lymphoblastic leukemia (ALL) has become a significant long-term concern. Excessive weight gain often occurs during treatment, particularly during induction and the first 6 months of maintenance therapy, and it may be potentially modifiable. This retrospective study aimed to evaluate the impact of an early, 3-visit nutrition intervention on weight gain during maintenance therapy in ALL patients. Medical records of the intervention group were compared with historical controls who were treated on the same ALL treatment protocols during an earlier time period. Anthropometrics were collected throughout intensive therapy and at every monthly visit during the first 12 months of maintenance therapy. In total, 67 patients were evaluated (33 in the intervention group and 34 in the control group). After controlling for significant predictors of body mass index (BMI) z-scores in maintenance therapy-including higher BMI at diagnosis and weight gain throughout intensive therapy-the intervention group demonstrated more controlled weight gain during maintenance therapy (P<0.0001). A 3-visit nutrition intervention was effective in attenuating weight gain trends during ALL maintenance therapy.

Role of TPMT and ITPA variants in mercaptopurine disposition.

To explore the levels of thioguanine incorporated into DNA (DNA-TG), and erythrocyte levels of 6-thioguanine nucleotides (Ery-TGN) and methylated metabolites (Ery-MeMP) during 6-mercaptopurine (6MP)/Methotrexate (MTX) therapy of childhood acute lymphoblastic leukemia (ALL) and the relation to inosine triphosphatase (ITPA) and thiopurine methyltransferase (TPMT) gene variants. Blood samples were drawn during 6MP/MTX maintenance therapy from 132 children treated for ALL at Rigshospitalet, Copenhagen. The samples were analysed for thiopurine metabolites and compared to TPMT (rs1800460 and rs1142345) and ITPA (rs1127354) genotypes. Median DNA-TG (mDNA-TG) levels were higher in TPMT and ITPA low-activity patients as compared to wildtype patients (TPMTLA 549 vs. 364 fmol/µg DNA, p = 0.007, ITPALA 465 vs. 387 fmol/µg DNA, p = 0.04). mDNA-TG levels were positively correlated to median Ery-TGN (mEry-TGN)(rs = 0.37, p = 0.001), but plateaued at higher mEry-TGN levels. DNA-TG indices (mDNA-TG/mEry-TGN) were 42% higher in TPMTWT patients as compared to TPMTLA patients but no difference in DNA-TG indices was observed between ITPAWT and ITPALA patients (median 1.7 vs. 1.6 fmol/µg DNA/ nmol/mmol Hb, p = 0.81). DNA-TG indices increased with median Ery-MeMP (mEry-MeMP) levels (rs = 0.25, p = 0.001). TPMT and ITPA genotypes significantly influence the metabolism of 6MP. DNA-TG may prove to be a more relevant pharmacokinetic parameter for monitoring 6MP treatment intensity than cytosolic metabolites. Prospective trials are needed to evaluate the usefulness of DNA-TGN for individual dose adjustments in childhood ALL maintenance therapy.

Dihydrofolate Reductase Genetic Polymorphisms Affect Methotrexate Dose Requirements in Pediatric Patients with Acute Lymphoblastic Leukemia on Maintenance Therapy

Methotrexate (MTX) is the cornerstone of childhood acute lymphoblastic leukemia (ALL) protocols. Its main target is dihydrofolate reductase (DHFR), whose increased expression has been associated with MTX-resistant phenotypes. We have aimed to determine the effect of polymorphisms in regulatory regions of the DHFR gene in relation to MTX dose adjustments and drug-induced toxicity in children on maintenance therapy for ALL. Forty-one children diagnosed with ALL and treated with SHOP/ALL protocols were screened for three tag-SNPs in the DHFR promoter (C-1610G, C-680G/T, A-317G) and an intronic 19-bp insertion/deletion. Genotypes were analyzed in relation to dose requirements and toxicity. The percentage of MTX dose administered (with respect to protocol-recommended values) was affected by DHFR polymorphisms. Carriers of the -680AA genotype displayed a median (IQ range) percentage of 44.08 (34.69)% compared to 77.98 (33.90)% for CC and CA carriers (p=0.01). Statistical trends (p=0.06) were also found for the 19bp ins/del and A-317G SNPs. The number of blood tests with white blood cell count (WBC) < 3 109/L was also significantly higher for -680AA carriers than for CC/CA carriers (p<0.005]. With regard to toxicity, carriers of the -680AA genotype displayed a higher number of treatment interruptions than CC/CG carriers did (p=0.03), as well as more episodes of severe (grade 3-4) neutropenia (p<0.05) and a higher frequency of elevated LDH levels (>400 mg/dL). Overall, our findings suggest that the identification of DHFR polymorphisms in the promoter region of the gene may be helpful in tailoring MTX doses for ALL pediatric patients on maintenance therapy.

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.

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.

Prognostic impact of IKZF1 deletions in association with vincristine-dexamethasone pulses during maintenance treatment of childhood acute lymphoblastic leukemia on trial AIEOP-BFM ALL 95

Background: Previous studies suggested that patients with IKZF1-deleted acute lymphoblastic leukemia (ALL) may benefit from intensification of conventional maintenance therapy by application of vincristine-steroid pulses (Clappier E, Leukemia 2015; 29: 2154 – 2161). Here, we investigated the impact of additional pulses during maintenance therapy for IKZF1-deleted ALL in a large cohort of intermediate risk patients treated according to the AIEOP-BFM ALL 95 protocol.

The impact of dexamethasone and prednisone on sleep in children with acute lymphoblastic leukemia.

Corticosteroids can affect sleep patterns, mood, and behavior. Two of the most commonly prescribed corticosteroids in acute lymphoblastic leukemia (ALL), dexamethasone and prednisone, may impact sleep differently, but no research has compared these medications in children. The current study tested the hypothesis that dexamethasone and prednisone differentially affect sleep in children with ALL to understand how these medications contribute to health-related quality of life (HRQL). Parents of 81 children 3-12years old in maintenance therapy for ALL completed a baseline measure of child sleep (dexamethasone n = 55, prednisone n = 26), and 61 parents returned 28days of child sleep diaries starting the first day of a 5-day steroid course (dexamethasone n = 43, prednisone n = 18). Parents also completed measures of HRQL and fatigue on the last day of steroids and the last day of the month. At baseline, parents reported more sleep disturbances in children taking dexamethasone than prednisone. Across the month, children taking dexamethasone experienced poorer sleep quality compared to children taking prednisone. During corticosteroid treatment, children taking dexamethasone also experienced more night awakenings than children taking prednisone. Sleep variables accounted for almost half of the variance in HRQL during time off steroids and also significantly contributed to fatigue during the corticosteroids course and time off corticosteroids. Sleep is an essential component of HRQL in children taking corticosteroids, and the impact on sleep is more pronounced in children taking dexamethasone compared to prednisone. Screening for sleep disturbances and offering brief interventions to manage steroid-related sleep disruptions may improve HRQL.

Quality of life Evaluation in patients receiving Steroids (the QuESt tool): initial development in children and young people with acute lymphoblastic leukaemia

BackgroundThe powerful cytotoxic and immunomodulatory effects of corticosteroids are an important element of the success that has been achieved in the treatment of acute lymphoblastic leukaemia (ALL). In addition to...

6-Mercaptopurine (6MP) Intake during Maintenance for Childhood Acute Lymphoblastic Leukemia (ALL) - a Comparison of Self-Report and Electronic Monitoring: A Report from the Children's Oncology Group (COG) Study AALL03N1

▪Background: Adequateexposure to oral 6MP during maintenance is critical to sustain durable remissions. We have previously shown that poor systemic exposure to 6MP (as measured by poor adherence to oral 6MP) is associated with increased risk of relapse (JCO 30[17]:2094-101; Blood 124[15]:2345-53). Accurate assessment of 6MP intake is therefore critical to ensure timely interventions. Self-report is a convenient and inexpensive method to monitor 6MP intake in the clinical setting; however, literature in the non-oncology setting indicates that self-report is subject to over-reporting, and the extent of over-reporting is directly related to the number of missed doses. The accuracy of self/parent-report of 6MP intake during ALL maintenance is not known. We address this issue by comparing self-reported 6MP intake to electronic monitoring, and identify predictors of over-reporting of prescribed 6MP intake.Methods: Participants included 416 children with ALL in first remission receiving oral 6MP (75 mg/m2/d) during maintenance. 6MP intake was measured electronically using the Medication Event Management System (MEMS - objective record), which recorded the dates/times of each 6MP bottle opening over 4 study months per patient (28 days/month). The patient (or parent if <12y-old) self-reported the number of days that 6MP had been taken over the past month at the end of each of the 4 study months (subjective record). A total of 1344 patient-months of self-report and MEMS data were evaluated. Objective and subjective records of 6MP intake were compared for each patient by study month, and patients were categorized as "perfect reporters" (self-report = MEMS report), "over-reporters" (self-report > MEMS report: ≥5 days/month for >50% of study months) and "others." Logistic regression examined characteristics (age at study, sex, race/ ethnicity, 6MP non-adherence [MEMs-based adherence rate <95%], TPMT genotype, red cell TGN levels and 6MP dose-intensity) associated with over-reporting.Results: Median age at study entry was 6y (2-20); 36% were non-Hispanic white; 67% were male; 38.4% had high-risk disease; 40.4% were non-adherent to oral 6MP. Subjective vs objective 6MP intake: Mean (±SD) days of 6MP ingestion per month ranged from 25.8±5.3 to 26.1±4.5 by subjective reporting vs 22.8±6.4 to 25.4±4.5 by objective measurement (adjusted mean values by generalized estimating equations analysis, Figure 1A). The correlation between self-report and MEMS by study month ranged from 0.36 to 0.58 (Table). The difference between subjective and objective reporting was 0 for 39.6% patient-months; the difference was <0 for 7.7% patient-months, and was >0 for 52.7% patient-months (Figure 1B). A total of 50 (12%) patients were identified to be perfect reporters, 98 (23.6%) as over-reporters, and 64.4% as others. Predictors of over-reporting: Logistic regression modeling (adjusted for TPMT genotype, 6MP dose intensity and red cell TGN levels) identified the following independent predictors of over-reporting: i) Older age (Odds Ratio [OR]=1.07/y increase in patient age, 95% Confidence Interval [CI]=1.0-1.1, p=0.04); ii) Non-white race: Hispanic, OR=2.4, 95%CI=1.2-5.0, p=0.02); Asian, OR=3.1, 95%CI 1.2-8.3, p=0.02; African-American, OR=5.3, 95%CI 2.2-12.5, p<0.001 iii) Paternal education <college (OR=2.1, 95%CI=1.1-4.1, p=0.02); and iv) 6MP non-adherence (OR=8.6, 95%CI=4.7-15.9, p<0.0001) (Figure 1C). While 77/98 (78.6%) of over-reporters were non-adherent, only 1 of the 50 (2%) of the perfect reporters was non-adherent.Conclusions: Over-reporting of 6MP intake is common during maintenance therapy for childhood ALL. Over-reporting was more likely in patients who were non-adherent, older, of non-white race, and came from households with lower paternal education. Subjective reporting of 6MP ingestion during maintenance therapy for childhood ALL may be unreliable, particularly in non-adherent patients, and should be used with caution.Table6MP ingestion by self-report vs. MEMSStudy monthPatients (N)Self-report (days)(mean, SD)MEMS (days)(mean, SD)Correlationp-value127526.1 (4.5)25.4 (4.5)0.58<0.0433237026.1 (4.3)22.8 (6.4)0.44<0.0001335525.9 (4.9)23.7 (6.3)0.36<0.0001434425.8 (5.3)23.2 (6.7)0.43<0.0001 [Display omitted] [Display omitted] [Display omitted] DisclosuresEvans:Prometheus Labs: Patents & Royalties: Royalties from licensing TPMT genotyping. Relling:Prometheus Labs: Patents & Royalties: Royalties from licensing TPMT genotyping.

Molecular insight into thiopurine resistance: transcriptomic signature in lymphoblastoid cell lines.

BackgroundThere has been considerable progress in the management of acute lymphoblastic leukemia (ALL) but further improvement is needed to increase long-term survival. The thiopurine agent 6-mercaptopurine (6-MP) used for ALL maintenance therapy has a key influence on clinical outcomes and relapse prevention. Genetic inheritance in thiopurine metabolism plays a major role in interindividual clinical response variability to thiopurines; however, most cases of thiopurine resistance remain unexplained.MethodsWe used lymphoblastoid cell lines (LCLs) from healthy donors, selected for their extreme thiopurine susceptibility. Thiopurine metabolism was characterized by the determination of TPMT and HPRT activity. We performed genome-wide expression profiling in resistant and sensitive cell lines with the goal of elucidating the mechanisms of thiopurine resistance.ResultsWe determined a higher TPMT activity (+44%; P = 0.024) in resistant compared to sensitive cell lines, although there was no difference in HPRT activity. We identified a 32-gene transcriptomic signature that predicts thiopurine resistance. This signature includes the GTPBP4 gene coding for a GTP-binding protein that interacts with p53. A comprehensive pathway analysis of the genes differentially expressed between resistant and sensitive cell lines indicated a role for cell cycle and DNA mismatch repair system in thiopurine resistance. It also revealed overexpression of the ATM/p53/p21 pathway, which is activated in response to DNA damage and induces cell cycle arrest in thiopurine resistant LCLs. Furthermore, overexpression of the p53 target gene TNFRSF10D or the negative cell cycle regulator CCNG2 induces cell cycle arrest and may also contribute to thiopurine resistance. ARHGDIA under-expression in resistant cell lines may constitute a novel molecular mechanism contributing to thiopurine resistance based on Rac1 inhibition induced apoptosis and in relation with thiopurine pharmacodynamics.ConclusionOur study provides new insights into the molecular mechanisms underlying thiopurine resistance and suggests a potential research focus for developing tailored medicine.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-015-0150-6) contains supplementary material, which is available to authorized users.

6-MP based maintenance therapy of childhood ALL in Slovenia: a retrospective study from 1970 to 2004

Background: Maintenance therapy with 6-mercaptopurine (6-MP) as its major component has been one of the main reasons for the drastic increase in overall survival of paediatric acute lymphoblastic leukaemia (ALL) patients. In our cohort, consisting of patients receiving maintenance therapy for ALL and encompassing time period of three decades, we evaluated dosage, safety and efficiency of 6-MP in the treatment of childhood ALL according to treatment protocol, age and gender. Methods: Slovenian paediatric ALL patients diagnosed and treated from 1970 to 2004 were identified through the national oncology patients` registry. Of 414 registered paediatric ALL patients, 320 received maintenance therapy for ALL and were included into the final study cohort. Information about age, gender, treatment protocol, 6-MP related toxic events and ALL relapse was extracted from patients` files. Differences in 6-MP dose reduction, 6-MP side effects and relapse according to gender, age and treatment protocol were statistically evaluated. Results: After adjustment for gender and age incidence of 6-MP dose reduction (p&lt;0.001) and bone marrow suppression (p = 0.019) was higher in recent treatment protocols, while relapse was more common in older protocols (p &lt; 0.001). Younger patients had greater risk for sepsis/infection (p = 0.002), while greater age was a risk factor for osteonecrosis (p = 0.001). No statistically significant associations were found according to gender. Conclusions: In the retrospective study, encompassing three decades of maintenance treatment of childhood ALL in Slovenia, recent protocols exhibited greater effectiveness and toxicity than older protocols.

G416(P) Hypoglycaemia secondary to 6-mercaptopurine in leukaemia treatment

Aims To highlight a significant side effect of a chemotherapy drug that is currently poorly recognised in the UK. Hypoglycaemia is a rare but potentially serious side effect of 6-mercaptopurine that forms an integral part of current maintenance chemotherapy for children with acute lymphoblastic leukaemia (ALL). There are now multiple well documented cases in the literature from the USA, Italy and Finland. However in the UK it does not feature in the drug information. This means it is not being discussed with families as a potential side effect to look out for in their children. Methods We reviewed the case notes and results of 3 children who over the past 5 years were receiving maintenance therapy for ALL and developed symptomatic hypoglycaemia. A literature review was performed looking at hypoglycaemia in children on chemotherapy for ALL and possible risk factors and management strategies that have been identified. Results We describe 3 cases of symptomatic hypoglycaemia occurring within aUKoncology shared care department after varying periods of fasting. The children were aged 4 years 8 months, 5 years 2 months and 8 years 4 months. Other causes of hypoglycaemia were excluded. On further investigation other unprovoked episodes were identified in these children and strategies put in place to try and prevent and manage them. The children all required treatment in the form of oral or IV glucose at their initial presentation. The hypoglycaemic episodes ceased once the chemotherapy was completed. Conclusion Symptomatic hypoglycaemia remains a rare but real risk in children receiving maintenance chemotherapy for ALL. Relatively short periods of starvation have been known to cause hypoglycaemia. These children are regularly fasted for procedures such as lumbar punctures and bone marrow aspirates it is essential that the medical and nursing teams are aware of the potential risk. It is also our responsibility to educate families of the signs of hypoglycaemia so they can be aware, particularly in the younger children who appear to be at increased risk.

Tolerability of 6-Mercaptopurine (6MP) in Patients with Thiopurine Methyltransferase (TPMT) Heterozygosity in the Context of Multi-Agent Therapy for Acute Lymphoblastic Leukemia (ALL)

Background: Genetic polymorphisms in the TPMT gene cause inter-individual variability in 6MP metabolism and tolerability. In the context of ALL maintenance therapy (SJCRH Total XII) that was heavily reliant upon 6MP and methotrexate (MTX) and without individualizing 6MP based on TPMT genetics, dose-limiting toxicity due to TPMT defects resulted in interruptions of 6MP and MTX administration, which have been associated with worse ALL outcomes in some studies (McLeod, Br J Haematol 1999; Welch, Cancer Chemother Pharmacol 1996). Overall 6MP dose intensity (i.e. prescribed dose /protocol dose) was 83% (Relling, Blood 1999). Here we characterized the dose intensity (DI) and tolerance of 6MP among patients with different TPMT genotypes in a more contemporary ALL regimen that included multiple agents in addition to 6MP and MTX. Our goal was to determine the tolerability of 6MP in patients with heterozygous vs wild-type TPMT in the context of multi-agent ALL therapy. Method: 388 children with ALL on the SJCRH Total XV protocol were evaluable for this study. TPMT genotype was analyzed at day 5 of remission induction using PCR and exome sequencing. Of the 388 patients, 347 (89%) were classified as wild-type and 41 (11%) carried a low activity allele, including *2, *3A, *3C and 677G>A (Udaka, Genet Test 2005). No homozygous deficient patients were identified. It was generally recommended that patients with TPMT heterozygosity receive a starting 6MP dose of 50-60 mg/m2/d regardless of risk arm. Wild-type patients on the low-risk (LR) arm (n = 202) received daily 6MP at 75 mg/m2, while those on the standard/high-risk (SHR) arm (n = 186) started with 50 mg/m2/d in weeks 1-16, then increased to 75 mg/m2/d until week 120 (girls) or week 146 (boys). No 6MP was given during reinductions I (weeks 7-9) and II (weeks 17-19). The daily dosage, days of treatment, and DI of 6MP were analyzed for each phase of maintenance therapy. 6MP dosages were re-evaluated every 8-16 weeks to maintain a desired degree of leukopenia. Dosage was decreased if patients had myelosuppression (WBC 4000/mm3) and ANC (> 1000/mm3). In addition to the two reinductions, SHR patients received weekly asparaginase during weeks 1-19 and monthly cyclophosphamide/cytarabine until week 68. After week 20, patients received daily 6MP and weekly MTX with addition of monthly vincristine/dexamethasone (VCR/DEX) pulses until week 96, after which only 6MP and MTX were given. Result: The median cumulative DI was 83% (range 14-135%) in wild-type and 68% (range 5-102%) in heterozygotes, similar to that reported for SJCRH Total XII (Relling, Blood 1999). The DI of each phase differed by TPMT genotype (Fig 1). During week 10-16, wild-type patients on the SHR arm had lower median DI (77%, range 12-173%) than those on the LR arm (85%, range 0-110%; P = 6.4 × 10-5) despite the lower protocol dose in the SHR arm, supporting the practice of lowering the protocol 6MP dose during the early intensive weeks of therapy for the SHR arm, and suggesting the higher dose of 75 mg/m2/d is well tolerated even during early intensive therapy for the LR arm. The DI was similar in weeks 20-95 (6MP/MTX plus monthly VCR/DEX pulses) and in weeks 96-146 (6MP/MTX only) after stratifying by genotype and risk arm (Fig 1), suggesting that VCR/DEX pulses do not alter 6MP tolerance. TPMT heterozygotes received lower median daily 6MP doses (61 mg/m2) than wild-type (73 mg/m2; P = 3.2 × 10-7) during maintenance therapy. By using the lowered daily dose in heterozygotes, we prevented dose interruptions: the median percentage of days with no 6MP therapy was similar in heterozygotes and wild-type (12% vs 11% missed, P = 0.5). Conclusion: Using the approach of lowering the 6MP dose from 75 to 50 mg/m2/d during early intensive therapy for SHR patients results in reasonable DI in both groups. The lower tolerated daily dose of 6MP 60 mg/m2 in heterozygotes, compared to 75 mg/m2 in TPMT wild-type patients, supports the recommendation for a lower starting dose of 6MP for TPMT heterozygotes. 6MP DI was similar during phases that did vs did not include VCR/DEX, and similar in this contemporary regimen that includes VCR/DEX pulses compared to older studies without VCR/DEX pulses. *P-value of comparison between TPMT genotypes, and #P-value of comparison between weeks 20-95 and weeks 96-146. Disclosures Evans:St. Jude: In accordance with institutional policy (St. Jude), I and/or my spouse have in the past received a portion of the income St. Jude receives from licensing patent rights related to TPMT polymorphisms as clinical diagnostics. Patents & Royalties. Relling:St. Jude: In accordance with institutional policy (St. Jude), I and/or my spouse have in the past received a portion of the income St. Jude receives from licensing patent rights related to TPMT polymorphisms as clinical diagnostics. Patents & Royalties.

Multidrug resistance protein 4 (MRP4) polymorphisms impact the 6-mercaptopurine dose tolerance during maintenance therapy in Japanese childhood acute lymphoblastic leukemia.

Multidrug resistance protein 4 (MRP4) is involved in the efflux of nucleoside derivatives and has a role in the determination of drug sensitivity. We investigated the relationship between MRP4 genetic polymorphisms and doses of the 6-mercaptopurine (6-MP) and methotrexate. Further, we evaluated the frequency of therapeutic interruption during maintenance therapy in Japanese children with acute lymphoblastic leukemia (ALL). Ninety-four patients received an initial 6-MP dose in the range of 30-50 mg m(-2) in this analysis. Patients with homozygous variant allele in any of MRP4 G2269A, C912A and G559T required high frequency of 6-MP dose reduction compared with non-homozygous individuals. Average 6-MP dose for patients with homozygous variant allele on either MRP4 or inosine triphosphate pyrophosphatase was significantly lower than that for patients with non-homozygous variant allele during maintenance therapy (30.5 versus 40.0 mg m(-2), P=0.024). Therefore, MRP4 genotyping may be useful for personalizing the therapeutic dose of 6-MP during the ALL maintenance therapy in Japanese.

Perception of Indian Parents on Health-related Quality of Life of Children During Maintenance Therapy of Acute Lymphoblastic Leukemia

Advancements in treatment have improved the prognosis of children with acute lymphoblastic leukemia (ALL). Therefore, there is a need to explore health-related quality of life (HRQOL) in depth, specifically in maintenance therapy, where the available data are minimal. This study was conducted to assess the varied items listed in the domains of HRQOL of Children with ALL during maintenance therapy from a parent's perspective. Forty children on the maintenance therapy of ALL, 40 siblings, and 40 healthy children were enrolled, and the HRQOL was assessed by parent proxy reports and child self-reports using PedsQL generic core 4.0 in local language. Parents significantly overrated the HRQOL of ALL patients, their siblings, and healthy children in comparison with child self-report in all domains of health. The HRQOL of children with ALL on maintenance therapy was significantly poorer than siblings and healthy children, but their ability to self-care, household work, attentiveness, and ability to do homework were not affected as per parents' reports. Parents reported that absenteeism because of sickness and hospital visits was more among children with ALL than siblings and healthy children. Children with ALL had emotional problems such as fear, anger, sleeping problems, and worries. In a social health domain, parents reported difficulty in competing among children with ALL. The HRQOL of siblings was as good as healthy children in physical, social, and school health domains as per parents' reports. In our cohort, parents overrated HRQOL in all groups of children. The study identified the various items in each domain of HRQOL that were affected in children with ALL from parents' perspective; this would guide health care professionals to focus on these specific items so as to improve the overall HRQOL of children with ALL.

The circadian schedule for childhood acute lymphoblastic leukemia maintenance therapy does not influence event‐free survival in the NOPHO ALL92 protocol

The event-free survival of childhood acute lymphoblastic leukemia (ALL) has been reported to be superior when oral methotrexate (MTX) and 6-mercaptopurine (6MP) maintenance therapy (MT) is administered in the evening compared to the morning. In the ALL92 MT study we prospectively registered the intake of MTX/6MP. The registration was done when blood samples for erythrocyte MTX/6MP metabolite measurements were collected, and referred to the time of intake in the period since last registration. Nine thousand one hundred ninety-five registrations in total. The administration of MTX/6MP was scored as morning, midday, or evening. Of 532 patients, 296 took their medication consistently in the evening, 129 in the evening 50.0-99.9% of the time, and 101 in the evening <50% of the time, six did not have any registrations. The circadian schedule did not differ significantly by age, sex, MTX/6MP doses, and average absolute neutrophil counts. The circadian schedule groups did differ on risk groups (P = 0.003) with fewer HR patients in the 50-99.9% group, and there was a negative correlation between percentage of time on evening schedule and average WBC (Spearman's rho -0.15; P = 0.0004). Average WBC was not associated with relapse on ALL92. In a Cox multivariate model the circadian schedule of MTX/6MP was not of prognostic significance for the risk of relapse, and the 10-year cumulative relapse risk was below 20% in all groups. An evening schedule may still be recommended based on the previous publications, but in this study morning administration of MTX and 6MP does not seem to impact EFS.

Methylenetetrahydrofolate reductase gene haplotypes affect toxicity during maintenance therapy for childhood acute lymphoblastic leukemia in Japanese patients

The aim of this study was to investigate the influence of daily 6-mercaptopurine (6-MP) and low-dose weekly methotrexate (MTX) combination treatment and methylenetetrahydrofolate reductase (MTHFR) haplotypes on toxicity during maintenance therapy in Japanese childhood acute lymphoblastic leukemia (ALL). We retrospectively analyzed the MTHFR C677T and A1298C polymorphisms and influence of haplotypes on toxicity in 73 patients. Patients with the MTHFR 677TT and 677CT + 1298AC were associated with severe liver toxicity (p = 0.014, odds ratio [OR] = 3.82, 95% confidence interval [CI] = 1.27–11.46) and more rapid onset of liver toxicity (p = 0.010). Patients with MTHFR 677TT and 677CT + 1298AC were associated with lower frequency of 6-MP and MTX dose reduction due to leukopenia (p < 0.05). No difference was observed in average drug doses in the MTHFR genotypes. In conclusion, the MTHFR C677T and A1298C haplotypes might be useful for monitoring adverse effects in childhood ALL maintenance therapy in Japanese patients.

Obesity and insulin resistance in pediatric acute lymphoblastic leukemia worsens during maintenance therapy

Pediatric acute lymphoblastic leukemia (ALL) survivors are at increased risk for the metabolic syndrome (MS). To establish the trajectory of development during active treatment, we followed patients longitudinally over the first year of maintenance therapy. In a prospective cohort of 34 pediatric ALL patients, followed over the first 12 months of ALL maintenance, we evaluated changes in body mass index (BMI), blood pressure, fasting insulin and glucose, lipids, Homeostatic Metabolic Assessment (HOMA), leptin, and adiponectin. Over the study time period, the median BMI z-score increased from 0.29 to 0.66 (P = 0.001), median fasting insulin levels increased from 2.9 to 3.1 µU/ml (P = 0.023), and the proportion of patients with insulin resistance by HOMA (>3.15) increased from 3% to 24% (P = 0.016). Median leptin increased from 2.5 to 3.5 ng/ml (P = 0.001), with levels correlated with BMI z-score. Median adiponectin level decreased from 18.0 to 14.0 µg/ml (P = 0.009), with levels inversely correlated to BMI z-score. No change in median total cholesterol and LDL levels was observed. Median triglycerides decreased (P < 0.001) and there was a trend to increase in HDL (P = 0.058). Blood pressure did not significantly change, although overall prevalence of systolic and diastolic hypertension was high (23.5% and 26.4%, respectively). Following patients over the first year of ALL maintenance therapy demonstrated that components of the MS significantly worsen over time. Preventive interventions limiting increases in BMI and insulin resistance during maintenance therapy should be targeted during this time period to avoid long-term morbidity associated with the MS in long-term survivors.

Comparison of health-related quality of life of children during maintenance therapy with acute lymphoblastic leukemia versus siblings and healthy children in India

Data on quality of life (QOL) specifically in maintenance therapy of acute lymphoblastic leukemia (ALL) are minimal. This study was done to assess various items listed in domains of QOL (physical, emotional, social and school health domains) of children with ALL during maintenance therapy, and compare the same with those of their siblings and other healthy children. Forty children on maintenance therapy of ALL, 40 siblings and 40 healthy children were assessed for QOL by child self-report using PedsQL 4.0 Generic Core in the local language. Means were computed and compared for each domain with one-way analysis of variance (ANOVA), wherein higher values reflected better QOL. Overall QOL of children with ALL in maintenance therapy (77.16 ± 10.98) was significantly poorer than that of siblings (93.56 ± 4.41) and healthy children (93.02 ± 3.76) (p < 0.001), but their abilities of self-care, household work, exercise, attentiveness, memory and homework were unaffected. There was significantly higher absenteeism due to sickness and hospital visits, and increased emotional problems (fear, anger, sleeping problems) among children with ALL. In the social health domain, children with ALL reported difficulty in maintaining friendships and competing. QOL of siblings was as good as that of healthy children in physical, social and school health domains, but they had increased emotional problems such as anger and sadness. Healthy children reported significantly higher future worries and bullying than children with ALL and siblings. This study validated that the QOL of children with ALL during maintenance therapy was significantly poorer than that of siblings and healthy children. The study identified various items in each domain of QOL that were affected in these children, and thus would assist in guiding healthcare professionals to focus on these specific items so as to improve their overall QOL.