Maintenance Therapy For Acute Lymphoblastic Leukemia Research Articles

Antimetabolite Dose Intensity and Adverse Outcomes in Children with Acute Lymphoblastic Leukemia: A COG-AALL03N1 Report

AbstractThe association between antimetabolite dose intensity (DI) and adverse events among children receiving maintenance therapy for acute lymphoblastic leukemia (ALL) remains unclear, especially in the context of antimetabolite adherence. Using Children’s Oncology Group AALL03N1 data, we examined the association between high DI during the first 4 study months and (i) treatment-related toxicities during the subsequent 2 study months; and (ii) relapse risk. Patients were classified into a high DI phenotype (either 6-mercaptopurine [6-MP] or methotrexate [MTX] DI ≥110% during the first 4 study months, or 6-MPDI or MTXDI 100%-110% at study enrollment and ≥25% increase over the 4 study months) and normal DI phenotype (all others). Only patients with wild-type TPMT and NUDT15 were included. 6-MP adherence data were available for 63.7% of study participants and used to stratify as adherent (median adherence ≥85%) and nonadherent (median adherence <85%) participants. Multivariable analyses were adjusted for sociodemographic and clinical prognosticators. Of the 644 patients, 29.3% were exposed to high DI. High DI was associated with a 2.1-fold greater odds of hematologic toxicity (95% confidence interval [CI] = 1.4-3.1; reference: normal DI) in the entire cohort and 2.9-fold higher among adherers (95% CI = 1.6-5.1); odds were comparable among nonadherers (2.1-fold; 95% CI = 0.4-10.1). Although high DI was not associated with relapse in the entire cohort (adjusted hazard ratio [aHR] = 1.4; 95% CI = 0.8-2.4), it was associated with a greater hazard of relapse among adherent participants (aHR = 2.4; 95% CI = 1.0-5.5) but not among nonadherent participants (aHR = 0.9; 95% CI = 0.2-3.8). Dose escalation above protocol doses during maintenance therapy for ALL should be done cautiously after assessing adherence to prescribed therapy.

Poverty and relapse risk in children with acute lymphoblastic leukemia: a Children’s Oncology Group study AALL03N1 report

AbstractThe association between individual-level poverty and relapse in children receiving maintenance treatment for acute lymphoblastic leukemia (ALL) remains unclear. In a secondary analysis of COG-AALL03N1, we used data from US Census Bureau to categorize patients living below year-specific federal poverty thresholds, calculated using self-reported annual household income and size of household. Participants with federal poverty thresholds above 120% of their yearly household income were categorized as living in extreme poverty. Hazard of relapse was estimated using multivariable proportional subdistributional hazards regression for patients living in extreme poverty while receiving ALL maintenance therapy after adjusting for relevant predictors. Among 592 patients in this analysis, 12.3% of the patients were living in extreme poverty. After a median follow-up of 7.9 years, the cumulative incidence of relapse at 3 years from study enrollment among those living in extreme poverty was significantly higher (14.3%) than those not living in extreme poverty (7.6%). Multivariable analysis demonstrated that children living in extreme poverty had a 1.95-fold greater hazard of relapse than those not living in extreme poverty; this association was mitigated after the inclusion of race/ethnicity in the model, likely because of collinearity between race/ethnicity and poverty. A greater proportion of children living in extreme poverty were nonadherent to mercaptopurine (57.1% vs 40.9%); however, poor adherence did not completely explain the association between poverty and relapse risk. Future studies need to understand the mechanisms underlying the association between extreme poverty and relapse risk. This trial was registered at www.clinicaltrials.gov as #NCT00268528.

Impact of vincristine-steroid pulses during maintenance for B-cell pediatric ALL: a systematic review and meta-analysis

AbstractThe benefit associated with the incorporation of vincristine-corticosteroid pulses in maintenance therapy for pediatric acute lymphoblastic leukemia (ALL) is unclear, particularly in the context of modern intensive therapy. This systematic review and meta-analysis examined the impact of reducing the frequency of vincristine-steroid pulses during maintenance for pediatric patients newly diagnosed with B-cell ALL. Two authors reviewed all eligible studies identified through a comprehensive search, extracted data from 25 publications (12 513 patients), and assessed the risk of bias. We created historical and contemporary subgroups; the latter included trials providing both a version of Protocol III from the early Berlin-Frankfurt-Munster trials and eliminating routine prophylactic cranial radiation. Meta-analysis of event-free survival data suggested no benefit between more frequent or less frequent pulses in contemporary trials (hazard ratio [HR], 0.96; 95% confidence interval [CI], 0.85-1.09), which differed significantly from historical trials (HR, 0.79; 95% CI, 0.68-0.91; P = .04). We found no significant impact of reduced pulse frequency on overall survival or relapse risk. There was however increased odds of grade 3+ nonhepatic toxicity in the high-pulse frequency group (odds ratio, 1.31; 95% CI, 1.12-1.52). This systematic review suggests that the previous benefit conferred by frequent pulses of vincristine-steroids in maintenance therapy for pediatric B-cell ALL in historical trials no longer applies in contemporary trials but is associated with toxicity. These results will help guide the development of the next phase of clinical trials in the field of pediatric ALL and question the continued use of pulses in maintenance among patients not in clinical trials, particularly those experiencing toxicity.

Poverty during Maintenance and Relapse Risk in Children with Acute Lymphoblastic Leukemia (ALL): A Report from Children's Oncology Group Study (COG-AALL03N1)

Introduction: There is conflicting evidence regarding the association between poverty and survival in children with cancer. Most studies have relied on surrogate indicators of poverty, such as zip code-based median income for area of residence or on insurance status (Bona, PBC 2016; Kehm, Cancer 2019; Bona, JNCI 2021). We hypothesized that household poverty (measured at the individual level, using self-reported annual household income) during maintenance would be associated with a greater hazard of relapse among children with ALL. Methods: In this secondary analysis of COG-AALL03N1 (primary aim: adherence to oral mercaptopurine during maintenance), we examined the association between household poverty during maintenance and relapse risk in children with ALL. Eligibility for enrollment on AALL03N1 included (1) age <21y at ALL diagnosis; (2) receiving maintenance therapy in first remission. The current analysis was restricted to patients living in US who provided information on annual household income and the number of household members. We used national yearly median poverty thresholds provided by CDC; these take into account the annual household income and the size of family unit (i.e., number of adults and children <18y). For example, the annual income of a three-person household (two parents and one child [patient]) would need to be >$14,480 to be above the poverty threshold in the year 2002 (or >$21,831 in the year 2021). Among those below poverty threshold, we classified families with annual income under 120% federal threshold (median percent below poverty threshold for this cohort) as living in extreme poverty. Hazard of relapse from study enrollment during ALL maintenance therapy was estimated using proportional subdistribution hazard regression models, treating extreme poverty as the primary exposure and adjusting for age at study, sex, NCI risk group, blast cytogenetics, average 6MP and methotrexate dose intensity and time from start of maintenance to study entry. Results: We summarize sociodemographic and disease characteristics of 592 eligible patients in the Table. Median household income of the cohort was $35,000/year (range $10,000->$150,000). Overall, 73 (12.3%) patients met criteria for extreme poverty. Families living in extreme poverty were more likely to self-report their race/ethnicity as Hispanic or African-American and report parental education as high school (HS) or lower. Of note, clinical factors did not differ by poverty level. In a logistic regression, non-white race/ethnicity (odds ratio [OR]=7.9, 95%CI=2.4-26.1, P=0.007; reference: non-Hispanic white) and low parental education (≤HS: OR=4.2, 95%CI=2.4-7.4, P=<0.001; reference: college degree or higher) were associated with greater odds of living in extreme poverty. Cumulative incidence of relapse at 3y (Figure) from study entry among patients living in extreme poverty was higher compared to those without extreme poverty (14.3% [95%CI, 7-24] vs 7.6% [95%CI, 5-10], P=0.04). Patients living in extreme poverty had a 1.97-fold higher hazard of relapse compared to those not living in extreme poverty after adjusting for above mentioned covariates (95%CI=1.03-3.76, P=0.04). The reasons for the association between individual level poverty and relapse risk are likely multifactorial and possibly include poor adherence to oral chemotherapy. We found that patients living in extreme poverty had lower adherence to 6MP compared to those not living in extreme poverty (85.2±19.6% vs 90.6±14.8%, P=0.03). Conclusions: Extreme household poverty is associated with increased hazard of relapse in children receiving maintenance therapy for ALL compared to those living without extreme household poverty. Mechanisms investigating this association need to be explored in future studies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Vincristine and Steroid Pulses in Maintenance for B-Cell Pediatric Acute Lymphoblastic Leukemia: A Systematic Review and Meta-Analysis

Background Vincristine (VCR)-steroid pulses have been a component of the maintenance phase of therapy for pediatric acute lymphoblastic leukemia (ALL) since the 1970s. However, major cooperative groups differ in how these are incorporated, if at all. Two previous systematic reviews (Richards 1996, Yetgin 2010) examining this question supported the inclusion of VCR/Steroid pulses. Yet, two recent randomized control trials (RCTs; Angiolillo 2021, Yang 2021) demonstrated no impact on event-free survival (EFS) with decreased frequency of maintenance pulses. Objectives The objectives of this systematic review and meta-analysis were to examine the impact of reducing frequency of VCR/steroid pulses in maintenance therapy for newly diagnosed pediatric patients with B-cell ALL overall, and according to era of therapy (historical versus contemporary). Methods We searched MEDLINE, EMBASE, and Cochrane CENTRAL for RCTs and meta-analyses of RCTs from inception until February 2022. Additional studies were identified from clinical trials databases, grey literature, and screening reference lists of previous systematic reviews. Two authors reviewed all studies and included those which addressed newly diagnosed pediatric patients with B-cell ALL, where randomization examined a change in how VCR/steroid pulses were provided in maintenance, and provided at minimum EFS outcomes. We excluded trials which compared VCR/steroid pulses to more intensive maintenance therapies with additional chemotherapy agents. Study data were extracted and risk of bias assessed using Cochrane Risk of Bias 2.0 tool by two authors. Hazard (HR) and odds ratios (OR) with associated 95% Confidence Intervals (CI) were calculated for EFS, overall survival (OS), incidence of relapse, and adverse events, including a composite measure of non-hepatic toxicities. We created historical and contemporary subgroups; the latter were defined as treatment protocols that: 1) provided a delayed intensification or re-intensification phase based on Protocol III from early Berlin-Frankfurt-Munster (BFM) trials, and; 2) avoided prophylactic cranial radiation in all but the highest risk patients. A random effects meta-analysis was completed using the generic inverse variance method for time-to-event data and the Mantel-Haenszel method for dichotomous events. Heterogeneity was assessed using I2 statistics. Results Our systematic review included 25 publications representing 16 completed and 2 ongoing RCTs, with a total of 12,513 patients (low pulse frequency, 6,269 and high pulse frequency, 6,244). No study was at low risk of bias; however, trials in the contemporary sub-group were more robust, with only minor concerns identified mainly due to the lack of blinding. Meta-analysis of EFS data from 14 trials (Figure 1) suggested no benefit between high or low pulse frequency in contemporary trials (HR 0.96, 95% CI 0.85-1.09, p=0.57), while in historical trials high pulse frequency was favored (HR 0.79, 95%CI 0.68-0.91, p<0.001). The difference between these two subgroups was statistically significant (p= 0.04). Similar findings were found in our meta-analysis of overall relapse risk, with no benefit seen for higher pulse frequency in contemporary trials (OR 1.02, 95%CI 0.83-1.25, p=0.85) but seen in historical trials (OR 0.68, 95%CI 0.47-0.99, p=0.05; p=0.07 for difference between groups). We found no significant impact of reduced pulse frequency on OS or isolated central nervous system (CNS) relapse in either subgroup. In 5 trials with toxicity data, high frequency pulses were associated with increased risk of Grade 3+ non-hepatic events (OR 1.31, 95%CI 1.12-1.52; p<0.001, Figure 2). Conclusions This systematic review suggests that the previous benefit conferred by frequent pulses of VCR/steroids in maintenance therapy for pediatric B-cell ALL in historical trials no longer significantly improves outcomes in contemporary protocols, but is associated with increased toxicity. These results will help guide development of the next phase of clinical trials in the field of pediatric ALL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

EBV-driven lymphoid neoplasms associated with pediatric ALL maintenance therapy

AbstractThe development of a second malignancy after the diagnosis of childhood acute lymphoblastic leukemia (ALL) is a rare event. Certain second malignancies have been linked with specific elements of leukemia therapy, yet the etiology of most second neoplasms remains obscure and their optimal management strategies are unclear. This is a first comprehensive report of non-Hodgkin lymphomas (NHLs) following pediatric ALL therapy, excluding stem-cell transplantation. We analyzed data of patients who developed NHL following ALL diagnosis and were enrolled in 12 collaborative pediatric ALL trials between 1980-2018. Eighty-five patients developed NHL, with mature B-cell lymphoproliferations as the dominant subtype (56 of 85 cases). Forty-six of these 56 cases (82%) occurred during or within 6 months of maintenance therapy. The majority exhibited histopathological characteristics associated with immunodeficiency (65%), predominantly evidence of Epstein-Barr virus–driven lymphoproliferation. We investigated 66 cases of post-ALL immunodeficiency-associated lymphoid neoplasms, 52 from our study and 14 additional cases from a literature search. With a median follow-up of 4.9 years, the 5-year overall survival for the 66 patients with immunodeficiency-associated lymphoid neoplasms was 67.4% (95% confidence interval [CI], 56-81). Five-year cumulative risks of lymphoid neoplasm– and leukemia-related mortality were 20% (95% CI, 10.2-30) and 12.4% (95% CI, 2.7-22), respectively. Concurrent hemophagocytic lymphohistiocytosis was associated with increased mortality (hazard ratio, 7.32; 95% CI, 1.62-32.98; P = .01). A large proportion of post-ALL lymphoid neoplasms are associated with an immunodeficient state, likely precipitated by ALL maintenance therapy. Awareness of this underrecognized entity and pertinent diagnostic tests are crucial for early diagnosis and optimal therapy.

Thiopurine Enhanced ALL Maintenance (TEAM): study protocol for a randomized study to evaluate the improvement in disease-free survival by adding very low dose 6-thioguanine to 6-mercaptopurine/methotrexate-based maintenance therapy in pediatric and adult patients (0\u201345\u2009years) with newly diagnosed B-cell precursor or T-cell acute lymphoblastic leukemia treated according to the intermediate risk-high group of the ALLTogether1 protocol

BackgroundA critical challenge in current acute lymphoblastic leukemia (ALL) therapy is treatment intensification in order to reduce the relapse rate in the subset of patients at the highest risk of relapse. The year-long maintenance phase is essential in relapse prevention. The Thiopurine Enhanced ALL Maintenance (TEAM) trial investigates a novel strategy for ALL maintenance.MethodsTEAM is a randomized phase 3 sub-protocol to the ALLTogether1 trial, which includes patients 0–45 years of age with newly diagnosed B-cell precursor or T-cell ALL, and stratified to the intermediate risk-high (IR-high) group, in 13 European countries. In the TEAM trial, the traditional methotrexate (MTX)/6-mercaptopurine (6MP) maintenance backbone (control arm) is supplemented with low dose (2.5–12.5 mg/m2/day) oral 6-thioguanine (6TG) (experimental arm), while the starting dose of 6MP is reduced from 75 to 50 mg/m2/day. A total of 778 patients will be included in TEAM during ~ 5 years. The study will close when the last included patient has been followed for 5 years from the end of induction therapy. The primary objective of the study is to significantly improve the disease-free survival (DFS) of IR-high ALL patients by adding 6TG to 6MP/MTX-based maintenance therapy. TEAM has 80% power to detect a 7% increase in 5-year DFS through a 50% reduction in relapse rate. DFS will be evaluated by intention-to-treat analysis. In addition to reducing relapse, TEAM may also reduce hepatotoxicity and hypoglycemia caused by high levels of methylated 6MP metabolites. Methotrexate/6MP metabolites will be monitored and low levels will be reported back to clinicians to identify potentially non-adherent patients.DiscussionTEAM provides a novel strategy for maintenance therapy in ALL with the potential of improving DFS through reducing relapse rate. Potential risk factors that have been considered include hepatic sinusoidal obstruction syndrome/nodular regenerative hyperplasia, second cancer, infection, and osteonecrosis. Metabolite monitoring can potentially increase treatment adherence in both treatment arms.Trial registrationEudraCT, 2018–001795-38. Registered 2020-05-15,Clinicaltrials.gov, NCT04307576. Registered 2020-03-13, https://clinicaltrials.gov/ct2/show/NCT04307576

Dexamethasone-Induced Sarcopenia and Physical Frailty in Children With Acute Lymphoblastic Leukemia: Protocol for a Prospective Cohort Study.

BackgroundDuring treatment for pediatric acute lymphoblastic leukemia (ALL), children receive high doses of dexamethasone for its apoptotic effect on leukemia cells; however, muscle atrophy is a well-known serious side effect. Muscle atrophy (loss of muscle mass) accompanied by a decreased muscle strength may lead to a generalized impaired skeletal muscle state called sarcopenia. Loss of muscle mass is also an indicator of physical frailty, which is defined as a state of increased vulnerability that is characterized by co-occurrence of low muscle mass, muscle weakness, fatigue, slow walking speed, and low physical activity. Both sarcopenia and physical frailty are related to an increased risk of infections, hospitalizations, and decreased survival in children with chronic diseases.ObjectiveThis study aims to (1) estimate the occurrence of sarcopenia and physical frailty in children during ALL maintenance therapy, (2) evaluate the effect of administering dexamethasone, and (3) explore determinants associated with these outcomes.MethodsThis prospective study is being pursued within the framework of the DexaDays-2 study: a randomized controlled trial on neurobehavioral side effects in pediatric patients with ALL. A total of 105 children (3-18 years) undergoing ALL maintenance treatment at the Princess Máxima Center for Pediatric Oncology are included in this study. Sarcopenia/frailty assessments are performed before and just after a 5-day dexamethasone course. A subset of 50 children participating in the DexaDays-2 trial because of severe dexamethasone-induced neurobehavioral problems were assessed at 3 additional timepoints. The sarcopenia/frailty assessment consists of bioimpedance analysis (skeletal muscle mass [SMM]), handheld dynamometry (handgrip strength), Pediatric Quality of Life Inventory Multidimensional Fatigue Scale (fatigue), Timed Up and Go Test (TUG; walking speed), and physical activity questionnaires. To evaluate potential change in sarcopenia/frailty components after a 5-day dexamethasone administration, a paired Student t test or Mann-Whitney U test will be used. Because of the presence of repeated measurements, generalized linear mixed models will be used to estimate the effect of dexamethasone on sarcopenia and frailty outcomes. Multivariable regression models will be estimated to investigate associations between the assessment scores and patient and treatment-related factors.ResultsPatient accrual started in 2018 and was finalized in spring 2021. From autumn 2021 onward final data analyses will be performed.ConclusionsThis first study combining parameters of sarcopenia and physical frailty is of importance because these conditions can seriously complicate continuation of ALL therapy, independence in physical functioning, reaching motor milestones, and participating in daily life activities. The results will provide knowledge about these complications, the association between dexamethasone treatment and muscle loss and other components of frailty, and therefore insights into the severity of this side effect. By exploring potential determinants that may be associated with sarcopenia and physical frailty, we may be able to identify children at risk at an earlier stage and provide timely interventions.International Registered Report Identifier (IRRID)DERR1-10.2196/33517

Perceptions of parents of pediatric patients with acute lymphoblastic leukemia on oral chemotherapy administration: A qualitative analysis.

To describe the experiences and perspectives of parents of pediatric patients with acute lymphoblastic leukemia (ALL) regarding oral chemotherapy administration during maintenance therapy. English-speaking parents of patients 4 to <18years who were receiving ALL maintenance oral chemotherapy were eligible to participate in this mixed methods study. Using semi-structured interviews, we asked participants how difficult they found oral chemotherapy administration. We also probed regarding barriers and facilitators of oral chemotherapy administration and strategies used to overcome challenges. Lastly, we asked participants for their advice to future parents giving oral chemotherapy to their children. Twenty-three participants were interviewed. One-fifth of participants stated that oral chemotherapy administration at home was hard or very hard. Common factors influencing oral chemotherapy administration were product-related (e.g., formulation) and treatment-related adverse effects (e.g., nausea), lifestyle adjustment (e.g., fitting in with family schedule), and attitudes (e.g., onus of medication administration). Strategies to address oral chemotherapy administration included several administration techniques, scheduling of medication administration, and normalization of medication taking. Oral chemotherapy administration during ALL maintenance therapy was hard for some parents. Identification of these parents and discussion of strategies to facilitate adherence to oral chemotherapy regimens may optimize patient outcomes.

Pneumocystis Jiroveci Pneunomia Prophylaxis during Maintenance Therapy with Hyper-CVAD Regimens for Adult Acute Lymphoblastic Leukemia

BACKGROUNDPneumocystis jiroveci pneumonia (PCP) can be a deadly opportunistic infection in immunocompromised patients. Patients with acute lymphoblastic leukemia (ALL) are at risk for PCP due to their underlying disease, use of high doses of corticosteroids and receipt of lymphocyte-depleting chemotherapy. It is recommended that patients receive PCP prophylaxis during treatment for ALL. Trimethoprim/sulfamethoxazole (TMP/SMZ) is a common agent utilized but some practitioners are concerned about myelosuppression induced by TMP/SMZ. HyperCVAD regimens are the standard treatment strategy for ALL patients at our institution. Historically, PCP prophylaxis with TMP/SMZ was delayed until the beginning of maintenance therapy. This retrospective analysis evaluated PCP prophylaxis and incidence in ALL patients receiving maintenance therapy on a HyperCVAD regimen. Any influence of PCP prophylaxis on clinical outcomes was also evaluated. METHODSNewly diagnosed adult (≥ 18 yo) patients with ALL or lymphoblastic lymphoma who received at least one cycle of maintenance therapy on a HyperCVAD regimen between April 2000 to December 2016 were reviewed. Interim chart reviews were performed to identify the use of PCP prophylaxis and definite or suspected cases of PCP, as well as to document maintenance therapy doses or change in patient status, until the completion of maintenance therapy. Suspected PCP cases (missing microbiological documentation of Pneumocystis) were defined as those patients receiving PCP active therapy based on clinical presentation and imaging. RESULTSDuring the study period, 363 frontline ALL patients received at least one cycle of HyperCVAD maintenance therapy. 346 (198 males and 148 females) patients had sufficient documentation. Of these 346 patients, 145 never received PCP prophylaxis, 67 received i ntermittent PCP prophylaxis, and 134 received uninterrupted PCP prophylaxis throughout maintenance therapy. Only 3 cases of PCP (0.9%) were identified, one confirmed and 2 suspected. All cases occurred within the first 6 months of maintenance therapy and in patients never receiving PCP prophylaxis. The majority of patients receiving prophylaxis were on TMP/SMZ (97%); the most common regimen was 160 mg of the TMP component (1 DS tablet) twice daily two days per week. PCP prophylaxis rates have decreased over time - 55% of patients received uninterrupted PCP prophylaxis if initiated ALL maintenance therapy in 2000-2005 versus 10% of patients received uninterrupted maintenance if initiated ALL maintenance therapy in 2010-2016 (p=<0.001). Philadelphia-positive patients (106/346, 31%) received TKI-based maintenance therapy (TKI, corticosteroid, vincristine). Philadelphia-positive patients were less likely to receive uninterrupted PCP prophylaxis (p<0.0001). Doses of TKI were not statistically different between PCP prophylaxis groups. Philadelphia-negative patients received maintenance therapy containing mercaptopurine and methotrexate (plus corticosteroid, vincristine). Doses of mercaptopurine and methotrexate were not statistically different between PCP prophylaxis groups (p=0.75, p=0.4 respectively). ANC values were analyzed over time and were not significantly different between PCP prophylaxis groups (p=0.36 for never versus uninterrupted PCP prophylaxis). ALC values were also evaluated and were significantly lower in the uninterrupted PCP prophylaxis group at baseline, maintenance year 1 and maintenance year 2 (p=0.0464, p=0.0002, p=0.0001 respectively). Relapse rate, PFS and OS did not differ between the never, intermittent and uninterrupted PCP prophylaxis groups. CONCLUSIONSThe rate of PCP was low in this group of adult patients with newly diagnosed ALL undergoing maintenance therapy as part of a HyperCVAD regimen. All PCP cases occurred in patients not receiving PCP prophylaxis. TMP/SMZ prophylaxis had no significant effect on doses of ALL maintenance therapy provided as well as PFS and OS. TMP/SMZ remains a safe, effective choice for PCP prophylaxis in adult ALL patients. Given the low incidence of PCP in this population, future studies are warranted to identify risk factors that allow selection of patients who would benefit the most from PCP prophylaxis. DisclosuresJabbour:Bristol-Myers Squibb: Consultancy.

Increments in DNA-thioguanine level during thiopurine-enhanced maintenance therapy of acute lymphoblastic leukemia.

Maintenance therapy containing methotrexate and 6-mercapto - purine is essential to cure acute lymphoblastic leukemia (ALL). Cytotoxicity is elicited by incorporation of thioguanine nucleotides into DNA (DNA-TG), and higher leukocyte DNA-TG is associated with increased relapse-free survival. As 6-thioguanine provides 6- fold higher cytosolic levels of thioguanine nucleotides than does 6- mercapto purine, we added low-dose 6-thioguanine to methotrexate/6- mercapto purine maintenance therapy to explore if this combination results in significantly higher DNA-TG. The target population of the “Thiopurine Enhanced ALL Maintenance therapy” (TEAM) study was 30 patients with non-high-risk ALL, aged 1-45 years on methotrexate/6-mercaptopurine maintenance therapy receiving no other systemic chemotherapy. Incremental doses of 6-thioguanine were added to methotrexate/6-mercaptopurine maintenance therapy (starting 6-thioguanine dose: 2.5 mg/m2/day, maximum: 12.5 mg/m2/day). The primary endpoint was DNA-TG increments. Thirty-four patients were included, and 30 patients completed maintenance therapy according to the TEAM strategy. Of these 30 patients, 26 (87%) tolerated 10.0-12.5 mg/m2/day as the maximum 6-thioguanine dose. TEAM resulted in significantly higher DNA-TG levels compared to those in both TEAM patients before their inclusion in TEAM (on average 251 fmol/mg DNA higher [95% confidence interval: 160-341; P<0.0001]), and with historical patients receiving standard methotrexate/6-mercapto - purine maintenance therapy (on average 272 fmol/mg DNA higher [95% confidence interval: 147-398; P<0.0001]). TEAM did not increase myelotoxicity or hepatotoxicity. In conclusion, TEAM is an innovative and feasible approach to improve maintenance therapy and results in higher DNA-TG levels without inducing additional toxicity. It may therefore be an effective strategy to reduce the risk of ALL relapse through increased DNA-TG. This will be tested in a randomized ALLTogether-1 substudy.

Dynamics of leucocyte DNA thioguanine nucleotide levels during maintenance therapy of childhood acute lymphoblastic leukemia.

Methotrexate (MTX)/6-Mercaptopurine (6MP)-based maintenance therapy is crucial to cure childhood acute lymphoblastic leukemia (ALL). Cytotoxicity is mediated by incorporation of thioguanine nucleotides (TGN) into DNA (DNA-TG) with higher levels in leucocytes being associated with reduced relapse risk. To further understand the dynamics of DNA-TG formation, we measured DNA-TG levels in leucocyte subsets during maintenance therapy and in the months following its discontinuation. DNA-TG levels were measured in leucocytes (DNA-TGTotal), polymorph nucleated granulocytes (neutrophils, eosinophils, basophils [DNA-TGPMN]) and mononucleated cells (lymphocytes, monocytes [DNA-TGMNC]) in 1013 samples from 52 patients on ALL maintenance therapy (951 samples during therapy and 62 samples after therapy discontinuation, respectively). Median DNA-TGTotal, DNA-TGPMN and DNA-TGMNC during maintenance therapy were 539, 563 and 384 fmol/µg DNA, respectively. DNA-TGPMN displayed more pronounced fluctuation than DNA-TGMNC (range 0-3084 [interquartile range IQR 271-881] versus 30-1411 [IQR 270-509] fmol/µg DNA). DNA-TGTotal was more strongly correlated with DNA-TGPMN (rS = 0.95, p < 0.0001) than DNA-TGMNC (rS = 0.73, p < 0.0001). DNA-TGPMN correlated less with DNA-TGMNC (rS = 0.64, p < 0.0001) and to a much lesser extent with absolute neutrophil count (rS = 0.35, p < 0.0001). Following discontinuation of therapy, DNA-TGPMN was rapidly eliminated, and not measurable beyond day 22 after discontinuation, whereas DNA-TGMNC was slowly eliminated, and five patients demonstrated a measurable DNA-TGMNC more than 365days after therapy discontinuation. Fluctuations in DNA-TGTotal are predominantly caused by corresponding fluctuations in DNA-TGPMN, thus DNA-TGTotal measures recent TGN incorporation in these short-lived cells. Measurement of DNA-TGTotal at 2-4weeks intervals provides a reliable profile of DNA-TG levels.

Do we need separate screening strategies for cytomegalovirus retinitis in different underlying immunosuppressed states? A retrospective study from Western India.

Purpose:The aim of this study was to describe the clinical features, course, and clinical outcomes of eyes with cytomegalovirus (CMV) retinitis in immunosuppressed patients of different etiologies.Methods:This was a retrospective observational study from a single ophthalmic tertiary care center. The patients included referrals from the nodal cancer center and the local human immunodeficiency virus (HIV) treatment clinic. Demographics, history, visual acuity, ocular features, treatment protocol, and final visual outcome of patients who were diagnosed with CMV retinitis in the period of five years from 2014 to 2019 were studied.Results:CMV retinitis was diagnosed in 25 eyes of 14 patients. Age of the patients ranged from 11–54 years. Ten (71.43%) patients were male and four (29.57%) were female. Eight of them had acute lymphoblastic leukemia (ALL), four were suffering from HIV infection and one patient each had lymphoma and history of a kidney transplant. The treatment for CMV retinitis ranged from two to sixty weeks depending on disease activity and systemic condition. Three of the patients were on maintenance therapy for ALL at the time of reactivation.Conclusion:Duration of treatment for CMV retinitis in patients of ALL was longer as compared to the other etiologies, and in recurrences, it needed to be continued till the completion of maintenance therapy for ALL. It is prudent to advise regular ophthalmic screening of all immunocompromised patients, as they are at a high risk of developing CMV retinitis. Patients of ALL, especially while on maintenance therapy, should be monitored for possible development or reactivation of CMV retinitis.

Allopurinol use during pediatric acute lymphoblastic leukemia maintenance therapy safely corrects skewed 6-mercaptopurine metabolism, improving inadequate myelosuppression and reducing gastrointestinal toxicity.

Background:Inadequate myelosuppression during maintenance therapy for acute lymphoblastic leukemia (ALL) is associated with an increased risk of relapse. One mechanism is skewed metabolism of 6-mercaptopurine (6MP), a major component of maintenance therapy, which results in preferential formation of the hepatotoxic metabolite (6-methyl mercaptopurine [6MMP]) with low levels of the antileukemic metabolite, 6-thioguanine nucleotides (6TGN). Allopurinol can modify 6MP metabolism to favor 6TGN production and reduce 6MMP.Methods:Patients in maintenance were considered for allopurinol treatment who had the following features: (a) Grade ≥3 hepatotoxicity; (b) Grade ≥2 nonhepatic gastrointestinal (GI) toxicity; or (c) persistently elevated absolute neutrophil count (ANC) despite >150% protocol dosing of oral chemotherapy.Results:From 2013 to 2017, 13 ALL patients received allopurinol: nine for hepatotoxicity, five for inadequate myelosuppression, and three for nonhepatic GI toxicity (four met multiple criteria). Allopurinol was well tolerated, without significant adverse events. Allopurinol resulted in a significant decrease in the average 6MMP/6TGN ratio (mean reduction 89.1, P = .0001), with a significant increase in 6TGN (mean 550.4, P = .0008) and a significant decrease in 6MMP (mean 13 755, P = .0013). Patients with hepatotoxicity had a significant decrease in transaminase elevation after starting allopurinol (alanine transaminase [ALT] mean decrease 22.1%, P = .02), and all with nonhepatic GI toxicity had improved symptoms. Those with inadequate myelosuppression had a significant increase in the time with ANC in goal (mean increase 26.4%, P = .0004).Conclusions:Allopurinol during ALL maintenance chemotherapy is a safe, feasible, and effective intervention for those who have altered metabolism of 6MPcausing toxicity or inadequate myelosuppression.

Use of Allopurinol to Mitigate 6-Mercaptopurine Associated Gastrointestinal Toxicity in Acute Lymphoblastic Leukemia.

An essential component of acute lymphoblastic leukemia (ALL) therapy is the prolonged maintenance phase with daily 6-mercaptopurine (6-MP) as the cornerstone. While 6-MP is generally well-tolerated, some patients suffer from significant side effects such as gastrointestinal (GI) toxicity, including hepatitis, hypoglycemia, nausea, and pancreatitis, which can substantially limit the tolerated dose of 6-MP. These toxicities are thought to result from skewed metabolism of 6-MP leading to an accumulation of the 6-methylmercaptopurine (6-MMP) metabolite. Here, we describe current knowledge behind the use of allopurinol to modify 6-MP metabolism and improve tolerance to therapy. This method has been successfully used in adults with inflammatory bowel disease refractory to purine therapy and has been modified for use in children with GI toxicities related to 6-MP in maintenance therapy for ALL. Use of allopurinol for 6-MP related toxicities should be reserved for patients in which an alternative cause of signs or symptoms has been excluded and for whom non-pharmacologic measures have failed. When allopurinol is used, simultaneous dose reduction of 6-MP is required to avoid severe myelosuppression and related side effects, though overall combination therapy appears to be well-tolerated and effective when instituted appropriately.

Increased Risk of Early Hematologic Toxicity during Maintenance Therapy in Acute Lymphoblastic Leukemia Patients of South Indian Origin Carrying NUDT15*3 Allele

Background and Objectives: Globally the survival of ALL has increased tremendously with the five-year overall survival (OS) reaching 90% in high-income countries (HICs) (1, 2). However, in India, the five-year OS has been reported to be 30-70 %( 3) and deaths due to treatment related toxicity (TRT) in ALL were ranged from 2-24 % (4), which is ten times higher compared to HICs suggesting increased susceptibility to the toxicity of the chemotherapeutic drugs. This could be due to frequent variants in candidate genes determining the pharmacodynamic response or pharmacokinetics of the chemotherapeutic drugs used during maintenance therapy of ALL. Variations in the patient management, supportive care therapy are the other possible reasons of this increased incidence of TRT. Many patients are lost to follow-up due to the TRT, and eventually will die of the disease progression. The present study aimed to explore the association of common genetic variants in the candidate genes with early treatment related hematological toxicities (grade 3-4) in patients with Acute Lymphoblastic Leukemia (ALL) receiving low-dose MTX (LDMTX) and 6-Mercaptopurine (6-MP) based maintenance therapy. Materials and Methods: This prospective study was conducted between August 2011 and May 2016 and approved by institutional scientific and ethics committees. A total of 71 patients (43 males and 28 females aged between 1-51 years) with ALL were enrolled in the study after obtaining written informed consent and in the case of children, from legally accepted guardians. Patients below 25 years of age were treated using protocol-841 (MCP) I2A and those older than 25 years were treated with modified GMALL-84 protocols. MTX and 6-MP doses did not differ across both the protocols during maintenance therapy. Germline DNA samples collected at the time of remission from peripheral mononuclear cells was used to genotype15 selected variants frequent in the following candidate genes : ABCB1, DHFR, GGH, FPGS, MTHFR, RFC1, SLCO1B1, TPMT, and NUDT15 using allele discrimination assay by real-time PCR. LC-MS/MS method was used to measure methotrexate polyglutamate (MTXPG3-5) levels in RBC's.Toxicities were graded according to the Common Terminology Criteria for Adverse Events (CTCAE-version 4.03). Early grade 3-4 hematological toxicities occurring within first 100 days of the maintenance therapy was studied for its association with the genetic variants and other risk factors. Cumulative incidence curves were plotted and a risk factor analysis was performed using multivariate Cox regression. Co-linearity between variables was assessed. We used a back-ward selection method, retaining those variables with P-values&lt;0.05 in the final model. Data analysis was done using statistical software « R ». Results: The cumulative incidences of early hematological TRT (grade 3-4) and relapse were 54.9 %, and 38.0 %, respectively. The relapse free survival was 59.2 %. The median follow-up of all patients from the start of maintenance was 1018 days. In multivariate analysis including all genetic variants, age, and WBC counts at diagnosis, we observed a significant increase in the risk of TRT in carriers of NUDT15*3 allele(rs116855232 ; p=0.002 ; univariate Hazards ratio : 2.81 (95% CI : 1.41-5.59). 3435C&gt;T variant in ABCB1 gene showed a trend of association with that of relapse free survival. Neither the genetic variants studied were associated with the methotrexate polyglutamate levels, nor were the levels associated with the clinical outcomes. Conclusion: The NUDT15*3 allele carriers status could be used as one of the stratifying markers in South Indian ALL patients at the time of diagnosis to distinguish high and low-risk patients to develop early hematological toxicity, especially related to 6-mercaptopurine based ALL maintenance therapy protocols. Disclosures No relevant conflicts of interest to declare.

Lack of Benefit of Extended Vincristine and Dexamethasone Pulses during Maintenance Treatment of Childhood Acute Lymphoblastic Leukemia: A Multicenter Randomized Controlled Study of Chinese Children Cancer Group (CCCG)-ALL-2015

Introduction: The efficacy of extended duration of vincristine (VCR) and dexamethasone (DEX) pulses in the treatment of childhood acute lymphoblastic leukemia (ALL) is uncertain in the context of contemporary chemotherapy. By contrast, the long-term sequelae of vincristine-induced peripheral neuropathy and dexamethasone-related metabolic syndrome, osteonecrosis, and neurocognitive impairment are well recognized. We therefore conducted a randomized study in the CCCG-ALL-2015 protocol participated by 20 hospitals in China to compare the event-free survival (EFS) and overall survival (OS) between children with newly diagnosed ALL who did or did not receive extended duration of VCR+DEX pulses during maintenance treatment. Methods: After remission induction and consolidation treatment with high-dose methotrexate and mercaptopurine, all patients received antimetabolite-based maintenance treatment. During the initial 20-week of maintenance treatment, low-risk (LR) patients received two reinduction cycles and three pulses of VCR+DEX pulses, while intermediate-/high-risk (I/HR) patients received daily mercaptopurine interrupted every three weeks with PEG-asparaginase, mercaptopurine, daunorubicin, and VCR+DEX pulses for 5 courses followed by a reinduction treatment. During the subsequent maintenance treatment, all patients received VCR+DEX pulses every 4 weeks for 5 cycles. All Philadelphia chromosome (Ph)-negative patients were then stratified and randomized during the fifth cycle of maintenance course (between weeks 51 and 53) to or not to receive the VCR+DEX pulse every 8 weeks for 7 cycles between weeks 54 and 109; the remaining maintenance treatment between weeks 110 and 125 consisted of only mercaptopurine and methotrexate. Results: Between January 2015 and December 2018, 3985 eligible Ph-negative patients, including 2318 (58.2%) LR patients and 1667 (41.8%) I/HR patients, were enrolled in the study. With a median follow-up of 2.53 years (IQR 1.82-3.26), the 4-year event-free survival (EFS) and overall survival (OS) rates were 91.6% (95% CI 89.4-93.9) and 98.8% (95% CI 98.2-99.4) in the LR patients, and 85.9% (95% CI 83.2-88.7) and 95.4% (95% CI 93.8-96.9) in the I/HR patients, respectively. The 4-year OS were 99.0% (95%CI, 98.3%-99.8%) in the 1145 LR patients randomized to receive VCR+DEX pulse (LR-A) and 98.6% (95% CI, 97.7%-99.5%) in the 1173 LR patients not to receive the pulse (LR-B, hazard ratio 1.5, 95% CI 0.6-4.0; p=0.374, Fig 1A). The 4-year EFS were 91.1% (95% CI, 87.4%-95.1%) in LR-A group and 92.0% (95% CI, 89.6%-94.5%) in LR-B group (hazard ratio 1.3, 95% CI 0.8-1.9; P=0.27; Figure 1B). There were no significant differences between LR-A and LR-B group among patients with or without the t (12;21) (ETV6-RUNX1) in univariate analysis (Table1). Likewise, there was no significant difference in the 4-year OS between the 834 I/HR patients who did (I/HR-A) and the 833 I/HR patients who did not (I/HR-B) receive the pulse: 94.3% (95% CI, 91.7%-97.0%) versus 96.3% (95%CI 94.6%-98.0%, hazard ratio 0.8, 95% CI 0.4-1.4; P=0.421) (Fig 1C). The 4-year EFS were 83.6% (95%CI 79.2%-88.3%) for I/HR-A group and 88.1% (95%CI 85.1%-91.2%, P=0.372) for I/HR-B group (hazard ratio 0.9, 95% CI 0.6-1.2; P=0.37) (Figure 1D). There were no significant differences between I/HR-A and I/HR-B group among patients with B-ALL, T-ALL or t (1;19) (TCF3-PBX1) in the univariate analysis (Table1). Conclusion: The additional pulses of VCR+DEX pulse beyond one year of maintenance treatment had no impact on 4-year EFS or OS among LR or I/HR patients. If this finding remains unchanged with additional follow-up, the VCR+DEX pulses can be omitted after one year of maintenance therapy in childhood ALL. Disclosures No relevant conflicts of interest to declare.

ITPA, TPMT, and NUDT15 Genetic Polymorphisms Predict 6-Mercaptopurine Toxicity in Middle Eastern Children With Acute Lymphoblastic Leukemia.

Background: Acute lymphoblastic leukemia (ALL) is the most common cancer seen in children worldwide and in the Middle East. Although there have been major advances in treatment approaches for childhood ALL, serious toxicities do occur but with significant inter-individual variability. The aim of this study is to measure the frequency of polymorphisms in candidate genes involved in 6-Mercaptopurine (6-MP) disposition in a combined cohort of Middle Eastern Children with ALL, and evaluate whether these polymorphisms predict 6-MP intolerance and toxicity during ALL maintenance therapy. Methods: The study includes children treated for ALL on two treatment protocols from two cohorts; one from Lebanon (N = 136) and another from Kurdistan province of Iran (N = 74). Genotyping for the following six candidate genetic polymorphisms: ITPA 94C > A (rs1127354) and IVS2+21A > C (rs7270101), TPMT*2 238G > C (rs1800462), TPMT*3B 460G > A (rs1800460) and *3C 719A > G (rs1142345), and NUDT15 415C > T (rs116855232) was performed and analyzed in association with 6-MP dose intensity and toxicity. Results: As expected, TPMT and NUDT15 variants were uncommon. As for ITPA, both polymorphisms were more common in the Lebanese as compared to the Kurdish cohort with a minor allele frequency of 0.05 for 94C > A and 0.14 for IVS2+21A > C in the Lebanese only (N = 121), and of 0.01 for either ITPA polymorphism in Kurds. The most significant toxic effects were depicted with the NUDT15 polymorphism with a median 6-MP dose intensity of 33.33%, followed by 46.65% for TPMT*3A polymorphism, followed by 65.33% for two ITPA risk allele carriers and 74% for one ITPA risk allele carriers, in comparison to a median of 100% for the homozygous wild type in the combined cohort (P < 0.001). In addition, the onset of febrile neutropenia was significantly higher in variant allele carriers in the combined cohorts. Conclusions: These data confirm the predictive role of TPMT, NUDT15, and ITPA in 6-MP intolerance in Middle Eastern children with ALL. Given the relatively high frequency of ITPA variants in our study and their significant association with 6-MP dose intensity, we recommend that physicians consider genotyping for ITPA variants in conjunction with TPMT and NUDT15 prior to 6-MP therapy in these children.

Severely bothersome fatigue in children and adolescents with cancer and hematopoietic stem cell transplant recipients.

Objectives were to describe bothersome fatigue in children with cancer and hematopoietic stem cell (HSCT) recipients and to identify factors associated with severely bothersome fatigue. We included children ages 8-18years treated for cancer or HSCT recipients from three groups: [1] receiving active cancer treatment and admitted to hospital for at least 3days, [2] attending outpatient clinic for acute lymphoblastic leukemia maintenance therapy, and [3] attending outpatient clinic following treatment completion. Fatigue was measured using the Symptom Screening in Pediatrics Tool (SSPedi); severely bothersome fatigue was defined as a lot or extremely bothersome fatigue (score of 3-4 on 0-4 scale). Factors associated with severely bothersome fatigue were examined using univariate and multiple logistic regression. Of 502 children included, 414 (82.5%) reported some degree of bothersome fatigue (scores 1-4), and 123 (24.5%) reported severely bothersome fatigue (score 3 or 4). In multiple regression analysis, factors significantly associated with severely bothersome fatigue were child age 11-14 and 15-18years vs 8-10years (odds ratio (OR) 2.11, 95% confidence interval (CI) 1.21-3.77 and OR 2.96, 95% CI 1.66-5.44), and inpatients receiving cancer treatment vs outpatients who had completed therapy (OR 3.85, 95% CI 2.17-7.27). We found that 82.5% of children with cancer or HSCT recipients reported bothersome fatigue and 24.5% of children reported severely bothersome fatigue. Risk factors for severely bothersome fatigue were older age and inpatients receiving active cancer treatment. Future work should evaluate systematic symptom screening in clinical practice and apply interventions to reduce fatigue.

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.