Background and Aims

Acute lymphoblastic Leukemia (ALL) is the most common pediatric malignancy worldwide. While the overall survival for ALL in high-income countries is over 90%, the estimated survival in low-and middle-income countries ranges from 22-79%. This study retrospectively analyzed the outcomes of children with ALL in South America, at 5 pediatric centers in Bolivia, Ecuador, Peru, and Paraguay.

Methods

A retrospective review examined data for children less than 18 years old diagnosed and treated for ALL these centers between 2013-2017. Descriptive indices of demographic, clinical, and biological parameters were analyzed, as well as reasons for treatment failure.

Results

Interim analysis of 595 patients included patients with B-cell (92.1%) and T-cell (7.4%) ALL, with a mean age of 7 years. At the time of diagnosis, 49.2% of patients were categorized as standard risk and 50.8% high risk. Most patients (58.2%) were CNS1 status, however CNS status was not evaluated in 38.7% of patients and not available in 1%. MRD evaluation was obtained in 66.7% of total patients. Of 588 patients, 485 experienced chemotherapy delays with a median of 17 days (1-100). Delays were attributed to infection (63.8%, 204/320), multiple drug related toxicities (43.8%, 140/320), resource constraints including bed availability (21.9%, 70/320), and abandonment (5%, 16/320). The 5-year event-free and overall survival (EFS, OS) were 62.0+3.5% and 74.9+3.2%, respectively. EFS events included: 4 induction failures, 41 induction deaths, 124 relapses (70 marrow, 32 CNS, 17 combined, 5 other), and 27 remission deaths.

Conclusions

EFS and OS estimated in this study support recently published estimates for the region. This work provides important insight into causes for treatment delay and treatment-related mortality such as infections and toxicities, which may be related to treatment intensity and contribute to mortality and relapse. The details of this analysis provide opportunities for interventions to further improve outcomes for ALL patients in this region.

Background and Aims

Risk-stratified and response-adapted therapy is considered standard for Childhood Acute Lymphoblastic Leukemia(cALL). Response-assessment by Minimal Residual Disease(MRD) on Flowcytometry(FCM) has become fundamental to therapeutic decisions. We piloted ICiCLe-2014, a multicenter-trial for cALL at our center for 5-years before commencing on-trial enrollment. Outcomes of B-ALL patients on this strategy were analyzed.

Methods

B-ALL patients <15-years age treated on ICiCLe-pilot protocol from Feb-2013 – Feb-2018 were included. Risk-stratification was by NCI criteria to standard and intermediate risks. Children with high-risk cytogenetics, CNS involved and poor Day-8 prednisolone-response(PR) were further classified as high-risk. MRD by 10-color multiparametric-FCM at the end-of-induction(EoI) ≥0.01% were subsequently treated as high-risk. 3-year Event-free and Overall Survival(EFS & OS) were estimated by Kaplan-Meir method, and risk-factors by Odds-ratio using Jamovi (Version-1.6).

Results

There were 1406 patients with median follow-up 32-months(range:24-84), median age 5-years(range:1-15), M:F-2:1, median baseline total leucocyte-count(BTLC)-32000/µL, CNS-involved-57(4.2%), and Testis-involved-21(2%). Cytogenetics showed No translocations:1029(73.19%), ETV6-RUNX1:176(12.5%), TCF3-PBX1:114(8.1%), BCR-ABL:53(3.7%), MLLr:24(1.7%), HLF-TCF3:2(0.14%), iAMP21:2(0.14%) (6 patients(0.43%)-no records). Day-8PR was Good in 1124(85%) (79 not-evaluated:5-early deaths, 74-no records). On initial risk-stratification, Standard Risk(SR) were 431(30.76%), Intermediate Risk(IR):492(35.12%), and High Risk(HR):478(34.12%). Of these, 1322 patients evaluated for EoI-MRD (84 not evaluated:79 induction-deaths, 5-no records); 967(73%) were Negative, 355(27%)-Positive. Three-year EFS and OS 69.1±1.4% and 80.4±1.1% respectively. By final-risk, 3-year EFS for SR, IR and HR were 85.5±4.3%, 76.5±4.9%, 65.8±4.1%, and OS, 93.68±3.0%, 88.39±3.6%, 78.39±3.5% respectively. Univariate analyses showed significant hepato-splenomegaly, BTLC>33.4/µL, MLLr, Poor D-8PR, Initial and Final Risk-stratification, and EoI-MRD as significant, of which only BTLC>33.4/µL(p<0.001%), MLLr(p=0.004%)and EoI-MRD(p=0.001%) retained significance on multi-variate analyses.

Conclusions

A risk-stratified, response-adapted strategy for B-ALL was piloted successfully in a single-center, yielding improved outcomes and the risk/response parameters held true, with poor biology and EoI-MRD emerging as the most important risk-factors for outcome.

Acknowledgements: ICiCLe-2014 Study Group, National Cancer Grid, Indian Council of Medical Research

Background and Aims

Ten to fifteen percent of children with acute lymphoblastic leukemia (ALL) relapse following treatment. Of these, only few display ophthalmic relapses, which owing to their scarcity are largely undocumented leaving clinicians with few diagnostic and therapeutic recommendations, despite serious functional sequelae.

Methods

We conducted a national French multicenter spanning over 20 years to collect all clinical, radiological, biological, and therapeutic data and outcome for children with ALL ophthalmic relapses.

Results

From 2000 to 2020, 31 ophthalmic relapses were diagnosed, with an estimated rate of ophthalmic relapse of 2.8%. Among them, 19 B-ALL and 12 T-ALL: 25 patients (81%) had concomitant involvement of Central Nervous System (CNS), 18 (58%) a combined bone marrow relapse, and only 1 had an isolated ophthalmic relapse. The most frequent symptoms were reduced visual acuity (n=22, 71%) and ocular pain (n=7, 23%). Ten (32.6%) had a bilateral ophthalmic involvement and 20 patients (65%) had papilledema. Combined medullary relapse was not a significant worse prognosis factor (OR 3.39 p:0.15) contrary to hypopyon (p:0.04). Total body irradiation (p = 0.001) was associated with an improvement in overall survival. More patients alive in complete remission (CR) underwent an allogenic hematopoietic stem cell transplantation (OR 0.13; p:0.01). All the patients who received chimeric antigen receptor T cells (n=4) relapsed afterwards. Ten children (31%) died, 9 from a refractory disease and 1 from toxic death. Five patients have recently relapsed. Among the 16 survivors in CR, 8 display severe ophthalmic sequelae including complete blindness with a median follow-up of 19.9 months.

Conclusions

Although rare, ophthalmic relapses have a significant impact on the functional prognosis of survivors. These observations confirm the important role of CNS prophylaxis in 1^rst line and indicate the need to define optimal management approaches for ophthalmic relapse, including cerebral irradiation. Their management must be multidisciplinary, with a fundamental role for ophthalmologists.

Background and Aims

Children with B-acute lymphoblastic leukemia (B-ALL) are at risk for chemotherapy-induced peripheral neuropathy (CIPN) from vincristine. AALL0932 randomized reduction in vincristine/dexamethasone (every 4 week [VCR/DEX4] vs every 12 week [VCR/DEX12]) during maintenance in the average-risk subset of NCI standard-B-ALL (SR AR B-ALL) and did not find a difference in disease-free survival. We longitudinally measured CIPN, overall, and in VCR/DEX4 vs VCR/DEX12.

Methods

SR AR B-ALL patients from AALL0932 ≥3 years old, without prior neuromuscular disease, and with an English/Spanish speaking parent were evaluated at four time-points (end-consolidation [n=150], start of maintenance [n=108], month 18 of maintenance [n=102], 12 months post-therapy [n=73]. CIPN was assessed by motor (hand/ankle strength, ankle dorsiflexion/plantarflexion range of motion [ROM]), sensory (finger/toe vibration), and functional (dexterity; Purdue Pegboard, gait; 6 Minute Walk) impairment. Age/sex matched z-scores and proportion impaired (z-score < -1.3) were measured longitudinally and compared between groups.

Results

Among 150 participants (mean age 5.1 years [SD=1.7], 48.7% female) at end consolidation, there was frequent impairment in motor/sensory function (59.3% handgrip strength, 31.8% ankle strength, 32.5% plantarflexion ROM, 27.9% dorsiflexion ROM, 27.4% toe vibration, 13.8% finger vibration) and daily function (83.5% gait, 55.0% dexterity). By 12 months post-therapy, only handgrip strength (p<0.001) and gait (p=0.02) had improved; there was no improvement in sensation, ankle strength/range of motion, or dexterity (vs end-consolidation). In VCR/DEX4 (n=50) vs VCR/DEX12 (n=63) there was no difference in frequency of impairments at month 18 of maintenance or 12 months post-therapy except impaired ankle dorsiflexion ROM (VCR/DEX4 46.7% vs. VCR/DEX12 14.7%, p=0.007). Group comparisons did not change after adjusting for baseline functioning.

Conclusions

SR AR B-ALL patients frequently experience CIPN early in therapy that can persist at least 12 months post-therapy. Except dorsiflexion ROM, outcomes were similar in VCR/DEX4 vs VCR/DEX12. Children with SR AR B-ALL should be monitored for CIPN, even with reduced vincristine frequency.

Background and Aims

Background: Long-term survivors of pediatric acute lymphoblastic leukemia (ALL) are at increased risk for developing neurocognitive deficits and corresponding brain dysfunction. The aim of this study was to investigate functional brain activity associated with working memory in long-term pediatric ALL survivors, with a particular focus on sex-based differences.

Methods

Methods: Functional magnetic resonance imaging (fMRI) and neurocognitive testing were obtained in 123 survivors treated on the St. Jude Total 15 treatment protocol (46% male; median [min-max] age = 14.2 [8.3-26.5] years; time since diagnosis = 7.7 [5.1-12.5] years). FMRI was obtained on a 3T scanner during a n-back working memory task. Functional neuroimaging data were preprocessed (realigned, slice time corrected, normalized and smoothed) and analyzed using Statistical Parametric Mapping with contrasts developed for the 1-back, 2-back, and 2-back vs 1-back conditions, which reflect varying degrees of working memory load. Group level fMRI contrasts were stratified by sex and adjusted for age at evaluation and methotrexate dosage (i.e., methotrexate area-under-the-curve).

Results

Results: Female survivors displayed less activation (i.e., reduced blood-oxygen-dependent-level signaling) in the right parietal operculum, supramarginal gyrus and inferior occipital gyrus, and reductions in the bilateral superior frontal medial segment and anterior cingulate gyrus during increased working memory task load (FWE corrected p<0.01, adjusting for age and methotrexate dose) in comparison to males. Although there were no differences in mean performance accuracy by sex, female survivors displayed slower reaction times during the 2-back condition compared to males (p<0.05). Male survivors demonstrated greater deficits in cognitive flexibility as measured using a standardized neurocognitive battery (p<0.05).

Conclusions

Conclusion: These results suggest that female survivors display a reduced pattern of activation in the working memory network, which may reflect an unidentified sex-based chemosensitivity.

Background and Aims

Introduction: Children with acute lymphoblastic leukemia (ALL) have excellent survival with current therapy. This shifts the focus to the burden of therapy. Serious toxicity is common and the knowledge how the child’s leukemia and its treatment impacts the quality of life of parents is incomplete.

Aims: The aim was to assess health-related quality of life (HRQoL) in mothers and fathers of patients from Sweden, Finland and Denmark, who had been treated on the NOPHO ALL-2008 protocol 2008-2019.

Methods

Methods: The 36-Item Short Form Survey Instrument (SF-36) was used to determine parent HRQoL, approximately 6 months after completed treatment. 526 parents of 310 children treated for ALL were recruited 2010-2019. Normative data for SF-36 from Norway was used as reference. The influence of parental background factors on their HRQoL was analysed in linear regression models.

Results

Results: Participating parents scored lower than the reference population on both physical and mental summary indexes (-1.16, 95% CI [-1.88, -0.45] and -7.72, 95% CI [-8.84, -6.61], respectively). Mothers scored lower than fathers in both indexes. Mothers were more likely than fathers to stop working and take care of the affected child. Higher income was associated with higher physical HRQoL. Higher mental HRQoL was associated with male gender and living in Finland or Denmark (compared to Sweden). Correlation in scores between spouses was weak (0.278, p < 0.001 and 0.375, p < 0.001, physical and mental scores respectively).

Conclusions

Conclusions: Parents of children treated for ALL report reduced HRQoL after cessation of therapy. The effect on HRQoL was more pronounced for mothers. These findings suggest that the need for support is different for mothers and fathers.