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The management of Refractory/Relapsed B-cell Acute Lymphoblastic Leukemia (R/R ALL) remains challenging. Incorporating blinatumomab in R/R ALL treatment has shown encouraging results. We describe the outcome and predictors of response in children receiving blinatumomab as a bridge to definitive therapy. Immunoglobulin (Ig) G and viral serology before and after therapy were evaluated. Thirty-three patients that failed standard first-line treatments due to relapsed ALL ( n =  22), persistent minimal residual disease (MRD) ( n =  8), or refractory disease ( n =  3) received blinatumomab. Grade 2 toxicity occurred in 27.2% of patients. MRD remission (<0.01%) was achieved in 72.7% of patients. Pre-blinatumomab absolute lymphocyte count (ALC) and MRD/ALC ratio significantly associated with MRD-response. Patients with t(1;19) translocation had lower response rate, compared to all other cytogenetic categories ( p =  0.013). One-year event-free survival (EFS) and overall survival (OS) were 69.2% and 79.7%, respectively. Analysis of OS and EFS showed pre-blinatumomab MRD level, ALC, MRD/ALC ratio, t(1;19) , and post-blinatumomab MRD remission associated with survival. Following blinatumomab, 83% (15/18) of tested patients had low IgG levels. IgG seronegative status was observed in 83% (12/15) for varicella zoster, 35% (6/17) for herpes zoster, 18% (3/17) for cytomegalovirus, and 26% (5/17) for Epstein Barr virus. Blinatumomab produced encouraging results in children with R/R ALL and low disease burden bridging to definitive therapy. Incorporating baseline genetics and biomarkers may help identify subgroups likely to be responsive/resistant to therapy. Viral serological testing pre- and post-blinatumomab is recommended to optimize supportive and preemptive therapy.Supplemental data for this article is available online at https://doi.org/10.1080/08880018.2022.2049936 .

Introduction: The incidence of childhood acute lymphoblastic leukemia (cALL) varies between countries likely as a result of competing risks including infections, access-to-care, socioeconomic influences, and/or ethnicity. However, little is known about disease burden in high-income Arab countries offering free-of-charge healthcare. The hypothesis was that, due to population characteristics (young age, high fertility and parental consanguinity rate), the incidence of cALL in Saudi Arabia is equal or higher than that observed in high-income Western countries., Methods: Saudi databases were used to calculate the incidence of cALL from 2001 to 2014. Incidence trends over time of children with ALL, 14-years of age or younger, were analyzed and compared with those reported in USA., Results: The age-adjusted incidence over the years was lower in Saudi Arabia compared to USA. However, the incidence trend of cALL in Saudi Arabia was increasing at a rate higher than that observed in USA (p < 0.001). The overall incidence of cALL in Saudi Arabia increased from 1.58/100,000 in 2001 to 2.35/100,000 population in 2014. The median annual increase was 4.58 %. The incidence in males increased from 1.88 to 2.71/100,000, and from 1.21 to 1.86/100,000 population in females., Conclusions: The reported incidence of cALL in Saudi Arabia is rapidly increasing. The increasing trend may reflect evolving socioeconomic structure, improved access-to-cancer care, and improved diagnosis/ reporting capacity. This highlights the need for better understanding of cALL causes and the need for the formation of separate national pediatric cancer registries in different countries to monitor childhood cancer incidence trends., Competing Interests: Declaration of Competing Interest The author declares that there are no conflicts of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objectives: Acute lymphoblastic leukemia (ALL) with CNS2 status predicts inferior outcome and a high rate of CNS relapse, similar to overt CNS leukemia (CNS3). The purpose of this study was to determine if intrathecal (IT) dose intensification during induction would improve outcomes and reduce CNS relapse for CNS2 disease., Methods: From January 2001 to December 2014, children (1-14 years) with newly diagnosed ALL were treated at the Princess Noorah Oncology Centre (PNOC) following modifications of the Children's Oncology Group (COG) protocols. We intensified IT methotrexate (ITM) during induction for patients with CNS2 disease. Patients were evaluated for overall survival (OS), disease-free survival (DFS), and cumulative incidence of relapse (CIR)., Results: 449 children with T-cell (14.3%) or B-cell (85.7%) ALL were treated using PNOC-SR or PNOC-HR regimens (Jan 2001- Dec 2007) or CALL08 regimens (Arm A [SR], Arm B [IR], and Arm C [HR]) (Jan 2008 - Dec 2014). The 5-year OS, DFS, and CIR were 87.2 ± 1.6%, 81.7 ± 1.9%, and 13.0 ± 1.7%, respectively. The OS and DFS of patients with CNS2 were significantly superior to that of patients with CNS3 (P = 0.025 and P = 0.019, respectively). Patients with CNS2 had similar OS and DFS to those with CNS1. None of the patients with CNS2 at initial diagnosis experienced CNS relapse., Conclusions: ITM intensification during induction was associated with elimination of CNS recurrence in patients with CNS2 disease and childhood ALL. Controlled studies are needed to confirm this observation.

Background: Outcomes of relapsed/refractory childhood acute leukemia remain poor. We analyzed the safety/efficacy of fludarabine, cytarabine, and granulocyte colony stimulating factor, with/without idarubicin (FLAG ± IDA) as salvage therapy compared with recent published results of novel therapies., Methods: This retrospective study included children aged 1 to 15 years with relapsed/refractory acute leukemia who received FLAG ± IDA salvage therapy from January 2000 to December 2014. Patients with infant leukemia, mixed lineage leukemia, Philadelphia-positive acute leukemia, or secondary leukemia were excluded., Result: Fifty patients were identified: 25 with acute lymphoblastic leukemia and 25 with acute myeloid leukemia. The median age at initiation of FLAG ± IDA was seven years. Site of relapse was the bone marrow in 29, isolated central nervous system in 11, and combined in 10 patients. FLAG ± IDA was used after first relapse in 68% and after multiple relapses in 32%. Complete remission was achieved in 34 (68%) patients. No variables predictive of complete remission were identified. Grade 3 or greater toxicity was observed in 96% and 6% died from toxicity. Toxicities included hematologic toxicity (96%), infection (52%), and enterocolitis (28%). Twenty-four of 50 (48%) patients achieved a sustained complete remission and survived to bone marrow transplantation. The five-year overall survival was 23.9% ± 6.9%. Patients achieving second complete remission and patients proceeding to bone marrow transplantation following second complete remission demonstrated significantly improved overall survival (p = 0.001)., Conclusion: Despite a 68% complete remission rate using FLAG ± IDA, only 48% of patients survived to bone marrow transplantation. The regimen was associated with 96% toxicity and only one in four patients was alive at five years. This underscores the need to find more effective lower toxicity salvage regimens.

Introduction: The development of cancer programs in developing countries to meet the standards observed in high-income developed countries is not well documented., Methods: An analysis of patient care of children with acute lymphoblastic leukemia (ALL) at the Princess Noorah Oncology Center over 25 years was performed. A number of improvements were introduced over time including optimizing the cancer care delivery culture, improving access to care, optimizing supportive care, and refining diagnostic and therapeutic capabilities. Outcomes were evaluated over three time periods (period 1, 1989-2000; period 2, 2001-2007; and period 3, 2008-2014). These findings were compared with results of collaborative clinical trials (CCT)., Results: Of the 686 patients treated, the five-year overall survival (OS) rate improved from 74% ± 2.7% in period 1 to 89.5% ± 2.3% in period 3 (P < 0.0001). Among all patients, the five-year cumulative incidence of death decreased from 26% in period 1 to 10.5% in period 3 (P < 0.0001). This decrease was mainly due to reduction in the incidence of death from disease (P < 0.00001). In contrast, significant improvement in T-cell ALL survival outcomes (P < 0.0001) was observed overtime (from period 1 to period 3) as a result of significant reduction in both toxic deaths (P = 0.005) and disease-related deaths (P = 0.001)., Conclusions: Survival outcomes in Saudi Arabia have improved with five-year OS rate now approaching 90%. However, further population-based research is needed to understand variance in outcomes from those reported by CCT groups., (© 2019 Wiley Periodicals, Inc.)

Geographic variation and ethnicity have been implicated to influence the outcome of pediatric acute myeloid leukemia (AML). Furthermore, survival outcomes from developing countries are reported to be inferior to developed nations. We hypothesized that risk- and response-based outcome in high-income resource-rich developing countries would be comparable to developed nations as access to care and supportive measures would be similar. A total of 193 children diagnosed with de novo AML between January 2005 and December 2012 were identified, of those 175 were evaluable for outcome. Patients were stratified into low-risk (LR), intermediate-risk (IR), or high-risk (HR) groups. The complete remission (CR), early death, and induction failure rates were: 85.7%, 2.3%, and 12%; respectively. The 5-year cumulative incidences of relapse (CIR) and non-relapse mortality (NRM) were 43.1% and 9.8% respectively; overall survival (OS) was 58.8±4% and event-free survival (EFS) 40.9±4.1%. The 5-year OS for LR, IR, and HR groups were 72.0±6.9%, 59.8±6.2%, and 45.1±7.4%; respectively (p=0.003); and EFS 50.5±8.0%, 46.3±6.4%, and 23.3±6.4%; respectively (p=0.001). This study demonstrated comparable outcomes to those reported from developed countries. This suggests that utilization of risk- and response-based protocols in developing countries can overcome ethnic and geographic variation, if access to care and supportive measures were similar., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objectives: Treatment regimens tested in major clinical trials, conducted by cooperative groups, are often adapted as standard of care by cancer centers with the hope to replicate the treatment outcomes reported in these landmark studies. It is therefore postulated that applying clinical trial regimens in a non-clinical trial setting yield similar outcomes. The aim of the present study was to explore this hypothesis in the context of childhood acute lymphoblastic leukemia (ALL) in our institution., Methods: We retrospectively evaluated 224 consecutive pediatric ALL cases treated between January 2001 and December 2007. Standard-risk (SR) patients were treated on CCG-1991 (regimen OD) while high-risk (HR) patients were treated on CCG-1961 (regimen D). Results were compared with those of the equivalent regimen in the original clinical trials. Statistical analysis was carried using chi-square or Fisher's exact test, Kaplan-Meier and log-rank tests., Results: Comparison of treatment outcomes revealed that SR patients had inferior 5-year overall survival (OS) of (89.0 ± 2.9 vs. 96.0% ± 0.9%); event-free survival of (82.3 ± 3.5 vs. 88.7% ± 1.4%); and relapse rate of (15.8 vs. 9.3% (P = 0.034)) compared to patients treated in the clinical trial. However, no statistically significant difference in treatment outcomes was observed between HR patients., Conclusions: Despite using comparable regimens, suboptimal outcomes were noted in SR patients implying that similar treatments do not necessarily yield similar outcomes. This underscores the need to evaluate outcomes of adapted regimens to identify areas that need further improvement in centers not enrolling patients on prospective collaborative clinical trials.

Objectives: We aimed to determine whether the addition of two extra intrathecal methotrexate (ITM) doses during induction in acute lymphoblastic leukemia (ALL) patients eliminate the prognostic significance of CNS2/TLP+ status., Methods: We retrospectively analyzed 224 patients according to the central nervous system (CNS) involvement at diagnosis: CNS1, CNS2, or CNS3. Patients with CNS2/TLP+ received two additional ITM doses during induction. Patients were treated according to the Children's Cancer Group (CCG)-1991/1961 protocols between January 2001 and December 2007., Results: The 5-year relapse-free survival (RFS) rates for the ALL patients in the CNS1, CNS2, and CNS3 groups were 80.4 ± 3.0, 100, and 73.5 ± 11.3%, respectively; a non-significant difference was observed between the groups (P = 0.063). However, the patients with CNS2 had significantly better survival compared with the CNS3 patients (P = 0.03). The 5-year cumulative incidence of relapse (CIR) rates for the three groups were 17 (95% confidence interval (CI): 11.9-22.9), 0, and 18.8% (95% CI: 4.3-41.1), respectively; (P = 0.214) and those of isolated or combined CNS relapse were 9.6 (95% CI: 5.8-14.5), 0 and 6.3% (95% CI: 0.3-25.8), respectively (P = 0.424)., Conclusions: This study shows that the intensification of ITM therapy during induction improves outcomes in patients with CNS2/TLP+ status and eliminates its prognostic significance. This suggests that early intensification using CNS-directed therapy is beneficial in controlling minimal CNS disease.

Background: The outcome of children with acute lymphoblastic leukemia (ALL) in developing countries is less favorable than in developed countries, primarily due to resource constraints. However, it is unknown whether the therapeutic results differ. Thus, we hypothesized that outcomes in resource-rich developing countries would be similar to those in industrialized regions., Procedure: We performed a retrospective analysis of 224 consecutive children with ALL, who were treated according to the Children's Cancer Group (CCG) protocols between January 2001 and December 2007. High-risk (HR) and standard-risk (SR) patients were treated with modified CCG-1961 and CCG-1991 protocols, respectively. Modifications included substitution of dexamethasone for prednisone in HR patients and addition of two intrathecal methotrexate treatments for CNS2 patients during induction. All patients received double delayed intensification with two interim maintenance phases., Results: Five-year overall survival (OS), event-free survival (EFS) and disease-free survival (DFS) were 84.7 ± 2.4%, 77.0 ± 2.9%, and 81.4 ± 2.7%, respectively. Remission was achieved in 98.1% of the patients. Induction failure and relapse rates were 1.9% and 15.1%, respectively. Death as the first event occurred in 6.4% of cases, of which 2.7% and 3.7% involved deaths in induction and remission, respectively. Interestingly, a significant reduction in induction deaths was observed over time., Conclusions: Despite the encouraging results observed in the present study, our patients displayed significantly lower survival outcomes compared to subjects treated in major clinical trials conducted by leading leukemia cooperative groups. Furthermore, this work underscores the need for targeted interventions to reduce death as the first event in developing regions., (© 2014 Wiley Periodicals, Inc.)