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Legacy data show that ∼40% of children with acute lymphoblastic leukemia (ALL) were cured with limited antimetabolite-based chemotherapy regimens. However, identifying patients with very-low-risk (VLR) ALL remains imprecise. Patients selected based on a combination of presenting features and a minimal residual disease (MRD) level <0.01% on day 19 of induction therapy had excellent outcomes with low-intensity treatment. We investigated the impact of MRD levels between 0.001% and <0.01% early in remission induction on the outcome of VLR ALL treated with a low-intensity regimen. Between October of 2011 and September of 2015, 200 consecutive patients with B-precursor ALL with favorable clinicopathologic features and MRD levels <0.01%, as assessed by flow cytometry in the bone marrow on day 19 and at the end of induction therapy, received reduced-intensity therapy. The 5-year event-free survival was 89.5% (± 2.2% standard error [SE]), and the overall survival was 95.5% (± 1.5% SE). The 5-year cumulative incidence of relapse (CIR) was 7% (95% confidence interval, 4-11%). MRD levels were between 0.001% and <0.01% on day 19 in 29 patients. These patients had a 5-year CIR that was significantly higher than that of patients with undetectable residual leukemia (17.2% ± 7.2% vs 5.3% ± 1.7%, respectively; P = .02). Our study shows that children with VLR ALL can be treated successfully with decreased-intensity therapy, and it suggests that the classification criteria for VLR can be further refined by using a more sensitive MRD assay., (© 2021 by The American Society of Hematology.)

Treatment-related mortality is common among children with acute lymphoblastic leukemia (ALL) treated in poor-resource settings. We applied a simplified flow cytometric assay to identify patients with precursor B-cell ALL (B-ALL) at very low risk (VLR) of relapse and treated them with a reduced-intensity treatment plan (RELLA05). VLR criteria include favorable presenting features (age ≥ 1 and < 10 years), white blood cell count of <50 ×109/L, lack of extramedullary leukemia, and minimal residual disease level of <0.01% on remission induction day 19. Except for 2 doses of daunorubicin, treatment of patients with VLR B-ALL consisted of a combination of agents with relatively low myelotoxicity profiles, including corticosteroids, vincristine, L-asparaginase, methotrexate, and 6-mercaptopurine. Cyclophosphamide, systemic cytarabine, and central nervous system radiotherapy were not used. Of 454 patients with ALL treated at the Instituto de Medicina Integral Professor Fernando Figueira in Recife, Brazil, between December 2005 and June 2015, 101 were classified as having VLR B-ALL. There were no cases of death resulting from toxicity or treatment abandonment during remission induction. At a median follow-up of 6.6 years, there were 8 major adverse events: 6 relapses, 1 treatment-related death (from septicemia) during remission, and 1 secondary myeloid leukemia. The estimated 5-year event-free and overall survival rates were 92.0% ± 3.9% and 96.0% ± 2.8%, respectively. The 5-year cumulative risk of relapse was 4.24% ± 2.0%. The treatment was well tolerated. Episodes of neutropenia were of short duration. Patients with B-ALL selected by a combination of presenting features and degree of early response can be successfully treated with a mildly myelosuppressive chemotherapy regimen., (© 2020 by The American Society of Hematology.)

Cure rates for pediatric acute lymphoblastic leukemia differ markedly in higher- and lower-income countries due to disparate hospital infrastructure and resources. Where means are limited, treatment-related mortality is higher and compliance may be suboptimal. Upfront risk assignment is aimed at individualizing therapy according to presenting features in order to avoid over- or under-treatment. However, the necessary technical resources and expertise are not always readily available. The authors provide suggestions for management of childhood acute lymphoblastic leukemia in developing nations. To improve patient care locally, the authors recommend that communication technology be used to sustain partnerships between sponsoring and partner pediatric oncology programs. The aims of these collaborations should be to prioritize resources, identify existing problems and reduce treatment intensity and hence treatment-related morbidity and mortality in patients at lower risk of relapse.

Background: Pediatric oncology nurses in low- and middle-income countries have limited access to specialized education and clinical training. This is a major impediment for treating children with cancer and contributes to the disparity in survival rates between high- and low-income countries. The International Outreach Nursing Program at St Jude Children's Research Hospital established full-time nurse educator positions at partner sites throughout Latin America. Experienced nurses were hired as educators; however, they had no formal pediatric oncology education, limited teaching experience, and no mentors as this was a new nursing role in low- and middle-income countries., Objective: Our objective was to create a regional education center to prepare nurse educators to succeed in this pioneering role., Interventions: The Latin American Center for Pediatric Oncology Nursing Education was created at Calvo Mackenna Hospital in Santiago, Chile, to provide education, resources, and support to educators. Education resources, including a comprehensive orientation program and courses in chemotherapy and central venous line care, were developed. A 4-week on-site comprehensive educator course and an organized support system were implemented., Results: Education, resources, and support have been provided to 13 nurse educators representing 7 Latin American countries. The educators have provided pediatric oncology education to more than 1000 nurses., Conclusions: The center promotes excellence in pediatric oncology nursing by preparing and supporting educators, who in turn educate the entire nursing staff at partner sites., Implications for Practice: Nurse educators equipped with knowledge and skills can improve the quality of care and ultimately survival of patients throughout Latin America.

Background: The Chilean population is ethnically diverse, and more than 50% of children referred for hematopoietic stem cell transplantation (HSCT) lack a suitable donor., Procedure: To expand the donor pool, we assessed the feasibility, tolerance, and efficacy of using a haploidentical (HI) donor and a reduced-intensity conditioning regimen for high-risk pediatric leukemia. This study was facilitated by technology transfer from St. Jude Children's Research Hospital over the 2 preceding years., Results: Between March 2006 and April 2009, 10 patients (median age, 9.8 years) received T cell-depleted grafts at Calvo Mackenna Hospital in Santiago. Median cell doses were CD34+: 7.45 × 10(6)/kg (range, 4.00-20.20 × 10(6)/kg); CD3+: 0.88 × 10(5)/kg (0.11-1.35 × 10(5)/kg); and CD56+: 71.30 × 10(6)/kg (31.50-131.80 × 10(6)/kg). Nine patients experienced complete engraftment; six of the nine remain alive and clinically well 13-50 months post-HSCT. Three patients died after bone marrow relapse, while only one died of transplant-related causes. Virus reactivation was the main post-transplant complication: 5/10 had positive CMV PCR but none had CMV disease. One patient developed acute GvHD > grade II and only one had chronic GvHD., Conclusions: HI-HSCT is feasible in our setting, offers a rational treatment option, and expands the donor pool significantly for children with high-risk leukemia in a developing country. This information is especially relevant to other ethnically diverse populations that are poorly represented in international donor registries., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: A frontline protocol for newly diagnosed osteosarcoma was conducted simultaneously at St. Jude Children's Research Hospital (sponsor) and Calvo Mackenna Hospital (CMH, partner), a public pediatric hospital and national center for the treatment of bone tumors in Santiago, Chile., Procedure: Of 72 eligible patients, 22 (31%) were enrolled and managed in Santiago, without travel to Memphis. Pathology specimens and imaging material were centrally reviewed at St. Jude. Patients received 12 intensive courses of systemic chemotherapy with hematopoietic growth factor support over 35 weeks, and amputation or limb-salvage surgery as indicated for local control. The sponsor assisted the partner site to establish a clinical research infrastructure and obtain hematopoietic growth factor. Communication among medical and nursing teams was maintained throughout the study. Patient-care and protocol issues were discussed frequently between the two centers via scheduled videoconferences and electronic communications. Auditors monitored appropriate study conduct at the international site., Results: No major discrepancies were identified in histologic findings, staging, or imaging studies. Preliminary results demonstrated similar outcome and treatment tolerance; the 2-year event-free survival estimate was 78.5% (95% CI, 51-100%) for patients treated at CMH (median follow-up, 1.6 years) and 74.3% (95% CI, 62-87%) for patients treated at St. Jude (median follow-up, 4 years). Overall per-patient costs were significantly lower in Chile., Conclusions: Through a twinning mechanism, it is feasible to simultaneously conduct complex front-line osteosarcoma clinical trials at two institutions in countries with different levels of resources., ((c) 2007 Wiley-Liss, Inc.)

Background: The authors evaluated the response rate, toxicity, and pharmacokinetics of topotecan given before standard induction therapy for childhood acute lymphoblastic leukemia (ALL) in first relapse., Methods: Patients received topotecan (2.4 mg/m(2) daily as a 30-minute infusion) for 5 days before induction therapy with dexamethasone, vincristine, and asparaginase (native or pegylated Escherichia coli). The pharmacokinetics of topotecan were measured with the first dose of treatment in 23 patients., Results: Twenty-eight of 31 patients with circulating blast cells were evaluable for response to topotecan. Twenty-five patients (89.3%) had a response (>25% decrease in circulating blast cells). The leukocyte count (P = .0001) and blast cell count (P = .0009) declined significantly during topotecan therapy. The median (range) topotecan lactone area under the concentration-time curve after the first dose was 85.4 L/hour/m(2) (range, 38.7-229.3 L/hour/m(2)). At the end of induction, 23 patients (74.2%) had a complete response, 1 patient (3.2%) had a partial response, 5 patients (16.1%) had no response, and 2 patients had died of infection. Six of the 17 patients who were studied for minimal residual disease (MRD) achieved MRD-negative status at the end of induction. The main toxicities were hematologic, gastrointestinal, and hepatic. The estimated 5-year survival rate, event-free survival rate, and cumulative incidence of second relapse were 24.1% +/- 7.9%, 18.2% +/- 7.4%, and 22.8% +/- 8.7%, respectively, in the 29 patients who had a hematologic first relapse., Conclusions: A regimen comprising single-agent topotecan given with a standard 3-drug combination was effective in inducing remission in pediatric patients with relapsed ALL and was tolerated well.

Context: Little is known about the incidence of secondary neoplasms after 15 to 20 years in children and adolescents who were treated for acute lymphoblastic leukemia., Objectives: To investigate the cumulative incidence of secondary neoplasms in pediatric patients treated for acute lymphoblastic leukemia over 30 years and to characterize late-occurring tumors., Design, Setting, and Patients: Retrospective study of 2169 patients with acute lymphoblastic leukemia treated between 1962 and 1998 at St Jude Children's Research Hospital, Memphis, Tenn, who achieved complete remission and had a median follow-up time of 18.7 years (range, 2.4-41.3 years)., Main Outcome Measures: Cumulative incidences of secondary neoplasms in first remission and standard incidence ratios of observed rates compared with rates of cancer development in the general US population., Results: Secondary neoplasms developed as the first event in 123 patients and comprised 46 myeloid malignancies, 3 lymphomas, 14 basal cell carcinomas, 16 other carcinomas, 6 sarcomas, 16 meningiomas, and 22 other brain tumors. The cumulative incidence of secondary neoplasm was 4.17% (SE, 0.46%) at 15 years and increased substantially after 20 years, reaching 10.85% (SE, 1.27%) at 30 years. When meningiomas and basal cell carcinomas were excluded, the overall cumulative incidence was 3.99% (SE, 0.44%) at 15 years and 6.27% (SE, 0.83%) at 30 years, representing a 13.5-fold increase in overall risk compared with the general population. The cumulative incidence of each tumor type at 30 years was 2.19% (SE, 0.32%) for myeloid malignancy, 0.17% (SE, 0.10%) for lymphoma, 3.00% (SE, 0.59%) for brain tumor, 4.91% (SE, 1.04%) for carcinoma, and 0.57% (SE, 0.37%) for sarcoma., Conclusions: The cumulative incidence of secondary neoplasms increases steadily over 30 years after treatment of acute lymphoblastic leukemia. Although the majority of the late-occurring secondary neoplasms are low-grade tumors, the increase in incidence of more aggressive malignant neoplasms is significantly higher than expected in the general population. These results suggest that lifelong follow-up of acute lymphoblastic leukemia survivors is needed to ascertain the full impact of treatment and other leukemia-related factors on secondary neoplasm development.

Bone marrow normal lymphoid progenitors (CD19+, CD10+, and/or CD34+) are exquisitely sensitive to corticosteroids and other antileukemic drugs. We hypothesized that, in patients with B-lineage acute lymphoblastic leukemia (ALL), cells with this phenotype detected early in treatment should be leukemic rather than normal. We therefore developed a simple and inexpensive flow cytometric assay for such cells and prospectively applied it to bone marrow samples collected on day 19 from 380 children with B-lineage ALL. In 211 patients (55.5%), these cells represented 0.01% or more of the mononuclear cells; results correlated remarkably well with those of more complex flow cytometric and molecular minimal residual disease (MRD) evaluations. Among 84 uniformly treated children, the 10-year incidence of relapse or remission failure was 28.8% +/- 7.1% (SE) for the 42 patients with 0.01% or more leukemic cells on day 19 detected by the simplified assay versus 4.8% +/- 3.3% for the 42 patients with lower levels (P = .003). These assay results were the strongest predictor of outcome, even after adjustment for competing clinicobiologic variables. Thus, this new assay would enable most treatment centers to identify a high proportion of children with ALL who have an excellent early treatment response and a high likelihood of cure.

Background: In Chile, survival estimates for pediatric patients with cancer are comparable to those in the United States and Western Europe. Approximately 80% of these patients are treated at government-supported centers, and an estimated 65% are cured. We reasoned that cure rates could be further improved if transplantation with hematopoietic stem cells were available for patients with chemotherapy-resistant malignancy., Patients and Methods: Physicians and nurses were selected to be trained in international centers, and a transplantation unit was developed at Luis Calvo Mackenna Hospital in Santiago. Between October 1999 and December 2003, 59 patients received transplants. Of these, 42 were from HLA-matched family members and 11 were autologous., Results: The 3-year event-free survival estimate was 72 +/- 10% overall, and it was 81 +/- 10% for the subgroup treated with matched related transplants. Peritransplant mortality was 6.6%. The average cost for an allogeneic transplant in our unit was 50,000 US dollars., Conclusions: We are encouraged by this experience as well as by the overall survival rates and hope to expand the program. Our goal is to extend treatment to all children in the country for whom HSCT is indicated, including those who do not have HLA-identical family donors., ((c) 2005 Wiley-Liss, Inc.)

To assess the prognosis of overt testicular disease at diagnosis of acute lymphoblastic leukemia, and any therapeutic role of irradiation for this involvement, we reviewed the data of 811 boys treated on St Jude studies Total X--XI (early period) and Total XII-XIV (recent period). In all, 19 boys (2.3%) had testicular disease at diagnosis. In the early period, patients with testicular leukemia had a poorer overall survival (OS) (P=0.003), event-free survival (EFS) (P=0.064), and higher cumulative incidence of relapse (P=0.041) than did other patients. During the recent period, patients with and without overt testicular leukemia did not differ in OS (P=0.257), EFS (P=0.102), or cumulative incidence of relapse (P=0.51). In a multivariate analysis, OS was lower for patients with testicular disease than for those without the involvement in the early period (P=0.047) but not in the recent one (P=0.75). Both patients who received irradiation for residual testicular disease at the end of induction subsequently died of leukemia. Of the other 17 patients who did not receive irradiation, only one developed testicular relapse in combination with bone marrow relapse. In conclusion, the prognostic impact of overt testicular disease has diminished. Irradiation appears to provide no survival advantage to this patient population., (Leukemia (2005) 19, 1399-1403.)

Background: Although most pediatric oncologists obtain routine blood counts in patients who have completed treatment for acute lymphoblastic leukemia (ALL), the value of this practice is unproven. We therefore sought to determine if detection of relapse by blood counts before the onset of symptoms provided any clinical benefit., Procedures: We performed a retrospective review of 72 patients with ALL who suffered isolated or combined hematologic relapses after the completion of therapy. We compared attainment of second remission and survival after relapse among patients who were asymptomatic and diagnosed by routine blood count, those who had symptoms suggestive of relapse and were diagnosed at the time of a scheduled follow-up, and those whose relapse was diagnosed because of the appearance of symptoms., Results: Only 11% of patients who suffered a relapse were asymptomatic at the time of relapse and diagnosed solely by routine blood counts. There were no significant differences in the survival distributions for the three groups of patients., Conclusions: In this cohort of patients with relapsed ALL, we found no evidence that detection of relapse by routine blood counts before the onset of symptoms leads to a better outcome.

Background: The authors studied the clinical outcome of 106 children with acute lymphoblastic leukemia (ALL) who developed a bone marrow recurrence as the first adverse event after contemporary intensified therapy., Methods: Endpoints were the rates and lengths of second remission, the cumulative incidence of second hematologic recurrence, second event-free survival (EFS), and survival., Results: Bone marrow recurrences were isolated in 79 patients, and combined with an extramedullary site in 27 patients. The median time to recurrence was 2.6 years (range, 0.3-11.6 years). Seventy-six patients (71.7%) attained a second remission (median length, 0.7 year; range, 0.03-13.3 years). The 5-year survival probability among all patients was 24.2% +/- 4.2% (standard error). On multivariate analysis, time to first disease recurrence and blast cell lineage were found to be independent predictors of a second EFS (P = 0.008 and P = 0.028, respectively). The 5-year EFS estimate in patients with an initial disease remission of >/= 36 months was 42.6% +/- 7.8% but was only 12.5% +/- 3.9% among children with a short duration of disease remission (< 36 months). These estimates were 28.7% +/- 4.9% and 5.0% +/- 3.4%, respectively, for B blast and T blast cell lineages., Conclusions: Despite acceptable long-term second EFS rates for certain subgroups, overall bone marrow recurrence after intensified first-line therapy for childhood ALL signals a poor outcome., ((c) 2004 American Cancer Society.)

St Jude Total Therapy Study XIIIB for childhood acute lymphoblastic leukemia (ALL) incorporated more stringent risk classification, early intensification of intrathecal chemotherapy, reinduction treatment, and the addition of dexamethasone to postremission therapy to increase the proportion of event-free survivors without jeopardizing their quality of life. Cranial irradiation was reserved for the 12% of patients who had T-cell ALL and a presenting leukocyte count of 100 x 10(9)/L or more, or CNS-3 (5 or more leukocytes/microL with identifiable blast cells in an atraumatic sample or the presence of cranial nerve palsy) status. Among the 247 consecutive patients enrolled in the study, 117 were classified as having lower-risk leukemia and received mainly antimetabolite-based continuation therapy; the 130 cases with higher-risk leukemia received more intensive continuation chemotherapy with multiple drug pairs administered in weekly rotation. The 5-year event-free survival estimate was 80.8% +/- 2.6% (SE); the 8-year rate was 78.6% +/- 5.8%. The 5-year cumulative risk of an isolated central nervous system (CNS) relapse was 1.7% +/- 0.8%, and that of isolated plus combined CNS relapse was 3.0% +/- 1.1%. The 5-year cumulative risks of etoposide-related myeloid malignancies were 1.8% +/- 1.3% in the lower-risk patients who received a cumulative dose of 1.2 g/m(2) and 5.0% +/- 2.0% in the higher-risk patients who received a cumulative dose of up to 14.4 g/m(2) (P = .18). Independent adverse prognostic features included the presence of MLL-AF4 or BCR-ABL fusion gene and minimal residual leukemia of 0.01% or more at the end of the 6-week remission induction phase. Our results suggest the efficacy of early intensification of intrathecal chemotherapy and provide the basis for studies omitting cranial irradiation altogether.

We evaluated the clinical response to low-dose etoposide in relapsed acute lymphoblastic leukemia (ALL). Of the 45 patients with ALL in first bone marrow relapse enrolled on the ALL R15 protocol, 44 had received epipodophyllotoxins during frontline therapy. In the first week of remission induction therapy, patients received etoposide (50 mg/m(2) per day) administered orally as a single agent once or twice daily. On Day 8, patients started to receive dexamethasone, vincristine, and L-asparaginase. Etoposide was administered until Day 22. Two courses of consolidation therapy were followed by continuation therapy or hematopoietic stem cell transplantation. After 7 days of single-agent etoposide treatment, peripheral blast cell counts (P=0.013) and percentages of bone marrow blasts (P=0.016) were significantly reduced. In all, 38 (84.4%) attained second remission. Only time to relapse was significantly associated with outcome (P=0.025): the 5-year event-free survival estimates (+/-se) were 52.0+/-9.6% for those with late relapse and 20.0+/-8.0% for those with early relapse. We conclude that low-dose etoposide administered orally has a cytoreductive effect in relapsed ALL.

Using flow cytometric techniques capable of detecting 0.01% leukemic cells, we prospectively studied minimal residual disease (MRD) in patients with acute lymphoblastic leukemia (ALL) after first relapse. At the end of remission reinduction, 41 patients had a bone marrow sample adequate for MRD studies; 35 of these were in morphologic remission. Of the 35 patients, 19 (54%) had MRD >/=0.01%, a finding that was associated with subsequent leukemia relapse. The 2-year cumulative incidence of second leukemia relapse was 70.2+/-12.3% for the 19 MRD-positive patients and 27.9+/-12.4% for the 16 MRD-negative patients (P=0.008). Among patients with a first relapse off therapy, 2-year second relapse rates were 49.1+/-17.8% in the 12 MRD-positive and 0% in the 11 MRD-negative patients (P=0.014); among those who received only chemotherapy after first relapse, the 2-year second relapse rates were 81.5+/-14.4% (n=12) and 25.0+/-13.1% (n=13), respectively (P=0.004). Time of first relapse and MRD were the only two significant predictors of outcome in a multivariate analysis. We conclude that MRD assays should be used to guide the selection of postremission therapy in patients with ALL in first relapse.