Reduced-intensity therapy for pediatric lymphoblastic leukemia: impact of residual disease early in remission induction.

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.

Reduced-dose intensity therapy for pediatric lymphoblastic leukemia: long-term results of the Recife RELLA05 pilot study.

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.

Improving treatment of children with acute lymphoblastic leukemia in developing countries through technology sharing, collaboration and partnerships.

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.

The Latin American Center for Pediatric Oncology Nursing Education: development, implementation, and accomplishments.

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.

Haploidentical stem cell transplantation for children with high-risk leukemia.

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.

Phase II study of topotecan in combination with dexamethasone, asparaginase, and vincristine in pediatric patients with acute lymphoblastic leukemia in first relapse.

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.

Transfer of complex frontline anticancer therapy to a developing country: the St. Jude osteosarcoma experience in Chile.

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.

Cumulative incidence of secondary neoplasms as a first event after childhood acute lymphoblastic leukemia.

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.

A simplified flow cytometric assay identifies children with acute lymphoblastic leukemia who have a superior clinical outcome.

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.

Establishment of a pediatric HSCT program in a public hospital in Chile.

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.

Lack of benefit of early detection of relapse after completion of therapy for acute lymphoblastic leukemia.

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.

Bone marrow recurrence after initial intensive treatment for childhood acute lymphoblastic leukemia.

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.

Improved outcome for children with acute lymphoblastic leukemia: results of Total Therapy Study XIIIB at St Jude Children's Research Hospital.

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.

Reassessment of the prognostic significance of hypodiploidy in pediatric patients with acute lymphoblastic leukemia.

BACKGROUND: The purpose of the current study was to evaluate the cytogenetic features of the hypodiploid leukemic cells of pediatric patients with this rare subgroup of acute lymphoblastic leukemia (ALL). In addition, the authors determined whether subdivision of the hypodiploid category served a prognostic purpose for these patients. METHODS: The authors evaluated the cytogenetic records of 979 patients with ALL admitted to St. Jude Children's Research Hospital (Memphis, TN) between 1984 and 1999. RESULTS: Of 67 patients (6.8%) whose leukemic cells contained a modal number (MN) of chromosomes less than or equal to 45 (i.e., hypodiploid leukemic cells), 57 had an MN of 45 and 10 had an MN of less than 45. In 19 patients, cells with an MN of 45 had a whole chromosome missing (42%), which was a sex chromosome in 12 patients (63%). Leukemic cells with an MN of 45 contained dicentric chromosomes (n = 33) formed from chromosome 9p (55%), 12p (18%), or both (21%). The ETV6-CBFA2 fusion was present in 39% of 28 evaluable B-lineage cases with an MN of 45. The event-free survival rate (EFS) for patients with hypodiploid leukemic cells of MN less than 45 (5-year EFS = 20.0% +/- 10.3%) was significantly (P < 0.001) lower than that for patients with leukemic cells of MN greater than or equal to 45 (5-year EFS = 74.9% +/- 1.6%). CONCLUSIONS: Low hypodiploidy (MN < 45) should be recognized as a high-risk feature in pediatric ALL. Only two hypodiploid groups (MN < 45 and MN = 45) may be necessary in prognostic assessments.

Results of therapy for acute lymphoblastic leukemia in black and white children.

CONTEXT: Treatment results for acute lymphoblastic leukemia (ALL) clearly have improved over the past decade, but black children have not fared as well as white children in large national trials. OBJECTIVE: To compare the clinical outcomes of therapy for black and white children with ALL treated at a single institution. DESIGN, SETTING, AND PATIENTS: A retrospective analysis of 412 children and adolescents (68 black, 338 white, and 6 other race) with newly diagnosed ALL who were treated consecutively at a pediatric cancer center in Memphis, Tenn. Patients were enrolled from December 1991 to July 1998 in successive Total Therapy studies regardless of race, ethnicity, or ability to pay and received risk-directed therapy according to stringent criteria. INTERVENTIONS: All patients received the same intensive, remission-induction therapy followed by 120 weeks of risk-assigned postremission therapy that included reinduction treatment, pulses of high-dose methotrexate, and early intensification of intrathecal chemotherapy. MAIN OUTCOME MEASURES: Event-free and overall survival rates for black and white children were estimated by the method of Kaplan and Meier and compared with the Mantel-Haenszel test and by Cox proportional hazards regression analysis, adjusting for known prognostic factors. RESULTS: The 68 black children were significantly more likely than the 338 white children to have higher-risk prognostic features, including an initial leukocyte count greater than 100 x 10(3)/ microL, a T-cell immunophenotype, and the t(1;19) chromosomal translocation with E2A-PBX1 fusion, and were less likely to have hyperdiploid blast cells, a favorable prognostic factor in childhood ALL. However, the clinical outcomes for these 2 cohorts were not significantly different: 5-year event-free and overall survival rates were 80.7% (95% confidence interval [CI], 70.3%-91.1%) and 86.2% (95% CI, 77.2%-95.2%) for black children vs 79.4% (95% CI, 74.7%-84.1%) and 85.0% (95% CI, 80.9%-89.1%) for white children. Ten-year results also were comparable, but the CIs were wide because of the small numbers of patients who had been followed up for 10 years or more. The lack of a racial effect on the long-term outcome of therapy was still apparent in a multivariate Cox regression analysis, adjusting for sex, age, presenting leukocyte count, leukemic cell DNA index, immunophenotype, and central nervous system status. CONCLUSION: With equal access to effective antileukemic therapy, black and white children with ALL can expect the same high rate of cure.

Extended follow-up of long-term survivors of childhood acute lymphoblastic leukemia.

BACKGROUND: Children who survive acute lymphoblastic leukemia are at risk for leukemia-related or treatment-related complications, which can adversely affect survival and socioeconomic status. We determined the long-term survival and the rates of health insurance coverage, marriage, and employment among patients who had attained at least 10 years of event-free survival. METHODS: A total of 856 eligible patients were treated between 1962 and 1992 in 13 consecutive clinical trials. Survival rates, the cumulative risk of a second neoplasm, and selected indicators of socioeconomic status were analyzed for the entire group and for patients who did or did not receive cranial or craniospinal radiation therapy during initial treatment. RESULTS: Fifty-six patients had major adverse events, including 8 deaths during remission, 4 relapses, and 44 second neoplasms (41 of them radiation-related); most of the second neoplasms were benign or of a low grade of malignant potential. The risk of a second neoplasm was significantly higher in the 597 patients who received radiation therapy (irradiated group) than in the 259 patients who did not receive radiation therapy (nonirradiated group) (P=0.04; estimated cumulative risk [+/-SE] at 20 years, 20.9+/-3.9 percent vs. 0.95+/-0.9 percent). The death rate for the irradiated group slightly exceeded the expected rate in the general U.S. population (standardized mortality ratio, 1.90; 95 percent confidence interval, 1.12 to 3.00), whereas that for the nonirradiated group did not differ from the population norm (standardized mortality ratio, 1.75; 95 percent confidence interval, 0.34 to 5.00). The rates of health insurance coverage, marriage, and employment in the nonirradiated group were similar to the age- and sex-adjusted national averages. Despite having health insurance rates similar to those in the general population, men and women in the irradiated group had higher-than-average unemployment rates (15.1 percent vs. 5.4 percent and 35.4 percent vs. 5.2 percent, respectively), and women in the irradiated group were less likely to be married (35.2 percent vs. 48.8 percent). CONCLUSIONS: Children with acute lymphoblastic leukemia who did not receive radiation therapy and who have attained 10 or more years of event-free survival can expect a normal long-term survival. Irradiation is associated with the development of second neoplasms, a slight excess in mortality, and an increased unemployment rate.

Antagonism by methotrexate on mercaptopurine disposition in lymphoblasts during up-front treatment of acute lymphoblastic leukemia.

BACKGROUND: Methotrexate is postulated to enhance mercaptopurine activation to thioguanine (INN, tioguanine) nucleotides, but the interaction has never been studied in vivo in cancer cells. METHODS: We investigated the effect of methotrexate on mercaptopurine disposition in plasma and leukemic blasts during up-front treatment of 233 children with newly diagnosed acute lymphoblastic leukemia. Children were randomized to receive intravenous mercaptopurine (1 g/m(2) over a 6-hour period) or to receive methotrexate (low dose, 6 oral doses of 30 mg/m(2), or high dose, 1 g/m(2) intravenously), followed by intravenous mercaptopurine. All combinations have been previously used in frontline trials for acute lymphoblastic leukemia. RESULTS: Compared with mercaptopurine alone, methotrexate resulted in higher plasma mercaptopurine concentrations (30.3 +/- 14.7 micromol/L versus 23.5 +/- 18.0 micromol/L, P <.001) but, conversely, a 13-fold lower thioguanine nucleotide concentration (0.57 +/- 0.66 pmol/5 x 10(6) cells versus 7.4 +/- 15.2 pmol/5 x 10(6) cells, P <.001) in bone marrow leukemic lymphoblasts. Methotrexate was also associated with higher plasma hypoxanthine concentrations compared with those of patients given mercaptopurine alone (8.7 +/- 13.5 micromol/L versus 3.8 +/- 2.5 micromol/L, P =.029). The percentage change in leukocyte counts measured over a 3-day period showed that mercaptopurine alone had little effect (mean decrease, 20% +/- 33%). In contrast, despite causing lower intracellular thiopurine active metabolite concentrations, methotrexate produced a greater decrease in leukocyte counts (mean, 53% +/- 35%) compared with those in patients receiving mercaptopurine alone (P <.0001). CONCLUSION: These pharmacologic findings in the target tissue are consistent with the recently demonstrated lack of clinical benefit of intravenous mercaptopurine in combination with methotrexate. We conclude that, in the setting of newly diagnosed acute lymphoblastic leukemia, methotrexate antagonizes thiopurine metabolite disposition in leukemic blasts after intravenous mercaptopurine.

Pharmacokinetics and pharmacodynamics of oral etoposide in children with relapsed or refractory acute lymphoblastic leukemia.

PURPOSE: To study the pharmacokinetics and pharmacodynamics of once- versus twice-daily oral etoposide in children with relapsed or refractory acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Fifty-eight patients were randomly assigned to etoposide at 50 mg/m(2)/d with once- versus twice-daily doses for 22 days. On day 8, vincristine, asparaginase, and dexamethasone were started. Etoposide pharmacokinetics and pharmacodynamics were studied for 47, 28, and 26 patients on day 1, 8, and 22, respectively, of remission reinduction therapy. RESULTS: Of 48 patients with pharmacokinetic data, 42 (87.5%) achieved complete remission, three (6.3%) failed to achieve remission, and three (6.3%) died during induction. Median etoposide day 8 area under concentration-time curve (AUC) and cumulative AUC tended to be greater (P =.06 and P =.07, respectively) in patients (n = 23) who achieved complete remission (24 and 522 micro mol/L x h, respectively) than in patients (n = 3) who did not (14 and 303 micro mol/L x h, respectively). Three of eight patients with plasma concentrations exceeding 1.7 micro M (1 micro g/mL) for more than 8 hours daily, compared with one of 20 patients with concentrations exceeding 1.7 micro M for

Granulocyte colony-stimulating factor and the risk of secondary myeloid malignancy after etoposide treatment.

Event-free survival for children with acute lymphoblastic leukemia (ALL) now exceeds 80% in the most effective trials. Failures are due to relapse, toxicity, and second cancers such as therapy-related myeloid leukemia or myelodysplasia (t-ML). Topoisomerase II inhibitors and alkylators can induce t-ML; additional risk factors for t-ML remain poorly defined. The occurrence of t-ML among children who had received granulocyte colony-stimulating factor (G-CSF) following ALL remission induction therapy prompted us to examine this and other putative risk factors for t-ML in 412 children treated on 2 consecutive ALL protocols from 1991 to 1998. All children received etoposide and anthracyclines, 99 of whom received G-CSF; 284 also received cyclophosphamide, 58 of whom also received cranial irradiation. There were 20 children who developed t-ML at a median of 2.3 years (range, 1.0-6.0 years), including 16 cases of acute myeloid leukemia, 3 myelodysplasia, and 1 chronic myeloid leukemia. Stratifying by protocol, the cumulative incidence functions differed (P =.017) according to the use of G-CSF and irradiation: 6-year cumulative incidence (standard error) of t-ML of 12.3% (5.3%) among the 44 children who received irradiation without G-CSF, 11.0% (3.5%) among the 85 children who received G-CSF but no irradiation, 7.1% (7.2%) among the 14 children who received irradiation plus G-CSF, and 2.7% (1.3%) among the 269 children who received neither irradiation nor G-CSF. Even when children receiving irradiation were excluded, the incidence was still higher in those receiving G-CSF (P =.019). In the setting of intensive antileukemic therapy, short-term use of G-CSF may increase the risk of t-ML.