Outcomes after induction failure in childhood acute lymphoblastic leukemia.

BACKGROUND: Failure of remission-induction therapy is a rare but highly adverse event in children and adolescents with acute lymphoblastic leukemia (ALL). METHODS: We identified induction failure, defined by the persistence of leukemic blasts in blood, bone marrow, or any extramedullary site after 4 to 6 weeks of remission-induction therapy, in 1041 of 44,017 patients (2.4%) 0 to 18 years of age with newly diagnosed ALL who were treated by a total of 14 cooperative study groups between 1985 and 2000. We analyzed the relationships among disease characteristics, treatments administered, and outcomes in these patients. RESULTS: Patients with induction failure frequently presented with high-risk features, including older age, high leukocyte count, leukemia with a T-cell phenotype, the Philadelphia chromosome, and 11q23 rearrangement. With a median follow-up period of 8.3 years (range, 1.5 to 22.1), the 10-year survival rate (±SE) was estimated at only 32±1%. An age of 10 years or older, T-cell leukemia, the presence of an 11q23 rearrangement, and 25% or more blasts in the bone marrow at the end of induction therapy were associated with a particularly poor outcome. High hyperdiploidy (a modal chromosome number >50) and an age of 1 to 5 years were associated with a favorable outcome in patients with precursor B-cell leukemia. Allogeneic stem-cell transplantation from matched, related donors was associated with improved outcomes in T-cell leukemia. Children younger than 6 years of age with precursor B-cell leukemia and no adverse genetic features had a 10-year survival rate of 72±5% when treated with chemotherapy only. CONCLUSIONS: Pediatric ALL with induction failure is highly heterogeneous. Patients who have T-cell leukemia appear to have a better outcome with allogeneic stem-cell transplantation than with chemotherapy, whereas patients who have precursor B-cell leukemia without other adverse features appear to have a better outcome with chemotherapy. (Funded by Deutsche Krebshilfe and others.).

Prediction of outcome by early bone marrow response in childhood acute lymphoblastic leukemia treated in the ALL-BFM 95 trial: differential effects in precursor B-cell and T-cell leukemia.

BACKGROUND: In the ALL-BFM 95 trial for treatment of acute lymphoblastic leukemia, response to a prednisone pre-phase (prednisone response) was used for risk stratification in combination with age and white blood cell count at diagnosis, response to induction therapy and specific genetic high-risk features. DESIGN AND METHODS: Cytomorphological marrow response was prospectively assessed on Day 15 during induction, and its prognostic value was analyzed in 1,431 patients treated on ALL-BFM 95. RESULTS: The 8-year probabilities of event-free survival were 86.1%, 74.5%, and 46.4% for patients with M1, M2, and M3 Day 15 marrows, respectively. Compared to prednisone response, Day 15 marrow response was superior in outcome prediction in precursor B-cell and T-cell leukemia with, however, a differential effect depending on blast lineage. Outcome was poor in T-cell leukemia patients with prednisone poor-response independent of Day 15 marrow response, whereas among patients with prednisone good-response different risk groups could be identified by Day 15 marrow response. In contrast, prednisone response lost prognostic significance in precursor B-cell leukemia when stratified by Day 15 marrow response. Age and white blood cell count retained their independent prognostic effect. CONCLUSIONS: Selective addition of Day 15 marrow response to conventional stratification criteria applied on ALL-BFM 95 (currently in use in several countries as regular chemotherapy protocol for childhood acute lymphoblastic leukemia) may significantly improve risk-adapted treatment delivery. Even though cutting-edge trial risk stratification is meanwhile dominated by minimal residual disease evaluation, an improved conventional risk assessment, as presented here, could be of great importance to countries that lack the technical and/or financial resources associated with the application of minimal residual disease analysis.

Low platelet counts after induction therapy for childhood acute lymphoblastic leukemia are strongly associated with poor early response to treatment as measured by minimal residual disease and are prognostic for treatment outcome.

BACKGROUND: Numerous reports have been published on the association between kinetics of leukemic cells during early treatment of childhood acute lymphoblastic leukemia and therapeutic outcome. In contrast, little is known about the prognostic relevance of normal blood counts in this setting. DESIGN AND METHODS: Normal hematopoiesis during and after induction treatment (days 8, 15 and 33) was correlated with therapeutic outcome in a cohort of 256 children with acute lymphoblastic leukemia treated in one of three consecutive ALL-BFM trials at a single institute. Replication analysis of positive findings was performed in an independent cohort of 475 patients from the ALL-BFM 2000 multicenter trial. RESULTS: A platelet count in the first quartile on treatment day 33 and a neutrophil count above the median on day 8 were significantly associated with treatment outcome, conferring multivariate risk ratios for an event of 3.27 (95% confidence interval 1.60-6.69) and 2.26 (95% confidence interval 1.23-4.29), respectively. Replication analysis confirmed the prognostic effect of platelet count on treatment day 33 and demonstrated a strong association with minimal residual disease-based risk group distribution (P<0.00001). CONCLUSIONS: Platelet counts after induction treatment may improve treatment stratification for patients with childhood acute lymphoblastic leukemia and be of particular interest in non-minimal residual disease-based trials. (ALL-BFM 2000 is registered at: ClinicalTrials.gov: NCT00430118. National Cancer Institute: Protocol ID 68529).

Thiopurine methyltransferase genetics is not a major risk factor for secondary malignant neoplasms after treatment of childhood acute lymphoblastic leukemia on Berlin-Frankfurt-Münster protocols.

Thiopurine methyltransferase (TPMT)is involved in the metabolism of thiopurines such as 6-mercaptopurine and 6-thioguanine. TPMT activity is significantly altered by genetics, and heterozygous and even more homozygous variant people reveal substiantially decreased TPMT activity. Treatment for childhood acute lymphoblastic leukemia (ALL) regularly includes the use of thiopurine drugs. Importantly, childhood ALL patients with low TPMT activity have been considered to be at increased risk of developing therapy-associated acute myeloid leukemia and brain tumors. In the present study, we genotyped 105 of 129 patients who developed a secondary malignant neoplasm after ALL treatment on 7 consecutive German Berlin-Frankfurt-Münster trials for all functionally relevant TPMT variants. Frequencies of TPMT variants were similarly distributed in secondary malignant neoplasm patients and the overall ALL patient population of 814 patients. Thus, TPMT does not play a major role in the etiology of secondary malignant neoplasm after treatment for childhood ALL, according to Berlin-Frankfurt-Münster strategies.

Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95.

The trial ALL-BFM 95 for treatment of childhood acute lymphoblastic leukemia was designed to reduce acute and long-term toxicity in selected patient groups with favorable prognosis and to improve outcome in poor-risk groups by treatment intensification. These aims were pursued through a stratification strategy using white blood cell count, age, immunophenotype, treatment response, and unfavorable genetic aberrations providing an excellent discrimination of risk groups. Estimated 6-year event-free survival (6y-pEFS) for all 2169 patients was 79.6% (+/- 0.9%). The large standard-risk (SR) group (35% of patients) achieved an excellent 6y-EFS of 89.5% (+/- 1.1%) despite significant reduction of anthracyclines. In the medium-risk (MR) group (53% of patients), 6y-pEFS was 79.7% (+/- 1.2%); no improvement was accomplished by the randomized use of additional intermediate-dose cytarabine after consolidation. Omission of preventive cranial irradiation in non-T-ALL MR patients was possible without significant reduction of EFS, although the incidence of central nervous system relapses increased. In the high-risk (HR) group (12% of patients), intensification of consolidation/reinduction treatment led to considerable improvement over the previous ALL-BFM trials yielding a 6y-pEFS of 49.2% (+/- 3.2%). Compared without previous trial ALL-BFM 90, consistently favorable results in non-HR patients were achieved with significant treatment reduction in the majority of these patients.

Pulses of vincristine and dexamethasone in addition to intensive chemotherapy for children with intermediate-risk acute lymphoblastic leukaemia: a multicentre randomised trial.

BACKGROUND: Studies in the 1970s and 1980s suggested that the outcome of childhood acute lymphoblastic leukaemia (ALL) could be improved by intensification of conventional continuation chemotherapy with pulses of vincristine sulfate and steroids. We aimed to investigate the efficacy and toxic effects of vincristine-dexamethasone pulses as an addition to the continuation-therapy phase in a large cohort of children with intermediate-risk disease who were treated with the Berlin-Frankfurt-Münster (BFM) treatment strategy. METHODS: 3109 children, diagnosed with ALL and intermediate-risk features, were enrolled by eight participating organisations in eleven countries. All were treated with very similar protocols based on the BFM treatment strategy, which included induction, consolidation, reinduction, and continuation-therapy phases. At the beginning of the continuation-therapy phase, those patients in complete remission were randomly assigned to either a treatment or a control group. Control patients were given conventional mercaptopurine and methotrexate chemotherapy only. Patients in the treatment arm were also given pulses of vincristine (1.5 mg/m2 weekly for 2 weeks) and dexamethasone (6 mg/m2 daily for 7 days) every 10 weeks for six cycles. The primary outcome measure was disease-free survival. Analysis was by intention to treat. The study is registered at http://www.clinicaltrials.gov with the identifier NCT00411541. FINDINGS: 174 patients (5.6%) relapsed or died in complete remission before randomisation. Of the remaining 2935 patients, 2618 (89.2%) were randomly assigned: 1325 to the treatment group and 1293 to the control group. With median follow-up of 4.8 years, 240 children in the treatment group and 241 in the control group had relapses; 15 in the treatment group and 14 controls died in complete remission or developed second malignant neoplasms. The 5-year and 7-year disease-free survival estimates were 79.8% (SE 1.2) and 77.5% (1.5) in the treatment group and 79.2% (1.2) and 78.4% (1.3) in the control group, respectively. Treatment with pulses of vincristine and dexamethasone was associated with a non-significant 3% relative-risk reduction (hazard ratio 0.97; 95% CI 0.81-1.15; p=0.70). INTERPRETATION: Children with intermediate-risk ALL who received intensive chemotherapy based on BFM protocols did not benefit from intensification of the continuation-therapy phase with a schedule of pulses of vincristine and dexamethasone.

Diagnostic cerebrospinal fluid examination in children with acute lymphoblastic leukemia: significance of low leukocyte counts with blasts or traumatic lumbar puncture.

PURPOSE: To determine the significance of leukemic blasts or traumatic lumbar puncture (TLP) in diagnostic CSF of children enrolled in the Berlin-Frankfurt-Münster (BFM) Acute Lymphoblastic Leukemia-BFM-95 trial. PATIENTS AND METHODS: A total of 2,021 patients were retrospectively evaluated according to initial central nervous system (CNS) status. Patients were classified as follows: CNS1 (CNS negative, n = 1,605), CNS2 (< or = 5 WBC/ micro L CSF with blasts, n = 103), CNS3 (CNS positive, n = 58), TLP+ (TLP with blasts, n = 135), or TLP- (TLP without blasts, n = 111). Patients with CNS2 and TLP+ status were eligible for two additional doses of intrathecal (IT) methotrexate (MTX). CNS3 patients received additional IT MTX and cranial irradiation (18 Gy). RESULTS: CNS2, CNS3, and TLP+ groups contained a higher percentage of patients with unfavorable characteristics. Cox regression analysis identified TLP+ and CNS3 status as prognostically significant (CNS3): risk ratio (RR) = 2.3; 95% confidence interval [CI], 1.4 to 3.6; P =.0005; TLP+: RR = 1.5; 95% CI, 1.02 to 2.2; P =.04. Overall 5-year event-free survival (EFS) is 79%, for CNS1 it is 80%, and for TLP- it is 83%. CNS2 patients have an EFS of 80%, but the cumulative incidence of relapses with CNS involvement is higher compared with CNS1 patients (0.10 v 0.04). TLP+ patients have a significantly reduced EFS (73%, P =.003) because of an increased incidence of CNS relapses. CNS3 patients suffer from more systemic and CNS relapses (EFS 50%). CONCLUSION: CNS2 patients have the same prognosis as patients with CNS1 status, whereas the EFS of TLP+ patients is inferior to CNS1 but superior to CNS3 patients (P =.001). Both subgroups may have benefitted from additional IT MTX.

Treatment results of childhood acute lymphoblastic leukemia in Austria--a report of 20 years' experience.

Between 1981 and 1999, 890 Austrian children with acute lymphoblastic leukemia (ALL) were treated in 5 consecutive trials using protocols from the Berlin-Frankfurt-Münster (BFM) Group. In the trials BFM-A (Austria) 81 and ALL A 84, treatment stratification was performed using a risk factor, which was calculated from the initial peripheral blast cell count, and size of liver and spleen. In the following studies (BFM-A 86, 90 and 95) early response to a 7-day systemic mono-therapy with prednisone (as measured by the peripheral blast cell count) was used as an overriding stratification factor; in order to reduce the need for cranial radiotherapy, all patients received high-dose methotrexate (5 g/m2) for preventive central nervous system treatment. Event-free survival (EFS) rates increased from study BFM-A 81 (n = 141, probability (p) of EFS: 59% +/- 4%) and study ALL A 84 (n = 127, pEFS: 67% +/- 4%) to 77% +/- 4% in trial BFM-A 86 (n = 142), 79% +/- 3% in trial BFM-A 90 (n = 256), and 84% +/- 3% in trial BFM-A 95 (n = 224). However, the prognosis for high-risk patients has not significantly improved within the last 20 years (pEFS: 50%). Furthermore, conventional risk factors such as leukocyte count and age at time of diagnosis, could not be used to indicate patients in the low and intermediate risk group who might eventually relapse. Thus, in trial BFM-A 2000, detection of minimal residual disease by polymerase chain reaction-based methods after 5 and 12 weeks of therapy was introduced for treatment stratification. Minimal residual disease was prospectively shown to predict relapses more precisely and, as a matter of fact, may allow a more exact definition of which patients are at risk and which patients belong to the subgroup with a good prognosis despite reduced treatment.

Malignant non-Hodgkin's lymphoma of childhood and adolescence in Austria--therapy results between 1986 and 2000.

Between 1986 and 2000 183 Austrian children and adolescents with non-Hodgkin's lymphoma (NHL) and mature B-cell acute leukemia (B-ALL) were enrolled in 3 consecutive studies of the Berlin-Frankfurt-Münster (BFM) Group. In trial NHL-BFM 86, patients were stratified according to the histologic subtype and clinical stage. In the succeeding studies NHL-BFM 90 and 95, treatment stratification was additionally based on the speed of tumor response to therapy and for children with B-cell NHL/B-ALL also on the pre-therapeutic serum lactic dehydrogenase level. Event-free survival rates were 84% +/- 6% in trial NHL-BFM 86 (n = 39) and 86% +/- 4% in both trials NHL-BFM 90 (n = 67) and NHL-BFM 95 (n = 77). Patients with lymphoblastic lymphoma (mainly with T-cell phenotypes) had an excellent prognosis with an ALL-type chemotherapy regimen (n = 49; relapse, n = 1), whereas an intensive, short-pulse therapy delivered within a 2- to 4-month period was found to be highly efficacious in children with B-cell NHL/B-ALL (n = 114; relapse, n = 6; progression, n = 5). Patients with anaplastic large cell lymphoma (ALCL) who were treated with similar alternating short courses of multi-agent chemotherapy had a less good outcome (n = 20; relapse, n = 6, progression, n = 3). Children with B-cell NHL and B-ALL who failed initial therapy also had a dismal prognosis (10/11 patients died). Local radiotherapy as a part of lymphoma therapy was completely abandoned in study NHL-BFM 90 and surgical interventions were confined to specific situations such as complete resection in localized B-cell NHL and ALCL, diagnostic biopsy and second-look operation. In conclusion, our results showed that the BFM treatment strategy for lymphoblastic lymphoma and B-cell NHL/B-ALL was highly successful in the majority of patients; however, optimal treatment for children with ALCL has not yet been defined. As a consequence, larger trials at an international level are necessary to find new prognostic markers that might define more precisely those patients who need further intensification of first-line treatment or novel therapy.

Intensive chemotherapy for childhood acute lymphoblastic leukemia: results of the randomized intercontinental trial ALL IC-BFM 2002.

PURPOSE: From 2002 to 2007, the International Berlin-Frankfurt-Münster Study Group conducted a prospective randomized clinical trial (ALL IC-BFM 2002) for the management of childhood acute lymphoblastic leukemia (ALL) in 15 countries on three continents. The aim of this trial was to explore the impact of differential delayed intensification (DI) on outcome in all risk groups. PATIENTS AND METHODS: For this trial, 5,060 eligible patients were divided into three risk groups according to age, WBC, early treatment response, and unfavorable genetic aberrations. DI was randomized as follows: standard risk (SR), two 4-week intensive elements (protocol III) versus one 7-week protocol II; intermediate risk (IR), protocol III × 3 versus protocol II × 1; high risk (HR), protocol III × 3 versus either protocol II × 2 (Associazione Italiana Ematologia Oncologia Pediatrica [AIEOP] option), or 3 HR blocks plus single protocol II (Berlin-Frankfurt-Münster [BFM] option). RESULTS: At 5 years, the probabilities of event-free survival and survival were 74% (± 1%) and 82% (± 1%) for all 5,060 eligible patients, 81% and 90% for the SR (n = 1,564), 75% and 83% for the IR (n = 2,650), and 55% and 62% for the HR (n = 846) groups, respectively. No improvement was accomplished by more intense and/or prolonged DI. CONCLUSION: The ALL IC-BFM 2002 trial is a good example of international collaboration in pediatric oncology. A wide platform of countries able to run randomized studies in ALL has been established. Although the alternative DI did not improve outcome compared with standard treatment and the overall results are worse than those achieved by longer established leukemia groups, the national results have generally improved.

Integrating molecular information into treatment of childhood acute lymphoblastic leukemia--a perspective from the BFM Study Group.

Acute lymphoblastic leukemia (ALL) is the most common malignancy of childhood and is treated with chemotherapy alone or, in particular subgroups, with additional radiation therapy and/or stem cell transplantation. The treatment intensity is adjusted according to prognostic factors associated with the risk of ALL recurrence. On Berlin-Frankfurt-Münster (BFM) protocols, the widely applicable early in vivo response to treatment as measured by the reduction of leukemic cells in the blood or bone marrow is currently the most important prognostic factor. However, although overall long-term cure rates for childhood ALL treated on risk-adapted protocols have dramatically improved over the last decades and, to date, are higher than 75%, a significant number of patients still die due to recurrent disease or the toxicity of treatment applied. One goal in future BFM trials will be to take advantage of a better molecular understanding of leukemia and host characteristics to dissect the mechanisms underlying the differences in treatment response. This short review focuses on the evolution of treatment response in BFM trials and provides a perspective on our strategy for improving molecular characterization of childhood ALL and implementing more individualized and novel therapeutic approaches.

Superiority of allogeneic hematopoietic stem-cell transplantation compared with chemotherapy alone in high-risk childhood T-cell acute lymphoblastic leukemia: results from ALL-BFM 90 and 95.

PURPOSE: The role of hematopoietic stem-cell transplantation (SCT) in first complete remission (CR1) for children with very high-risk (VHR) acute lymphoblastic leukemia (ALL) is still under critical discussion. PATIENTS AND METHODS: In the ALL-Berlin-Frankfurt-Münster (BFM) 90 and ALL-BFM 95 trials, 387 patients were eligible for SCT if there was a matched sibling donor (MSD). T-cell ALL (T-ALL) patients with poor in vivo response to initial treatment represented the largest homogeneous subgroup within VHR patients. RESULTS: Of 191 high-risk (HR) T-ALL patients, 179 patients (94%) achieved CR1. Twenty-three patients received an MSD-SCT. Furthermore, in trial ALL-BFM 95, eight matched unrelated donors (MUDs) and five mismatched family donors (MMFDs) were used. The median time to SCT was 5 months (range, 2.4 to 10.8 months) from diagnosis. The 5-year disease-free survival (DFS) was 67% +/- 8% for 36 patients who received an SCT in CR1 and 42% +/- 5% for the 120 patients treated with chemotherapy alone having an event-free survival time of at least the median time to transplantation (Mantel-Byar, P = .01). Overall survival (OS) rate for the SCT group was 67% +/- 8% at 5 years, whereas patients treated with chemotherapy alone had an OS rate of 47% +/- 5% at 5 years (Mantel-Byar, P = .01). Outcome of patients who received MSD-SCT versus MUD-/MMFD-SCT was comparable (DFS, 65% +/- 10% v 69% +/- 13%, respectively). However, relapses only occurred after MSD-SCT (eight of 23 patients), whereas treatment-related mortality only occurred after MUD-/MMFD-SCT (four of 13 patients). CONCLUSION: SCT in CR1 is superior to treatment with chemotherapy alone for childhood HR-T-ALL.