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Health-related quality of life (HRQL) improved progressively during therapy and beyond in children treated for acute lymphoblastic leukemia on the Dana-Farber Cancer Institute (DFCI) 95-01 protocol. This study aimed to validate that trajectory in a successor study (DFCI 00-01) and to compare the HRQL of patients in the 2 studies. Children aged above 5 years were assessed during each phase of treatment (N=4) and 2 years after completion of therapy. Health status and HRQL were measured using Health Utilities Index (HUI) instruments, HUI2 and HUI3. Quality-adjusted life years (QALYs) were calculated and compared with the general population, and patients treated on DFCI 95-01. Over 5 intervals and 758 HUI assessments, mean HRQL increased progressively from remission induction to the time after treatment (P

For adults with Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukemia (ALL) in first complete remission (CR1), allogeneic hematopoietic cell transplantation (HCT) is an established curative strategy. However, pediatric-inspired chemotherapy may also offer durable leukemia-free survival in the absence of HCT. We compared 422 HCT recipients aged 18-50 years with Ph-ALL in CR1 reported to the CIBMTR with an age-matched concurrent cohort of 108 Ph- ALL CR1 patients who received a Dana-Farber Consortium pediatric-inspired non-HCT regimen. At 4 years of follow-up, incidence of relapse after HCT was 24% (95% CI 19-28) versus 23% (95% CI 15-32) for the non-HCT (chemo) cohort (P=0.97). Treatment-related mortality (TRM) was higher in the HCT cohort [HCT 37% (95% CI 31-42) versus chemo 6% (95% CI 3-12), P

Cardiotoxicity related to doxorubicin chemotherapy is a major late effect in childhood cancer survivors. Serum cardiac troponin concentrations (cTnT) can be elevated during doxorubicin therapy but the cellular associations with this myocardial injury are not well understood. We evaluate a novel nanotechnology-based biomarker discovery approach on a pilot set of serial serum samples from 11 children with acute lymphoblastic leukemia receiving doxorubicin therapy to determine if a proteomic signature of myocardial injury could be identified. This nanoparticle-based biomarker capture technology was utilized to analyze 40 serial serum samples from these children, 3 of whom seroconverted, 2 from cTnT-negative to cTnT-positive and 1 from cTnT-positive to cTnT-negative. High-resolution mass spectrometry analysis of the captured material identified 13 differentially expressed candidate proteins, whose spectral count values reflected changes in cTnT concentrations, which were verified in the serum samples from the 3 consistently cTnT-negative and 5 consistently cTnT-positive children. Of the 13 candidate proteins, 5 were significantly elevated (p Significance Identification of new biomarkers for early detection of chemotherapy-induced cardiotoxicity is of critical importance so that administration of cardioprotectants can be utilized before substantial heart damage has occurred. We developed and utilized a unique biomarker workflow based on a novel nanotechnology method in order to demonstrate the potential for such an approach to uncover low abundance markers that could be useful in a clinical setting once extensively validated.

Supplemental Digital Content is available in the text., Background: Epidemiologic studies worldwide have provided substantial evidence of the contributions of environmental exposures to the development of childhood cancer, yet this knowledge has not been integrated into the routine practice of clinicians who care for children with this disease. To identify the basis of this deficit, we sought to assess the environmental history-taking behavior and perceptions of environmental health among pediatric hematologists and oncologists. Procedure: A web-based survey was sent from June to October 2012 to 427 pediatric oncologists, fellows, and nurse practitioners from 20 US institutions, with an overall response rate of 45%. Results: Survey responses indicated that environmental exposures are of concern to clinicians. The vast majority of respondents (88%) reported receiving questions from families about the relationship between certain environmental exposures and the cancers they regularly treat. However, a lack of comfort with these topics seems to have limited their discussions with families about the role of environmental exposures in childhood cancer pathogenesis. Although 77% of respondents suspected that some of the cases they saw had an environmental origin, their methods of taking environmental histories varied widely. Over 90% of respondents believed that more knowledge of the associations between environmental exposures and childhood cancer would be helpful in addressing these issues with patients. Conclusions: Although limited in size and representativeness of participating institutions, the results of this survey indicate a need for increased training for hematology/oncology clinicians about environmental health exposures related to cancer and prompt translation of emerging research findings in biomedical journals that clinicians read.

Treatment advances have increased survival in children with cancer, but subclinical, progressive, irreversible, and sometimes fatal treatment-related cardiovascular effects may appear years later. Cardio-oncologists have identified promising preventive and treatment strategies. Dexrazoxane provides long-term cardioprotection from doxorubicin-associated cardiotoxicity without compromising the efficacy of anticancer treatment. Continuous infusion of doxorubicin is as effective as bolus administration in leukemia treatment, but no evidence has indicated that it provides long-term cardioprotection; continuous infusions should be eliminated from pediatric cancer treatment. Angiotensin-converting enzyme inhibitors can delay the progression of subclinical and clinical cardiotoxicity. All survivors, regardless of whether they were treated with anthracyclines or radiation, should be monitored for systemic inflammation and the risk of premature cardiovascular disease. Echocardiographic screening must be supplemented with screening for biomarkers of cardiotoxicity and perhaps by identification of genetic susceptibilities to cardiovascular diseases; optimal strategies need to be identified. The health burden related to cancer treatment will increase as this population expands and ages.

In certain human cancers, the expression of critical oncogenes is driven from large regulatory elements, called super-enhancers, that recruit much of the cell’s transcriptional apparatus and are defined by extensive acetylation of histone H3 lysine 27 (H3K27ac). In a subset of T-cell acute lymphoblastic leukemia (T-ALL) cases, we found that heterozygous somatic mutations are acquired that introduce binding motifs for the MYB transcription factor in a precise noncoding site, which creates a super-enhancer upstream of the TAL1 oncogene. MYB binds to this new site and recruits its H3K27 acetylase–binding partner CBP, as well as core components of a major leukemogenic transcriptional complex that contains RUNX1, GATA-3, and TAL1 itself. Additionally, most endogenous super-enhancers found in T-ALL cells are occupied by MYB and CBP, which suggests a general role for MYB in super-enhancer initiation. Thus, this study identifies a genetic mechanism responsible for the generation of oncogenic super-enhancers in malignant cells.

With growing numbers of childhood cancer survivors, it becomes increasingly important to understand the long-term toxicities associated with cure from malignancy. Many survivors were exposed to cardiotoxic chemotherapeutic agents at young ages. Indeed, cardiotoxicity is a leading cause of treatment-related morbidity and mortality in survivors of childhood cancer, and anthracycline exposure is a leading cause of these late cardiac effects. Nonetheless, anthracyclines remain critical agents in treating many pediatric cancers. Strategies to prevent anthracycline-associated cardiotoxicity include limiting lifetime cumulative anthracycline doses and adding cardioprotectant agents, such as dexrazoxane, to anthracycline-based regimens. However, attempts to reduce the cardiotoxicity of anthracyclines must also consider their effect on anti-cancer efficacy as well as new potential toxicities. In survivors of childhood acute lymphoblastic leukemia, the data suggest that including dexrazoxane in anthracycline-based regimens can prevent heart damage, does not reduce anti-leukemic efficacy, and can be safely administered. The controversies associated with dexrazoxane exemplify the challenges of changing therapy in cancers with a relatively good chance of event-free survival in efforts to prevent long-term sequelae. Studies of very-long-term survivor cohorts will continue to inform current practices. Continued efforts are needed to minimize cardiotoxic exposures during cancer treatment, to deliver safe and effective cardioprotectant measures when cardiotoxic agents cannot be avoided, to identify patients at greatest risk of serious cardiac toxicity, and to educate providers in the optimal care of survivors.

Advances in treating childhood cancers over the past 40 years have more than doubled 5-year survival rates. More effective use of chemotherapeutic agents has been key to this success. However, the increase has come at a price: chronic conditions are significantly more prevalent in long-term survivors of childhood cancer than they are in the general population, and managing these survivors can be challenging. In patients receiving anthracyclines, cardiotoxicity is the leading cause of morbidity and mortality after relapse and second malignancies. More than 50% of patients exposed to anthracyclines exhibit some form of cardiac dysfunction within 20 years after completing chemotherapy, and about 5% develop heart failure. These conditions greatly reduce the quality of life of the individual and also consume substantial amounts of healthcare resources. Dexrazoxane has been used to reduce anthracycline-related cardiotoxicity in children with cancer, but in 2011, the European Medicines Agency determined, on what it acknowledged were limited data, that dexrazoxane was contraindicated in children. Here, we review the evidence for the clinical effects of dexrazoxane in children. Studies published since 2011 have confirmed the efficacy of dexrazoxane in preventing or reducing anthracycline-related cardiotoxicity in children with cancer, and no new evidence of increased risks for recurrence of primary or second malignancies, or reductions in antitumor efficacy has been reported. As a result, we believe that dexrazoxane should be available to children with high-risk cancers to reduce the risk of cardiotoxicity associated with high-dose anthracycline treatment.

Background: Vincristine (VCR) is a standard component in the treatment of childhood acute lymphoblastic leukemia (ALL). VCR cytotoxicity is primarily due to its ability to disrupt the formation of microtubules of the mitotic spindle. Patients & methods: Seventeen polymorphisms in regulatory and coding regions of genes controlling VCR targets (TUBB1, MAP4, ACTG1 and CAPG) or potentially influencing VCR levels (ABCB1 and CYP3A5) were investigated for an association with peripheral neuropathy and outcome in childhood ALL patients. Results: High-grade neurotoxicity was more frequent in carriers of the A allele of synonymous (Ala310) G to A (rs1135989) variation in the ACTG1 gene. Substitution (rs4728709) in the promoter of the ABCB1 gene had a protective effect against lower grade neurotoxicity and C to A variation (rs3770102) located 17 nucleotides upstream from the transcription start site had a protective effect against high-grade neurotoxicity. Patients with the ABCB1 3435TT genotype had lower event-free survival; the association with event-free survival was not supported by the analysis in the replication patient set. Conclusion: The polymorphisms in the ACTG1, CAPG and ABCB1 genes may modulate VCR-related neurotoxicity, whereas the risk of relapse seems not to be affected by the genes of the VCR pathway. Original submitted 19 June 2013; Revision submitted 31 March 2014

Treatment resistance in T-cell acute lymphoblastic leukemia (T-ALL) is associated with phosphatase and tensin homolog (PTEN) deletions and resultant phosphatidylinositol 3'-kinase (PI3K)-AKT pathway activation, as well as MYC overexpression, and these pathways repress mitochondrial apoptosis in established T-lymphoblasts through poorly defined mechanisms. Normal T-cell progenitors are hypersensitive to mitochondrial apoptosis, a phenotype that is dependent on the expression of proapoptotic BIM. In a conditional zebrafish model, MYC downregulation induced BIM expression in T-lymphoblasts, an effect that was blunted by expression of constitutively active AKT. In human T-ALL cell lines and treatment-resistant patient samples, treatment with MYC or PI3K-AKT pathway inhibitors each induced BIM upregulation and apoptosis, indicating that BIM is repressed downstream of MYC and PI3K-AKT in high-risk T-ALL. Restoring BIM function in human T-ALL cells using a stapled peptide mimetic of the BIM BH3 domain had therapeutic activity, indicating that BIM repression is required for T-ALL viability. In the zebrafish model, where MYC downregulation induces T-ALL regression via mitochondrial apoptosis, T-ALL persisted despite MYC downregulation in 10% of bim wild-type zebrafish, 18% of bim heterozygotes and in 33% of bim homozygous mutants (P=0.017). We conclude that downregulation of BIM represents a key survival signal downstream of oncogenic MYC and PI3K-AKT signaling in treatment-resistant T-ALL.

BACKGROUND Doxorubicin is associated with progressive cardiac dysfunction, possibly through the formation of doxorubicin-iron complexes leading to free-radical injury. The authors determined the frequency of hemochromatosis (HFE) gene mutations associated with hereditary hemochromatosis and their relationship with doxorubicin-associated cardiotoxicity in survivors of childhood high-risk acute lymphoblastic leukemia. METHODS Peripheral blood was tested for 2 common HFE allelic variants: C282Y and H63D. Serum cardiac troponin-T (cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP), which are biomarkers of cardiac injury and cardiomyopathy, respectively, were assayed during therapy. Left ventricular (LV) structure and function were assessed with echocardiography. RESULTS A total of 184 patients had DNA results for at least 1 variant, and 167 had DNA results for both: 24% carried H63D and 10% carried C282Y. Heterozygous C282Y genotype was associated with multiple elevations in cTnT concentrations (P = .039), but not NT-proBNP. At a median of 2.2 years (range, 1.0 years–3.6 years) after diagnosis, the mean Z-scores for LV fractional shortening (−0.71 [standard error (SE), 0.25]; P = .008), mass (−0.84 [SE, 0.17]; P

Background Dexamethasone is more efficacious than prednisone in the treatment of acute lymphoblastic leukemia (ALL), but has also been associated with greater toxicity. We compared neuropsychological outcomes for patients treated on DFCI ALL Consortium Protocol 00-01, which included a randomized comparison of the two steroid preparations during post-induction therapy in children and adolescents with ALL. Procedure Between 2000 and 2005, 408 children with standard-risk or high-risk ALL treated on Dana-Farber Cancer Institute Consortium Protocol 00-01 were randomly assigned to prednisone or dexamethasone administered as 5-day pulses every 3 weeks for 2 years, beginning at week 7 of treatment. Blinded neuropsychological testing was completed for 170 randomized patients (prednisone, N = 76; dexamethasone, N = 94), all of whom were in continuous complete remission after completion of therapy. Results Outcomes were comparable for most variables, although patients on the dexamethasone arm performed more poorly on a measure of fluid reasoning (P = 0.02). They also tended to be more likely to be enrolled in special education (dexamethasone, 33% vs. prednisone, 20%, P = 0.09). Conclusions Dexamethasone has well documented benefit in treatment of ALL. Although formal testing provided little indication of increased risk for neurotoxicity relative to prednisone, the somewhat greater utilization of special education services by patients treated with dexamethasone merits further investigation. Pediatr Blood Cancer 2013;60:1785–1791. © 2013 Wiley Periodicals, Inc.

The objective was to quantify the health-related quality of life (HRQL) of children treated for acute lymphoblastic leukemia (ALL) and identify specific disabilities for remediation.Two types of subjects were included: ALL patients 5 plus years old in a multi-center clinical trial and general population control groups. Patients were assessed during all four major phases of active treatment and approximately 2 years after treatment. Health status and HRQL were measured using HEALTH UTILITIES INDEX® (HUI®) Mark 2 (HUI2) and Mark 3 (HUI3). HRQL scores were used to calculate quality-adjusted life years (QALYs). Excess disability rates identified attributes for remediation.HUI assessments (n = 749) were collected during the five phases. Mean HRQL increased from induction through the post-treatment phase (P0.001). There were no significant demographic or treatment effects on HRQL, except for type of asparaginase during continuation therapy (P = 0.005 for HUI2 and P = 0.007 for HUI3). Differences in mean HRQL scores between patients and controls were important (P0.001) during the active treatment phases but not during the post-treatment phase. Relative to controls, patients lost approximately 0.2 QALYs during active treatment. Disability was evident in mobility/ambulation, emotion, self-care and pain, and declined over time.Patients with ALL experienced important but declining deficits in HRQL during active treatment phases: Equivalent to losing approximately 2 months of life in perfect health. HRQL within the 2-years post-treatment phase was similar to controls. The policy challenge is to develop new treatment protocols producing fewer disabilities in mobility/ambulation, emotion, self-care, and pain without compromising survival.

Background Dexrazoxane reduces the risk of anthracycline-related cardiotoxicity. In a study of children with Hodgkin lymphoma, the addition of dexrazoxane may have been associated with a higher risk for developing second malignant neoplasms (SMNs) including acute myelogenous leukaemia (AML) and myelodysplastic syndrome (MDS). We determined the incidence of SMNs in children and adolescents with acute lymphoblastic leukaemia (ALL) who were treated with dexrazoxane. Methods Between 1996 and 2010, the Dana-Faber Cancer Institute ALL Consortium conducted three consecutive multicentre trials for children with newly diagnosed ALL. In the first (1996–2000), high risk patients were randomly assigned to receive doxorubicin (30mg/m 2 /dose, cumulative dose 300mg/m 2 ) preceded by dexrazoxane (300mg/m 2 /dose, 10 doses), or the same dose of doxorubicin without dexrazoxane, during induction and intensification phases. In subsequent trials (2000–2005 and 2005–2010), all high risk and very high risk patients received doxorubicin preceded by dexrazoxane. Cases of SMNs were collected prospectively and were pooled for analysis. The frequency and 5-year cumulative incidence (CI) of SMNs were determined for patients who had received dexrazoxane. Findings Among 553 patients treated with dexrazoxane (1996–2000, N =101; 2000–2005, N =196; and 2005–2010, N =256), the number of SMNs observed by protocol was 0 (median follow-up 9.6years), 0 (median follow-up 5.2years), and 1 (median follow-up 2.1years). The only SMN was a case of AML, which developed in a patient with MLL-rearranged ALL 2.14years after initial diagnosis. The overall 5-year CI of SMNs for all 553 patients was 0.24±0.24%. Interpretation In a large population of children with high risk ALL who received dexrazoxane as a cardioprotectant drug, the occurrence of secondary AML was a rare event.

The optimal management of asparaginase-associated thrombotic complications is not well-defined. We report the features, management and outcome of paediatric (ages 0-18years) and adult (18-50years) patients with acute lymphoblastic leukaemia (ALL) with asparaginase-related venous thromboembolic events (VTE) treated at Dana-Farber Cancer Institute on clinical trials for newly diagnosed ALL between 1991-2008. Of 548 patients, 43 (8%) had VTE, including 27/501 (5%) paediatric and 16/47 (34%) adult patients. Sinus venous thrombosis occurred in 1·6% of patients. Age was the only significant predictor of VTE, with those aged >30years at very high risk (VTE rate 42%). 74% of patients received low molecular weight heparin after VTE. Complications of anticoagulation included epistaxis (9%), bruising (2%) and, in two adult patients, major bleeding. Thirty patients (70%) ultimately received at least 85% of the intended doses of asparaginase. 33% of patients experienced recurrent VTE (paediatric 17% vs. adults 47%, P=0·07). The 48-month event-free survival for patients with VTE was 85±6% compared with 88±2% for those without VTE (P=0·36). This study confirms that, after VTE, asparaginase can be restarted with closely monitored anticoagulation after imaging demonstrates clot stabilization or improvement. With this management strategy, a history of VTE does not appear to adversely impact prognosis.

Cardiac signaling proteins regulate the intrinsic cardioprotective and repair response to doxorubicin cardiotoxicity. We estimated the relationship between these proteins, serum biomarkers of cardiac status and imaging in doxorubicin-treated children with ALL. Concentrations of the proteins

Background Asparaginase, an agent used in the treatment of acute lymphoblastic leukemia (ALL), is associated with the development of pancreatitis. The clinical course and long-term outcome of patients experiencing this complication has not been extensively detailed.

Purpose Survivors of childhood acute lymphoblastic leukemia (ALL) exhibit increased rates of neurocognitive deficits. This study was conducted to test whether interpatient variability in neurocognitive outcomes can be explained by polymorphisms in candidate genes conferring susceptibility to neurocognitive decline. Methods Neurocognitive testing was conducted in 350 pediatric leukemia survivors, treated on Dana-Farber Cancer Institute ALL Consortium Protocols 95-01 or 00-01. Genomic DNA was isolated from bone marrow collected at remission. Candidate polymorphisms were selected on the basis of prior literature, targeting genes related to drug metabolism, oxidative damage, altered neurotransmission, neuroinflammation, and folate physiology. Single nucleotide polymorphisms were detected using either a customized multiplexed Sequenom MassARRAY assay or polymerase chain reaction–based allelic discrimination assays. Multivariable logistic regression models were used to estimate the effects of genotype on neurocognitive outcomes, adjusted for the effects of demographic and treatment variables. False-discovery rate correction was made for multiple hypothesis testing, indicated as a Q value. Results Inferior cognitive or behavioral outcomes were associated with polymorphisms in three genes related to oxidative stress and/or neuroinflammation: NOS3 (IQ, Q = 0.008; Vocabulary Q = 0.011; Matrix Reasoning Q = 0.008), SLCO2A1 (IQ Q = 0.043; Digit Span Q = 0.006; Block Design Q = 0.076), and COMT (Behavioral Assessment System for Children-2 Attention Q = 0.080; and Hyperactivity Q = 0.084). Survivors homozygous for NOS3 894T, with at least one SLCO2A1 variant G allele or with at least one GSTP1 variant allele, had lower mean estimated IQ scores than those without these genotypes. Conclusion These data are consistent with the hypothesis that oxidative damage contributes to chemotherapy-associated neurocognitive decline among children with leukemia.

SummaryDrug resistance remains a major obstacle to successful cancer treatment. A database of drug-associated gene expression profiles was screened for molecules whose profile overlapped with a gene expression signature of glucocorticoid (GC) sensitivity/resistance in acute lymphoblastic leukemia (ALL) cells. The screen indicated that the mTOR inhibitor rapamycin profile matched the signature of GC sensitivity. We tested the hypothesis that rapamycin would induce GC sensitivity in lymphoid malignancy cells and found that it sensitized to GC-induced apoptosis via modulation of antiapoptotic MCL1. These data indicate that MCL1 is an important regulator of GC-induced apoptosis and that the combination of rapamycin and glucocorticoids has potential utility in lymphoid malignancies. Furthermore, this approach represents a strategy for identification of promising combination therapies for cancer.

Extensive endothelial cell proliferation and marked neovascularization are the most pronounced microenvironmental changes consistently observed in the bone marrow (BM) of patients with acute lymphoblastic leukemia (ALL). It is not known whether ALL cells induce this phenotype and whether they receive critical signals from the tumor-associated BM endothelium. Here, we show that leukemia cells actively stimulate BM endothelium, promote de novo angiogenesis, and induce neovascularization in the leukemic BM. Soluble factors, present in the leukemic BM microenvironment, promote the proliferation, migration, and morphogenesis of BM endothelial cells, which are critical processes in tumor angiogenesis. We also show in vitro that leukemia cells display directional motion towards assembled BM endothelium and following adherence exhibit cell polarization, pseudopodia, and ultrastructural features that suggest the existence of leukemia-endothelium cross-talk. Finally, we show that BM endothelium promotes leukemia cell survival through a mechanism mediated through the anti-apoptotic molecule bcl-2. These studies indicate that ALL cells actively recruit BM endothelium and mediate the leukemia-associated neovascularization observed in ALL. Therefore, disruption of interactions between leukemia cells and BM endothelium may constitute a valid therapeutic strategy.

Purpose Cross-sectional studies show that cardiac abnormalities are common in long-term survivors of doxorubicin-treated childhood malignancies. Longitudinal data, however, are rare. Methods Serial echocardiograms (N = 499) were obtained from 115 doxorubicin-treated long-term survivors of childhood acute lymphoblastic leukemia (median age at diagnosis, 4.8 years; median follow-up after completion of doxorubicin, 11.8 years). Results were expressed as z scores to indicate the number of standard deviations (SDs) above (+) or below (−) the normal predicted value. Median individual and cumulative doxorubicin doses were 30 mg/m2 per dose and 352 mg/m2, respectively. Results Left ventricular fractional shortening was significantly reduced after doxorubicin therapy, and the reduction was related to cumulative dose. z scores for fractional shortening transiently improved before falling to −2.76 more than 12 years after diagnosis. Reduced fractional shortening was related to impaired contractility and increasing afterload, consequences of a progressive reduction of ventricular mass, and wall thickness relative to body-surface area. Left ventricular contractility fell significantly over time and was depressed at last follow-up in patients receiving more than 300 mg/m2 of doxorubicin. Systolic and diastolic blood pressures were below normal more than 9 years after diagnosis. Even patients receiving lower cumulative doxorubicin doses experienced reduced mass and dimension. Fractional shortening and dimension at the end of therapy predicted these parameters 11.8 years later. Conclusion Cardiac abnormalities were persistent and progressive after doxorubicin therapy. Inadequate ventricular mass with chronic afterload excess was associated with progressive contractile deficit and possibly reduced cardiac output and restrictive cardiomyopathy. The deficits were worst after highest cumulative doses of doxorubicin, but appeared even after low doses.

PurposeMembers of a family with hereditary gastrointestinal stromal tumors (GISTs) and a germline KIT oncogene mutation were evaluated for other potential syndrome manifestations. A tumor from the proband was analyzed to compare features with sporadic GISTs.Patients and MethodsMembers of a kindred in which six relatives in four consecutive generations comprised an autosomal dominant pattern of documented GISTs and cutaneous lesions underwent physical examination, imaging studies, and germline KIT analysis. A recurrent GIST from the proband was studied using microarray, karyotypic, immunohistochemical, and immunoblotting techniques.ResultsIn addition to evidence of multiple GISTs, lentigines, malignant melanoma, and an angioleiomyoma were identified in relatives. A previously reported gain-of-function missense mutation in KIT exon 11 (T → C) that results in a V559A substitution within the juxtamembrane domain was identified in three family members. The proband's recurrent gastric GIST had a 44,XY−14,−22 karyotype and immunohistochemical evidence of strong diffuse cytoplasmic KIT expression without expression of actin, desmin, or S-100. Immunoblotting showed strong expression of phosphorylated KIT and downstream signaling intermediates (AKT and MAPK) at levels comparable with those reported in sporadic GISTs. cDNA array profiling demonstrated clustering with sporadic GISTs, and expression of GIST markers comparable to sporadic GISTs.ConclusionThese studies provide the first evidence that gene expression and mechanisms of cytogenetic progression and cell signaling are indistinguishable in familial and sporadic GISTs. Current investigations of molecularly targeted therapies in GIST patients provide opportunities to increase the understanding of features of the hereditary syndrome, and risk factors and molecular pathways of the neoplastic phenotypes.

Objectives We and others have shown that B cell precursor acute lymphoblastic leukemia cells (ALL) stimulated with CD40 ligand become efficient antigen-presenting cells (APC) capable of expanding autologous, tumor-specific T cells from patients. Translation of these preclinical findings to a novel treatment strategy required four separate issues to be determined: (1) if a CD40-ALL vaccine could be generated for clinical use; (2) whether clinical translation could be achieved; (3) whether the vaccination was safe; and (4) whether a window of time could be identified that would optimize the efficacy of vaccination. Patients and methods Nine patients with relapsed/refractory ALL were enrolled in a phase I trial of vaccination with autologous CD40-ALL. Immunologic reconstitution was measured in a separate cohort of 23 patients with newly diagnosed ALL. Results We successfully prepared autologous vaccines for all nine patients in the phase I trial. CD40-ALL were potent APC, capable of stimulating allogeneic and peptide-specific T cells in vitro. Two patients were vaccinated without adverse events. Five patients died or progressed before vaccination, suggesting that rapid disease progression limits vaccination in patients with relapse disease, thus limiting clinical translation. We therefore sought to identify a window of time for vaccination during which this approach might be feasible. To achieve this end, we evaluated immunological reconstitution in newly diagnosed patients with ALL patients. Despite recovery of myelopoiesis, most patients had profound defects in T, B, and natural killer (NK) cell numbers that failed to recover at any point during therapy. Conclusion Autologous tumor vaccination at a time of ALL relapse is not feasible. Alternative strategies for immunotherapy of ALL may require ex vivo generation of antigen specific T cells and adoptive therapy.

Doxorubicin chemotherapy is very effective in children with acute lymphoblastic leukemia (ALL) but also injures myocardial cells. Dexrazoxane, a free-radical scavenger, may protect the heart from doxorubicin-associated damage.To determine whether dexrazoxane decreases doxorubicin-associated injury of cardiomyocytes, we randomly assigned 101 children with ALL to receive doxorubicin alone (30 mg per square meter of body-surface area every three weeks for 10 doses) and 105 to receive dexrazoxane (300 mg per square meter) followed immediately by doxorubicin. Serial measurements of serum cardiac troponin T were obtained in 76 of 101 patients in the doxorubicin group and 82 of 105 patients in the group given dexrazoxane and doxorubicin. A total of 2377 serum samples (mean, 15.1 samples per patient) were obtained before, during, and after treatment with doxorubicin. Troponin T levels were evaluated in a blinded fashion to determine whether they were elevated (0.01 ng per milliliter)--the primary end point--or extremely elevated (0.025 ng per milliliter).Elevations of troponin T occurred in 35 percent of the patients (55 of 158). Patients treated with doxorubicin alone were more likely than those who received dexrazoxane and doxorubicin to have elevated troponin T levels (50 percent vs. 21 percent, P0.001) and extremely elevated troponin T levels (32 percent vs. 10 percent, P0.001). The median follow-up was 2.7 years. The rate of event-free survival at 2.5 years was 83 percent in both groups (P=0.87 by the log-rank test).Dexrazoxane prevents or reduces cardiac injury, as reflected by elevations in troponin T, that is associated with the use of doxorubicin for childhood ALL without compromising the antileukemic efficacy of doxorubicin. Longer follow-up will be necessary to determine the influence of dexrazoxane on echocardiographic findings at four years and on event-free survival.

To assess the clinical heterogeneity among patients with acute lymphoblastic leukemia (ALL) and various 11q23 abnormalities, we analyzed data on 497 infants, children and young adults treated between 1983 and 1995 by 11 cooperative groups and single institutions. The substantial sample size allowed separate analyses according to age younger or older than 12 months for the various cytogenetic subsets. Infants with t(4;11) ALL had an especially dismal prognosis when their disease was characterized by a poor early response to prednisone (P=0.0005 for overall comparison; 5-year event-free survival (EFS), 0 vs 23+/-+/-12% s.e. for those with good response), or age less than 3 months (P=0.0003, 5-year EFS, 5+/-+/-5% vs 23.4+/-+/-4% for those over 3 months). A poor prednisone response also appeared to confer a worse outcome for older children with t(4;11) ALL. Hematopoietic stem cell transplantation failed to improve outcome in either age group. Among patients with t(11;19) ALL, those with a T-lineage immunophenotype, who were all over 1 year of age, had a better outcome than patients over 1 year of age with B-lineage ALL (overall comparison, P=0.065; 5-year EFS, 88+/-+/-13 vs 46+/-14%). In the heterogeneous subgroup with del(11)(q23), National Cancer Institute-Rome risk criteria based on age and leukocyte count had prognostic significance (P=0.04 for overall comparison; 5-year EFS, 64+/-+/-8% (high risk) vs 83+/-+/-6% (standard risk)). This study illustrates the marked clinical heterogeneity among and within subgroups of infants or older children with ALL and specific 11q23 abnormalities, and identifies patients at particularly high risk of failure who may benefit from innovative therapy.

We recently found that MLL-rearranged acute lymphoblastic leukemias (MLL) have a unique gene expression profile including high level expression of the receptor tyrosine kinase FLT3. We hypothesized that FLT3 might be a therapeutic target in MLL and found that 5 of 30 MLLs contain mutations in the activation loop of FLT3 that result in constitutive activation. Three are a newly described deletion of I836 and the others are D835 mutations. The recently described FLT3 inhibitor PKC412 proved cytotoxic to Ba/F3 cells dependent upon activated FLT3 containing either mutation. PKC412 is also differentially cytotoxic to leukemia cells with MLL translocations and FLT3 that is activated by either overexpression of the wild-type receptor or mutation. Finally, we developed a mouse model of MLL and used bioluminescent imaging to determine that PKC412 is active against MLL in vivo.

Although L-asparaginase (ASP) is associated with several toxicities, its myelosuppressive effect has not been well characterized. On DFCI ALL Consortium Protocol 05-01 for children with newly diagnosed acute lymphoblastic leukemia, the Consolidation phase and the initial portion of the Continuation phase were identical for standard risk patients, except ASP was given only during Consolidation. Comparing the two treatment phases revealed that low blood counts during Consolidation with ASP resulted in more dosage reductions of 6-mercaptopurine and methotrexate. The myelosuppressive effect of ASP should be considered when designing treatment regimens to avoid excessive toxicity and dose reductions of other critical chemotherapy agents.

PURPOSE: A common late effect of doxorubicin therapy for childhood cancer is reduced left-ventricular (LV) wall thickness resulting in elevated LV afterload and depressed LV function. Many children are given angiotensin-converting enzyme inhibitors, which have been studied primarily in adults. We document the long-term effects of angiotensin-converting enzyme inhibitors in doxorubicin-treated survivors of childhood cancer. PATIENTS AND METHODS: In this retrospective study, we reviewed records of 18 children who had regular echocardiographic examinations during enalapril therapy (mean age at cancer diagnosis, 8 years; mean time between completion of doxorubicin therapy and start of enalapril, 7 years; median follow-up since the start of enalapril, 10 years). RESULTS: Over the first 6 years of enalapril therapy, there was progressive improvement toward normal values in LV dimension, afterload, fractional shortening, and mass, but all these parameters deteriorated between 6 and 10 years. LV wall thickness deteriorated throughout the study period, as did LV contractility and systolic blood pressure. Diastolic blood pressure fell slightly. By 6 years on enalapril, all six patients who had had congestive heart failure at the start of enalapril therapy had either died or undergone cardiac transplantation, compared with three of the 12 asymptomatic patients. CONCLUSION: In doxorubicin-treated long-term survivors of childhood cancer, enalapril-induced improvement in LV structure and function is transient. The primary defect, which is LV wall thinning, continues to deteriorate, and thus the short-term improvement was mostly related to lowered diastolic blood pressure.

Purpose: The cognitive sequelae of treatment for childhood acute lymphoblastic leukemia (ALL) were compared in a group of patients who received dexamethasone during the intensification and maintenance phases of therapy with those in a historical control group for whom antileukemia therapy was similar, except that the corticosteroid component of therapy was prednisone. Methods: Patients treated for ALL on Dana-Farber Cancer Institute protocols 87-01 (n = 44) and 91-01 (n = 23) were evaluated by standard cognitive and achievement tests. Corticosteroid therapy was delivered in 5-day pulses given every 3 weeks during intensification and continuation phases of therapy for a total of 2 years. Results: Children treated on protocol 87-01 received prednisone at a dose of 40 mg/m 2 /d (standard risk, SR) or 120 mg/ m 2 /d (high risk, HR); those treated on protocol 91-01 received dexamethasone at a dose of 6 mg/m 2 per day (SR) or 18 mg/m 2 per day (HR). Children treated on protocol 91-01 performed less well on cognitive testing. Subsample analysis indicated that cranial radiation therapy and methotrexate dose did not account for differences in cognitive outcomes. Conclusions: The findings of this preliminary study are consistent with the hypothesis that dexamethasone therapy can increase risk for neurocognitive late effects in children treated for ALL and indicate that further investigation of this question is warranted.

BACKGROUND The authors report the occurrence of fatal or near-fatal sepsis in 16 of 38 children with newly diagnosed acute lymphoblastic leukemia (ALL) treated with a new induction regimen that differed from its predecessor by the substitution of dexamethasone for prednisone. METHODS The frequency of septic deaths among 38 children who received multiagent remission induction therapy, including dexamethasone (6 mg/m2) daily for 28 days (pilot protocol 91-01P), was compared with the frequency of septic deaths among children previously treated (protocol 87-01) and subsequently treated (protocol 91-01) in consecutive Dana-Farber Cancer Institute (DFCI) ALL trials with induction therapy that included 21 and 28 days of prednisone (40 mg/m2), respectively. Except for dexamethasone in protocol 91-01P, the remission induction agents used were identical in substance to those used in protocol 87-01. Protocol 91-01, the successor 91-01P, was also similar, with the exception of the deletion of a single dose of L-asparaginase. RESULTS Sixteen of the 38 children (42%) treated on the DFCI 91-01P had documented gram positive or gram negative sepsis (17 episodes) during remission induction, including 4 toxic deaths (11%). In contrast, there were 4 induction deaths among 369 children (1%) treated on protocol 87-01 (P = 0.0035) and 1 induction death among 377 children (

Doxorubicin is associated with progressive cardiac dysfunction, possibly through the formation of doxorubicin-iron complexes leading to free-radical injury. The authors determined the frequency of hemochromatosis (HFE) gene mutations associated with hereditary hemochromatosis and their relationship with doxorubicin-associated cardiotoxicity in survivors of childhood high-risk acute lymphoblastic leukemia.Peripheral blood was tested for 2 common HFE allelic variants: C282Y and H63D. Serum cardiac troponin-T (cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP), which are biomarkers of cardiac injury and cardiomyopathy, respectively, were assayed during therapy. Left ventricular (LV) structure and function were assessed with echocardiography.A total of 184 patients had DNA results for at least 1 variant, and 167 had DNA results for both: 24% carried H63D and 10% carried C282Y. Heterozygous C282Y genotype was associated with multiple elevations in cTnT concentrations (P = .039), but not NT-proBNP. At a median of 2.2 years (range, 1.0 years-3.6 years) after diagnosis, the mean Z-scores for LV fractional shortening (-0.71 [standard error (SE), 0.25]; P = .008), mass (-0.84 [SE, 0.17]; P .001), and end-systolic (-4.36 [SE, 0.26], P .001) and end-diastolic (-0.68 [SE, 0.25]; P = .01) posterior wall thickness were found to be abnormal in children with either allele (n = 32). Noncarriers (n = 63) also were found to have below-normal LV mass (-0.45 [SE, 0.15]; P = .006) and end-systolic posterior wall thickness (-4.06 [SE, 0.17]; P .001). Later follow-up demonstrated similar results.Doxorubicin-associated myocardial injury was associated with C282Y HFE carriers. Although LV mass and wall thickness were found to be abnormally low overall, they were even lower in HFE carriers, who also had reduced LV function. Screening newly diagnosed cancer patients for HFE mutations may identify those at risk for doxorubicin-induced cardiotoxicity.

BACKGROUND Topotecan is a topoisomerase I inhibitor that has good penetration across the blood-brain barrier and significant antitumor activity against human brain tumor xenografts. In a Phase I trial in children with refractory cancer, topotecan was well tolerated when administered as a 24-hour infusion. The maximum tolerated dose was 5.5 mg/m2 and the dose-limiting toxicity was myelosuppression. This Phase II study of topotecan was performed to assess the activity of topotecan against childhood brain tumors. METHODS Forty-five children with either a previously treated primary brain tumor that was refractory to standard therapy, or an untreated brain stem glioma or glioblastoma multiforme, received topotecan administered as a 24-hour intravenous infusion every 21 days. The initial dose was 5.5 mg/m2 with escalation to 7.5 mg/m2 on the second and subsequent doses in patients who did not experience dose-limiting toxicity. RESULTS There were no complete or partial responses in the patients with high grade glioma (n = 9), medulloblastoma (n = 9), or brain stem glioma (n = 14). One of 2 patients with a low grade glioma had a partial response lasting more than 17 months; 3 patients with a brain stem glioma had stable disease for 12 to 28 weeks; and 1 patient with a malignant neuroepithelial tumor and 1 patient with an optic glioma had stable disease for 41 weeks and 22 weeks, respectively. Dose esalation from 5.5 mg/m2 to 7.5 mg/m2 was well tolerated in the first 11 patients enrolled on this study who had not received prior craniospinal radiation therapy. The starting dose was subsequently increased to 7.5 mg/m2 for patients without prior craniospinal radiation. CONCLUSIONS Topotecan administered as a 24-hour infusion every 21 days is inactive in high grade gliomas, medulloblastomas, and brain stem tumors. Cancer 1996;78:527-31.

Objective. To review the basis for recommendations of the Cardiology Committee of the Children's Cancer Study Group, published in Pediatrics, for serial cardiac monitoring of cancer patients during anthracycline therapy and reduction of therapy should cardiac studies show abnormalities. Design. Because the effects of overall morbidity and mortality should be considered when a recommendation is made to withhold potentially lifesaving chemotherapy based on abnormal cardiac findings of patients without clinical evidence of cardiac dysfunction, supporting studies referenced in the published recommendations were reviewed. Specifically, studies were evaluated to determine whether a reduction in anthracycline dose, as a result of abnormal cardiac findings by monitoring, reduced cardiac morbidity and related mortality compared with a prospectively followed control population without dose modification. In addition, the effects of cardiac monitoring and subsequent anthracycline dose modification on oncologic morbidity and mortality were reviewed in these studies. Finally, the contributions of the cardiac and oncologic effects of dose modification were examined to determine the effect of this change in therapy on overall morbidity and mortality. Results. None of the studies cited in developing these recommendations prospectively determined, with controls, the effects of cardiac monitoring and anthracycline dose modification on cardiac, oncologic, or overall morbidity and mortality. Therefore, none of the studies cited in support of cardiac monitoring and subsequent dose reduction demonstrated the efficacy of such an approach. In the absence of such data, concerns are raised as to whether such a monitoring program with subsequent dose modification might do more harm than good. In addition, none of the methods of screening for anthracycline cardiotoxicity has been shown to be adequately predictive of early or late cardiac outcomes. Finally, adoption of these recommendations would inhibit the investigation of the efficacy of the proposed plan. Conclusion. Given the absence of supportive data and the potential to do harm, no recommendation for dose modification based on abnormal cardiac findings in patients without clinical evidence of cardiotoxicity can be endorsed, including those of the Cardiology Committee of the Children's Cancer Study Group. When clinical evidence of cardiotoxicity is present, anthracycline dose modification is recommended. A prospective controlled study to determine the effects of dose modification based on cardiac test results is indicated.

Long‐term survivors of childhood acute lymphoblastic leukemia (ALL) can exhibit increased difficulty with visuospatial reasoning tasks. The present study was undertaken to ascertain whether this difficulty reflects underlying spatial/visuoperceptual deficits or has a metacognitive basis. Two studies were carried out investigating performance on the Rey‐Osterrieth Complex Figure test. In Study 1, 51 survivors performed the task in the standard format. They recalled fewer organizing‐scheme components than normative expectation but more incidental features. In Study 2 the encoding phase of the task was manipulated. Thirty‐four survivors were randomized to a linear (LIN) or configurational (CON) presentation and memory productions were evaluated. Organization scores for the CON group were above normative expectation, whereas those of the LIN group remained unchanged. Visuospatial reasoning problems in these children have a metacognitive basis and do not represent a fundamental visuoperceptual or spatial deficit.

The optimal management of asparaginase-associated thrombotic complications is not well-defined. We report the features, management, and outcome of paediatric (ages 0–18 years) and adult (18–50 years) patients with acute lymphoblastic leukaemia (ALL) with asparaginase-related venous thromboembolic events (VTE) treated at Dana-Farber Cancer Institute on clinical trials for newly diagnosed ALL between 1991–2008. Of 548 patients, 43 (8%) had VTE, including 27/501 (5%) paediatric and 16/47 (34%) adult patients. Sinus venous thrombosis occurred in 1.6% of patients. Age was the only significant predictor of VTE, with those aged >30 years at very high risk (VTE rate 42%). 74% of patients received low molecular weight heparin after VTE. Complications of anticoagulation included epistaxis (9%), bruising (2%), and, in two adult patients, major bleeding. 30 patients (70%) ultimately received at least 85% of the intended doses of asparaginase. 33% of patients experienced recurrent VTE (paediatric 17% vs. adults 47%, p=0.07). The 48-month event-free survival for patients with VTE was 85 ± 6% compared with 88 ± 2% for those without VTE (p=0.36). This study confirms that, after VTE, asparaginase can be restarted with closely monitored anticoagulation after imaging demonstrates clot stabilization or improvement. With this management strategy, a history of VTE does not appear to adversely impact prognosis.

Introduction Chemotherapy alone is rarely curative for children with recurrent acute lymphoid leukemia (ALL). Although allogeneic bone marrow transplantation has been reported to provide disease-free survival rates of from 40 to 70%, its application is severely limited by the lack of sibling donors. The use of autologous bone marrow transplantation (ABMT) allows the application of therapy of comparable intensity to a larger number of patients. A potential problem associated with transplanting autologous marrow, the reinfusion of residual leukemic cells in the harvested marrow, can be addressed through purging. The most widely used purging techniques involve either immunologic or pharmacologic techniques. Patients and methods Since 1980, the Dana-Farber Cancer Institute has had an active autologous bone marrow transplantation program for children with recurrent ALL. Sixty-six children underwent autologous marrow transplants with a conditioning regimen consisting of teniposide, cytarabine, cyclophosphamide, and total body irradiation. This was followed by infusion of autologous marrow purged with two monoclonal antibodies directed against CD9 and CD10 and complement. Results Twelve patients died of acute complications, 26 experienced relapse of ALL, one patient had acute myeloid leukemia 6 years after marrow transplant, and 27 remain in continuous complete remission. The event-free survival rate was 47% for patients with a first remission of at least 2 years, as compared with a rate of 10% for those with a shorter first remission. Since 1989, we have used a new conditioning regimen consisting of fractionated total body irradiation followed by high-dose etoposide and cyclophosphamide for patients with a short first remission. For the first 11 patients, the event-free survival rate is 61%. Literature review We reviewed reports of 552 patients with ALL who underwent ABMT at 17 centers. To our knowledge, only four series, including our own, were limited to pediatric patients. Some form of purging was used in 483 (87%) patients. Although conditioning regimens varied greatly, more than 80% of patients received at least total body irradiation and cyclophosphamide. Failure of engraftment was reported in only three patients. The rates of disease-free survival in these series clustered between 25-35%. The most common cause of treatment failure after ABMT was relapse, which occurred in 40-85% of patients. Early deaths from toxicity occurred in 5-21% of patients. Two studies attempted to compare the results of allogeneic and autologous bone marrow transplantation by using the same conditioning regimen for all. Neither series reported significant differences in overall survival.

PURPOSE Long-term adverse neurobehavioral sequelae frequently are observed in pediatric patients treated for acute lymphoblastic leukemia (ALL). To clarify the relative contribution of cranial irradiation (CRT) therapy and drug therapy to these outcomes, we evaluated neuropsychologic outcomes associated with different doses of CRT and intravenous (IV) methotrexate (MTX) in long-term survivors. PATIENTS AND METHODS Fifty-one patients treated for ALL on Dana-Farber Cancer Institute protocol 81-01 were evaluated by standardized cognitive and academic achievement tests. These children had been assigned at diagnosis to a standard-risk (SR) or high-risk (HR) group and received 1,800 cGy or 2,800 cGy CRT, respectively. A subgroup of these patients was randomized to receive MTX during remission induction, either as a single low dose (LD; 40 mg/m2) or a single high dose (HD; 4 g/m2) with leucovorin rescue. RESULTS Sex and MTX randomization jointly predicted the intelligence quotient (IQ). Fifty percent of girls versus 14% of boys exhibited low IQ (less than 90; P = .01); 80% of girls who received HD MTX versus 25% of girls who received LD MTX exhibited low IQ (P = .03). In contrast, risk group better predicted performance on tasks sensitive to verbal memory and/or coding. CONCLUSIONS We conclude that (1) significant neurotoxicity occurred principally in girls; (2) increased dose intensity of IV MTX was associated with lower IQ, but only in girls; and (3) increased dose of CRT may have been associated with impairment of verbal memory and coding.

Approximately five percent of pediatric acute lymphoblastic leukemias (ALL) contain a translocation (9;22)(q34;q11) which results in rearrangement of the bcr and abl genes. At a median follow-up of 5 years, we assessed the prognostic implications of translocation (9;22) in 434 children receiving intensive treatment for ALL. Four-year event-free and overall survivals were only 0% and 20%, respectively, in 15 children with translocation (9;22), but were 81% and 89%, respectively, in 419 children lacking translocation (9;22) (P < 0.001). Based on these findings, we recommend very intensive treatment approaches for all children with translocation (9;22)-positive ALL.

Asparaginase, an agent used in the treatment of acute lymphoblastic leukemia (ALL), is associated with the development of pancreatitis. The clinical course and long-term outcome of patients experiencing this complication has not been extensively detailed.We reviewed the clinical course for all children with ALL diagnosed with pancreatitis at the Dana-Farber Cancer Institute/Children's Hospital Boston between 1987 and 2003. The outcome of these patients was compared with that of patients with ALL who did not experience pancreatitis.Twenty-eight of 403 children (7%) were diagnosed with pancreatitis. Patients 10-18 years old at diagnosis had 2.4 times the risk of developing pancreatitis compared with younger patients. Pancreatitis typically occurred early in the course of therapy (median 4 weeks after first dose of asparaginase). Ninety-three percent of affected patients were hospitalized and 57% received parenteral nutrition. No patient developed chronic sequelae or died as a result of pancreatitis. Sixteen (57%) patients were re-treated with asparaginase, 10 of whom had another episode of pancreatitis. No significant differences in event-free survival were observed when comparing patients with and without a history of pancreatitis.Asparaginase-associated pancreatitis was more common in older children, and caused significant acute morbidity. It tended to occur after the first few doses of asparaginase, suggesting a predisposition to this complication rather than a cumulative drug effect. Re-treatment with asparaginase after an episode of pancreatitis was associated with a high risk of recurrent pancreatitis.

We analyzed two of the most successful trials for childhood acute lymphoblastic leukemia, from the Berlin-Frankfurt-Münster group (BFM) and the Dana-Farber Cancer Institute (DFCI), to determine their similarities and differences and suggest ways to improve future treatments. Protocol ALL-BFM 81 (n = 611) was conducted between 1981-1983 in 37 centers in West Germany and Austria; Protocol DFCI 81-01 (n = 286) was conducted between 1981-1985 in seven centers within the United States. The BFM study used a risk score, based on peripheral lymphoblast count, liver size, and spleen size at the time of diagnosis to assign patients into one of the three treatment arms. The DFCI study classified patients into two groups: standard risk patients (age 2-9 years, with white blood count less than 20,000/mm3, and with no T-cell markers, mediastinal mass, nor central nervous system disease), and high risk patients (all others). Both studies involved intensive chemotherapy, although treatment strategies, cumulative drug doses and cranial radiation protocols differed. Study populations in the two trials were comparable with respect to age, sex, white blood count and proportion of patients with T-cell markers at the time of diagnosis. Using DFCI risk group criteria, 37% of BFM and 38% of DFCI patients were classified as standard risk. Median follow-up times were 6.8 years and 6.1 years, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiotoxicity is a recognized complication of doxorubicin therapy, but the long-term effects of doxorubicin are not well documented. We therefore assessed the cardiac status of 115 children who had been treated for acute lymphoblastic leukemia with doxorubicin 1 to 15 years earlier in whom the disease was in continuous remission.Eighteen patients received one dose of doxorubicin (45 mg per square meter of body-surface area), and 97 received multiple doses totaling 228 to 550 mg per square meter (median, 360). The median interval between the end of treatment and the cardiac evaluation was 6.4 years. Our evaluation consisted of a history, 24-hour ambulatory electrocardiographic recording, exercise testing, and echocardiography.Fifty-seven percent of the patients had abnormalities of left ventricular afterload (measured as end-systolic wall stress) or contractility (measured as the stress-velocity index). The cumulative dose of doxorubicin was the most significant predictor of abnormal cardiac function (P less than 0.002). Seventeen percent of patients who received one dose of doxorubicin had slightly elevated age-adjusted afterload, and none had decreased contractility. In contrast, 65 percent of patients who received at least 228 mg of doxorubicin per square meter had increased afterload (59 percent of patients), decreased contractility (23 percent), or both. Increased afterload was due to reduced ventricular wall thickness, not to hypertension or ventricular dilatation. In multivariate analyses restricted to patients who received at least 228 mg of doxorubicin per square meter, the only significant predictive factors were a higher cumulative dose (P = 0.01), which predicted decreased contractility, and an age of less than four years at treatment (P = 0.003), which predicted increased afterload. Afterload increased progressively in 24 of 34 patients evaluated serially (71 percent). Reported symptoms correlated poorly with indexes of exercise tolerance or ventricular function. Eleven patients had congestive heart failure within one year of treatment with doxorubicin; five of them had recurrent heart failure 3.7 to 10.3 years after completing doxorubicin treatment, and two required heart transplantation. No patient had late heart failure as a new event.Doxorubicin therapy in childhood impairs myocardial growth in a dose-related fashion and results in a progressive increase in left ventricular afterload sometimes accompanied by reduced contractility. We hypothesize that the loss of myocytes during doxorubicin therapy in childhood might result in inadequate left ventricular mass and clinically important heart disease in later years.

Purpose Dexrazoxane is a drug used to prevent anthracycline-induced cardiotoxicity. A recent report found an association between the use of dexrazoxane and the risk of developing secondary malignant neoplasms (SMNs) in children with Hodgkin's disease. We report the absence of an association of SMNs in children with acute lymphoblastic leukemia (ALL) treated on Dana-Farber Cancer Institute ALL Consortium Protocol 95-01. Patients and Methods Two hundred five children with high-risk (HR) ALL were randomly assigned to receive doxorubicin alone (n = 100) or doxorubicin with dexrazoxane (n = 105) during the induction and intensification phases of multiagent chemotherapy. We compared incidence of SMNs in these two groups. Results With a median follow-up of 6.2 years, no differences in the incidence of SMNs were noted between the group that received dexrazoxane and the group that did not (P = .66). One SMN (a melanoma located outside of the cranial radiation field) occurred in a patient who was randomly assigned to doxorubicin alone. No SMNs were observed in patients randomly assigned to receive dexrazoxane. Conclusion Dexrazoxane was not associated with an increased risk of SMNs in children treated for HR ALL. Given the potential importance of dexrazoxane as a cardioprotectant, we recommend that dexrazoxane continue to be used and studied in doxorubicin-containing pediatric regimens.