High-dose Anthracycline Research Articles

Hyaluronan synthase 3 variant and anthracycline-related cardiomyopathy: a report from the children's oncology group.

The strong dose-dependent association between anthracyclines and cardiomyopathy is further exacerbated by the co-occurrence of cardiovascular risk factors (diabetes and hypertension). The high morbidity associated with cardiomyopathy necessitates an understanding of the underlying pathogenesis so that targeted interventions can be developed. By using a two-stage design, we investigated host susceptibility to anthracycline-related cardiomyopathy by using the ITMAT/Broad CARe cardiovascular single nucleotide polymorphism (SNP) array to profile common SNPs in 2,100 genes considered relevant to de novo cardiovascular disease. By using a matched case-control design (93 cases, 194 controls), we identified a common SNP, rs2232228, in the hyaluronan synthase 3 (HAS3) gene that exerts a modifying effect on anthracycline dose-dependent cardiomyopathy risk (P = 5.3 × 10(-7)). Among individuals with rs2232228 GG genotype, cardiomyopathy was infrequent and not dose related. However, in individuals exposed to high-dose (> 250 mg/m(2)) anthracyclines, the rs2232228 AA genotype conferred an 8.9-fold (95% CI, 2.1- to 37.5-fold; P = .003) increased cardiomyopathy risk compared with the GG genotype. This gene-environment interaction was successfully replicated in an independent set of 76 patients with anthracycline-related cardiomyopathy. Relative HAS3 mRNA levels measured in healthy hearts tended to be lower among individuals with AA compared with GA genotypes (P = .09). Hyaluronan (HA) produced by HAS3 is a ubiquitous component of the extracellular matrix and plays an active role in tissue remodeling. In addition, HA is known to reduce reactive oxygen species (ROS) -induced cardiac injury. The high cardiomyopathy risk associated with AA genotype could be due to inadequate remodeling and/or inadequate protection of the heart from ROS-mediated injury on high anthracycline exposure.

Evaluation of anthracycline incuced cardiotoxicity by speckle tracking echocardiography.

e11585 Background: Anthracyclines have been widely used in the treatment of solid and hematologic malignancies. Cardiotoxicity is the most serious adverse effect that limits anthracycline treatment. Cardiotoxicity is classified by time of onset as acute, subacute and chronic. Conventional echocardiography is not sensitive enough for early detection of cardiotoxicity. In this study we aimed to evaluate anthracycline induced cardiac toxicity by speckle tracking echocardiography (STE) before left ventricular dysfunction occurs. Methods: The study included newly diagnosed breast cancer (BC) and lymphoma patients (pts) who were treated with an anthracycline containing chemotherapy (CT) regimen. They had examination with conventional echocardiyography, STE before and after anthracycline treatment. Longitudinal strain values were assessed by automated function image (AFI). Results: Thirty five pts with BC and 15 pts with lymphoma were included in the study. Ejection fraction (EF) and fractional shortening values were decreased in lymphoma pts receiving high dose anthracycline treatment (346 mg/m2) compared to BC pts receiving low dose (168 mg/m2) anthracycline. There was statistically significant increase in myocardial performance index in both groups after anthracycline CT (p=0.001 and p=0.004 for BC and lymphoma group respectively). In STE measurements, apical long axis, apikal 4 chamber and global peak systolic strain showed significant reduction in lymphoma group who had a post-therapy EF <55% (p=0.002, p=0.041, and p=0.004, respectively). Apical long axis and global peak systolic strain were also significantly decreased among the lymphoma pts with normal systolic function after CT (p=0.01 and p=0.05, respectively). Conclusions: STE can display the effect of anthracycline induced cardiotoxicity early before left ventricular dysfunction occurs. Larger prospective studies are needed to verify these data and direct the treatment of pts receiving anthracycline.

Hyaluronidase synthase 3 (HAS3) variant and anthracycline-related cardiomyopathy: A report from the Children’s Oncology Group.

10004 Background: The strong dose-dependent association between anthracyclines and cardiomyopathy limits the therapeutic potential of this extremely effective class of agents, demanding identification of those at highest risk, such that anthracycline exposure may be tailored. Methods: In a two-stage design, we investigated host susceptibility to anthracycline-related cardiomyopathy in cancer survivors by using the ITMAT/Broad/CARe cardiovascular SNP-array to profile common SNPs in 2100 genes considered most relevant to de novo cardiovascular disease. All cases of cardiomyopathy fulfilled American Heart Association (AHA) criteria for cardiac compromise and were confirmed echocardiographically. Results: Using a matched case-control design (93 cases, 194 controls, all non-Hispanic white survivors of childhood cancer) we identified a common SNP rs2232228 in hyaluronan synthase (HAS3) gene that exerts a substantial modifying effect on anthracycline dose-dependent risk of cardiomyopathy. Among individuals with GG genotype, cumulative anthracycline exposure was not associated with cardiomypathy risk at any dose. Individuals with AA genotype, exposed to >250mg/m2 anthracyclines, had an 8.5-fold increased cardiomyopathy risk (95%CI, 2.0-35.6, p=0.004). Replication in an independent set of 76 patients (adult-onset and childhood cancer; all races) with anthracycline-related cardiomyopathy revealed the odds of cases with AA genotype in the high-dose anthracycline group to be 4.5-times higher (95%CI, 1.1-18.4, p=0.04). Hyaluronan (HA) – produced by HAS3 – is a ubiquitous component of extracellular matrix (ECM). ECM is involved in tissue remodeling; the extent of cardiac remodeling/repair after anthracycline-induced cardiac injury is possibly modulated by variability in HA production. Conclusions: The significant modifying effect of HAS3 genotype on the dose-dependent association between anthracycline and cardiomyopathy risk suggests that, upon confirmation in prospective studies, genotyping HAS3 may be considered when evaluating risk of anthracycline-related cardiomyopathy.

β-Adrenergic Blockade for Anthracycline- and Trastuzumab-Induced Cardiotoxicity

Breast cancer is the second leading cause of cancer-related death among women in the United States.1 Approximately 25% to 30% of breast cancers have overexpression of human epidermal growth factor receptor 2 (HER2), which is associated with an adverse prognosis.2 Adjuvant chemotherapy with trastuzumab, the humanized monoclonal antibody that directly targets HER2, significantly improves disease-free and overall survival in these patients.3 However, trastuzumab, especially when given in combination with anthracyclines, has been associated with asymptomatic and symptomatic left ventricular (LV) dysfunction3 that can lead to premature discontinuation of trastuzumab therapy and significant cardiac morbidity. Article see p 420 In this issue of Circulation: Heart Failure , Seicean et al4 retrospectively evaluated the incidence of new symptomatic heart failure (HF) in patients with breast cancer treated with anthracyclines, trastuzumab, or both, at the Cleveland Clinic between 2005 and 2010. Using 1:2 propensity matching, they compared patients on continuous β-blockers during cancer treatment to those not on β-blockade, and assessed the effect of incidental β-blocker use on new symptomatic HF and noncardiac mortality during a median follow-up of ≈3 years. The results of this study show that trastuzumab, when given alone or in combination with anthracyclines, substantially increased the risk of symptomatic HF compared with anthracyclines alone (hazard ratio, 9.5; 95% confidence interval, 3.9–23.1). Furthermore, incidental β-blocker use significantly reduced the incidence of symptomatic HF (hazard ratio, 0.2; 95% confidence interval, 0.1–0.7) but did not affect noncardiac mortality in patients with breast cancer treated with trastuzumab, anthracyclines, or both. This article highlights 2 important issues: (1) it emphasizes the magnitude of trastuzumab cardiotoxicity in the real world, and (2) it provides support for the hypothesis that prophylactic β-blocker use may be cardioprotective in patients receiving trastuzumab, anthracyclines, or both. Anthracyclines cause a dose-dependent toxicity that is felt …

Abstract 4699: Responsecharacteristics and overall survival of 781 patients with triple-negativebreast cancer - a meta-analysis on 7 German neoadjuvant studies.

Abstract Background: A specific chemotherapy for patients with early triple-negative breast cancer (TNBC, <10% expression of oestrogen- and progesterone receptor (ER, PR) as well as normal HER2 expression) has not been proven so far. Patients and methods: We analysed baseline and treatment characteristics of 4592 patients who received anthracycline/taxane+/-trastuzumab-containing therapy within one of 7 German prospective neoadjuvant studies during the years 1999 to 2008 and had information on hormone- and HER2-receptor status available for their prognostic and predictive impact on pathologic complete remission (pCR; ypT0 ypN0) and overall survival (OS). Results: 781 patients had TNBC and 3188 patients had non-TNBC. Compared to non-TNBC patients, TNBC patients had a significantly higher pCR rate (29.7% versus 9.9%, p<.0001); but showed a significantly lower OS-rate (5 yr OS for TNBC 75%, for non-TNBC 88%; p<.0001). In case a pCR was achieved, TNBC patients showed a trend towards better OS compared to non-TNBC patients (5 yr OS for TNBC 97%, for non-TNBC 93%; p=.192). OS of TNBC and non-TNBC patients did not differ regarding duration of therapy (≤12 versus >12 weeks), type of regimen (combination versus sequential), dosing (conventional versus dose dense), dose of anthracyclines or taxanes (high versus low) or substance (docetaxel versus paclitaxel) in baseline factor adjusted multivariate analyses; despite univariate analyses suggested a better outcome for TNBC patients if treated by combination chemotherapy (p=.018) or higher anthracycline dose (p=.079). However, early partial or complete clinical response to the first 2-4 cycles of neoadjuvant therapy (74.0% in TNBC versus 65.7% in non-TNBC) correlated strongly with OS for TNBC patients (p=.004), but only marginally for non-TNBC patients (p=.055). Conclusion: Patients with TNBC achieving a pCR after neoadjuvant therapy have a highly favourable prognosis at least as good as patients with non-TNBC and pCR. Different therapeutic approaches don't show an impact on OS in TNBC. However, pCR and interestingly, early clinical response to neoadjuvant treatment, correlates with favourable OS in patients with TNBC. Citation Format: Gunter von Minckwitz, Claudia Mamouhdian-Dekordi, Sibylle Loibl, Jens-Uwe Blohmer, Serban Dan Costa, Carsten Denkert, Holger Eidtmann, Bernd Gerber, Claus Hanusch, Joern Hilfrich, Jens Huober, Andreas Schneeweiss, Stefan Paepke, Keyur Mehta, Michael Untch, Christian Jackisch. Responsecharacteristics and overall survival of 781 patients with triple-negativebreast cancer - a meta-analysis on 7 German neoadjuvant studies. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4699. doi:10.1158/1538-7445.AM2013-4699

Tissue Doppler and myocardial deformation imaging to detect myocardial dysfunction in pediatric cancer patients treated with high doses of anthracyclines

To detect subtle changes in myocardial function in pediatric cancer patients treated with high dose anthracyclines. In all, 19 pediatric cancer patients with no cardiotoxicity findings treated with a cumulative anthracycline dose of ≥350 mg/m(2) and healthy participants of the same age were included in the study. Transthoracic echocardiography measurements, pulsed-wave tissue Doppler from the basal portions of all walls and strain and strain rate imaging of all walls from basal portion were obtained. A total of 19 patients (13 boys and six girls) and 17 participants (10 boys and seven girls) in the control group were enrolled. Three patients had subnormal ejection fraction (EF) and fractional shortening (FS) values. There was no significant difference in EF and FS between the two groups. The left ventricle isovolumic relaxation time was prolonged (P = 0.02) and the mitral color propagation velocity was decreased in patients (P = 0.001). Peak systolic strain and strain rates of the right ventricle, septal, lateral and inferior wall basal region of the left ventricle were significantly lower in patients than controls (all P < 0.05). Tissue Doppler measurements of early and late diastolic myocardial velocities of the right ventricular free wall, lateral wall of left ventricle and septum, and peak systolic myocardial velocity of the left ventricle anterior wall were significantly lower in patients (all P < 0.05). Myocardial Doppler and deformation imaging techniques provide a thorough evaluation of cardiac functions with the advantage of detecting subtle early changes before a global cardiac functional impairment occurs.

Getting to the Heart of the Matter

Getting to the Heart of the Matter

Incidence and predictors of congestive heart failure after autologous hematopoietic cell transplantation

AbstractAdvances in autologous hematopoietic cell transplantation (HCT) strategies have resulted in a growing number of long-term survivors. However, these survivors are at increased risk of developing cardiovascular complications due to pre-HCT therapeutic exposures and conditioning and post-HCT comorbidities. We examined the incidence and predictors of congestive heart failure (CHF) in 1244 patients undergoing autologous HCT for a hematologic malignancy between 1988 and 2002. The cumulative incidence of CHF was 4.8% at 5 years and increased to 9.1% at 15 years after transplantation; the CI for female lymphoma survivors was 14.5% at 15 years. The cohort was at a 4.5-fold increased risk of CHF (standardized incidence ratio = 4.5), compared with the general population. The risk of CHF increased substantially for patients receiving ≥ 250 mg/m2 of cumulative anthracycline exposure (odds ratio [OR]: 9.9, P < .01), creating a new and lower threshold for cardiac surveillance after HCT. The presence of hypertension among recipients of high-dose anthracycline (≥ 250 mg/m2) resulted in a 35-fold risk (OR: 35.3, P < .01) of CHF; the risk was nearly 27-fold (OR: 26.8, P < .01) for high-dose anthracycline recipients with diabetes, providing evidence that hypertension and diabetes may be critical modifiers of anthracycline-related myocardial injury after HCT and creating targeted populations for aggressive intervention.

Anthracycline-related cardiomyopathy after childhood cancer: role of polymorphisms in carbonyl reductase genes--a report from the Children's Oncology Group.

Carbonyl reductases (CBRs) catalyze reduction of anthracyclines to cardiotoxic alcohol metabolites. Polymorphisms in CBR1 and CBR3 influence synthesis of these metabolites. We examined whether single nucleotide polymorphisms in CBR1 (CBR1 1096G>A) and/or CBR3 (CBR3 V244M) modified the dose-dependent risk of anthracycline-related cardiomyopathy in childhood cancer survivors. One hundred seventy survivors with cardiomyopathy (patient cases) were compared with 317 survivors with no cardiomyopathy (controls; matched on cancer diagnosis, year of diagnosis, length of follow-up, and race/ethnicity) using conditional logistic regression techniques. A dose-dependent association was observed between cumulative anthracycline exposure and cardiomyopathy risk (0 mg/m(2): reference; 1 to 100 mg/m(2): odds ratio [OR], 1.65; 101 to 150 mg/m(2): OR, 3.85; 151 to 200 mg/m(2): OR, 3.69; 201 to 250 mg/m(2): OR, 7.23; 251 to 300 mg/m(2): OR, 23.47; > 300 mg/m(2): OR, 27.59; P(trend) < .001). Among individuals carrying the variant A allele (CBR1:GA/AA and/or CBR3:GA/AA), exposure to low- to moderate-dose anthracyclines (1 to 250 mg/m(2)) did not increase the risk of cardiomyopathy. Among individuals with CBR3 V244M homozygous G genotypes (CBR3:GG), exposure to low- to moderate-dose anthracyclines increased cardiomyopathy risk when compared with individuals with CBR3:GA/AA genotypes unexposed to anthracyclines (OR, 5.48; P = .003), as well as exposed to low- to moderate-dose anthracyclines (OR, 3.30; P = .006). High-dose anthracyclines (> 250 mg/m(2)) were associated with increased cardiomyopathy risk, irrespective of CBR genotype status. This study demonstrates increased anthracycline-related cardiomyopathy risk at doses as low as 101 to 150 mg/m(2). Homozygosis for G allele in CBR3 contributes to increased cardiomyopathy risk associated with low- to moderate-dose anthracyclines, such that there seems to be no safe dose for patients homozygous for the CBR3 V244M G allele. These results suggest a need for targeted intervention for those at increased risk of cardiomyopathy.

Young Adults Presenting with Extramedullary Acute Myeloid Leukemia Have A Unique Sensitivity to High Doses of Anthracyclines: Subset Analysis of ECOG 1900,

Abstract 3619Extramedullary (EM) acute myeloid leukemia (AML) is generally associated with a poor prognosis. We evaluated the baseline characteristics, response and survival characteristics in a subset of patients age ≤ 60 years with de novo AML and EM manifestations at presentation, treated on the Eastern Cooperative Oncology Group E1900 protocol: daunorubicin 45 or 90 mg /m2 x3 days in conjunction with cytarabine 100 mg/m2 × 7 days followed by risk-stratified consolidation. (Fernandez et al New Engl J Med 2009) Methods:Patient baseline characteristics were compared using Fisher's exact test if they were categories and Wilcoxon rank sum tests if they were continuous. Logistic regression models were used for complete remission (CR) rates and Cox regression models were used for overall survival (OS) and disease-free survival (DFS). The univariate models included indication of whether patient had extramedullary disease involvement, adjusted by induction treatment. The multivariate models were further adjusted for age, gender, cytogenetic risk, ECOG PS, WBC, platelets, marrow blast, hemoglobin, peripheral blasts, and secondary AML. All P values were based on 2-sided tests. Results:58 (8.9%) of 651 patients in the study presented with evidence of EM at diagnosis. Patients with EM disease were younger and presented with higher peripheral WBC counts and circulating blasts than those without. Immunophenotyping did not demonstrate a difference in baseline CD56 expression (p=0.77). Sites of EM involvement included gingival hypertrophy (n= 33), skin (n= 7), central nervous system (n= 6), lymphadenopathy (n=6), mediastinum (n=2) and other (n=6). 3 patients had multiple sites. Cytogenetic risk in the EM subgroup was favorable (8.6%), indeterminate (inadequate/missing) (34.5%), intermediate (37.9%) and unfavorable (19%) and did not differ statistically from those without EM disease.The complete remission (CR) rates were similar for patients with EM disease compared to those patient's without, regardless of the anthracycline dose (univariate model p= 0.93; multivariate model p=0.88. DFS (patients in CR) and OS of patients with EM disease was not significantly different in the univariate (p= 0.99, p=0.49) or multivariate models (p= 0.92, p=0.37), respectively. On multivariate modeling patients with EM AML who received the standard-dose of daunorubicin had a shorter OS (HR 1.86, 95% CI 1.20 to 2.91, p=0.006). OS was not improved in EM patients treated with high-dose daunorubicin (HR 0.62, 95% CI 0.34 to 1.14, p=0.12) (Table). There was a significant difference in OS for patients with EM treated with the 90 mg/m2 dose of daunorubicin compared to patients with EM treated with the 45 mg/m2 dose (multivariate model: HR 0.30, 95% CI 0.12 to 0.76, p=0.01). Conclusion:Younger patients with de novo EM AML are sensitive to higher doses of anthracycline in induction therapy and should be treated in a similar fashion as patients without EM involvement. For both groups the higher doses of anthracycline are recommended as CR rates, DFS and OS are improved. Further evaluation of immunophenotypic and molecular/ genetic characteristics should be undertaken in this subset of patients. Disclosures:No relevant conflicts of interest to declare.

Long-term echocardiogram monitoring and cardiac outcomes of childhood cancer survivors with exposure to high doses of anthracyclines.

9576 Background: Improvements in therapy for childhood cancer has increased overall survival and decreased long term toxicities for most survivors; however, some children will still require substantial therapy to achieve cure. These contemporary survivors, in addition to past survivors, are at risk for cardiac complications including cardiomyopathy, congestive heart failure, and valvular heart disease. Risk factors include anthracyclines and radiation therapy. Methods: A retrospective review of survivors in our CCHMC Cancer Survivor Program was performed. All patients were diagnosed = 5 years out from diagnosis and received at least 350mg/m2 of anthracyclines. Cardiac dysfunction was assessed by ECHO shortening fraction (SF <30%) or MUGA ejection fraction (EF <60%). Demographic and treatment variables were also examined. Results: 120 anthracycline exposed patients (51 females) were identified out of a cohort of 1340 survivors with an average age of 8.3 years (0.1-20.4y) at diagnosis an...

Incidence and predictors of delayed congestive heart failure (CHF) after hematologic malignancies treated with autologous hematopoietic cell transplantation (aHCT).

9042 Background: aHCT survivors are at risk for CHF due to exposure to cardiotoxic agents (pre-aHCT anthracyclines, chest radiation, aHCT conditioning). The magnitude of risk of CHF and risk factors are not defined, nor is the modifying effect of preventable causes, such as cardiovascular risk factors (CV RF). Methods: A retrospective cohort design was used to describe the cumulative incidence (CI) of CHF and examine the role of aHCT conditioning and sociodemographic factors. Next, a nested case-control approach was used to evaluate the role of pre-aHCT exposures and post-aHCT CV RF. Results: Eighty-one cases of CHF were observed in a cohort of 1,010 aHCT survivors transplanted at City of Hope between 1988 and 2002, followed for a median of 6.7 yrs (1-21). Median age at aHCT was 44.4 yrs (17-69); median time to CHF: 3.0 yrs (0.02-18.6); 40% were females; 71% non-Hispanic white; 68% underwent aHCT for lymphoma. CI of CHF was 7.8% at 10 yrs and 10.4% at 15 yrs post-aHCT. Female gender (Hazard Ratio [HR] 2.5, p<0.01), diagnosis of Hodgkin lymphoma (HR 2.9, p=0.02), and older age at aHCT (35-44 yrs: HR 2.2, p=0.03; 45-54 yrs: HR 2.9, p<0.01; ≥55 yrs: HR 4.5, p<0.01; referent group <35 yrs) were independent predictors of CHF. Risk was highest for female lymphoma survivors: CI of 17.5% at 15 yrs. Conditioning-related exposures were not associated with CHF risk. A clear interaction between cumulative anthracycline exposure ≥250 mg/m2 and post-aHCT CV RF (hypertension and diabetes) were identified (Table). Overall survival was 28% at 5 yrs after diagnosis of CHF. Conclusions: Cumulative incidence of CHF exceeds 10% at 15 years after aHCT. Female lymphoma survivors constitute a vulnerable population. Post-aHCT diabetes and hypertension interact with high-dose anthracycline exposure to significantly increase risk. These data form the basis for targeted surveillance and aggressive management of comorbidities. Hypertension Diabetes Dyslipidemia OR P OR P OR P No CV RF, no HD anthracycline 1.0 1.0 1.0 CV RF, no HD anthracycline 2.9 0.14 4.1 0.13 3.2 0.16 No CV RF, HD anthracycline 3.7 <0.01 3.8 <0.01 4.7 <0.01 CV RF + HD anthracycline 27.4 <0.01 21.5 <0.01 4.0 0.03 Abbreviation: HD, high dose.

Recent advances in the diagnosis and management of childhood acute promyelocytic leukemia.

Since the successful introduction of all-trans-retinoic acid (ATRA) and its combination with anthracycline-containing chemotherapy, the prognosis for acute promyelocytic leukemia (APL) has markedly improved. With ATRA and anthracycline-based-chemotherapy, the complete remission rate is greater than 90%, and the long-term survival rate is 70-89%. Moreover, arsenic trioxide (ATO), which was introduced for APL treatment in 1994, resulted in excellent remission rates in relapsed patients with APL, and more recently, several clinical studies have been designed to explore its role in initial therapy either alone or in combination with ATRA. APL is a rare disease in children and is frequently associated with hyperleukocytosis, which is a marker for higher risk of relapse and an increased incidence of microgranular morphology. The frequency of occurrence of the promyelocytic leukemia/retinoic acid receptor-alpha (PML/RARα) isoforms bcr 2 and bcr 3 is higher in children than in adults. Although recent clinical studies have reported comparable long-term survival rates in patients with APL, therapy for APL in children is challenging because of the risk of early death and the potential long-term cardiac toxicity resulting from the need to use high doses of anthracyclines. Additional prospective, randomized, large clinical trials are needed to address several issues in pediatric APL and to possibly minimize or eliminate the need for chemotherapy by combining ATRA and ATO. In this review article, we discuss the molecular pathogenesis, diagnostic progress, and most recent therapeutic advances in the treatment of children with APL.

Brain Natriuretic Peptide (BNP) Elevations In Allogeneic Stem Cell Transplant (ASCT) Recipients at the Time of WBC Engraftment. Correlation with Engraftment Syndrome and Cardiac Dysfunction.

AbstractAbstract 1309Engraftment syndrome (ES) may occur in ASCT recipients at the time of neutrophil recovery and is suspected to reflect increased capillary permeability due to increases in proinflammatory cytokines. Clinical features of ES may include fever, weight gain, rash, hypoxia and pulmonary infiltrates, which are by definition non-cardiogenic and non-infectious in origin. We have observed elevations in BNP in ASCT recipients at the time of WBC engraftment who appear to meet clinical criteria for ES and therefore chose to monitor BNP at the time of hospital admission, on day + 0, and at engraftment to further characterize the relationship between conditioning intensity, ES and cardiac dysfunction.A retrospective review was conducted of pretransplant cardiac features and transplant course in 139 patients undergoing ASCT between January, 2007 and April, 2010. Informative data was available for 122 transplants in 121 pts (74 males, 48 females). Median follow up of survivors was 266 days (minimum 100 days). Median age was 52 yrs (range 17–72). Transplant indication was AML 80 (66%), NHL 20 (16%), other 22 (18%). There were 58 (48%) matched related (MRD) and 64 (52%) unrelated donor (MUD) transplants. Graft source was PBSC (118) and BM (4). High dose (HD) therapy (Busulfan/Fludarabine or TBI/Cyclophosphamide [Cy]) was used in 61 transplants (50%), and reduced intensity (RI) conditioning (Busulfan/Fludarabine based or Pentostatin/TBI based) was used in 61 (50%). Tacrolimus and Mycophenolate were used for GVHD prophylaxis in 104 (85%), and Tacrolimus, Sirolimus, and Methotrexate were used in 18 (15%) mismatched transplants. Filgrastrim was routinely used from day +7 to engraftment. Forty pts (33%) had a history of HTN, CAD, CHF, or arrhythmias, 28 (25%) had received a high cumulative anthracycline dose (≥300 mg/m2 adriamycin equivalent), and 22 (18%) received HD Cy in the conditioning regimen. Results were analyzed according to a clinical diagnosis of ES noted in the medical record as well as by fulfillment of two or more diagnostic criteria (fever, rash, weight gain >2.5%, hypoxia/pulmonary infiltrate of noncardiac and noninfectious origin) present within 96 h of engraftment, as noted by Gorak et al. (BBMT 11:542, 2005).Median admission BNP (nl<100pg/ml) was 57 pg/ml (range 40–386, n=99). Median Day 0 BNP was 59.50 pg/ml (range 40–2580, n=120). Median engraftment BNP was 216 pg/ml (range 40–11200, n=122). Abnormal BNP at admission, on day 0, and at engraftment was seen in 24%, 45% and 76% of pts respectively, with engraftment BNP>400 in 37%. The incidence of ES was 11% by clinical impression and 25% by definition criteria. Ninety four percent of pts with ES had abnormal BNP at engraftment and 61% had BNP >400. Seventy percent of pts with no evidence of ES or overt cardiac complications were noted to have abnormal BNP at engraftment, and 53% had BNP >400. Weight gain occurred in 27% of all pts and of these 90% had elevation in BNP. Six pts experienced acute cardiac complications at the time of WBC engraftment with markedly elevated BNP. There were no primary cardiac deaths.A high cumulative anthracycline dose was associated with elevated BNP on day 0 and at WBC engraftment. High BNP on day 0 was also associated with reduced intensity conditioning but not with age. There was no correlation between cardiac history or HD Cy with elevations in BNP at any point. Elevated BNP at engraftment as well as presence of ES were significantly more common in MUD recipients. No correlation was observed between elevated engraftment BNP or presence of ES with acute GVHD or survival. One-year non relapse mortality was higher in pts with high anthracycline dose (28 vs. 18%%), high BNP at engraftment (22 vs. 7%), or MUD transplant (22 vs. 13%); High anthracycline dose was the only significant predictor of NRM in multivariate analysis. However, in the group of patients with normal BNP on day 0, a BNP >400 at engraftment was an independent predictor of both NRM and OS.Conclusions: Elevations in BNP following ASCT are common and are associated with anthracycline exposure and MUD source. Marked elevations were noted in patients with or without ES or evidence of cardiac compromise and are of uncertain etiology. The high frequency of abnormal BNP in pts with ES and the prognostic value of a de novo elevation in BNP at the time of engraftment suggest the physiologic stress of WBC engraftment following ASCT has important cardiac consequences which deserve further study. Disclosures:No relevant conflicts of interest to declare.

Anthracycline dose intensification in adult acute lymphoblastic leukemia

In previous studies of frontline therapy for adult acute lymphoblastic leukemia (ALL), early treatment with higher doses of anthracyclines has been reported to improve outcome. The current study was conducted to evaluate whether addition of anthracycline-based consolidation chemotherapy (Course 2) with liposomal daunorubicin (150 mg/m2 intravenously [IV] on Days 1 and 2) and cytarabine (1.5 g/m2 IV on Days 1 and 2) to the standard hyper-CVAD regimen (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high dose methotrexate and cytarabine) would improve outcome. Sixty-eight consecutive adults with de novo ALL or lymphoblastic lymphoma were treated with this modified hyper-CVAD regimen inclusive of rituximab for CD20 expression≥20%. Sixty-three (93%) patients achieved complete response (CR). With a median follow-up of 90 months, the 5-year CR duration (CRD) and overall survival (OS) rates were 46% and 44%, respectively. Compared with 208 patients treated with standard hyper-CVAD (rates of 45% and 47%, respectively; P=not significant), outcome with the modified hyper-CVAD regimen was not improved overall. Outcome was improved by the addition of rituximab for the CD20-positive subset (rates of CRD and OS of 50% and 53%, respectively), whereas anthracycline intensification worsened outcome for the CD20-negative subset (rates of CRD and OS of 41% and 35%, respectively; P=.01) compared with standard hyper-CVAD. A high mortality rate related to infections in CR was noted among patients aged 60 years or older. In the context of the hyper-CVAD regimen, early anthracycline intensification did not improve outcome for adults with de novo ALL or lymphoblastic lymphoma.

Impact of treatment characteristics on response of different breast cancer subtypes: Pooled multilayer analysis of the German neoadjuvant chemotherapy trials.

501 Background: Eight German neoadjuvant chemotherapy trials including 6,625 patients with uniform protocol and outcome definitions were conducted between 1998 and 2006 with pathological complete response (pCR) as primary endpoint. Methods: We used a more sophisticated multilevel model with random effects at the level of trials and regimens to pooled individual patient data. The model fully accounted for heterogeneity between trials in pCR. The analysis was restricted to a data set of 3,332 patients from 7 trials and 12 treatment arms with complete baseline parameters and no confounding by treatment indication based on interim response. Results: pCR was associated with an increase in cycle numbers (odds ratio [OR ] 1.2 with every two additional cycles; p = 0.009), with regimens using higher cumulative anthracycline doses (≥ 300 mg/m2 doxorubicin or ≥ 450 mg/m2 epirubicin; OR 1.6; p = 0.002), regimens with higher cumulative taxane doses (≥ 400 mg/m2 docetaxel or ≥ 700 mg/m2 paclitaxel; OR 1.6; p = 0.009), and with capecitabine containing regimens (OR 1.62; p = 0.022). Concurrent trastuzumab in patients with HER2-positive tumors increased the odds of pCR 3.2fold (p < 0.001). The association of pCR with increase in cycle numbers was more pronounced in hormone receptor (HR)-positive tumors (OR 1.35) than in HR-negative tumors (OR 1.04; p for interaction = 0.046). The anthracycline dose effect was pronounced in HER2-negative tumors (OR 1.61), as compared with HER2-positive tumors (OR 0.83; p for interaction p = 0.14). There was no evidence that the effect of taxane dose (p for interaction ≥ 0.64) and the effect of capecitabine (p for interaction ≥ 0.57) varied between subtypes. PCR was not different after 4, 8 or 12 trastuzumab cycles (OR per 4 cycles increase 0.97, p = 0.87) overall or in subgroups. Conclusions: We postulate that HR-positive tumors benefit more from longer neoadjuvant treatments, HER2-negative tumors more from higher anthracycline doses, triple negative tumors from short-term higher dose taxane and anthracycline based treatment, HER2-positive tumors already from a limited number of 4 trastuzumab cycles, and all subtypes from the addition of capecitabine. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca, Novartis, Roche, sanofi-aventis Amgen, AstraZeneca, Novartis, Roche, sanofi-aventis AstraZeneca, Roche

Close cardiac surveillance of patients treated with anthracyclines, also necessary after chemotherapy?

In women, breast cancer is the second most common form of cancer and the leading cause of death caused by malignancy. Anthracyclines are well known chemotherapeutics for treatment of these tumors, other solid tumors and hematologic malignancies. As adjuvant treatment in breast cancer it improves survival and reduces recurrence [1]. Unfortunately, their clinical use is currently limited by the development of a progressive dose-dependent cardiomyopathy that irreversibly evolves toward congestive heart failure, which is usually refractory to conventional therapy [2]. Studies have reported that 10–26% of patients administered cumulative anthracycline doses above those, develop congestive heart failure, and that more than 50% of patients administered these doses will experience measurable functional impairment months to years after the end of therapy [3]. The pathophysiology of this cardiomyopathy is incompletely understood. Anthracyclines decrease b-andrenoceptor density in the cell membrane, increase the permeability of myocytes and alter the ultrastructure of myofibrils and actin networks [4]. Risk factors for anthracycline-induced cardiotoxicity include high cumulative anthracycline doses, high anthracycline dose intensity, and radiotherapy. Radiotherapy in patients with cancer treated with anthracyclines can exacerbate cardiac tissue damage. Cardiovascular complications of treatment may be observed during administration of the drugs, days to months following administration, or years to decades following exposure. Several strategies have been developed to decrease the risk of cardiotoxicity while maintaining efficacy. These strategies include altered schedules of drug administration and adjunctive treatment with dexrazoxane. Unfortunately, none of these approaches have been successful, and patients remain at risk for the development of anthracycline cardiomyopathy, particularly with higher cumulative doses. Therefore careful serial monitoring is required for optimal medical management. Cardiomyopathy disease progression can be delayed in adults by using carvedilol or angiotensin-converting enzyme inhibitors [5, 6]. The permanent risk of cardiomyopathy by anthracyclines has made monitoring for the earliest evidence of cardiotoxicity necessary. In clinical practice monitoring is mostly performed using echocardiography or radionuclide angiography. The study of Appel et al. in the current issue of the International Journal of Cardiac Imaging shows that development of anthracycline toxicity is difficult to predict [7]. Although all patient in this study had a normal left ventricular function before receiving chemotherapy, 33% of the patients developed heart failure within a time period Editorial comment on the article of Appel et al. (doi:10.1007/ s10554-009-9518-2).

Cardiac complications in patients undergoing a reduced-intensity conditioning hematopoietic stem cell transplantation

Reduced-intensity conditioning (RIC) extends hematopoietic stem cell transplants (HSCT) to elderly or debilitated patients who are not candidates for HSCT. The incidence and outcomes of cardiac complications have been reported following myeloablative HSCT. We assessed the incidence and outcomes of cardiac complications in 278 recipients of RIC from July 2000 to July 2006. All patients received conditioning with BU, fludarabine and TBI. Patients were evaluated from conditioning therapy until 100 days after HSCT. Median age was 56 years. Cardiac events were defined as either one or more of the following: arrhythmias, myocardial infarction or congestive heart failure. Twenty-five patients developed arrhythmias at a median of 3 days post transplant, in 19 patients hemodynamic compromise occurred and mechanical ventilation was required in 15 patients. The arrhythmias included atrial fibrillation (n=17), atrial flutter (n=6) and supraventricular tachycardia (n=2). Troponin was elevated in 12 out of 25 patients. The mean brain natriuretic peptide was 679. All patients converted to a normal rhythm by medical therapy at a median of 2 days. Recurrence of arrhythmia occurred in 76% of patients. Day 100 mortality was 40% in this group. A history of high-dose anthracycline treatment and a low ejection fraction were risk factors for the development of cardiac complications.

Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results

AbstractAll-trans retinoic acid (ATRA) plus anthracycline chemotherapy is the reference treatment of newly diagnosed acute promyelocytic leukemia (APL), whereas the role of cytosine arabinoside (AraC) remains disputed. We performed a joint analysis of patients younger than 65 years included in Programa para el Estudio de la Terapéutica en Hemopatía Maligna (PETHEMA) LPA 99 trial, where patients received no AraC in addition to ATRA, high cumulative dose idarubicin, and mitoxantrone, and APL 2000 trial, where patients received AraC in addition to ATRA and lower cumulative dose daunorubicin. In patients with white blood cell (WBC) count less than 10 × 109/L, complete remission (CR) rates were similar, but 3-year cumulative incidence of relapse (CIR) was significantly lower in LPA 99 trial: 4.2% versus 14.3% (P = .03), although 3-year survival was similar in both trials. This suggested that AraC is not required in APL with WBC count less than 10 × 109/L, at least in trials with high-dose anthracycline and maintenance treatment. In patients with WBC of 10 × 109/L or more, however, the CR rate (95.1% vs 83.6% P = .018) and 3-year survival (91.5% vs 80.8%, P = .026) were significantly higher in APL 2000 trial, and there was a trend for lower 3-year CIR (9.9% vs 18.5%, P = .12), suggesting a beneficial role for AraC in those patients.

Adult life after surviving lymphoma in childhood

Almost all pediatric lymphomas are malignant, high-grade tumors. The combined incidence of Hodgkin's disease (HD) and non-Hodgkin lymphoma (NHL) reaches 10 to 12 new cases a year per million children under the age of 16 years, representing about 10% of all pediatric cancers. HD makes up to 40% and NHL 60% of pediatric lymphomas. During the last 20 years, cure rates raised dramatically so that currently over 90% of children and adolescents with HD and about 80% of those with NHL can be cured. As cure can be achieved in a large majority of patients, long-term effects and quality of life of the survivors are nowadays the principal challenges to pediatric oncologists. Like survivors from acute lymphoblastic leukemia, young adults cured from NHL may present with neurocognitive deficits, especially if treated at a young age and with cranial irradiation. Intrathecal or high-dose intravenous chemotherapy with methotrexate may induce the same problems, although in a lesser extent and severity. Large enough prospective cohort studies like the CCSS in the USA were able to show an increased risk of second malignant neoplasms, especially brain tumors in patients formerly treated with cranial irradiation. Reduced fertility can follow exposure to cyclophosphamide, especially in the male. Cardiac function must be serially evaluated over the long to very long-term because of potential cardiomyopathy after high anthracycline doses and/or mediastinal irradiation. Survivors from HD are at high risk of late complications. Radiation therapy to the neck and mediastinum (mantle field) induces a 50% risk of developing hypothyroidism and a 20% risk of developing thyroid nodules at 20 years. The risk of thyroid cancer is 18 times higher the expected rate for the general population. Secondary aggressive breast cancer shows a cumulative risk of 30% at 30 years after radiotherapy. Other structures affected by mediastinal irradiation are the heart (pericardial, myocardial and endocardial structures), the great arteries (fibrosis, stenosis, aneurysms) and the central portion of the lungs (diffusion troubles, restrictive pneumopathy). Cardiac toxicity can be enhanced by the concomitant therapy with adriamycin and lung toxicity by bleomycin. Radiotherapy to the paraaortic and iliacal lymph nodes can affect gonadal function both in males and females; concomitant chemotherapy with alkylating agents like cyclophosphamide and especially procarbazine have a synergistic action and can lead to premature menopause as well as infertility. Although the vast majority of survivors from pediatric lymphomas fare well, a minority present with extreme symptoms of depression and psychosomatic distress; female sex, low socio-economic status and treatment with intensive chemotherapy are important risk factors for a poor psychosocial outcome. It is therefore crucial, but not always easy, to inform patients and families about potential late effects and organize follow-up after the pediatric age. A well functioning network of pediatric oncologists, GP's, adult oncologists and other specialists of adult medicine must be developed in order to prevent, early detect and treat expected long-term toxicities.