Subclinical Cardiotoxicity Research Articles

Evaluation of Acute and Early Cardiotoxicity in Survivors of Hodgkin's Disease Treated with ABVD or BEACOPP Regimens

The study was conducted to compare the presence of cardiotoxicity after the treatment of Hodgkin's disease with the standard ABVD or BEACOPP protocol. We examined 29 patients treated by means of the ABVD regimen and 34 treated with the BEACOPP regimen. Using rest echocardiography we assessed the left ventricular function before and after the therapy. One year after the completion of therapy, a control examination was performed with a battery of tests; the rest and dynamic stress echocardiography and cardiopulmonary tests were carried out to assess cardiopulmonary performance. A similar significant deterioration of ejection fraction and diastolic function was apparent after the treatment in both sub-groups with a further progression at the one-year control. Only one patient from the BEACOPP sub-group showed a pathological drop of EF <50%. The most affected parameters of left ventricular function (LV) were Doppler indices. We found a significant relationship of the parameters of LV function compared with age, the cumulative dose of doxorubicin and the cumulative dose of radiotherapy. Multivariate analysis demonstrated that diastolic dysfunction correlated with advanced age and the cumulative dose of doxorubicin, and decreased cardiopulmonary performance with advanced age, radiotherapy, and female gender. Both parameters were significantly influenced by the presence of hypertension. The used regimens demonstrated similar subclinical cardiotoxicity, thus the most aggressive regimen, BEACOPP, is not accompanied by a higher rate of cardiac impairment. The clinical value of such subclinical cardiotoxicity will be estimated in a further prospective follow-up.

Suppression of mitoxantrone cardiotoxicity in multiple sclerosis patients by dexrazoxane

To explore the potential of dexrazoxane to suppress subclinical cardiotoxicity in MS patients receiving mitoxantrone. An open-label study was performed to evaluate possible subclinical cardiotoxicity in multiple sclerosis patients treated quarterly with mitoxantrone (48 mg/m(2) cumulative), with and without concomitant dexrazoxane, using blinded serial radionucleide ventriculography. No patient experienced symptoms of heart failure. Patients receiving dexrazoxane, which is cardioprotective for anthracyclines, exhibited a significantly lesser decline in left ventricular ejection fraction (mean change, -3.80% vs -8.55%, p < 0.001). These results support a cardioprotective effect of dexrazoxane in mitoxantrone treated multiple sclerosis patients.

Correlation of plasma N-terminal pro-brain natriuretic peptide levels with left ventricle mass in children treated with anthracyclines

Background The incidence of subclinical cardiotoxicity following anthracycline treatment for childhood cancer varies according to the method used for its detection. The aim of the study was to document the prevalence of left ventricular myocardial mass (LVM) reduction and its possible association with plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) levels in asymptomatic children treated with anthracyclines. Patients and methods Nineteen asymptomatic children who had received anthracyclines during their treatment for cancer were evaluated. They had received an equivalent of doxorubicin dose 240 mg/m 2 (22–1200 mg/m 2) on average 3.9 years (0.6–8.3) before (median age at diagnosis 3.8 years). The LVM was determined by M-Mode echocardiography and compared to the expected value, obtained from the regression equation of LVM on height of a group of 160 healthy children. Additionally the patients' plasma NT-pro BNP levels were determined. Results A high prevalence of reduced LVM associated with increased NT-proBNP levels was found. The average LVM value was − 14.4% (± 4.9) lower than expected whereas fourteen patients (73%) had a lower LVM than predicted. The NT-pro BNP levels in patients with reduced LVM were significantly higher than those measured in patients without LVM reduction (0.316 ± 0.02 versus 0.17 ± 0.01 pmol/ml respectively, p = 0.009). A cut off NT-pro BNP level of 0.2 pmol/ml could differentiate patients with LVM reduction from those with normal or greater than expected LVM. Conclusion The association of higher NT-proBNP levels with reduced LVM in asymptomatic children after anthracycline administration could be an early indication of subclinical cardiotoxicity.

Long-term serial echocardiographic examination of late anthracycline cardiotoxicity and its prevention by dexrazoxane in paediatric patients

The authors conducted an 8-year prospective non-randomised study to determine whether dexrazoxane (ICRF-187) would reduce late anthracycline-induced cardiotoxicity in patients treated in childhood for haematological malignancy. The authors examined prospectively 75 patients (40 male/35 female) aged 2-17 years (median 6.5 years) at the time of diagnosis. The cardioprotection was given to 53 patients (26 male/17 female) and the standard protocol was used in 22 patients (14 male/8 female). The prospective echocardiographic evaluation was done before and after the chemotherapy and every year during the follow-up period. Dynamic stress echocardiography (DSE) was assessed in the final year. The clinical cardiotoxicity was not diagnosed. Higher cumulative doses of anthracycline were given in the dexrazoxane group (234+/-58 mg/m(2), median 240 mg/m(2) versus 203+/-86 mg/m(2), median 210 mg/m(2), P <0.04) and a significantly higher percentage of patients received cumulative doses >240 mg/m(2) of anthracycline ( P <0.05). During the follow-up period, the fractional shortening (FS) declined in the no-dexrazoxane group only in the 8th year and was significantly lower compared to the dexrazoxane group ( P <0.05). The pathological decrease in FS was present in 24% of patients; 41% in the no-dexrazoxane and 17% in the dexrazoxane groups, respectively ( P <0.05). DSE demonstrated lower rest EF and cardiac index (CI) in the no-dexrazoxane group ( P <0.05); however, neither the response of EF and CI to the stress echocardiography nor the exercise tolerance significantly differed between sub-groups. A higher number of patients in the dexrazoxane group had very good exercise tolerance (ET) >3 Watts/kg ( P <0.05) and a lower number responded with a decreased ET <2 Watts/kg ( P <0.05) compared to the no-dexrazoxane group. Dexrazoxane seems to reduce the risk of late subclinical cardiotoxicity. Dexrazoxane-treated patients revealed better exercise tolerance; however the haemodynamic response to the stress was no different in both sub-groups.

Late anthracycline cardiotoxicity protection by dexrazoxane (ICRF-187) in pediatric patients: echocardiographic follow-up

The authors conducted a retrospective study to determine whether dexrazoxane (ICRF-187) would reduce late anthracycline-induced cardiotoxicity in patients treated in childhood for hematological malignancy. The authors examined 108 patients (63 male, 45 female) 5-29 years old, (median 15 years). All patients were in long-term remission of their malignancy. The cardioprotection was given to 68 patients (39 male, 29 female), and standard treatment was used in 40 patients (24 male, 16 female). Dexrazoxane (cardioxane, Chiron Company, The Netherlands) was given in 20:1 ratio to anthracycline. The follow-up time was 2-20 years (mean 7 years). The control group consisted of 41 volunteers (22 males, 19 females) 4-31 years old (median 18 years). The cardiotoxicity has been defined as the presence of heart failure or the decline of shortening fraction below 30% or ejection fraction (EF) below 55%. The end-systolic wall stress (ESS), myocardial performance index (MPI; Tei index), and parameters of left ventricular diastolic filling were also assessed. The anthracycline cardiomyopathy with the presence of heart failure was diagnosed in only one patient treated with a standard regimen. The pathological decline of fractional shortening was present in three (5%) and six (15%) patients with and without cardioprotection given, respectively. Similarly, none of the patients with cardioprotection revealed a pathological value of EF, while four (10%) patients without cardioprotection showed an EF decrease. Finally, ESS and isovolumic relaxation time were pathologically increased in the group without cardioprotection in comparison to the controls and to the group with cardioprotection. However, the MPI was significantly increased in both groups of patients. Dexrazoxane reduces the risk of late clinical and subclinical cardiotoxicity and does not affect the response rates to chemotherapy and overall survival during the median follow-up period of 7 years (follow-up period 2-20 years).

Subclinical late cardiomyopathy after doxorubicin therapy for lymphoma in adults.

To assess the cardiac status of the long-term survivors and to estimate the incidence and the features of subclinical cardiotoxicity induced after conventional treatment with doxorubicin for non-Hodgkin's lymphoma or Hodgkin's lymphoma. We analyzed a group of patients who previously received doxorubicin-based chemotherapy for lymphoma. Echocardiograms were performed at least 5 years after therapy with anthracyclines. Clinical cardiomyopathy was defined by the presence of clinical signs of congestive heart failure (CHF). Subclinical cardiomyopathy was defined by decrease of left ventricular fractional shortening (FS) without clinical signs of CHF. Cumulative dose of doxorubicin, male sex, older age, relapse, radiotherapy (mediastinal or total-body irradiation), autologous stem-cell transplantation, high-dose cyclophosphamide, and cardiovascular risk factors (hypertension, diabetes, hypercholesterolemia, familial history of cardiac disease, being overweight, and smoking history) were evaluated as potential risk factors for the development of cardiac dysfunction. Of 141 assessable patients (median age, 54 years; median cumulative dose of doxorubicin, 300 mg/m(2)), only one developed CHF. Criteria of subclinical cardiomyopathy were found in 39 patients. In multivariate analysis, factors that contributed to decreased FS were male sex (P <.01), older age (P <.01), higher cumulative dose of doxorubicin or association with another anthracycline (P =.04), radiotherapy (P =.04), and being overweight (P =.04). Cardiac abnormalities can occur in patients treated with doxorubicin for lymphoma in the absence of CHF, even in patients who received moderate anthracycline doses. Male sex, older age, higher dose of doxorubicin, radiotherapy, and being overweight were risk factors for the development of cardiomyopathy.

The late consequences of anthracycline treatment on left ventricular function after treatment for childhood cancer.

The purpose of this study was to determine the incidence of changes in left ventricular function in patients in long-term remission after treatment with anthracyclines for a childhood malignancy. The authors examined 155 patients in disease remission who underwent treatment protocols utilising anthracyclines in childhood. The group comprised 90 males and 65 females aged 15+/-4.9 years (range 5-29 years, median 15 years). The age at the time of diagnosis and start of treatment was 8.6+/-4.9 years (range 1-18 years, median 8 years). The time of follow-up was 7.3+/-4 years (range 1-21 years, median 6.3 years). The patients were given a cumulative dose of doxorubicin or daunorubicin of 250+/-131 mg/m2 (range 50-1200 mg/m2, median 240 mg/m2). The values of ejection fraction below 55% and fractional shortening below 30% assessed by means of echocardiography were considered as pathological. The control group consisted of 41 volunteers. Pathological values of fractional shortening were found in 12 patients (8%). Only one patient (0.64%) showed the development of heart failure due to cardiomyopathy. The group of the patients after chemotherapy revealed significantly worse values of left ventricular endsystolic wall stress, mean velocity of circumferential fibre shortening, Tei index, and isovolumic relaxation period in comparison with the control group. We found a correlation between the given cumulative dose of anthracyclines and indicators of systolic function of the left ventricle, but not a relation to the time indicators (age at diagnosis, time of follow-up). in the mean period of 6 years after chemotherapy, subclinical cardiotoxicity was found in 11 patients (7%) and cardiomyopathy with heart failure in one patient. Further indicators of subclinical damage are elevation of afterload (end-systolic stress), impaired relaxation and increased value of the Doppler index of global left ventricular function. Further monitoring and evaluation of the relevant subclinical abnormalities over a longer period of time are needed.

Early cardiotoxicity of the CHOP regimen in aggressivenon-Hodgkin’s lymphoma

To determine the incidence of early cardiotoxicity induced by the CHOP regimen in patients with aggressive non-Hodgkin's lymphoma (NHL) and to identify associated risk factors. A retrospective analysis included 135 consecutive patients who had been treated with the CHOP (cyclophosphamide, doxorubicin, vincristin, prednisone) regimen as first-line therapy between 1994 and 2000. The cardiac evaluation was based on a determination of the resting left ventricular ejection function (LVEF) by gated blood-pool imaging. Cardiotoxicity was defined as a significant decrease in LVEF or clinical evidence of congestive heart failure (CHF). Twenty-seven (20%) patients developed a cardiac event within 1 year of treatment. Among these, 14 patients had clinical signs of CHF. Three patients died suddenly from presumed cardiac causes. In multivariate analysis, a cumulative dose of doxorubicin >200 mg/m(2) [odds ratio (OR) = 4.2, P = 0.005)] and age over 50 years (OR = 2.9, P = 0.03) appeared to be significant risk factors. Early clinical and subclinical cardiotoxicity was frequent in patients receiving the CHOP regimen. The threshold of the cumulative dose of doxorubicin appeared to be low: at doses >200 mg/m(2), 27% of patients had cardiac events. Elderly patients appeared to be at higher risk. The development of cardioprotective strategies or alternative treatments are mandatory for aggressive NHL patients.

Non-endocrine late complications of bone marrow transplantation in childhood: part I.

Non-endocrine late complications of bone marrow transplantation in childhood: part I.

Doxorubicin Administration by Continuous Infusion Is Not Cardioprotective: The Dana-Farber 91-01 Acute Lymphoblastic Leukemia Protocol

PURPOSE: Acute doxorubicin-induced cardiotoxicity can be prevented in adults by continuous infusion of the drug, but mechanisms of cardiotoxicity are different in children. We compared cardiac outcomes in children receiving bolus or continuous infusion of doxorubicin. PATIENTS AND METHODS: In a randomized study, children with high-risk acute lymphoblastic leukemia received doxorubicin 360 mg/m2 in 30-mg/m2 doses every 3 weeks either by bolus (within 1 hour, n = 57) or by continuous infusion (over 48 hours, n = 64). Echocardiograms obtained before doxorubicin and at longest follow-up times were centrally remeasured, and z scores of cardiac measurements were calculated based on a healthy population. RESULTS: The groups were similar in age, sex distribution, doxorubicin dose, and duration of follow-up. Before treatment, measures of left ventricular (LV) structure and function did not reveal dilated cardiomyopathy and were not statistically different between bolus and continuous-infusion groups. The follow-up echocardiograms demonstrated no significant difference between the two groups for any cardiac characteristic, but both groups showed significant abnormalities of LV structure and function compared with normal and with baseline. For example, the mean LV fractional shortening fell by approximately two SD in both groups between the two echocardiograms. LV contractility was depressed in both groups (for bolus patients, median z score = −0.70 SD, P = .006; for continuous-infusion patients, median z score = −0.765, P = .005). Dilated cardiomyopathy and inadequate LV hypertrophy were noted in both groups. Clinical cardiac manifestations and event-free survival did not differ. CONCLUSION: Continuous doxorubicin infusion over 48 hours for childhood leukemia did not offer a cardioprotective advantage over bolus infusion. Both regimens were associated with progressive subclinical cardiotoxicity. Other cardioprotective strategies should be explored.

Troponin T in the first 24 hours after the administration of chemotherapy and the detection of myocardial damage in children

Early detection of damage to cardiac myocytes after cardiotoxic chemotherapy in paediatric patients may allow timely preventive measures to be taken. We investigated the diagnostic value of cardiac troponin T (cTnT) after the administration of cardiotoxic chemotherapy. In 38 children, cTnT levels were measured at three time points during the first 24 h after 58 cardiotoxic chemotherapy cycles (163 samples). An abnormal cTnT level, defined as a cTnT>0.010 ng/ml, was measured in only six samples from 3 patients. After completion of chemotherapy, 7 out of the 38 patients had left ventricular dysfunction (LV dysfunction). Only 1 of these 7 patients had an elevated cTnT level. 2 other patients with elevated cTnT levels did not develop LV dysfunction until 2 and 7 months after the cTnT measurement. Our data show that the measurement of cTnT within 24 h after administration of chemotherapy does not have a high sensitivity for the identification of patients with subsequent subclinical cardiotoxicity.

Sequential evaluation of left ventricular myocardial performance in children after anthracycline therapy

This study prospectively assessed subclinical cardiotoxicity in patients undergoing chemotherapy by using the Tei index combining systolic and diastolic time intervals. A significant difference in the Tei index was observed between patients who received a low dose and those who received a moderate to high dose of anthracycline antibiotic drugs. The Tei index is a sensitive, accurate, and easy approach for detecting subclinical anthracycline cardiotoxicity.

Cardiac Toxicity after Anthracycline Chemotherapy in Childhood

The clinical use of anthracyclines, a family of chemotherapeutic agents with efficacy against many solid tumors and leukemias is limited by unique cumulative dose-limiting cardiotoxicity. Overt heart failure occurs in 4.5% to 7% of patients treated with anthracyclines and the incidence of cardiac function abnormalities increases with the time. Anthracycline-induced congestive heart failure is usually due to permanent changes in the myocardium, changes most consistent with the contractile failure of cardiomyopathy. Although the causes of anthracycline-induced cardiotoxicity are probably many, a large body of evidence points to free-radical-mediated myocyte damage. The risk of developing cardiac heart failure is modified by the presence of certain risk factors that reduce cardiac tolerance to anthracyclines. Age and female gender seem to have an important role in the anthracycline cardiotoxicity. This cardiotoxicity can be divided, on the base of when it started, into acute, subacute and progressive late, chronic form. Various invasive and non-invasive methods have been used to measure the extent of cardiac damage done. Depending on the sensitivity of the method employed, the proportion of hearts found to be damaged has varied widely. Attempts to ameliorate anthracycline cardiotoxicity have been directed toward: 1. decreasing myocardial concentrations of anthracyclines and their metabolites, 2. developing less cardiotoxic analogous, and 3. concurrently administering cardioprotectants to attenuate the effects of anthracyclines on the heart. Much progress has been made in terms of monitoring of clinical and subclinical anthracycline cardiotoxicity, finding alternative schedules, introducing special carriers of anthracyclines and using cardioprotecting agents. It is hoped that with all these effects and with results of ongoing and future trials, we will be able to reduce further or even eliminate anthracycline cardiotoxicity.

Dobutamine Stress Echocardiography Identifies Anthracycline Cardiotoxicity

Anthracyclines are effective anti-cancer agents, but their therapeutic value is limited by their myocardial toxicity. We assessed the physiological responses of stress echocardiography at low doses of dobutamine (DSE) in patients treated with anthracycline. In a prospective study, 28 patients were studied before and 1 month after the end of chemotherapy. All patients had normal ejection fraction (EF) at rest before therapy and the mean dose of anthracycline was 212+/-15 mg/m(2). Echocardiographic Doppler studies were performed before and during dobutamine infusion (5 and 10 microg/kg per min). Rest echocardiography demonstrated a significant decrease of EF between the two examinations in ejection fraction (67+/-3% vs. 61+/-3%, P<0.001). The increase of the EF during dobutamine infusion was higher after chemotherapy compared to the initial examination (19+/-3% vs. 29+/-3%: P<.05). No difference in EF was observed at 10 microg/kg per min between before and after chemotherapy. In contrast, at rest no difference in diastolic parameters was observed between the two examinations. Moreover, a significant decrease of the peak E and the ratio E/A was observed during dobutamine infusion after chemotherapy (93+/-4 cm/s vs. 79+/-5 cm/s and 1.3+/-0.1 vs. 1.0+/-0.1, respectively;P<0.05). Stress echocardiography may prove to be a sensitive technique and useful non-invasive approach for evaluating subclinical anthracycline cardiotoxicity.

Automatic border detection identifies subclinical anthracycline cardiotoxicity in children with malignancy.

Anthracycline drugs for cancer therapy often cause functional myocardial impairment even in relatively low doses. We investigated the left ventricular function in asymptomatic anthracycline-treated children by automatic border detection (ABD) to assess its clinical usefulness for unmasking latent anthracycline-induced myocardial damage. Thirty-four children (0.7 to 17.6 years old) during or after anthracycline chemotherapy (26 to 1100 mg/m2) for malignancy (Chemo group) were studied, and 40 children (2.8 to 15.6 years old) without cardiac involvement served as normal control subjects (Control group). All patients underwent complete echocardiographic examination, including M-mode, Doppler, and ABD. Conventional echocardiography disclosed no difference between groups with regard to ejection fraction and the ratio of early to late transmitral flow velocity. In marked contrast, an investigation using ABD revealed that the Chemo group appeared to have some anthracycline-induced myocardial damage. In the apical 4-chamber view, peak filling rate in the Chemo group [2.3+/-0.4 end-diastolic area (EDA)/s] was significantly lower than that in the Control group (3.1+/-0.5 EDA/s) (P<0.0001), and time to peak filling rate in the Chemo group (106+/-31 ms) was clearly prolonged compared with that in the Control group (74+/-22 ms) (P<0.0001). Echocardiographic ABD may be a sensitive and useful noninvasive approach for evaluating subclinical anthracycline cardiotoxicity.

Abstract

Late cardiotoxicity after anthracycline therapy for childhood cancer is frequent, mostly subclinical, often progressive, potentially severe and sometimes fatal. The present article reviews all available studies of cardiac function more than 1 year after cessation of anthracycline therapy for childhood cancer. Late clinical cardiotoxicity occurs in 5–10% of long term survivors 5–10 years after therapy. Late clinical cardiotoxicity is often life threatening if not treated by cardiac transplantation. Clinical cardiotoxicity during or shortly after anthracycline therapy seems to be the most important risk factor for late clinical cardiotoxicity. In spite of many large studies on the subject, considerable controversy exists on the frequency, severity and risk factors of late subclinical cardiotoxicity following anthracycline therapy for childhood cancer. Some studies have found subclinical cardiac abnormalities in more than half of the participants 5–10 years after anthracycline therapy. Anthracycline cumulative dose and dose intensity are risk factors for late subclinical cardiotoxicity. Younger age at therapy, female sex and longer follow-up after therapy also seem to be associated with an increased risk. Risk factors for late subclinical cardiotoxicity may also increase the risk of late clinical cardiotoxicity, as subclinical cardiotoxicity may worsen over time and become clinical. During the first decade after anthracycline therapy for childhood cancer, cardiac toxicity only influences survival minimally. It is yet unknown whether late cardiotoxicity will significantly reduce the long-term survival or impair the quality of life of the survivors during the second and third decades following anthracycline therapy for childhood cancer.

Late cardiotoxicity following anthracycline therapy for childhood cancer

Late cardiotoxicity after anthracycline therapy for childhood cancer is frequent, mostly subclinical, often progressive, potentially severe and sometimes fatal. The present article reviews all available studies of cardiac function more than 1 year after cessation of anthracycline therapy for childhood cancer. Late clinical cardiotoxicity occurs in 5–10% of long term survivors 5–10 years after therapy. Late clinical cardiotoxicity is often life threatening if not treated by cardiac transplantation. Clinical cardiotoxicity during or shortly after anthracycline therapy seems to be the most important risk factor for late clinical cardiotoxicity. In spite of many large studies on the subject, considerable controversy exists on the frequency, severity and risk factors of late subclinical cardiotoxicity following anthracycline therapy for childhood cancer. Some studies have found subclinical cardiac abnormalities in more than half of the participants 5–10 years after anthracycline therapy. Anthracycline cumulative dose and dose intensity are risk factors for late subclinical cardiotoxicity. Younger age at therapy, female sex and longer follow-up after therapy also seem to be associated with an increased risk. Risk factors for late subclinical cardiotoxicity may also increase the risk of late clinical cardiotoxicity, as subclinical cardiotoxicity may worsen over time and become clinical. During the first decade after anthracycline therapy for childhood cancer, cardiac toxicity only influences survival minimally. It is yet unknown whether late cardiotoxicity will significantly reduce the long-term survival or impair the quality of life of the survivors during the second and third decades following anthracycline therapy for childhood cancer.

Cardiotoxicity from intensive chemotherapy combined with radiotherapy in breast cancer.

Cardiac function was evaluated in 86 breast cancer patients after standard chemotherapy, followed by ablative chemotherapy and chest irradiation. One patient died of subacute heart failure 3 months after ablative chemotherapy. At a minimum of 1 year's follow-up (range 1-11 years) left vertricular ejection fraction (LVEF) was marginally abnormal in 4 of 27 disease-free survivors. One exceptional patient who received two transplantations is alive, with serious heart failure occurring after the second ablative chemotherapy. Including this patient, the percentage of patients free of clinical and subclinical cardiac dysfunction at 7 years is 78% (95% CI 61-95%). After ablative chemotherapy, cardiotoxicity was rarely life-threatening. The impact of subclinical cardiotoxicity in the long term is not clear and needs continued evaluation.

Durable Remission After Aggressive Chemotherapy for Post-Cardiac Transplant Lymphoproliferation

A frequently fatal complication of organ transplantation, post-transplant lymphoproliferative disorder (PTLD) develops in 2%-6% of cardiac recipients. Treatment remains poorly defined. Reduction in immunosuppression is effective in a proportion of cases, but mortality in the order of 80% is reported for patients requiring chemotherapy. The reason for such poor outcomes is unclear, but may be partly due to the concomitant use of immunosuppressives. An update report is provided on nineteen consecutive cardiac recipients with PTLD, studied retrospectively in terms of clinical features and outcome. Patients were managed according to a uniform treatment approach. Initial therapy was a trial of reduced immunosuppression with concomitant acyclovir followed, if unsuccessful, by aggressive combination chemotherapy. The regimen used was predominantly ProMACE-CytaBOM. Six patients with phenotypically polyclonal PTLD presented <6 months after transplantation (median 6 weeks). Only 1/4 (25%) treated patients responded to reduced immunosuppression; the remainder died of multiorgan failure. Thirteen patients presented with phenotypically monoclonal disease ≥6 months after transplantation. In 8/12 (75%) treated patients initial therapy was reduction in immunosuppression. None achieved CR; 2 experienced fatal rejection. Two patients achieved durable surgical CR. The remaining 8 patients received chemotherapy; 2/8 (25%) died during treatment, 6/8 (75%) achieved CR. None have relapsed, at a median duration of follow-up of 64 months. Neutropenic sepsis, and subclinical doxorubicin cardiotoxicity at a mean cumulative dose of 63 mg/m2 were the principal toxicities. Our data indicate that aggressive chemotherapy is feasible and can produce very durable remissions in phenotypically monoclonal PTLD refractory to reduced immunosuppression. ProMACE-CytaBOM is well suited to cardiac recipients, minimizing doxorubicin exposure and obviating the need for concurrent immunosuppressives.

Aggressive Treatment for Postcardiac Transplant Lymphoproliferation

Posttransplant lymphoproliferative disorder (PTLD) is a frequently fatal complication of organ transplantation, occurring in 2% to 6% of cardiac recipients. Treatment remains poorly defined. Reduction in immunosuppression is effective in a proportion of cases, but mortality on the order of 80% is reported for patients requiring chemotherapy. The reason for such poor outcomes is unclear, but may be partly caused by the concomitant use of immunosuppressives. Nineteen consecutive cardiac recipients with PTLD were studied retrospectively in terms of clinical features and outcome. Patients were managed according to a uniform treatment approach. Initial therapy was a trial of reduced immunosuppression with concomitant acyclovir followed, if unsuccessful, by aggressive combination chemotherapy. The regimen used was predominantly ProMACE-CytaBOM. Six patients with phenotypically polyclonal PTLD presented less than 6 months after transplantation (median 6 weeks). Only 1 of 4 (25%) treated patients responded to reduced immunosuppression; the remainder died of multiorgan failure. Thirteen patients presented with phenotypically monoclonal disease > or = 6 months after transplantation. In 8 of 12 (75%) treated patients initial therapy was reduction in immunosuppression. None achieved complete remission (CR) and 2 experienced fatal rejection. Two patients achieved durable surgical CR. The remaining 8 patients received chemotherapy; 2 of 8 (25%) died during treatment, 6 of 8 (75%) achieved CR. None have relapsed, at a median duration of follow-up of 38 months. Neutropenic sepsis and subclinical doxorubicin cardiotoxicity at a mean cumulative dose of 63 mg/m2 were the principal toxicities. Our data indicate that aggressive chemotherapy is both feasible and effective in phenotypically monoclonal PTLD refractory to reduced immunosuppression. ProMACE-CytaBOM is well suited to cardiac recipients, minimizing doxorubicin exposure and obviating the need for concurrent immunosuppressives.