Cardiotoxicity and Treatment Efficacy of Not Pegilated Liposomal Doxorubicin in Haematological Malignancies: Our Experience.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4836-4836
Author(s):  
Alfredo Gagliardi ◽  
Maria Lucia Boffa ◽  
Gaetana Capobianco ◽  
Concetta Cotarelli ◽  
Donatella De Blasi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Null Hypothesis ◽  
Liposomal Doxorubicin ◽  
Alternative Hypothesis ◽  
Stage Iv ◽  
Left Ventricular ◽  
T Test ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Clinically Significant

Abstract Backgrounds. Not pegilated liposomal doxorubicin (Myocet®) has a better pharmacokinetic profile with less myelosuppression, much lower gastroenterological and cardiological toxicity than conventional doxorubicin. In order to reduce toxicity of conventional doxorubicin, in our department from 2002 to 2007 we have treated patients with Multiple Myeloma (MM) and Non-Hodgkin’s Lymphoma (NHL) with therapeutical regimens replacing conventional anthracyclines with not pegilated liposomal doxorubicin. Methods. In our department, from 2002 to 2007, 35 patients (17M,18F) with a median age of 68.8±9.6(range 82–33) affected by Multiple Myeloma (MM) received one or more cycles according to chemiotherapic scheme: VCR 1mg iv at day 1 + Myocet® 25mg/sm iv at day 2 + CTX 100mg/sm os days 1–4 + PDN 60mg/sm os days 1–4. Diagnosis concerned patients with IgG Myeloma (n=26), IgA Myeloma (n=7), micromolecular Myeloma (n=1) and PL (n=1). 22 patients (16M,6F) with a median age of 63.6±9.6 (range 45–79) affected by NHL received chemoimmunotherapy COMP21-R (CTX, Myocet®, VCR and PDN plus Rituximab). Four patients were stage I, 7 stage II, 6 stage III and 5 stage IV. According to IPI score: 2 patients were low risk, 6 low-intermediate, 8 intermediate-high and 6 high risk. In all patients, chemoimmunotherapy induced cardiologic evaluation was made considering Left Ventricular Ejection Fraction (LVEF): cardiotoxicity was evaluated testing the null hypothesis that the LVEF delta is more negative than −4% of the baseline value before chemotherapy (which was felt to be a reasonable clinical threshold separating non-clinically-significant cardiac toxicity from clinically significant damage due to chemotherapy). Results. In MM patients evaluation of treatment was made for 31 patients: mean Monoclonal Component (MC) has been reduced from 3048.2±2296.9 to 2353,7±1912.4 and the one sided t-test on the variable delta resulted statistically significant (P = 0.038). Response of treatment was CR 43,3%, PR 23,3%, DP 16,7%, NR 16,7% but no statistically significant correlations were present with both the line of treatment and the diagnosis. For NHL evaluation was made in 20 patients: 17 (77.3%) obtained a Complete Remission (CR), 1 (4.5%) a Partial Remission (PR) and 2 (9.1%) Not Respond (NR) to therapy: no statistically significant correlations were present with both the line of treatment and the diagnosis. In all patients (21 NHL and 30MM, totally 51 subjects), Myocet® cardiotoxicity has been evaluated by LVEF assessment at baseline and monitored along the course of the treatment: baseline mean was 57.8±5.4% and slightly lowered to 55.6±5.2% at the end of treatment. For each sub-population and for the entire population a one-sided t-test was performed in order to determine whether therapy with not pegilated liposomal doxorubicin determines relatively low cardiotoxicity: the tests resulted significant (NHL: P = 0.022, MM: P = 0.0021, All: P = 0.00020), leading to reject the null hypothesis in favour of the alternative hypothesis that cardiotoxicity is actually less severe and that the decrement of LVEF is not as negative as −4%. Conclusion. Myocet® reduce cardiotoxicity and is effective in the treatment of MM and NHL patients.

The combination of the HER2 antibody trastuzumab, the EGFR tyrosine kinase inhibitor gefitinib, and docetaxel as first-line therapy in patients with HER2 overexpressing stage IV breast carcinoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 1057-1057
Author(s):  
G. Somlo ◽  
M. Koczywas ◽  
T. Luu ◽  
M. McNamara ◽  
V. Bedell ◽  
...  
Keyword(s):  
Performance Status ◽  
Stage Iv ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Time To Progression ◽  
Ecog Performance Status ◽  
Ventricular Ejection Fraction ◽  
Grade 3 ◽  
Topo Ii ◽  
To Receive

1057 Background: Interference with both HER2 and epidermal growth factor (EGFR) dependent pathways may improve therapeutic efficacy of docetaxel (doc) in pts with HER2 overexpressing (+) BC. Methods: Patients (pts) without prior chemotherapy (Rx) exposure for stage IV HER-2 + BC were enrolled. Prior hormonal or adjuvant Rx inclusive of taxane or trastuzumab (tras) were allowed. A left ventricular ejection fraction of > 45% and ECOG performance status of ≥ 2 were required. Pts were to receive doc 75 m2, tras every 3 weeks, and gefitinib (gef) 250 mg daily. BC samples from 12 pts were analyzed by FISH for HER2 and EGFR amplification (amp), and topoisomerase II (topo II) amp or loss. IHC was to be performed to examine p-Src, p-STAT3, Ki67 and survivin expression. Results: The median age was 49 (range, 34–67) and ECOG performance status 0.5 (0–1). The first 9 patients received gef 250 mg daily; 2 pts received dox 75 mg/m2 and developed grade 3 febrile neutropenia (neu), hence, additional pts received doc at 60 mg/m2: 3 more episodes of grade 3 neu were seen. Gef was held due to grade 3 dermatitis (2 pts) and diarrhea (2 pts). Pts received a median of 6 cycles (3–10). Gef schedule then was changed, and was prescribed on days 2–14, only. Three of the next 9 pts experienced grades 3 or 4 neu, and we observed 3 cases of grade 3 gastrointestinal toxicities; pts were able to receive 11 + (range; 5–25+) cycles on this schedule (p<0.04). There were 4 complete (CR)and 6 partial R (23 % CR, 59 % overall R), and 3 pts had stable disease (SD; all R and SD confirmed); 3 pts progressed at 4, 4, and 5 mos, 1 pt was inevaluable. The median time to progression is 12 + mos. Samples from 3 pts revealed topo II amplification and one pt sample showed loss of one topo II allele; none were amplified for EGFR. Outcome will be correlated with IHC defined signal trasduction status and proliferation rates. Conclusions: The combination of doc, tras, and short course of gef is feasible, with encouraging R and SD rates and time to progression. Further exploration of simultaneous blockage of multiple signal transduction pathways is indicated in combination with chemoRx. Supported by NCI CA33572 and by a grant from AstraZeneca. No significant financial relationships to disclose.

Cardiac safety profile of patients receiving high cumulative doses of pegylated-liposomal doxorubicin (PLD): Use of left ventricular ejection fraction (EF).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14016-e14016
Author(s):  
Keith M. Skubitz ◽  
Anne Hudson Blaes ◽  
Suma Konety ◽  
Gary S. Francis
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Cumulative Dose ◽  
Liposomal Doxorubicin ◽  
Pegylated Liposomal Doxorubicin ◽  
Retrospective Chart Review ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Bolus Administration ◽  
Ventricular Ejection Fraction

e14016 Background: The use of doxorubicin (D) is limited by cardiotoxicity. Cumulative dose is an important risk factor for D-induced heart failure (D-HF). Retrospective studies found a ~7.5% incidence of clinical HF at a cumulative dose of 550 mg/m2, and prospective trials have found even higher rates. The administration of D by continuous intravenous infusion (CIVI) has less cardiotoxicity than when given by bolus administration. Pegylated-liposomal doxorubicin (PLD) has a longer half-life in blood, and may have lower cardiotoxicity. Limiting D use based on ejection fraction (EF) is commonly performed. Despite the wide use of EF to monitor D-HF, evidence for its utility to predict D-HF is limited, and monitoring adds cost. There is even less information regarding large cumulative doses of PLD and its effect on D-HF and EF. We examined the incidence of D-HF in patients who received a large cumulative dose of D as PLD, and its relation to EF and HF. Methods: A retrospective chart review of patients who received a large cumulative dose of PLD, sometimes following previous free D, was performed. Results: Definite clinical D-HF was not observed in 53 patients who received a cumulative D dose (free + PLD) of > 450 mg/m2, 46 of whom received > 500 mg/m2, 26 > 700 mg/m2, 14 > 1000 mg/m2, and 5 > 1400 mg/m2. The EF varied greatly over time in some patients in the absence of symptoms or signs of HF and was not a reliable predictor of the development of heart failure. Conclusions: The findings provide further evidence for the low risk of D-HF with PLD. Although this study is subject to the usual limits of a retrospective study, the doses received and long-term follow-up are noteworthy. While the determination of EF is commonly used to monitor D cardiotoxicity, it has many limitations. Serial monitoring of EF during treatment may not be helpful, at least in the case of PLD and CIVI-D in adults. Indeed, given the lack of prognostic clarity regarding modest EF changes, regular measurement of EF may sometimes inappropriately limit patient access to this useful drug. These findings may not apply to children or other liposomal formulations, such as non-pegylated formulations.

scholarly journals Effects of Carfilzomib Therapy on Left Ventricular Function in Multiple Myeloma Patients

2021 ◽  
Vol 8 ◽  
Author(s):  
Giulia Mingrone ◽  
Anna Astarita ◽  
Lorenzo Airale ◽  
Ilaria Maffei ◽  
Marco Cesareo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Left Ventricular Function ◽  
Diastolic Dysfunction ◽  
Ventricular Function ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Lv Function ◽  
Ventricular Ejection Fraction ◽  
Increased Risk ◽  
Cardiovascular Evaluation

Background: Carfilzomib improves the prognosis of multiple myeloma (MM) patients but significantly increases cardiovascular toxicity. The timing and effect of Carfilzomib therapy on the left ventricular function is still under investigation. We sought to assess the echocardiographic systo-diastolic changes, including global longitudinal strain (GLS), in patients treated with Carfilzomib and to identify predictors of increased risk of cardiovascular adverse events (CVAEs) during therapy.Methods: Eighty-eight patients with MM performed a baseline cardiovascular evaluation comprehensive of transthoracic echocardiogram (TTE) before the start of Carfilzomib therapy and after 6 months. All patients were clinically followed up to early identify the occurrence of CVAEs during the whole therapy duration.Results: After Carfilzomib treatment, mean GLS slightly decreased (−22.2% ± 2.6 vs. −21.3% ± 2.5; p &lt; 0.001). Fifty-eight percent of patients experienced CVAEs during therapy: 71% of them had uncontrolled hypertension, and 29% had major CVAEs or CV events not related to arterial hypertension. GLS variation during therapy was not related to an increased risk of CVAEs; however, patients with baseline GLS ≥ −21% and/or left ventricular ejection fraction (LVEF) ≤ 60% had a greater risk of major CVAEs (OR = 6.2, p = 0.004; OR = 3.7, p = 0.04, respectively). Carfilzomib led to a higher risk of diastolic dysfunction (5.6 vs. 13.4%, p = 0.04) and to a rise in E/e′ ratio (8.9 ± 2.7 vs. 9.7 ± 3.7; p = 0.006).Conclusion: Carfilzomib leads to early LV function impairment early demonstrated by GLS changes and diastolic dysfunction. Baseline echocardiographic parameters, especially GLS and LVEF, might improve cardiovascular risk stratification before treatment.

scholarly journals Histological evidence for the cardiac safety of high-dose pegylated liposomal doxorubicin in a patient with HIV-associated Kaposi sarcoma: a case report and literature review

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Ayaka Ishihara ◽  
Shuji Hatakeyama ◽  
Jun Suzuki ◽  
Yusuke Amano ◽  
Teppei Sasahara ◽  
...  
Keyword(s):  
Case Report ◽  
Literature Review ◽  
Cumulative Dose ◽  
Liposomal Doxorubicin ◽  
Cardiac Toxicity ◽  
Pegylated Liposomal Doxorubicin ◽  
Kaposi Sarcoma ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction

Abstract Background Pegylated liposomal doxorubicin plays an important role in the treatment of patients with severe refractory human immunodeficiency virus (HIV)-associated Kaposi sarcoma (KS). High cumulative doses of conventional doxorubicin exceeding 500 mg/m2 are known to cause cardiac toxicity. However, the safe cumulative dose of pegylated liposomal doxorubicin is unclear. Case presentation A 40-year-old Japanese man with HIV infection presented with pain, edema, and multiple skin nodules on both legs which worsened over several months. He was diagnosed with HIV-associated KS. He received long-term pegylated liposomal doxorubicin combined with antiretroviral therapy for advanced, progressive KS. The cumulative dose of pegylated liposomal doxorubicin reached 980 mg/m2. The patient’s left ventricular ejection fraction remained unchanged from baseline during treatment. After he died as a result of cachexia and wasting, caused by recurrent sepsis and advanced KS, an autopsy specimen of his heart revealed little or no evidence of histological cardiac damage. We also conducted a literature review focusing on histological changes of the myocardium in patients treated with a cumulative dose of pegylated liposomal doxorubicin exceeding 500 mg/m2. Conclusions This case report and literature review suggest that high (> 500 mg/m2) cumulative doses of pegylated liposomal doxorubicin may be used without significant histological/clinical cardiac toxicity in patients with HIV-associated KS.

scholarly journals The First Autopsy Case of Fatal Acute Cardiac Failure after Administration of Carfilzomib in a Patient with Multiple Myeloma

2019 ◽  
Vol 2019 ◽  
pp. 1-5
Author(s):  
Teruhito Takakuwa ◽  
Ippei Otomaru ◽  
Taku Araki ◽  
Akiko Miura ◽  
Yotaro Fujitani ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cardiac Failure ◽  
Myocardial Necrosis ◽  
Progression Free Survival ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Autopsy Case ◽  
Drug Induced ◽  
Ventricular Ejection Fraction ◽  
Acute Cardiac Failure

Carfilzomib (CFZ) improves progression-free survival for patients with relapsed or refractory multiple myeloma (MM) but has shown higher frequency of cardiovascular adverse events (CVAEs) than other proteasome inhibitors. We report the first autopsy case of acute death from cardiac failure shortly after administration of carfilzomib. A 74-year-old female was diagnosed with IgA MM after a 2-year period of smoldering MM. She was refractory to both bortezomib plus dexamethasone and lenalidomide plus dexamethasone therapies, so she subsequently received CFZ in combination with lenalidomide and dexamethasone. The day after the start of the therapy, she complained of severe dyspnea with a significant decline in left ventricular ejection fraction. Her acute cardiac failure rapidly progressed, and she died on day 7 of the start of CFZ. The autopsy showed invasion of inflammatory cells between the myocardial cells and very little myocardial necrosis. There was no obvious thrombus in the coronary artery of the heart, and no infarction or amyloid deposition was observed in the myocardium. Pathological findings of hypersensitivity myocarditis, a drug-induced cardiomyopathy, appeared to agree with this case except for absence of an eosinophilic infiltration of the myocardium. A CFZ-induced CVAE is generally considered reversible. However, rapidly progressing fatal heart failure like in our case is rare. To characterize CFZ-associated CVAE, further case collection is needed.

Phase I trial of pegylated liposomal doxorubicin and lapatinib in the treatment of metastatic breast cancer (MBC): Final results.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 610-610
Author(s):  
Mary E. Cianfrocca ◽  
Virginia G. Kaklamani ◽  
Steven T. Rosen ◽  
Jamie H. Von Roenn ◽  
Alfred Rademaker ◽  
...  
Keyword(s):  
Phase I ◽  
Liposomal Doxorubicin ◽  
Cardiac Toxicity ◽  
Metastatic Breast ◽  
Pegylated Liposomal Doxorubicin ◽  
Left Ventricular ◽  
Primary Objective ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Grade 3

610 Background: Liposomal formulations including pegylated liposomal doxorubicin (PLD) were developed to improve the therapeutic index of anthracyclines (A). Lapatinib (L) is a selective, highly competitive inhibitor of ErbB1 and ErbB2 tyrosine kinases. Conventional doxorubicin plus trastuzumab was effective but with unacceptable cardiac toxicity. PLD plus L may be effective with less cardiac risk. Methods: This is a phase I, dose-escalation trial of PLD 20, 30, 45 and 60 mg/m2 IV every 4 weeks (maximum of 8 doses) and L, 1500 mg po daily until progression in patients (pts) with MBC. ErbB2 positivity was not required. Prior chemotherapy, endocrine therapy and trastuzumab were allowed. A subsequent amendment allowed prior L. Prior A use was limited to 240 mg/m2 of doxorubicin or 600 mg/m2 of epirubicin. Concomitant CYP3A4 inducers/ inhibitors were not allowed. A left ventricular ejection fraction (LVEF) of > 50% was required. The primary objective was to evaluate the safety (particularly cardiac), tolerability and feasibility of PLD and L. Results: 23 pts (PLD: 20 mg/m2 - 4 pts; 30 mg/m2 - 3 pts; 45 mg/m2 – 13 pts; 60 mg/m2- 3 pts) have been treated; total of 73 treatment cycles. Dose-limiting toxicity (DLT) was not reached. One pt had an LVEF drop to < 50% after 4 cycles accompanied by a pericardial effusion due to progressive disease. Treatment-related grade III/IV adverse events included: 4 pts with hand-foot-syndrome (HFS), 2 pts each with leukopenia, infection, and skin changes, 1 pt each with pain, fatigue, diarrhea, mucositis, hypoalbuminemia, anemia, cough, pleural effusion, and edema. Grade 3 HFS occurred in 2 of 3 pts in the 60 mg/m2 cohort. Response data in 21 evaluable pts: 4 PR, 5 SD, and 12 PD. Preliminary pharmacokinetic (PK) analyses (7 pts) indicate L has no effect on PLD (45 mg/m2) concentrations, but L concentrations were approximately 2-fold higher the day of PLD dosing. Conclusions: In 23 pts treated, PLD plus L was well tolerated with manageable toxicities and no treatment-related cardiac toxicity. DLT was not reached however grade 3 HFS occurred in 2 of 3 pts in the 60 mg/m2 cohort. Preliminary PK analyses demonstrate no effect of L on PLD, but an effect of PLD on L the day of PLD dosing.

Modified-CHOP with Reduced Dose of Non-Pegylated Liposomal Doxorubicin ± Rituximab in First Line Treatment for Elderly Patients with Aggressive Lymphoma Non Suitables for Standard Chemotherapy.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4752-4752
Author(s):  
Eva Gimeno ◽  
Blanca Sánchez ◽  
Alberto Alvarez ◽  
Carme Pedro ◽  
Eugenia Abella ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Liposomal Doxorubicin ◽  
Conflicts Of Interest ◽  
Pegylated Liposomal Doxorubicin ◽  
Left Ventricular ◽  
Aggressive Lymphoma ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Reduced Dose

Abstract Abstract 4752 BACKGROUND CHOP ± Rituximab ( R) is the standard regimen for elderly patients (pts) with aggressive lymphoma but many of them are not suitable for it due to severe associated comorbidities. The aim was to evaluate retrospectively the efficacy and safety of a modified-CHOP (with reduced dose non-pegylated liposomal doxorubicin (NPLD) ± R in elderly pts with clinically aggressive lymphoma not tributary to standard anthracycline-containing chemotherapy. PATIENTS AND METHODS Retrospective analysis of 30 pts (16M/14W). Median age 76 years (60-88). Stage III-IV: 19 pts (58%). IPI 3-5: 16 pts (49%). Median baseline left ventricular ejection fraction (LVEF): 63% (33-80). Median NT-proBNP determination: 1431 ng/L (60-9120), 14 patients had NT-proBNP>900. All patients had one or more severe comorbidities. Schedule: NPLD 30mg/m2 (d1), cyclophosphamide 750mg/m2 (d1), vincristine 1.4mg/m2 (d1), prednisone 100mg/d (d1-5) ± R 375mg/m2 (d1) + Pegfilgrastim (d2) every 21 days. RESULTS Median follow-up time was 18 months. Median number of cycles was 4 (range 1-6). Complete response (CR/uCR): 24 pts (73%), Partial response: 4 pts (12%). Two pts progressed during chemotherapy and 10 pts relapsed during follow-up (5 of them dying with active disease). Overall Survival (OS) at 12 and 24 months was 76% (95%CI 61-91) and 70% (95%CI 49-91), respectively. Progression-free survival (PFS) at 12 and 24 months was 65% (95%CI 49-81) and 55% (95%CI 32-78), respectively. A total of 154 cycles were administered. 52% of patients showed grade III-IV neutropenia and 33% of them required hospital admission for febrile neutropenia. LVEF neither NT-proBNP value was significantly different before and after treatment with one patient showing an important improvement in his LVEF. Multivariate analysis recognized NT-proBNP determination >900ng/L as the most negative important factor in OS and PFD. CONCLUSION Disclosures: No relevant conflicts of interest to declare.

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