Liposomal Anthracyclines Research Articles

Rationale and design of the Children's Oncology Group study AAML1831 integrated cardiac substudies in pediatric acute myeloid leukemia therapy.

Pediatric acute myeloid leukemia (AML) therapy is associated with substantial short- and long-term treatment-related cardiotoxicity mainly due to high-dose anthracycline exposure. Early left ventricular systolic dysfunction (LVSD) compromises anthracycline delivery and is associated with inferior event-free and overall survival in de novo pediatric AML. Thus, effective cardioprotective strategies and cardiotoxicity risk predictors are critical to optimize cancer therapy delivery and enable early interventions to prevent progressive LVSD. While dexrazoxane-based cardioprotection reduces short-term cardiotoxicity without compromising cancer survival, liposomal anthracycline formulations have the potential to mitigate cardiotoxicity while improving antitumor efficacy. This overview summarizes the rationale and methodology of cardiac substudies within AAML1831, a randomized Children's Oncology Group Phase 3 study of CPX-351, a liposomal formulation of daunorubicin and cytarabine, in comparison with standard daunorubicin/cytarabine with dexrazoxane in the treatment of de novo pediatric AML. Children (age <22 years) with newly diagnosed AML were enrolled and randomized to CPX-351-containing induction 1 and 2 (Arm A) or standard daunorubicin and dexrazoxane-containing induction (Arm B). Embedded cardiac correlative studies aim to compare the efficacy of this liposomal anthracycline formulation to dexrazoxane for primary prevention of cardiotoxicity by detailed core lab analysis of standardized echocardiograms and serial cardiac biomarkers throughout AML therapy and in follow-up. In addition, AAML1831 will assess the ability of early changes in sensitive echo indices (e.g., global longitudinal strain) and cardiac biomarkers (e.g., troponin and natriuretic peptides) to predict subsequent LVSD. Finally, AAML1831 establishes expert consensus-based strategies in cardiac monitoring and anthracycline dose modification to balance the potentially competing priorities of cardiotoxicity reduction with optimal leukemia therapy. This study will inform diagnostic, prognostic, preventative, and treatment strategies regarding cardiotoxicity during pediatric AML therapy. Together, these measures have the potential to improve leukemia-free and overall survival and long-term cardiovascular health in children with AML. Clinical trial registration: https://clinicaltrials.gov/, identifier NCT04293562.

Effectiveness and safety of conventional systemic treatments in classical and endemic Kaposi sarcoma: A multicentric retrospective study of 110 patients.

e21584 Background: Apart from post-transplant Kaposi sarcoma (KS), 2 major subtypes of non-HIV-related KS are described: classical Kaposi sarcoma (CKS) in patients originated from Mediterranean countries and endemic KS (EKS) in patients of sub-Saharan Africa origin. Some patients with aggressive EKS or CKS require systemic treatments among which liposomal anthracycline (LA), taxanes and, to a lesser extent, low dose interferon (LDI) are generally recommended as first lines. Recently, anti-PD1 have shown promising results in an early phase II trial. At the dawn of a turning point in therapeutic era, we aim to map the effectiveness and safety of the main conventional systemic treatments usually available in KS. Methods: We performed a national multicentric retrospective study including all patients receiving a systemic treatment for a histologically proven KS between January 1st 2013 to July 1st 2019. HIV infected patients and patients treated with immunosuppressive drugs were excluded. Overall response was defined as a decrease of more than 50% of lesion area and serious adverse events encompassed grade 3 and 4 toxicity. Results: A total of 110 patients were included. Sixty-nine had CKS (62.7%) and 41 had EKS (37.2) with a median age at diagnosis of 69 (IQR: 57-77) and 41 years (37-59) (p = 0.011), respectively. At the time of diagnosis, EKS was associated with greater systemic involvement compared with CKS (36.6% vs 14.9%, p = 0.017). First-line therapy was initiated within a median of 13.8 months (2.9-43) after KS diagnosis. The 3 main regimens were taxanes (27.3%), LA (19.1%) and LDI (19.1%) with response rates of 82.8%, 80% and 52.6% (p = 0.063), respectively. The cumulative incidence of a second line of treatment in the first 2 years of follow-up was 49.5% (CI95% 38.7-59.4), without significant difference according to the different regimens. Toxicity, regardless of grade, was reported more frequently with LDI (55.3%) and taxanes (47.8%) than with LA (30.4%) (p = 0.035). Poor tolerability led to discontinuation of LDI more frequently than LA (OR = 4.17, p = 0.048), without difference for taxanes. There was no difference in serious adverse events between the 3 main regimens. CKS and EKS didn’t differ regarding overall response rate or time to next treatment regardless of treatment regimens. However, response rates tended to decrease as the lines went on for EKS (from 77.5% in 1st to 33.3% in 3rd line, p = 0.005), in contrast to CKS who maintained a sustained response, with more frequent systemic involvement (56% vs 25.4%, p = 0.002) during EKS course. Conclusions: Herein, we highlight LA, taxanes and LDI are safe and effective treatments for non-immunodeficient KS. Furthermore, EKS differed from CKS, occurring in younger patients, with more frequent systemic involvement and response loss through therapeutic lines, emphasizing the need to evaluate new agents in this form of KS.

Anthracycline-induced cardiotoxicity — are we about to clear this hurdle?

Anthracyclines have contributed significantly to remarkable improvements in overall survival and are regarded as the most effective cytostatic drug for cancer treatment in various malignancies. However, anthracyclines are a significant cause of acute and chronic cardiotoxicity in cancer patients, and long-term cardiotoxicity can lead to death in about one-third of patients. Several molecular pathways have been implicated in the development of anthracycline-induced cardiotoxicity, although the underlying mechanisms of some molecular pathways are not fully elucidated. It is now generally believed that anthracycline-induced reactive oxygen species (resulting from intracellular metabolism of anthracyclines) and drug-induced inhibition of topoisomerase II beta are the key mechanisms responsible for the cardiotoxicity. To prevent cardiotoxicity, several strategies are being followed: (i) angiotensin-converting enzyme inhibitors, sartans, beta-blockers, aldosterone antagonists, and statins; (ii) iron chelators; and (iii) by development of new anthracycline derivatives with little or no cardiotoxicity. This review will discuss clinically evaluated doxorubicin analogues that were developed as potentially non-cardiotoxic anticancer agents and include recent development of a novel liposomal anthracycline (L-Annamycin) for the treatment of soft-tissue sarcoma metastatic to the lung and acute myelogenous leukaemia.

S2431 A Rare Case of Esophageal Kaposi Sarcoma Causing Dysphagia

Introduction: Kaposi sarcoma (KS) is an angioproliferative disorder(low grade vascular tumor) caused by human herpesvirus-8 in immunocompromised patients. The disease is multifocal, ranging from indolent skin manifestations to extensive visceral involvement. We are describing a rare case of esophageal KS causing dysphagia. Case Description/Methods: A 57-year-old bisexual male with a medical history of hypertension, syphilis and recent diagnosis of HIV (untreated) admitted for hypotension, tachycardia, nausea, vomiting,hemoptysis and dysphagia to soilds. He was noted to have oropharyngeal lesions and biopsy of the lesions were obtained. An EGD performed for evaluation of dysphagia (denied odynophagia) showed circumferential erythema, purplish plaques and friability of the esophagus. Biopsies were obtained from esophagus. Pathology from tongue, gingiva, proximal and distal esophagus returned positive for Kaposi sarcoma with positive staining for HHV-8 and CD31. CD4 count was 31/uL and HSV8 PCR showed 1,000,000 copies. Patient was treated with Bictegravir, emtricitabine and tenofovir alafenamide. Hematology was consulted for potential pulmonary KS and patient was started on liposomal doxorubicin. He developed Ventricular fibrillation and cardiac arrest. He was revived and intubated. Patient improved initially but developed neutropenic fever. Infectious disease treated him with empirical antibiotics and antivirals. Patient further developed Castleman’s disease, respiratory failure, acute kidney failure requiring CRRT, and altered mental status. Despite aggressive measures patient did not survive (Figure). Discussion: AIDS-related KS varies in clinical progression and occurs in 20% of patients with AIDS. The CD4 count will typically be less than 150 cells per cubic millimeter with a high viral load ranging from greater than 10,000 copies per millimeter. Gastrointestinal manifestation is the most common extra-cutaneous site of KS in AIDS-related cases though rarely does it occur without cutaneous involvement. The majority of the patients are asymptomatic, roughly 75%. Symptomatic patients present with nonspecific findings such as abdominal discomfort, cramps, nausea, vomiting, diarrhea, and upper or lower GI bleed. KS lesions causing dysphagia are extremely rare. The mainstay of therapy is combined antiretroviral therapy (ART). Local intralesional chemotherapy can be utilized to manage limited lesions. Systemic therapy with liposomal anthracyclines is recommended for patients with advanced or rapidly progressive disease.Figure 1.: Kaposi Sarcoma Lesions.

Prevalent Heart Failure And Cardioprotective Medication Use In Older Individuals With Lymphoma: A SEER-Medicare Analysis

Background Older patients with lymphoma are at increased risk for cardiotoxicity with anthracycline-based cancer treatment. Dexrazoxane and liposomal anthracyclines may reduce the risk of heart failure (HF); although, neither clinical practice guidelines nor the FDA endorse the use of these cardioprotective medications in this population due to insufficient evidence. No studies to date have explored the prevalence of “off label” use of these cardioprotective strategies in clinical practice. Methods The Surveillance, Epidemiology and End Results-Medicare (SEER-Medicare) linked database was used to identify individuals with newly diagnosed Diffuse Large B Cell Lymphoma (DLBCL) and Hodgkin's Lymphoma (HL) diagnosed from 2000-2015 who had one year of Medicare Part A and B coverage in the year prior to diagnosis. Exclusion criteria included age <65 years, HMO membership, and lymphoma diagnosed on death certificate. Prevalent and incident HF/cardiomyopathy were defined using International Classification of Diseases codes using a validated algorithm (Go, JAMA 2006). HCPCS codes were used to identify doxorubicin (C9415, J9000), liposomal doxorubicin (J9001, Q2048, Q2049, Q2050) and dexrazoxane (J1190). Results Among newly diagnosed individuals with DLBCL (n=30,728) and HL (n=3,348), HF in the year prior to diagnosis was present in 14% of the population. Anthracycline-based chemotherapy was used in 34% of DLBCL cases and 52% of HL cases. Radiation was used in 19% of HL and DLBCL cases. In those free from HF at the time of lymphoma diagnosis, incident HF was very common, occurring in 28% of those treated for HL and 26% of those with DLBCL over a median of 2.4 years and 2.7 years, respectively. Among those treated with anthracyclines, liposomal formulations were used in 2.1% of those with DLBCL and 1.2% of those with HL; while dexrazoxane was used in 0.7% of those with DLBCL and 0.8% of those with HL. Conclusions Despite a high prevalence of HF at the time of lymphoma diagnosis and very high risk of incident HF, cardioprotective medications were rarely used. Randomized trials of cardioprotective strategies are needed to improve cancer and cardiovascular outcomes in this high-risk patient population. Older patients with lymphoma are at increased risk for cardiotoxicity with anthracycline-based cancer treatment. Dexrazoxane and liposomal anthracyclines may reduce the risk of heart failure (HF); although, neither clinical practice guidelines nor the FDA endorse the use of these cardioprotective medications in this population due to insufficient evidence. No studies to date have explored the prevalence of “off label” use of these cardioprotective strategies in clinical practice. The Surveillance, Epidemiology and End Results-Medicare (SEER-Medicare) linked database was used to identify individuals with newly diagnosed Diffuse Large B Cell Lymphoma (DLBCL) and Hodgkin's Lymphoma (HL) diagnosed from 2000-2015 who had one year of Medicare Part A and B coverage in the year prior to diagnosis. Exclusion criteria included age <65 years, HMO membership, and lymphoma diagnosed on death certificate. Prevalent and incident HF/cardiomyopathy were defined using International Classification of Diseases codes using a validated algorithm (Go, JAMA 2006). HCPCS codes were used to identify doxorubicin (C9415, J9000), liposomal doxorubicin (J9001, Q2048, Q2049, Q2050) and dexrazoxane (J1190). Among newly diagnosed individuals with DLBCL (n=30,728) and HL (n=3,348), HF in the year prior to diagnosis was present in 14% of the population. Anthracycline-based chemotherapy was used in 34% of DLBCL cases and 52% of HL cases. Radiation was used in 19% of HL and DLBCL cases. In those free from HF at the time of lymphoma diagnosis, incident HF was very common, occurring in 28% of those treated for HL and 26% of those with DLBCL over a median of 2.4 years and 2.7 years, respectively. Among those treated with anthracyclines, liposomal formulations were used in 2.1% of those with DLBCL and 1.2% of those with HL; while dexrazoxane was used in 0.7% of those with DLBCL and 0.8% of those with HL. Despite a high prevalence of HF at the time of lymphoma diagnosis and very high risk of incident HF, cardioprotective medications were rarely used. Randomized trials of cardioprotective strategies are needed to improve cancer and cardiovascular outcomes in this high-risk patient population.

Safety and effectiveness of gemcitabine for the treatment of classic Kaposi's sarcoma without visceral involvement.

Background:Classic Kaposi’s sarcoma (CKS) is a rare, multifocal, endothelial cell neoplasm that typically occurs in elderly people with previous infection by human herpes virus-8. Prospective trials are rare, and the choice of drugs relies on prospective trials performed on HIV-associated Kaposi’s sarcoma (KS). Pegylated liposomal anthracyclines and taxanes are considered the standard first- and second-line chemotherapy, respectively. Despite the indolent biologic behavior, the natural history is characterized by recurrent disease. This condition of chronic administration of cytotoxic drugs is often associated with immediate/long-term adverse events.Methods:This was an observational, retrospective study to evaluate the effectiveness and safety of gemcitabine in patients with CKS. From January 2016 to September 2021, the patients were treated with gemcitabine 1000 mg/m2 on days 1 and 8, with cycles repeated every 21 days. The treatment was administered as first or second line.Results:Twenty-seven (27) patients were included in the study. Twenty-one (21) out 27 patients (77.8%) achieved a partial response (PR), including 8 patients with major response (MR) (29.6%) and 13 patients with minor response (mR) (48.2%); 2 (7.4%) showed a complete response (CR), 3 (11.1%) a stable disease (SD), and 1 (3.7%) a progressive disease (PD). Tumor responses were generally rapid, with a median time to first response of 4 weeks (range, 3–12 weeks). Patients who responded had disease improvement with flattening of the skin lesions, decrease in the number of lesions, and substantial reduction in tumor-associated complications. Median duration of response was 19.2 months. Common adverse events were grades 1/2 thrombocytopenia, and grade 1 noninfectious fever. No patient discontinued treatment as a result of adverse events.Conclusion:Our study showed that gemcitabine is effective and well tolerated, acts rapidly on cutaneous lesions, and allows substantial symptom palliation, without dose-limiting toxicity. Gemcitabine represents a safe and effective option for the treatment of CKS.

Treatment Patterns, Type of Front-Line Regimen, and Outcomes Among Older Adults with Acute Myeloid Leukemia: A Population-Based Analysis in the Modern Era

Background: Traditionally, intensive induction chemotherapy has been the primary front-line treatment for AML; however, older adults are often poor chemotherapy candidates and as of 2009, nearly 50% of older AML patients did not receive any treatment (Mederios, Ann Hematol 2015). Recently, several non-traditional front-line AML regimens have emerged, including hypomethylating agents (HMA), the BCL-2 inhibitor venetoclax, liposomal anthracycline and cytarabine, and targeted therapies. These non-traditional agents may offer less intense side effects and provide novel front-line options for older adults. We hypothesized the advent of non-traditional options has allowed a greater proportion of older adults to receive effective treatment, thereby improving survival for this population. Using a population-based approach, we evaluated front-line treatment patterns and outcomes of older adults with AML in the modern era. Methods: Patients ≥ 60 years with a first diagnosis of AML in the California Cancer Registry (CCR) between 2014-2017 were included. Front-line regimen was manually abstracted from unstructured free-text fields in the CCR. The CCR was linked with California's Patient Discharge Database (PDD) to obtain hematopoietic cell transplantation (HCT) information. Multivariable logistic regression examined factors associated with front-line treatment regimen and multivariable Cox proportional hazards regression examined factors associated with survival. Results: Of the 4,086 patients identified, 3,068 (75%) had sufficient treatment information to classify front-line regimen and are included; 34% were 60-69 years at diagnosis, 39% were 70-79, and 27% were ≥ 80. Thirty-three percent received front-line therapy at an NCI-designated cancer center and 12% received HCT. The median follow-up time was 121 days. Across the time period studied, 36% received traditional cytotoxic chemotherapy, 42% received non-traditional therapy, and 22% received no treatment. Of the patients receiving traditional therapy, 84% received cytarabine plus anthracycline. Of those receiving non-traditional therapy, 85% received HMA monotherapy, 8% HMA plus venetoclax, and 3% liposomal cytarabine plus anthracycline. Use of both non-traditional therapy and HCT increased over time, with 38% of patients receiving non-traditional therapy in 2014 vs 47% in 2017 (p &amp;lt; 0.001) and 8.4% of patients receiving HCT in 2014 compared to 11.1% in 2017 (p &amp;lt; 0.001.) The proportion of patients not receiving treatment did not change significantly over time, with 23% in 2014 vs 24% in 2017 (p = 0.20). Multivariable analyses (MVA) revealed receipt of treatment was significantly associated with age &amp;lt; 80 (p &amp;lt; 0.001), &amp;lt; 2 comorbidities (p &amp;lt; 0.001), and receipt of front-line therapy at an NCI-designated cancer center (p &amp;lt; 0.001). Compared to traditional chemotherapy, non-traditional frontline therapy was associated with age ≥ 80 (p &amp;lt; 0.001) and ≥ 2 comorbidities (p = 0.001). Race/ethnicity, socioeconomic status, and type of insurance were not associated with receipt of treatment or type of front-line regimen. One-year overall survival (OS) of the full cohort was 25% (CI: 23.6 - 26.5%). One-year OS was 44% (CI: 40.8 - 47.1%) for patients receiving traditional chemotherapy, 31.4% (CI: 40.8 - 47.13%) for patients receiving non-traditional therapy, and 4.38% (CI: 2.73 - 6.04%) for patients who were not treated. The MVA for OS demonstrated age ≥ 80 (HR 1.19, CI 1.04 - 1.36), ≥ 2 comorbidities (HR 1.33, CI 1.19 - 1.49), and not receiving front-line therapy at an NCI cancer center (HR 1.49, CI 1.34 - 1.65) to be independently associated with inferior OS; receipt of traditional chemotherapy (HR 0.22, CI 0.19 - 0.25) and HCT (HR 0.75, CI 0.6 - 0.93) were associated with superior OS. Conclusion Using a population-based approach, we show the patterns of care for AML treatment in older adults is changing, with an increasing proportion of patients receiving both initial treatment and HCT relative to historical reports and a significant increase in the use of newer, non-traditional therapies. Similarly, survival estimates are improving over time for patients who receive therapy. During our study period, a significant proportion of older adults with AML remain untreated, which is strikingly impacted by location of front-line care. At the population level, there remain opportunities to increase access to therapy for older adults with AML. Disclosures Muffly: Amgen: Consultancy; Servier: Research Funding; Adaptive: Research Funding.

Intensity of Front-Line Regimen Is Associated with Admissions, in-Hospital Days, and Discharge Destination in Older Adults with Acute Myeloid Leukemia: A Population-Based Analysis

Introduction Acute myeloid leukemia (AML) is predominantly a cancer of older adults, with median age at diagnosis of 68 years. Traditionally, AML is treated with intensive induction chemotherapy; however, older adults with AML are often poor chemotherapy candidates due to reduced performance status and multiple comorbidities. Recently, several non-traditional treatment regimens for AML have emerged that may offer less intense toxicity profiles compared to traditional chemotherapy, can be administered in the outpatient setting, and provide new front-line options for older or frailer adults with AML. We hypothesized that relative to traditional cytotoxic chemotherapy, these non-traditional options would be associated with fewer hospital admissions, fewer days in-hospital, and more frequent discharges to home rather than skilled nursing facilities among newly diagnosed older AML patients. Methods Patients ≥ 60 years with a first diagnosis of AML in the California Cancer Registry (CCR) between 2014-2017 were included. Front-line treatment regimen was manually abstracted from unstructured free-text fields in the CCR and categorized as no treatment, traditional cytotoxic chemotherapy, or non-traditional therapy. Non-traditional therapy was defined as a hypomethylating agent and venetoclax in monotherapy or combination, liposomal cytarabine and anthracycline, or non-cytotoxic targeted agents. The CCR was linked with statewide hospitalization data to obtain number of in-hospital days and number of admissions during the first 100 days following diagnosis as well as discharge destination (home/usual care vs non-home location). Results Of the 4,086 patients identified, 3,068 (75.1%) had available treatment data and are included in the current analysis. Thirty-four percent of patients were 60-69 years at diagnosis, 39.0% were 70-90 years, and 27.1% were ³ 80 years. Nearly one-third (28.5%) had ≥ 2 comorbidities. During the study period, 36.3% received traditional cytotoxic chemotherapy, 41.6% received non-traditional therapy, and 22.0% received no treatment. WAcross the full cohort, during the first 100 days following diagnosis, the median number of in-hospital days was 22, and 79.8% of patients had at least one hospitalization. Compared to patients receiving traditional chemotherapy, patients receiving non-traditional therapy spent less time in the hospital (42 vs 15 days, p &amp;lt; 0.001). Patients receiving traditional chemotherapy also had more hospital admissions, with 63.4% having ≥ 2 admissions compared with 46.8% of patients receiving non-traditional therapy (p &amp;lt; 0.001) (Table 1). Of the 2,443 patients with at least one hospitalization, 2,046 (83.7%) were discharged alive to either a home or non-home location; of these, 68.4% were discharged to home and/or usual self-care, 8.6% to a non-home location, such as acute rehabilitation or a skilled nursing facility, and 6.7% to hospice. The remaining patients either died in the hospital (13.5%) or had an alternate discharge destination, such as intrahospital transfer (2.7%) WCompared to patients receiving traditional chemotherapy, a lower proportion of patients receiving non-traditional therapies died in the hospital (11.0% vs 6.4% p &amp;lt;0.001) and a greater proportion were discharged to hospice (1.6% vs 3.3%, p = 0.009). Although patients receiving non-traditional therapies were less commonly hospitalized, if hospitalized, these patients were more likely to require skilled care upon discharge. Of the patients receiving non-traditional therapy discharged alive and without hospice, 11.5% were discharged to a non-home location compared to only 5.8% of patients receiving traditional chemotherapy. Conclusions Using a population-based approach, we demonstrate that older adults with AML receiving non-traditional induction therapies have fewer admissions, in-hospital days, and in-hospital deaths, but did not have a decreased need for skilled services upon hospital discharge. At the population level, non-traditional therapies offer new treatment opportunities for older and frailer adults with AML. Additional studies evaluating health-related quality of life among older adults treated with these approaches are needed to delineate the patient-centered benefit of these therapies relative to traditional chemotherapy. Disclosures Muffly: Adaptive: Research Funding; Amgen: Consultancy; Servier: Research Funding.

Cardioprotective Strategies to Prevent Cancer Treatment-Related Cardiovascular Toxicity: a Review.

Patients with cancer have an elevated risk of cardiovascular disease. This review describes the cardiovascular risks of different cancer therapies and the evidence for cardioprotective strategies. Recent studies have provided additional support for the safety and efficacy of dexrazoxane and liposomal anthracycline formulations in certain high-risk patients receiving anthracyclines and for neurohormonal antagonist therapy in patients with breast cancer receiving sequential anthracyclines and trastuzumab. Ongoing studies are exploring the benefit of: (1) statins for anthracycline cardioprotection; (2) strict blood pressure control during vascular endothelial growth factor inhibitor treatment and; (3) dexrazoxane on long-term cardiac outcomes in pediatric populations. To date, there are no evidence-based cardioprotective strategies specifically for radiation-related heart and vascular disease, immunotherapy myocarditis, fluoropyrimidine cardiotoxicity, vascular endothelial growth factor inhibitor-related hypertension, BCR-Abl multikinase inhibitor vascular disease, and other established and emerging cancer therapeutics with cardiovascular effects. Current evidence supports specific cardioprotective strategies for high risk patients receiving anthracyclines or sequential anthracycline-trastuzumab therapy; however, major evidence gaps exist.

Abstract P1-18-28: Myocet or carboplatin as part of chemotherapy in HER2-positive operable breast cancer treated with trastuzumab and pertuzumab in the neoadjuvant setting: Efficacy data and cardiotoxicity in 60 patients diagnosed from 2016-2019 at a single institution

Abstract Objectives: To evaluate the efficacy and cardiotoxicity profile of liposomal anthracycline or Carboplatin as part of neoadjuvant therapy added to taxanes and dual blockade in HER2-positive operable breast cancer patients. Methods: A total of 60 patients diagnosed from August 2016 to May 2019 were included in the study. The treatment consisted of a sequential regimen of taxanes and non- pegilated liposomal anthracycline (Myocet) plus trastuzumab and pertuzumab, or taxanes in combination with carboplatin plus trastuzumab and pertuzumab. The clinical and pathologic responses were evaluated and correlated with clinical and biological factors. Pathologic complete response was defined as the total absence of invasive tumor in both breast and axillary nodes (ypT0/is ypN0).The cardiotoxicity profile was also analyzed. Results: The median age was 52(26-77) years and 5%, 62% and 33% of patients had stage I, II and III breast cancer, respectively, while 7% had inflammatory breast cancer at diagnosis. Hormone receptor (HR) status was negative in 48%, and 65% and 50% had grade III and ki-67 value up to 35%, respectively breast cancer. 65% of patients received weekly paclitaxelx12-trastuzumab-pertuzumab followed by Myocet-cyclophosphamide with -trastuzumab x 4 cycles or this sequence but beginning with the anthracycline, 23% of patients the same regimen but with pertuzumab concurrently with all chemotherapy treatment. The remaining 12% received docetaxel-carboplatin x6 cycles plus trastuzumab and pertuzumab. All treatment was administered previous surgery. The clinical complete response rate, was 57% and 63%, as assessed using ultrasound and MRI, respectively, and this allowed a high rate of conservative surgery (60%). The pathologic complete response (pCR) rate was 52%, and it was higher in HR-negative (61%) than in HR-positive (39%), in grade 3 (71%) than in grade 2(29%) tumors. There were not statistical significant differences in pCR between different chemotherapy treatments. Five patients showed a 10% decrease in left ventricular ejection fraction (LVEF) to below 50% at the end of neoadjuvant treatment. Asymptomatic drops in 2 patients and with heart failure symptoms in 3 of them. Myocet was part of chemotherapy in all of them. All patients recovered after discontinuation of adjuvant trastuzumab and heart medication. Two of these patients did not complete all preplanned adjuvant trastuzumab doses. Conclusion: A sequential regimen of taxanes and non-pegilated liposomal anthracycline or carboplatin plus trastuzumab and pertuzumab was effective, with high pCR rates and a good cardiotoxicity profile. Citation Format: Silvia Antolin, Cristina Reboredo, Rocío Lesta, Aurea Molina, Joaquin Mosquera, Patricia Cordeiro, Eva Pérez, Lourdes Calvo. Myocet or carboplatin as part of chemotherapy in HER2-positive operable breast cancer treated with trastuzumab and pertuzumab in the neoadjuvant setting: Efficacy data and cardiotoxicity in 60 patients diagnosed from 2016-2019 at a single institution [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-18-28.

Real-world use of chemotherapy for Kaposi\u2019s sarcoma in a large community-based HIV primary care system in Kenya

BackgroundKaposi’s sarcoma (KS) is one of the most common HIV-associated malignancies in sub-Saharan Africa. Worldwide, the availability of antiretroviral therapy (ART) has improved KS survival. In resource-rich settings, survival has also benefited from chemotherapy, which is widely available. Little is known, however, about the epidemiology of chemotherapy use for HIV-associated KS in resource-limited regions such as sub-Saharan Africa.MethodsWe identified all patients newly diagnosed with HIV-related KS from 2009 to 2012 in the 26-clinic AMPATH network, a large community-based care network in Kenya. We ascertained disease severity at diagnosis, frequency of initiation of chemotherapy, and distribution of chemotherapeutic regimens used. Indications for chemotherapy included AIDS Clinical Trial Group T1 stage and/or “severe” disease defined by WHO KS treatment guidelines.ResultsOf 674 patients diagnosed with KS, charts were available for 588; 61% were men, median age was 35 years, and median CD4 at KS diagnosis was 185 cells/μl. At time of diagnosis, 58% had at least one chemotherapy indication, and 22% had more than one indication. For patients with a chemotherapy indication, cumulative incidence of chemotherapy initiation (with death as a competing event) was 37% by 1 month and 56% by 1 year. Median time from diagnosis to chemotherapy initiation was 25 days (IQR 1–50 days). In multivariable regression, patients with > 3 chemotherapy indications at time of diagnosis had a 2.30 (95% CI 1.46–3.60) increased risk of rapid chemotherapy initiation (within 30 days of diagnosis) compared to those with only one chemotherapy indication (p < 0.001). Initial regimens were bleomycin-vincristine (78%), adriamycin-bleomycin-vincristine (11%), etoposide (7%), and gemcitabine (4%).ConclusionsA substantial fraction of patients with KS in East Africa are diagnosed at advanced disease stage. For patients with chemotherapy indications, nearly half did not receive chemotherapy by one year. Liposomal anthracyclines, often used in resource-rich settings, were not first line. These findings emphasize challenges in East Africa cancer care, and highlight the need for further advocacy for improved access to higher quality chemotherapy in this setting.

Liposomal Cytarabine as Cancer Therapy: From Chemistry to Medicine.

Cancer is the second leading cause of death worldwide. The main modality to fight against cancer is surgery, radiotherapy, and chemotherapy, and more recently targeted therapy, gene therapy and immunotherapy, which play important roles in treating cancer patients. In the last decades, chemotherapy has been well developed. Nonetheless, administration of the drug is not always successful, as limited drug dosage can reach the tumor cells.. In this context, the possibility to use an encapsulated anti-cancer drug may potentially solve the problem. Liposomal cytarabine is a formulation with pronounced effectiveness in lymphomatous meningitis and reduced cardiotoxicity if compared to liposomal anthracyclines. Thus, the future liposomal cytarabine use could be extended to other diseases given its reduction in cytotoxic side effects compared to the free formulation. This review summarizes the chemistry and biology of liposomal cytarabine, with exploration of its clinical implications.

Efficacy and prognostic factors of systemic therapies for metastatic adenoid cystic carcinoma.

e17587 Background: Metastatic cystic adenoid carcinoma (mCCA) is a rare entity of cancer associated with a poor prognostic. Only limited efficacy data based on case-reports and retrospective analysis are available and there is currently no standard for treatment. The aim of our study is to evaluate the efficacy and prognostic factors in recently diagnosed mCCA. Methods: We retrospectively collected demographic and efficacy data from patients treated for mCCA between September 2012 and January 2019 at the Pitié-Salpêtrière Hospital. Univariate analysis of prognostic factors was performed using the Cox model. Survival was estimated using the Kaplan-Meier method and long rank analysis. Results: Fifteen patients were included: 8 women and 7 men with a median age at diagnosis of 57 years (range 32-71). The primitive sites were accessory salivary glands in 9 patients, major salivary glands in 3 patients, lung, cervix and lacrimal glands in each of the 3 other patients. Histology of the primary tumor was available for 7 patients with 4 cribriform and 3 solid types respectively, an intermediate grade in 5 patients, a high in 2 patients, and a median of Ki67 at 35% (range 8.5-40%). Thirteen patients received a first line therapy, including 10 with platinum – LV5FU2, 2 with cisplatine anthracycline and cyclophosphamide association (CAP) and 1 with sunitinib. A stable disease was found in 7 patients (54%), a partial response in 4 patients (31%) and 2 patients had progression at first evaluation. The median 1st line PFS was 5.8 months (range 2.0-12.7). With a median time of follow-up at 12.9 months (range 4.0-61.3), 5 patients (33%) were dead, 8 patients (53%) were still receiving systemic therapy and 4 patients (27%) received 4 lines. A patient with partial response after 6 CAP cycles,received a liposomal anthracycline combined with carboplatin for 8 cycles with a response time of 12.7 months. In univariate analysis, no statistically significant prognostic factors were found. Conclusions: In our retrospective study, 1st line of systemic therapy is efficient in mACC with a 31% response rate. Furthermore, here we report the first patient treated with liposomal anthracycline associated with duration of response for 12.7 months. These preliminary results should be confirmed before becoming a new option for treatment in mACC.

Extravasation accidents with liposomal/liposomal pegylated anthracyclines treated with dexrazoxane: an overview and outcomes.

The extravasation of chemotherapeutic agents is a challenge for oncologic care teams. The management of nonliposomal (conventional) anthracyclines is well established in clinical practice guidelines, including general measures and specific antidotes, such as dexrazoxane. However, there is little scientific evidence on the management of liposomal and pegylated liposomal anthracyclines. The aim of this paper was to review the scientific literature on the extravasation of liposomal and pegylated liposomal anthracyclines and determine the clinical impact of this type of extravasation, focusing on dexrazoxane. The literature was searched using two databases: PubMed and Embase. Three searches were conducted, using liposomal anthracycline extravasation, pegylated liposomal anthracycline extravasation, and liposomal doxorubicin extravasation as keywords, respectively. Seven articles fulfilled the study eligibility criteria and included seventeen cases in humans. Extravasation occurred with three drugs: liposomal doxorubicin in nine (53%) patients, liposomal daunorubicin in four (23.5%) patients, and pegylated liposomal doxorubicin in four (23.5%) patients. General measures for extravasations were applied in all patients, but only three patients received dexrazoxane. All cases were completely resolved at 2-3 months, except for one patient, in whom dexrazoxane was not used. In animals, dexrazoxane decreased both the frequency of wounds produced by pegylated liposomal doxorubicin and their extent. The pharmacokinetic profiles of liposomal and pegylated liposomal anthracyclines differ from those of conventional anthracyclines, modifying their effectiveness and safety. General measures may be inadequate to heal areas affected by extravasation, which may require the administration of dexrazoxane. However, each case should be evaluated individually for the administration of dexrazoxane in off-label use until scientific evidence is available on its effectiveness and safety as an antidote for these formulations of anthracyclines.

HIV-associated Kaposi\u2019s sarcoma in Maputo, Mozambique: outcomes in a specialized treatment center, 2010\u20132015

BackgroundKaposi’s sarcoma (KS) is a common HIV-associated malignancy associated with disability, pain and poor outcomes. The cornerstone of its treatment is antiretroviral therapy, but advanced disease necessitates the addition of chemotherapy. In high-income settings, this often consists of liposomal anthracyclines, but in Mozambique, the first line includes conventional doxorubicin, bleomycin and vincristine, which is poorly-tolerated. Médecins Sans Frontières supports the Ministry of Health (MOH) in a specialized HIV and KS treatment center at the Centro de Referencia de Alto Maé in Maputo.MethodsWe performed a retrospective analysis of data collected on patients enrolled at the CRAM between 2010 and 2015, extracting routinely-collected clinical information from patient care databases. KS treatment followed national guidelines, and KS staging followed AIDS Clinical Trials Group and MOH criteria. Baseline description of the cohort and patient outcomes was performed. Risk factors for negative outcomes (death or loss to follow-up) were explored using Cox regression.ResultsBetween 2010 and 2015, 1573 patients were enrolled, and 1210 began chemotherapy. A majority were young adult males. At enrollment, CD4 was < 200 cells/μl in 45% of patients. Among patients receiving chemotherapy, 78% received combination doxorubicin-bleomycin-vincristine. Among patients receiving chemotherapy, 43% were lost to follow-up and 8% were known to have died. In multivariate regression, the only risk factors identified with poor outcomes were CD4 < 100 cells/μl at enrollment (Risk ratio 1.5, 95%CI 1.1–2.1, p = 0.02 and having S1 disease (RR 1.7, 95%CI 1.2–2.3, p = 0.001).DiscussionWe describe a large cohort of patients receiving care for HIV-associated KS in a specialized clinic in an urban setting. Outcomes were nonetheless unsatisfactory. Efforts should be made to decrease late referrals and entry into care and to increase access to more effective and better-tolerated treatments like liposomal doxorubicin.

Kaposi's sarcoma in HIV-infected patients in the era of new antiretrovirals.

Kaposi's Sarcoma (KS) is a multicentric angioproliferative cancer of endothelial cells (ECs) caused by Human Herpesvirus 8 (HHV8) characterized by clinical heterogeneity depending on the host immune conditions. Despite its incidence has dramatically decreased in developed countries after the introduction of Highly Active Antiretroviral Therapy (HAART), KS remains the most frequent tumor in HIV-infected patients worldwide. Clinical presentation varies from an indolent slowly progressive behavior, generally limited to the skin, to an aggressive and rapidly progressing disease. In more than 50% of cases, the skin lesions are often associated with a more or less important visceral involvement, particularly to the oral cavity and the gastrointestinal tract that are involved in 35% and 40% of cases respectively. A large number of treatments can be used both as local and as systemic therapy. Particularly, HAART represents the first treatment in patients with moderate lesions limited to skin, and it can be sufficient to reduce significantly the size of lesions and, often, the complete disappear in 35% of cases after 3-9 months of treatment. In case of a rapidly progressive disease with extensive cutaneous and/or visceral involvement systemic drugs are used such as the liposomal anthracyclines pegylated liposomal doxorubicin (PLD) and daunorubicin citrate liposome (DNX), the combined treatment adriamycin-bleomycin-vincristine (ABV) and bleomycin-vincristine (BV), Paclitaxel and Interferon-alfa. In patients with limited skin localization, the local treatment can play an important role. Local medical therapy is based on the use of alitretinoin, antineoplastic drugs vincristine, vinblastine and bleomycin and Sodium Tetradecyl Sulfate (STS). In addition to medical therapy, physical treatment, such as cryotherapy and radiotherapy, are also commonly used.

Modern Management of Anthracycline-Induced Cardiotoxicity in Lymphoma Patients: Low Occurrence of Cardiotoxicity with Comprehensive Assessment and Tailored Substitution by Nonpegylated Liposomal Doxorubicin.

Anthracyclines (AC) are still undeniable drugs in lymphoma treatment, despite occasionally causing cardiotoxicity. Liposomal AC may reduce cardiotoxicity while retaining clinical efficacy; also, biomarker monitoring during chemotherapy allows early detection of cardiac damage, enabling strategies to prevent left ventricular ejection fraction (LVEF) deterioration. We conducted a prospective observational trial in a real-life population of lymphoma patients, combining advanced echocardiography and biomarkers (Troponin I [TnI]) for early detection of cardiotoxicity; we applied a prespecified policy to minimize cardiotoxicity, selecting patients with higher baseline risk to replace doxorubicin with nonpegylated liposomal doxorubicin (NPLD) and starting cardioprotective treatment when subclinical cardiotoxicity was detected. Ninety-nine patients received ≥1 cycle of chemotherapy (39 with NPLD): 38 (NPLD = 34) were older than 65 years. At baseline, the NPLD subgroup had more cardiovascular risk factors and comorbidities than the doxorubicin subgroup. After treatment, echocardiographic parameters did not worsen in the NPLD subgroup; significant LVEF reduction occurred in two patients treated with doxorubicin. Over treatment course, TnI rises increased linearly in the doxorubicin subgroup but modestly in the NPLD subgroup. At doxorubicin doses >200 mg/m2 the difference was statistically significant, with more TnI rises in the doxorubicin subgroup. NPLD-treated patients did not experience higher rates of grade 3-4 adverse events. Within the diffuse large B-cell lymphomas category, we observed similar rates of complete and overall responses between doxorubicin- and NPLD-treated patients. A comprehensive strategy to prevent, detect, and treat cardiotoxicity allows an optimal management of the lymphoma with low incidence of cardiac complications. The Oncologist 2017;22:422-431 IMPLICATIONS FOR PRACTICE: Despite the recent advances of targeted therapy in cancer, old cytotoxic drugs such as anthracyclines (AC) still play a fundamental role in the treatment of many lymphoma patients. We tested and validated in a real-life setting a personalized approach to prevent, detect, and treat AC-induced cardiotoxicity; biomarker monitoring was accomplished by Troponin I measurements before and after chemotherapy infusions, allowing detection of early subclinical cardiotoxicity, which was preemptively treated with cardio-protectants (beta blockers and angiotensin-converting-enzyme inhibitors). A telemedicine system allowed interdisciplinary management of the patients with an expert cardiologist. Furthermore, tailored use of liposomal AC following a prespecified policy appeared to prevent the excess cardiotoxicity expected in high-risk patients.

Abstract ES2-3: Treatment of metastatic breast cancer in older adults

Abstract Estrogen receptors (ER) expression in breast cancer (BC) increasing according to age, hormonotherapy (HT) is the cornerstone of systemic treatment for the older patients with MBC, not differently from the adjuvant setting. However the debate on the best strategy in MBC may be perceived sometimes ironically less intense than in early stages, perhaps because strategy remains then palliative and because cancer competes with life expectancy earlier than when one targets a benefit assessed at 5 years or later, which is at least twice beyond MBC median survival. This unfair view is less and less acceptable with the moving landscape of research on endocrine resistance and BC molecular dissection. HT is the preferred choice in presence of ER. It has a benefit-risk balance surpassing (CT) and include anti-estrogens, aromatase inhibitors and selective estrogen receptor degraders. Compliance is usually less on an issue compared with earlier stages. It still requires accurate monitoring to avoid forsaking HT too early. Hormone-refractory situations are more difficult to define, depending on treatment previously given and on the timing of relapse, making consensus and guidelines less established. This is particularly true with the growing evidence that agents targeting mTOR (everolimus) or cyclin-dependent kinases 4 and 6 (e.g. palbociclib, ribociclib) may allow circumventing resistance to HT, with unprecedented delays in the need for CT. CT is indicated straight away in case of ER-negative disease or if the clinical picture suggests a visceral crisis. Single-agent is the preferred choice in order to avoid stacking side effects of polyCT while providing only marginal benefit. Most cytotoxics require dose-reduction in older patients, not that pharmacokinetics data necessarily differ compared with younger adults - on the proviso that end-organs do not show any damage - but rather because functional decline induced by ageing occur in most, with increased risk of side effects of higher grade or earlier onset. Oral CT is attractive but faces similar compliance issues as HT with higher rates of side effects; it is not for any patient, especially in elderly with cognitive impairments. Metronomic or assimilated (weekly, bi/multi weekly) schedules are other appealing strategies: decreased toxicity, simplified prescriptions [flat doses, (semi-)continuous administration], improved compliance, decreased stays in hospital, etc. Anthracylines and taxanes are theoretically considered as first choice. Given their cardiac and neurological toxicity, other agents have been successfully put forward: liposomal anthracyclines, albumin-bound paclitaxel, capecitabine, vinorelbine. Older patients with HER2-positive MBC and normal cardiac function should receive HER2-targeted therapy, usually with CT if judged fit. Those with cardiac dysfunction should be individually evaluated. In case of ER-positive disease with contraindication to CT, or without life-threatening disease, anti-HER2 therapy plus HT is an option. Skipping CT from standard combination with anti-HER2 therapy through multiple blockade of the HER2 and associated pathways is the main challenge in the future. More clinical research is needed for the elderly with MBC, with innovative designs including composite/coprimary endpoints and pharmacoguided strategies. Citation Format: Brain E. Treatment of metastatic breast cancer in older adults [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr ES2-3.

S63 - Treatment of Kaposi's Sarcoma (KS) with nab-paclitaxel

Background: Kaposi's sarcoma (KS) is a potentially life-threatening multifocal neoplasm that may represent a difficult therapeutic challenge in disseminated stages. Liposomal anthracyclines, or combination chemotherapy are widely used to treat this kind of patients. The efficacy of taxanes (paclitaxel and docetaxel), as agents with antiangiogenic properties, has been described previously in the treatment of KS patients butthe length of the infusion, the need for pre-medication with steroids and toxicity caused by solvents - Cremophor EL (CrEL) and polysorbate 80 (Tween80) - can limit their utilization, especially in elderly patients.Nab-paclitaxel has efficacy comparable with solvent-based taxanes without need for steroid premedication which can make it easier to tolerate. At the moment there are no studies on its efficacy and safety in older KS patients. Methods: After written informed consent was obtained a phase II trial was conducted with nab-paclitaxel in 6 patients with advanced-stage KS to assess its safety and antitumor activity. The mean age of patients was 74,8 years( range 71-83). Nab-paclitaxel was administered at a fixed dose of 100 mg intravenously over 30 minutes administered weekly on days 1, 8, and 15 of each 4-week cycle for 4 cycles. No premedication to prevent hypersensitivity reactions was required before administration. Thereafter, if the patient experienced stable disease or better response, treatment doses were given every two weeks until complete disease remission, disease progression, or unacceptable toxicity occurred. Results: All patients improved dramatically after chemotherapy. Partial desinfiltration (n = 2) or complete desinfiltration (n = 4) of all papulonodular skin lesions was observed with marked improvement of lymphedema in 1 patient. Grade 3 neutropenia and thrombocytopenia were observed in three of six and one of six patients, respectively. It was not observed any grade 4 toxicity Conclusions: Classic KS predominantly affects elderly people over 60 years, many of whom do not tolerate aggressive chemotherapy regimens well due to frequent comorbidity and diminished cardiovascular and bone marrow reserves. Nab-paclitaxel has a good and rapid efficacy in our experience which involved a setting of patients difficult to manage.

Weekly nab-paclitaxel in elderly patients with classic Kaposi sarcoma.

e22539Background: Kaposi's sarcoma (KS) is a potentially life-threatening multifocal neoplasm that may represent a difficult therapeutic challenge in disseminated stages. Liposomal anthracyclines, or combination chemotherapy are widely used to treat this kind of patients.. The efficacy of taxanes (paclitaxel and docetaxel), as agents with antiangiogenic properties,has been described previously in the treatment of KS patients but the length of the infusion, the need for pre-medication with steroids and toxicity caused by solvents can limit their utilization , especially in elderly patients. Nab-paclitaxel has efficacy comparable with solvent-based taxanes without need for steroid premedication which can make it easier to tolerate .At the moment there are no studies on its efficacy and safety in older KS patients . Methods: After written informed consent was obtained a phase II trial was conducted with nab-paclitaxel in 6 patients with advanced-stage KS to assess its safety and antitumor activity. The mean ...