Anthracycline-containing Chemotherapy Research Articles

Prediabetes is associated with increased cardiac events in patients with cancer who are prescribed anthracyclines.

Prediabetes, which is a precedent of overt diabetes, is a known risk factor for adverse cardiovascular outcomes. Its impact on adverse cardiovascular outcomes in patients with cancer who are prescribed anthracycline-containing chemotherapy (ACT) is uncertain. The objective of this study was to evaluate the association of prediabetes with cardiovascular events in patients with cancer who are prescribed ACT. The authors identified patients with cancer who received ACT from 2000 to 2019 from Clinical Data Analysis Reporting System of Hong Kong. Patients were divided into diabetes, prediabetes, and normoglycemia groups based on their baseline glycemic profile. The Primary outcome, a major adverse cardiovascular event (MACE), was the composite event of hospitalization for heart failure and cardiovascular death. Among 12,649 patients at baseline, 3997 had prediabetes, and 5622 had diabetes. Over median follow-up of 8.7 years, the incidence of MACE was 211 (7.0%) in the normoglycemia group, 358 (9.0%) in the prediabetes group, and 728 (12.9%) in the diabetes group. Compared with normoglycemia, prediabetes (adjusted hazard ratio [HR], 1.20; 95% confidence interval [CI], 1.01-1.43) and diabetes (adjusted HR, 1.46; 95% CI, 1.24-1.70) were associated with an increased risk of MACE. In the prediabetes group, 475 patients (18%) progressed to overt diabetes and exhibited a greater risk of MACE (adjusted HR, 1.76; 95% CI, 1.31-2.36) compared with patients who remained prediabetic. In patients with cancer who received ACT, those who had prediabetes at baseline and those who progressed to diabetes at follow-up had an increased risk of MACE. The optimization of cardiovascular risk factor management, including prediabetes, should be considered in patients with cancer who are treated before and during ACT to reduce cardiovascular risk. Patients with cancer who have preexisting diabetes have a higher risk of cardiovascular events, and prediabetes is often overlooked. In this study of 12,649 patients with cancer identified in the Clinical Data Analysis Reporting System of Hong Kong who were receiving treatment with anthracycline drugs, prediabetes was correlated with increased deaths from cardiovascular disease and/or hospitalizations for heart failure. Patients who progressed from prediabetes to diabetes within 2 years had an increased risk of combined hospitalization for heart failure and death from cardiovascular disease. These findings indicate the importance of paying greater attention to cardiovascular risk factors, including how prediabetes is managed, in patients who have cancer and are receiving chemotherapy with anthracyclines, emphasizing the need for surveillance, follow-up strategies, and consideration of prediabetes management in cancer care.

Tumor-infiltrating lymphocytes in HER2-positive breast cancer treated with neoadjuvant chemotherapy and dual HER2-blockade.

Tumor-infiltrating lymphocytes (TILs) have been associated with outcomes in HER2-positive breast cancer patients treated with neoadjuvant chemotherapy and trastuzumab. However, it remains unclear if TILs could be a prognostic and/or predictive biomarker in the context of dual HER2-targeting treatment. In this study, we evaluated the association between TILs and pathological response (pCR) and invasive-disease free survival (IDFS) in 389 patients with stage II-III HER2 positive breast cancer who received neoadjuvant anthracycline-containing or anthracycline-free chemotherapy combined with trastuzumab and pertuzumab in the TRAIN-2 trial. Although no significant association was seen between TILs and pCR, patients with TIL scores ≥60% demonstrated an excellent 3-year IDFS of 100% (95% CI 100-100), regardless of hormone receptor status, nodal stage and attainment of pCR. Additionally, in patients with hormone receptor positive disease, TILs as a continuous variable showed a trend to a positive association with pCR (adjusted Odds Ratio per 10% increase in TILs 1.15, 95% CI 0.99-1.34, p = 0.070) and IDFS (adjusted Hazard Ratio per 10% increase in TILs 0.71, 95% CI 0.50-1.01, p = 0.058). We found no interactions between TILs and anthracycline treatment. Our results suggest that high TIL scores might be able to identify stage II-III HER2-positive breast cancer patients with a favorable prognosis.

Phase II randomized trial comparing metronomic anthracycline-containing chemotherapy versus standard schedule in untreated HER2 negative advanced breast cancer: activity and quality of life results of the GOIM 21003 trial

BackgroundOptimizing chemotherapy to achieve disease and symptoms control is a noteworthy purpose in advanced breast cancer (ABC). We reported the activity and quality of life of a phase II study, comparing metronomic regimen with standard schedule as first line chemotherapy for ABC. MethodsPatients with HER2 negative ABC were randomized to non-pegylated liposomal doxorubicin (NPLD, 60 mg/m2 every 3 weeks) and cyclophosphamide (CTX, 600 mg/m2 every 3 weeks) (Arm A) or NPLD (20 mg/m2 day, on day 1, 8 and 15 every 4 weeks) and metronomic daily oral CTX 50 mg (ARM B). Primary end-points were overall response rate (ORR) and quality of life, secondary progression-free survival (PFS), overall survival (OS) and toxicity. ResultsFrom August 2012 to December 2017, 121 patients were enrolled, 105 evaluable. Median follow-up was 21.3 months. Most patients had hormone receptor positive. ORR was 43 % in arm A and 50 % in arm B. Median PFS was 8.9 months in arm A and 6,4 months in arm B. There was no difference in OS. Total score was not clinically different between the two arms. Grade 4 neutropenia was observed in 12 patients and 16 patients respectively; alopecia G2 in 41 % (77 %) vs 14 (27 %) in arm A and in arm B respectively. One cardiac toxicity was observed (arm A). ConclusionsFirst line metronomic chemotherapy for HER2 negative ABC had similar clinical activity and quite better tolerability than standard schedule and could be considered a further treatment option when chemotherapy is indicated.

Ki-67 Change in Anthracyline-containing Neoadjuvant Chemotherapy Response in Breast Cancer.

Anthracycline-containing regimens are irreplaceable in neoadjuvant chemotherapy (NAC) for breast cancer (BC) at present. However, 30% of early breast cancer (EBC) patients are resistant to anthracycline-containing chemotherapy, leading to poor prognosis and higher mortality. Ki-67 is associated with the prognosis and response to therapy, and it changes after NAC. A total of 105 BC patients who received anthracycline-containing NAC were enrolled. Then, the optimal model of Ki-67 was selected, and its predictive efficacy was analyzed. Immunohistochemistry (IHC) was used to determine the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) status and Ki-67 level. Fluorescent in situ hybridization (FISH) was used to verify the HER-2 when the IHC score was 2+. The post-NAC Ki67 level after treatment with anthracycline drugs was lower than pre-NAC Ki-67 (19.6%±23.3% vs. 45.6%±23.1%, P<0.001). Furthermore, patients with the Ki-67 decrease had a border line higher pathological complete response (pCR) rate (17.2% vs. 0.0%, P=0.068), and a higher overall response rate (ORR) (73.6% vs. 27.8%, P<0.001), when compared to patients without the Ki-67 decrease. The ΔKi-67 and ΔKi-67% were valuable markers for the prediction of both the pCR rate and ORR. The area under the curve (AUC) for ΔKi-67 on pCR and ORR was 0.809 (0.698-0.921) and 0.755 (0.655-0.855), respectively, while the AUC for ΔKi-67% on pCR and ORR was 0.857 (0.742-0.972) and 0.720 (0.618-0.822), respectively. Multivariate logistic regression model 1 revealed that ΔKi-67 was an independent predictor for both pCR [odds ratio (OR)=61.030, 95% confidence interval (CI)=4.709-790.965; P=0.002] and ORR (OR=10.001, 95% CI: 3.044-32.858; P<0.001). Multivariate logistic regression model 2 revealed that ΔKi-67% was also an independent predictor for both pCR (OR=408.922, 95% CI=8.908-18771.224; P=0.002) and ORR (OR=5.419, 95% CI=1.842-15.943; P=0.002). The present study results suggest that ΔKi67 and ΔKi67% are candidate predictors for anthracycline-containing NAC response, and that they may provide various information for further systematic therapy after surgery in clinical practice.

Sodium-glucose cotransporter-2 inhibitors improve clinical outcomes in patients with type 2 diabetes mellitus undergoing anthracycline-containing chemotherapy: an emulated target trial using nationwide cohort data in South Korea

Novel hypoglycemic agents, sodium-glucose cotransporter 2 inhibitors (SGLT2i), have shown protective effects against anthracycline (AC)-induced cardiotoxicity and exhibit partial anticancer effects in animal models. However, clinical evidence for this is scarce. This study aimed to evaluate whether SGLT2i improve the clinical outcomes of patients with type 2 diabetes mellitus (T2DM) undergoing AC-containing chemotherapy. A total of 81,572 patients who underwent AC chemotherapy between 2014 and 2021 were recruited from a nationwide Korean cohort. Patients were classified into three groups: patients with T2DM taking SGLT2i (n = 780) and other hypoglycemic agents excluding SGLT2i (non-SGLT2i; n = 3,455) during AC chemotherapy, and the non-DM group (n = 77,337). The clinical outcome was a composite of heart failure hospitalization, acute myocardial infarction, ischemic stroke, and death. After propensity score matching, 779 SGLT2i users were compared with 7800 non-DM patients and 2,337 non-SGLT2i users. The SGLT2i group had better composite outcomes compared with the non-DM group (adjusted hazard ratio [HR] = 0.35, 95% confidence interval [95% CI] = 0.25–0.51) and compared with the non-SGLT2i group (adjusted HR = 0.47, 95% CI = 0.32–0.69). In conclusion, SGLT2i may contribute to improving clinical outcomes in patients with T2DM undergoing AC-containing chemotherapy, through an emulated target trial using Korean nationwide cohort data.

Evaluation of cardiotoxicity of anthracycline-containing chemotherapy regimens in patients with bone and soft tissue sarcomas: A study of the FDA adverse event reporting system joint single-center real-world experience.

To assess the occurrence of cardiotoxicity in patients with tumors receiving anthracycline-based chemotherapy, especially for sarcomas. This study summarized the types and frequency of adverse events (AEs) for three anthracyclines from the FDA adverse event reporting system (FAERS) database. FAERS data from January 2004 to June 2022 were collected and analyzed. Disproportionality analyses, logistic regression, and descriptive analysis were used to compare the differences in cardiac disorders. A retrospective cohort study was conducted in a single center between December 2008 and May 2022. Our hospital-treated patients with bone and soft tissue sarcomas (BSTSs) with anthracycline-containing chemotherapy were analyzed. Serum markers, echocardiography, and electrocardiography have been used to evaluate cardiotoxic events. One hundred thousand and seventy-five AE reports were obtained for doxorubicin (ADM), epirubicin (EPI), and liposome doxorubicin (L-ADM) from the FAERS database. ADM (OR = 3.1, p < 0.001), EPI (OR = 1.5, p < 0.001), and sarcomas (OR = 1.8, p < 0.001) may increase the probability of cardiac disorders. Cardiac failure, cardiotoxicity, and cardiomyopathy were anthracyclines' top 3 frequent AEs. Among patients receiving ADM-containing therapy, those with ADM applied at doses ≥75 mg/m2 /cycle were more likely to develop cardiac disorders than the other subgroups (OR = 3.5, p < 0.001). Patients younger than 18 are more likely to benefit from dexrazoxane prevention of cardiac failure. Six hundred and eighty-three patients with BSTSs receiving anthracycline-based chemotherapy were analyzed in our center. Patients receiving ADM-containing chemotherapy were likelier to experience abnormalities in serum troponin-T and left ventricular ejection fraction (p < 0.05). 2.0% (6/300) of patients receiving ADM-containing chemotherapy required adjustment of the chemotherapy regimen because of cardiotoxicity, whereas none were in the EPI or L-ADM groups. Among patients receiving anthracycline-containing therapy, patients with BSTSs were more likely to develop cardiac disorders than other tumors. In addition, patients with BSTSs receiving ADM chemotherapy had a higher likelihood of cardiotoxic events than those receiving EPI or L-ADM.

Primary Effusion Lymphoma Prognostic Score (PEL-PS): A Validated International Prognostic Score in HIV-Associated Primary Effusion Lymphoma

Background: Primary effusion lymphoma (PEL) is a rare, B cell non-Hodgkin lymphoma (NHL) caused by Kaposi sarcoma herpesvirus (KSHV), also known as human herpesvirus 8, that is most common in people with HIV. It has a unique natural history among NHL presenting as malignant body cavity effusions, accompanying inflammatory signs and symptoms, and 80% of tumors are also EBV positive. PEL has poor survival compared with other HIV-associated lymphomas with fewer than 50% of patients alive 3 years after diagnosis. The International Prognostic Index (IPI) has not been validated in PEL due to its rarity. ECOG performance status, levels of interleukin (IL)-6, IL-10, and EBV positivity of the tumor have been shown to be prognostic in small cohorts of patients with PEL, but these factors have not been validated. In a large international cohort, we sought to develop and validate a prognostic model in HIV-associated PEL. Methods: We collected demographic and clinical data from patients with HIV-associated PEL who received first-line anthracycline-containing chemotherapy. The training set used to develop the predictive model was identified from patients treated in the HIV and AIDS Malignancy Branch at the National Cancer Institute (NCI) in the United States and Chelsea and Westminster Hospital (CWH) in the United Kingdom from 2000-2022. We performed univariate Kaplan-Meier analyses to determine prognostic factors of overall survival (OS). Factors with unadjusted p-values &amp;lt;0.10 were candidates for inclusion in the Cox proportional hazards model. We applied backward and stepwise selection to determine independent factors for inclusion in the final Cox model. The factors identified in the Cox model were able to form two groups of patients who were predicted to have good or poor survival. The factors included in the Cox model and the groupings formed were then applied to a validation set identified from patients with HIV-associated PEL treated with first-line anthracycline-containing chemotherapy at the Hôpital Saint-Louis in France over the same period. T cell counts and peripheral blood KSHV viral loads were not measured uniformly across institutions and could not be evaluated in the Cox model. Results: For the training cohort, we identified 59 patients with PEL treated with first-line anthracycline-containing chemotherapy at NCI and CWH. The median OS was 10.6 years and not statistically different between institutions (P=0.27). In univariate analysis, 5 factors were statistically negative prognostic factors: ECOG 3-4, hemoglobin &amp;lt;8 g/dL, albumin ≤2 g/dL, platelets &amp;lt;135 K/L, and IPI 4-5. Two factors were statistically positive prognostic factors: extracavitary only disease and EBV + tumors. In the multivariable Cox model, only 2 factors, ECOG ≥3 [P=0.007; hazard ratio (HR)=4.0 (95% CI: 1.5-11.1)] and hemoglobin &amp;lt;8 g/dL [P=0.006; HR=3.8 (95% CI: 1.5-9.7)] were jointly associated with lower survival probability. After forming groups based on the permutations of hemoglobin and ECOG, a scoring system was devised using patients with no negative prognostic factors (score 0: hemoglobin ≥8 g/dL and ECOG ≤2) versus patients with 1-2 negative prognostic factors (score 1: hemoglobin &amp;lt;8 g/dL and/or ECOG ≥3) resulting in a median OS of 10.6 years (95% CI: 10.6-not estimable) versus 0.8 years (95% CI: 0.3-2.8 years), p&amp;lt;0.0001, respectively. The validation cohort was very similar to the training cohort in terms of patient and disease characteristics. When we applied the multivariable model to the 58 patients from the validation cohort, ECOG and hemoglobin jointly predicted OS, validating the prognostic model [ECOG ≥3: P=0.0005; HR=15.6 (95% CI: 3.3-73.5) and hemoglobin &amp;lt;8 g/dL: P=0.04; HR=2.5 (95% CI: 1.05-5.8)]. Median OS in patients with score 0 was 16.9 years (95% CI:8.7-16.9) versus 0.6 years (95% CI: 0.3-1.0) in those with score 1. Conclusion: Using the largest international cohort of patients with HIV-associated PEL ever evaluated, we developed and validated the PEL-PS, which is easily implementable in any clinical setting using ECOG and hemoglobin. Low hemoglobin may be a surrogate marker for KSHV-associated inflammation and elevated IL-6 levels, and this association should be evaluated further. Patients with poor prognosis identified by the PEL-PS may benefit from novel therapies currently under investigation in PEL, such as immunomodulatory drugs, anti-CD38 monoclonal antibodies, and anti-PD-1 agents.

Acute heart failure following pazopanib treatment: a literature review featuring two case reports.

Tyrosine kinase inhibitors (TKIs) have transformed cancer treatment but are associated with cardiovascular toxicity, including heart failure. This review examines the cardiotoxicity of pazopanib, a VEGFR-TKI, through two case reports and explores potential mechanisms. The importance of vigilant clinical monitoring to prevent cardiac dysfunction in cancer patients receiving pazopanib is emphasized. We present two cases of acute heart failure following pazopanib treatment. Case 1 involves a comorbidity-free, 62-year-old woman with metastatic renal cell carcinoma who experienced irreversible heart failure. In case 2, a 40-year-old woman with a history of anthracycline-containing chemotherapy developed reversible left ventricular systolic dysfunction following pazopanib discontinuation. Both patients received appropriate management for their heart failure symptoms. Case 1's condition rapidly deteriorated, leading to her unfortunate demise 3 months after starting pazopanib. In contrast, case 2's cardiac function improved after discontinuing pazopanib. The advent of TKIs has revolutionized cancer treatment, but their association with cardiovascular toxicity necessitates meticulous monitoring of patients. The cases presented here highlight the importance of recognizing and managing cardiotoxicity, particularly in patients without prior cardiovascular risk factors. Understanding the underlying mechanisms and risk factors for TKI-induced heart failure is crucial to optimize patient care and treatment outcomes. Oncologists should be vigilant in identifying clinical symptoms and closely monitoring cardiac function throughout TKI therapy.

Survival and CNS Relapse in Patients with CD5-Positive Diffuse Large B-Cell Lymphoma: A Multi-Institutional Observational Study in Japan

Background: CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is usually characterized by activated B-cell type, poor prognosis, and frequent central nervous system (CNS) relapse. A sandwich therapy of dose-adjusted (DA)-EPOCH-R combined with high-dose methotrexate (HD-MTX) (DA-EPOCH-R/HD-MTX) showed excellent efficacy in a phase II study for newly diagnosed stage II-IV CD5+ DLBCL, including 2-year (yr) overall survival (OS), progression-free survival (PFS), and CNS relapse rates of 89%, 79%, and 9%, respectively (Miyazaki K, et al. Haematologica, 2020). It has been introduced in practice in Japan; however, the current status of treatment and the prognosis in patients with CD5+ DLBCL are unclear. Methods: We retrospectively analyzed the prognosis and CNS relapse rate of consecutive patients with untreated CD5+ DLBCL who were diagnosed at 30 hospitals in Japan from January 2016 to December 2021. Patients who were diagnosed with double-/triple-hit lymphoma, those with CNS involvement at diagnosis, and those who had not received any anthracycline-containing chemotherapy with rituximab (R-chemo) were excluded. We identified risk factors for OS using Cox proportional hazards method. The outcomes in the stage II-IV patients who received DA-EPOCH-R/HD-MTX were compared with those of the phase II study. To evaluate the efficacy of CNS prophylaxis, we divided patients into four groups: HD-MTX alone, intrathecal administration of MTX alone (IT MTX), both HD-MTX and IT MTX (HD/IT MTX), and no CNS prophylaxis. Results: Among the413 enrolled patients, 20 were excluded due to ineligible diagnosis or insufficient clinical information, 18 had CNS involvement at diagnosis, and 27 did not receive R-chemo. As a result, 348 patients were eligible and showed the following features: median age, 71 yrs (range, 23-92); male sex, 54%; stage II-IV, 90%; stage III or IV, 73%; ECOG performance status (PS) &amp;gt; 1, 30%; &amp;gt; 1 extranodal site, 42%; elevated serum lactate dehydrogenase (sLDH) level, 71%; high-intermediate or high International Prognostic Index (IPI), 63%; high CNS-IPI, 41%; and B symptoms, 29%. According to Hans's criteria, the nongerminal center B-cell type accounted for 67% of the 276 cases examined. Among the 348 patients, 62 (18%) received DA-EPOCH-R/HD-MTX, and 286 (82%) were treated with other R-chemo, such as R-CHOP (n = 254). The median age was 63.5 yrs (range, 29-75) in the DA-EPOCH-R/HD-MTX group and 72 yrs (range, 23-92) in the other R-chemo group. The DA-EPOCH-R/HD-MTX group included significantly more patients aged ≤ 60 yrs ( P &amp;lt; 0.001), although it tended to have more patients with ECOG PS &amp;gt; 1 than the other R-chemo group ( P = 0.069). Patients who received IT MTX made up 16% of the DA-EPOCH-R/HD-MTX group and 31% in the other R-chemo group. HD-MTX was used in 100% of patients in the DA-EPOCH-R/HD-MTX group and 17% of patients in the other R-chemo group. Details of CNS prophylaxis were HD-MTX alone in 84 patients (24%), IT MTX alone in 70 (20%), both HD/IT MTX in 28 (8%), and no CNS prophylaxis in 166 (48%). At a median follow-up of 43 months, the 2-yr OS, PFS, and CNS relapse rates of patients with stage II-IV disease in the DA-EPOCH-R/HD-MTX group were 87% (95% CI, 73-94%), 78% (95% CI, 63-87%), and 7.3% (95% CI, 2.8-18.2%), respectively. There were no significant differences in OS or PFS between stage I and stage II-IV patients in the DA-EPOCH-R/HD-MTX group. In all 348 patients with stage I-IV, both the OS ( P = 0.044) and PFS ( P = 0.043) in the DA-EPOCH-R/HD-MTX group were longer than those in the other R-chemo group. The 2-yr OS in these groups were 89% and 78%, and their 2-yr PFS were 78% and 64%, respectively. Multivariate analysis identified elevated sLDH ( P = 0.005), &amp;gt; 1 extranodal involvement ( P &amp;lt; 0.001), no IT MTX ( P = 0.005), and no DA-EPOCH-R/HD-MTX ( P = 0.005) as independent risk factors for OS. The 2-yr CNS relapse rate was 6.5% in the DA-EPOCH-R/HD-MTX group (n = 4) and 10.0% in the other R-chemo group. There were no significant differences in the CNS relapse rate between the two groups ( P = 0.54). The 2-yr CNS relapse rates of HD-MTX, IT MTX alone, both HD/IT MTX, and no prophylaxis were 9.8%, 9.1%, 3.7% (n = 1), and 10.3%, respectively. Conclusions: Our results confirmed favorable survival in the phase II study of DA-EPOCH-R/HD-MTX in clinical settings. DA-EPOCH-R/HD-MTX and IT MTX were associated with longer OS of patients with CD5+ DLBCL in our study cohort, warranting further investigation.

Mitoxantrone Hydrochloride Liposome, Gemcitabine, Vinorelbine with or without Rituximab (GVM±R) in Patients with Relapsed or Refractory Aggressive Non-Hodgkin's Lymphoma

Background: In patients with relapsed/refractory (r/r) aggressive non-Hodgkin lymphoma (aNHL), achieving a response to salvage therapy is a crucial predictor for long-term survival, as only chemosensitive patients have the opportunity to undergo autologous stem cell transplantation. Mitoxantrone hydrochloride liposome (PLM60) has shown good efficacy and safety in r/r peripheral T-cell lymphoma (PTCL) based on a prior study, with an objective response rate (ORR) of 40.7% and a complete response rate (CRR) of 20.4% (2020 ASH abstract 42). To determine the appropriate dosage of PLM60 in a multi-drug combination chemotherapy, we conducted a phase I clinical study aiming to explore the maximum tolerated dose (MTD) of PLM60 when combined with gemcitabine, vinorelbine, with or without rituximab (GVM±R). This trial was registered at www.clinicaltrials.gov as NCT05299164. Methods: The study was a prospective, single-center, single-arm, 3+3 dose-escalation study involving patients aged 18-70 years with r/r aNHL. PLM60 was administered on day 1 at four different dose levels (DL) (DL1: 16 mg/m 2, DL2: 18 mg/m 2, DL3: 20 mg/m 2, DL4: 22 mg/m 2), gemcitabine on day 1 and 8 at 800 mg/m 2, vinorelbine on day 1 and 8 at 20 mg/m 2, and rituximab on day 0 at 375 mg/m 2 (only administered in CD20+ lymphoma based on the investigator's judgment). The treatment was repeated every 21 days. Up to 6 cycles of therapy were planned. After the first cycle, dose-limiting toxicity (DLT) was assessed to determine the MTD of PLM60 in the GVM±R regimen. Results: As of July 15, 2023, the study had enrolled 12 eligible patients (DL1: n=6, DL2: n=6), with different aNHL subtypes, including 6 with diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS), 3 with angioimmunoblastic T-cell lymphoma (AITL), 2 with PTCL, NOS, and 1 with sezary syndrome (SS). The median age of the patients was 49 years (range, 23 to 69), with 41.7% being male. All patients had advanced-stage disease, with 33.3% in stage III and 66.7% in stage IV. They had received a median of 2.5 lines of therapy (range, 2 to 7), and 91.7% (11/12) of patients had received anthracycline-containing chemotherapy in their prior treatment. All patients with DLBCL, NOS had received rituximab during their prior therapy. 66.7% (8/12) of the patients were refractory to their last line therapy, and 2 out of the 6 patients with DLBCL, NOS experienced relapse after anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy. During the study, two patients experienced DLTs of grade 4 neutropenia lasting for more than 7 days, with one occurring in the DL1 group and the other in the DL2 group. In response to these observations, an additional three patients were enrolled in each of the groups. The most common grade 3/4 TRAEs with an incidence ≥10% were leucopenia (91.7%), neutropenia (83.3%), thrombocytopenia (66.7%), anemia (41.7%), febrile neutropenia (25.0%), pneumonia (25.0%), and hypokalemia (25.0%). With a median follow-up of 2.5 months, 11 patients were evaluated for efficacy, showing an ORR of 72.7% (95% CI 39.0% to 94.0%) and a CRR of 45.5% (95% CI 16.8% to 76.6%). In the DL1 group (16 mg/m 2), the CRR was 50.0% (3/6), and the ORR was 66.7% (4/6), while the DL2 group (18 mg/m 2) had a CRR of 40.0% (2/5) and an ORR of 80.0% (4/5) (Table 1). Among the DLBCL patients, the CRR was 60.0% (3/5), and among AITL patients, the CRR was 66.7% (2/3). Patients with PTCL NOS and SS achieved partial responses (PR). Two DLBCL patients who had previously received multiple lines of therapy, including anti-CD19 CAR T-cell therapy, achieved CR after GVM±R treatment. Conclusions: The GVM±R regimen exhibited manageable safety and encouraging efficacy in patients with r/r aNHL, despite the fact that the majority of these patients had received anthracycline-containing chemotherapy in their previous treatment. The trial is still ongoing to determine the recommended phase 2 dose for the subsequent phase 2 clinical study.

Pre-diabetes is associated with increased cardiac events in cancer patients prescribed anthracyclines

Abstract Background Pre-diabetes, a precedent of overt diabetes and metabolic disorder, is a known risk factor for adverse cardiovascular outcomes. Its impact on adverse cardiovascular outcomes in cancer patients prescribed anthracycline-containing chemotherapy (ACT) is uncertain. Objective To evaluate the association of pre-diabetes with cardiovascular events in cancer patients prescribed ACT. Methods We included cancer patients treated with ACT from 2000-2019, drawn from a previously validated territory-wide database. Patients were subsequently divided into diabetes, pre-diabetes, and normoglycaemia groups based on their baseline glycaemic profile. The primary outcome, major adverse cardiovascular events (MACE), was defined as a composite of hospitalization for heart failure and cardiovascular death. Results Among 12649 patients treated with ACT (55.5% male, median age 62 years), 3997 had pre-diabetes at baseline and 5622 had diabetes. Over a median follow-up of 8.7 years, the incidence of MACE was 211 (7.0%) in the normoglycaemia group, 358 (9.0%) in the pre-diabetes group, and 728 (12.9%) in the diabetes group. Compared with the normoglycaemia group, both pre-diabetes (adjusted hazard ratio [HR] = 1.20, 95% confidence interval [CI] 1.01-1.43) and diabetes (adjusted HR = 1.46, 95% CI 1.24-1.70) were associated with an increased risk of MACE. In the pre-diabetes group, 475 (18%) patients progressed to overt diabetes and exhibited a greater risk of MACE (adjusted HR = 1.76, 95% CI 1.31-2.36) than those who remained prediabetic. Conclusions In cancer patients treated with ACT, pre-diabetes at baseline, and those who progressed to diabetes at follow-up, had an increased risk of MACE. Our findings reveal that pre-diabetes is a key predictor and potential treatment target to reduce the risk of MACE in patients prescribed ACT.

Abstract 14091: Subclinical Cardiac Dysfunction in the Patients Treated With Anthracycline-Containing Chemotherapy in the Chronic Phase

Background: Anthracycline-induced cardiotoxicity is a concerning problem in the treatment of a variety of cancers. The highest incidence of anthracycline-induced cardiotoxicity was observed during the first year after the completion of chemotherapy, but the changes in cardiac function and biomarkers after the first year have not been adequately investigated. Methods: We analyzed 105 consecutive patients who were followed up for 24 months after starting anthracycline-containing chemotherapy in our hospital from June 2018 to April 2021. Echocardiography and blood test for troponin I and B-type natriuretic peptide (BNP) were performed at baseline, 3 months, 6 months, 12 months, and 24 months after starting the chemotherapy. Results: The cancer types included 71 breast cancers, 18 hematologic cancers, 11 gynecologic cancers, and 5 soft tissue tumors. Compared to baseline, troponin I levels were increased at 3 months (0.011±0.007 ng/ml vs. 0.021±0.021 ng/ml, P&lt;0.05) and 6 months (0.023±0.047 ng/ml, P&lt;0.001), then, recovered to baseline levels. In contrast, BNP levels remained unchanged for 12 months but increased at 24 months compared to baseline (31.9 [5.8-625.7] pg/ml vs. 15.5 [5.8-89.2] pg/ml, P&lt;0.01). In addition, the left ventricular ejection fraction was decreased from baseline to 6 months (65.4±4.8% vs. 63.6±4.5%, P&lt;0.05) and 24 months (63.6±4.7%, P&lt;0.05). Multivariate logistic analysis revealed that age (OR 1.049, 95% CI [1.006-1.097], P=0.029) and total anthracycline dose (OR 1.011, 95% CI [1.002-1.022], P=0.026) were predicting factors for elevated BNP levels above the normal range (&gt;18.2 pg/ml) at 24 months. Conclusion: Subclinical cardiac dysfunction was developed after more than one year. Long-term follow-up is desirable to detect cardiac dysfunction in patients treated with anthracycline-containing chemotherapy.

Abstract 12735: Investigating Cardiac Function After Anthracycline Exposure in Childhood Cancer Survivors With Modifiable Cardiovascular Risk Factors

Introduction: Anthracycline exposure can lead to cardiac dysfunction, which may possibly be worsened by secondary cardiovascular risk factors (CVRFs), such as hypertension, hyperlipidemia, obesity and diabetes. The prognostic impact of CVRFs in childhood cancer survivors is largely unknown. Now with advanced cardiac imaging, it is now possible to identify how CVRFs might influence subclinical cardiac function. Hypothesis: Anthracycline-exposed childhood cancer survivors with CVRFs will demonstrate echocardiogram-based subclinical cardiac dysfunction more frequently than those without. Methods: This is a single-center, retrospective study. Inclusion criteria are: &lt; 18 years old, history of anthracycline-containing chemotherapy and 2 echocardiograms performed. Exclusion criteria are: congenital cardiac disease, subsequent cancer relapse and inadequate imaging quality. Echocardiographic images were analyzed for longitudinal left ventricular strain, left ventricular ejection fraction (LVEF) and myocardial performance index (MPI). Wilcoxon rank-sum test was used to compare measures of cardiac function between patients with at least one CVRF (at time of cancer diagnosis) and patients without. Results: There were 111 patients identified with 49.5% having dysfunction at some point in time. CVRFs were identified in 19 patients with the majority of those being obese (52.6%). At baseline, there was a statistically significant difference in mean strain between those with CVRFs vs those without (-19.4% vs -21.3%). At 1-6 months after chemotherapy completion, LVEF was significantly reduced in those with CVRFs vs those without (48.7% vs 59.7%) as well as mean strain (-15.8% vs -20.0%). At &gt;5 years after chemotherapy, there was a decrease in strain magnitude in those with CVRFs vs those without (-17.7% vs -20.5%) along with abnormal mean MPI (0.57 vs 0.44). Conclusions: Anthracycline-exposed pediatric cancer survivors with CVRFs demonstrate reduced cardiac function at baseline and both at near-and long-term follow-up. Further investigation is warranted to investigate the significance of these reduced echocardiographic measures and CVRFs among childhood cancer survivors to mitigate cardiac morbidity as they age into adulthood.

Particularities of arterial stiffness dynamics on the background of breast cancer chemotherapy

Modern breast cancer chemotherapy regimens (BC) consider individual patient parameters and ranges of cardiotoxic doses. However, clinicians often record clinical and laboratory-instrumental signs of cardio- and vasculotoxicity in patients, which emphasizes the high importance of searching for markers of early toxic response. To study the characteristics of the response of arterial stiffness on the background of anthracycline-containing chemotherapy to determine potential markers of vasculotoxicity in BC patients. 20 women with a BC were included. The patients received 4 cycles of chemotherapy in the doxorubicin + cyclophosphane (AC) regimen with an interval of 2-3 weeks, then they were injected with paclitaxel weekly for 12 injections, or docetaxel once every 3 weeks. All patients underwent TTE, arterial stiffness determination by the "gold standard" method and using volumetric sphygmography before the start of treatment, after the completion of the anthracycline component and after the end of taxanes. The average age of the patients was 45.5±5.31 years. After completing the course of anthracyclines, there was a significant increase in heart rate (from 65.6±9.3 to 73.3±10.1 beats/min.), a decrease in SBP (from 122.6±9.9 to 116.5±12.3 mmHg) and DBP (from 78.9±8.5 to 76.2±8.6 mmHg), a decrease in carotid femoral pulse wave velocity (cfPWV) (from 9.32±1.41 to 7.85±1.57 m/s), CAVI index on the left (from 6.78±0.81 to 6.5±0.88), the velocity of the cardio-ankle pulse wave on the right and left (from 6.7±0.6 to 6.5±0.7 m/s; from 7.0±0.6 to 6.3±0.8 m/sc, respectively). After the completion of the taxane, there was a tendency to increase these indicators, however, they remained significantly lower compared to the values before the start of treatment. A comparative analysis of arterial stiffness indicators at different stages of chemotherapy showed a more pronounced reaction of cfPWV, CAVI, cardio-ankle pulse wave to the administration of anthracyclines, which presumably may be associated with concomitant hemodynamic restructuring.

Proof-of-concept study linking ex vivo sensitivity testing to neoadjuvant anthracycline-based chemotherapy response in breast cancer patients

We developed a functional ex vivo anthracycline-based sensitivity test. Surgical resection material of primary breast cancer (BC) was used to determine criteria for the ex vivo sensitivity assay based on morphology, proliferation and apoptosis. Subsequently, a proof-of-concept study was performed correlating results of this assay on primary BC biopsies with in vivo response after treatment with anthracycline-containing neoadjuvant chemotherapy (NAC). Cut off values for the ex vivo anthracycline-based sensitivity test were established based on analysis of 21 primary breast tumor samples obtained after surgery. In the proof-of-concept study based on a new set of tumor biopsies, 41 patients were included. Eight biopsies did not contain tumor cells and three patients could not be biopsied for various reasons. In the remaining 30 biopsies, the success rate of the ex vivo test was 77% (23/30); six out of seven failed tests were due to excessive apoptosis, our pre-specified test criteria. Of the 23 patients with a successful ex vivo test result, three patients did not undergo NAC after the biopsy. Here we report the ex vivo anthracycline-based sensitivity assay is feasible on biopsy material and shows 75% concordance between ex vivo outcomes and in vivo MRI response. Unfortunately, the percentage of unsuccessful tests is rather high. This study provides the foundation for further development of ex vivo sensitivity assays.

Chemotherapy-related cardiac dysfunction: the usefulness of myocardial work indices.

The role of left ventricular global longitudinal strain (GLS) in the diagnosis of subclinical cardiac damage induced by anticancer drugs is now consolidated. Considering some strain disadvantages such as the dependence on the haemodynamic loading conditions, the aim of our study was to investigate the usefulness of non-invasive myocardial work indices (MWI) derived from pressure-strain analysis, in the early diagnosis of cardiotoxicity. We enrolled 61 consecutive patients with breast cancer undergoing adjuvant treatment with anthracycline-containing chemotherapy followed by taxane + trastuzumab. Patients underwent a cardiological evaluation with 2D echocardiography including measurement of the left ventricular ejection fraction (LVEF) and other conventional parameters of systolic and diastolic function, GLS and MWI at baseline (T0), 3 months (T1) and 6 months (T2) after starting chemotherapy. At T1 and T2, we did not find a significant reduction in LVEF but we found a significant reduction in GLS and MWI (p value < 0.05). In addition, at T2, 31% of patients developed subclinical cardiac dysfunction defined as a relative decrease ≥ 12% of GLS from baseline. Global work index (GWI), global constructive work (GCW) and global work efficiency (GWE) decreased significantly in both patients with subclinical dysfunction and in those without subclinical dysfunction (p value < 0.05). Patients with subclinical dysfunction at T2 showed lower values of GCW at T0. MWI changed significantly during chemotherapy and appeared to alter precociously compared to GLS. Therefore, a multiparametric approach including left ventricular GLS and MWI measurements should be used in the evaluation of patients undergoing cardiotoxic antineoplastic treatment.

Incidence and predictors of anthracycline-related left ventricular dysfunction in acute myeloid leukemia

IntroductionAnthracycline-related left ventricular dysfunction (ARLVD) is a concern in patients with acute myeloid leukemia (AML) undergoing anthracyclinecontaining induction chemotherapy. However, the incidence of ARLVD in the modern era of routine pretreatment left ventricular ejection fraction (LVEF) echocardiographic assessment, as well as the clinical and genetic predictors of ARLVD are not well understood. MethodsConsecutive adult patients with AML receiving anthracycline-containing induction chemotherapy at the Dana-Farber Cancer Institute from 2014 to 2022 were studied. Inclusion criteria included availability of a pre and post chemotherapy echocardiogram to assess the LVEF, pre-treatment LVEF > 50 %, as well as comprehensive diagnostic next generation sequencing assessing for the presence of myeloid mutations. The primary endpoint was the incidence of ARLVD defined as LVEF < 50 % post-induction. ResultsOut of 419 patients meeting inclusion criteria, 34 (8%) patients developed ARLVD. Among the 122/419 patients who did not undergo planned allogeneic stem cell transplantation (allo-SCT), ARLVD was the deciding factor for ineligibility in 4 patients (1%). Baseline cardiovascular comorbidities (hypertension, diabetes mellitus, hyperlipidemia, smoking and coronary artery disease) and cumulative anthracycline dose were not predictive of post-induction ARLVD. However, the presence of a JAK2 mutation (but not other myeloid mutations) was associated with an increased risk of ARLVD in multivariable analysis (OR 8.34, 95 % CI 1.55–39.3, p = 0.007). DiscussionIn a group of AML patients with normal LVEF prior to anthracycline-containing induction chemotherapy, ARLVD was infrequent and did not commonly preclude post-remission allo-SCT consolidation. Genetic predictors of ARLVD require further investigation in a larger patient cohort.

ZUMA‐24: A PHASE 2, OPEN‐LABEL STUDY OF AXICABTAGENE CILOLEUCEL IN PATIENTS WITH RELAPSED/REFRACTORY LARGE B‐CELL LYMPHOMA GIVEN OUTPATIENT WITH CORTICOSTEROIDS

ZUMA‐24: A PHASE 2, OPEN‐LABEL STUDY OF AXICABTAGENE CILOLEUCEL IN PATIENTS WITH RELAPSED/REFRACTORY LARGE B‐CELL LYMPHOMA GIVEN OUTPATIENT WITH CORTICOSTEROIDS

PROGNOSTIC SIGNIFICANCE OF SEQUENTIAL 18F‐FDG PET/CT DURING THE TREATMENT OF ANTHRACYCLINE‐CONTAINING FRONTLINE CHEMOTHERAPY IN PERIPHERAL T CELL LYMPHOMAS

Introduction: Despite the prognostic significance of 18F-fluorodeoxyglucose (FDG)-positron emission tomography-computed tomography (PET/CT) assessment has important implications on determining the response-adapted therapy in patients with peripheral T-cell lymphomas (PTCLs), an optimal timing of the use and clinical application of PET/CT-based response are still up in the air. The aim of this study was to explore the prognostic impact of sequential 18F-FDG PET/CT analysis in patients with newly diagnosed PTCLs who treated with frontline anthracycline-based chemotherapy. Methods: Between February 2006 and September 2022, 143 patients with newly diagnosed PTCLs were included. All patients were treated with 6 cycles of anthracycline-containing chemotherapy. Sequential 18F-FDG PET/CT were obtained at the time of diagnosis, after three cycles of chemotherapy and finally at the end of chemotherapy. Baseline total metabolic tumor volume (TMTV) was computed with the sum of SUV2.5 threshold method, and the PET/CT response were assessed using the five-point scale (5-PS) of Deauville criteria. Results: Baseline MTV could be calculated in 126 patients, and the cut-off value of TMTV according to ROC analysis was 457.0 cm3 (Sensitivity 45.0%, specificity 74.0%). With a median follow-up of 52.0 months (range 3.8–153.9 months), patients with high TMTV more than cut-off value had inferior PFS and OS than those with low TMTV (PFS, 9.8 months vs. 26.5 months, HR 1.600, 95% CI 1.010–2.671, p = 0.043; OS, 18.9 months vs. 71.2 months, HR 2.135, 95% CI 1.261–3.615, p = 0.004, Figure 1A, B). Interim 18F-FDG PET/CT assessment was available in all 143 patients. When patients were categorized with three subgroups as response with grade 1, grade 2 and 3, and grade 4–5, PFS and OS showed significant difference according to interim visual assessment (PFS, 120.7 months vs. 34.1 months vs. 5.1 months, p < 0.001; OS, not reached vs. 61.1 months vs. 12.1 months, p < 0.001, Figure 1C, D), respectively. Among 77 patients who were assessed as grade 2 or 3 in interim PET/CT analysis, 19 patients (26.3%) turned over a remnant tumor metabolism or progressed at final PET response assessment. Moreover, the outcome of patients with interim grade 2 or 3 showed the significant differences based on the final achievement of complete metabolic response or not in PFS and OS (PFS, 59.9 months vs. 7.2 months, HR 4.754, 95% CI 2.267–9.971, p < 0.001; OS, not reached vs. 24.0 months, HR 3.706, 95% CI 1.592–8.630, p = 0.001), respectively. Keywords: aggressive T-cell non-Hodgkin lymphoma, diagnostic and prognostic biomarkers No conflicts of interests pertinent to the abstract.

The Association of Sodium-Glucose Cotransporter 2 Inhibitors With Cardiovascular Outcomes in Anthracycline-Treated Patients With Cancer

BackgroundSodium glucose cotransporter-2 inhibitors (SGLT2is) are hypothesized to reduce the risk of anthracycline-associated cardiotoxicity. ObjectivesThis study sought to determine the association between SGLT2is and cardiovascular disease (CVD) after anthracycline-containing chemotherapy. MethodsUsing administrative data sets, we conducted a population-based cohort study of people >65 years of age with treated diabetes and no prior heart failure (HF) who received anthracyclines between January 1, 2016, and December 31, 2019. After estimating propensity scores for SGLT2i use, the average treatment effects for the treated weights were used to reduce baseline differences between SGLT2i-exposed and -unexposed controls. The outcomes were hospitalization for HF, incident HF diagnoses (in- or out-of-hospital), and documentation of any CVD in future hospitalizations. Death was treated as a competing risk. Cause-specific HRs for each outcome were determined for SGLT2i-treated people relative to unexposed controls. ResultsWe studied 933 patients (median age 71.0 years, 62.2% female), 99 of whom were SGLT2i treated. During a median follow-up of 1.6 years, there were 31 hospitalizations for HF (0 in the SGLT2i group), 93 new HF diagnoses, and 74 hospitalizations with documented CVD. Relative to controls, SGLT2i exposure was associated with HR of 0 for HF hospitalization (P < 0.001) but no significant difference in incident HF diagnosis (HR: 0.55; 95% CI: 0.23-1.31; P = 0.18) or CVD diagnosis (HR: 0.39; 95% CI: 0.12-1.28; P = 0.12). There was no significant difference in mortality (HR: 0.63; 95% CI: 0.36-1.11; P = 0.11). ConclusionsSGLT2is may reduce the rate of HF hospitalization after anthracycline-containing chemotherapy. This hypothesis warrants further testing in randomized controlled trials.