Combination Of Anthracycline Research Articles

A Real-World Single-Institution Experience with Hypomethylating Agents Plus BCL-2 Inhibitor for the Treatment of Acute Myeloid Leukemia

Background: Acute myeloid leukemia (AML) is a heterogeneous clonal disease of myeloid progenitor cells resulting from alterations in cell differentiation, proliferation, and renewal. Treatment for young patients and those with favorable-to-intermediate risk remains a combination of cytarabine and anthracycline, while the optimal regimen for the elderly has yet to be established. First-line and salvage combination hypomethylating agents azacitidine or decitabine with BCL-2 inhibitor venetoclax (HMA+Ven) has shown promise for these patients and are becoming standard therapy. We present a cohort from our institution treated with HMA+Ven vs traditional therapy. We hypothesize HMA+Ven leads to improved overall survival (OS) and complete remission with or without count recovery (CR/CRi) compared to traditional therapy in the elderly and those with unfavorable risk as defined by the European LeukemiaNet (ELN-2017) risk stratification. Methods: 232 AML patients from Baylor St. Lukes Medical Center, and Michael E DeBakey VA Medical Center from 8/26/1997 to 7/31/2021 were reviewed. These patients were stratified by HMA+Ven vs. other standard treatment. Differential survival among groups was measured by Kaplan-Meier method. The independent effect of HMA+Ven against multiple intervening variables was evaluated by Cox proportional regression analysis. Chi-square and t-test detected potential intervening variables with impact on outcome. SAS software was used for analysis. Results: Those treated with HMA+Ven comprised 28 out of 227 patients (12.3%). Average age of patients was 65 (26-80) in the HMA+Ven group and 61.3 (20-93) in the other treatment group (p=0.05). Age, ELN-2017 risk stratification, and HMA+Ven treatment were predictors for survival (Table 1). OS in our cohort favors HMA+Ven vs other treatment (Fig. 1, 348 days vs 261 days, p=0.0004). Overall survival in the elderly population of interest favors HMA+Ven (270 days vs 135 days, p<0.0001). CR/CRi was superior for HMA+Ven in those age >60 (55% vs 24.7%, p=0.006) as well as those age >70 (55% vs 15.2% p=0.007). OS for those with adverse ELN-2017 stratification favors HMA+Ven (352 days vs 164 days, p=.002). Interestingly, overall survival trends for those with active smoking history favors HMA+Ven (p<0.0001). Lastly we found CR/CRi favors HMA+Ven for those with RUNX1 gene mutation (75% vs 25%, p=0.01). Conclusion: HMA+Ven demonstrated superior response in our elderly patients and those with unfavorable risk through OS as well as CR/CRi, compared to those treated with traditional therapy. This held true across all ELN-2017 risk categories when examined by cox regression models (Table 1) and was most notable in the adverse risk subgroup. The mechanism by which smoking may enhance HMA+Ven survival is uncharacterized and warrants investigation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Survival of Patients with Primary Mediastinal B-Cell Lymphoma Treated By Immunochemotherapy with or without Radiotherapy

Introduction: Primary mediastinal B-cell lymphoma (PMBL) is B-non-Hodgkin lymphoma subtype with unique clinical and biological characteristics mostly affecting younger patients. The current treatment standard is based on combination of rituximab and anthracycline based chemotherapy (R-CHT), either standard (R-CHOP) or intensified (DA-EPOCH-R). Radiotherapy (RT) consolidation has been standard of care for a long time, but its role is currently unclear, especially in the context of PET/CT guided therapy and long term toxicity prevention considering young patient population (Hayden at al.2020, Giulino-Roth 2018). In this analysis we evaluate the survival benefit of RT consolidation in patients with PMBL achieving PET negative (PET-neg) response after R-CHT. Methods: Patients with confirmed diagnosis of PMBL observed in NiHiL project (Gov Trial No: NCT03199066) were analysed. All patients were treated by R-CHT; PET/CT was performed at the end of the immunochemotherapy. The treatment response was evaluated according to Cheson 2007 criteria. Only patients achieving PET negativity were included in primary analysis. Results: The study included 230 patients out of whom 133 (57.8%) were women. Median age was 37 years (range 19-79); localised stage (I-II) was observed in 165 patients (71.7%) and low or low-intermed IPI in 189 patients (82.2%). The diagnosis was confirmed by central pathologist in all cases. Patients were treated by R-CHT, mostly R-CHOP (52.2%) and R-CHOEP-like (25.2%; i.e. R-CHOEP or DA-EPOCH-R); other intensive regimens, incl. platinum were used in 19.6% of patients; 48 patients (20.8%) received ASCT as part of first line induction. PET/CT was performed at the end of R-CHT (including ASCT); 174 patients (75.7%) achieved PET-neg remission at the end of the immunochemotherapy, 56 (24.3%) were PET positive (PET-pos). After reaching PET negativity, radiotherapy was performed in 68 patients (39.1%) with median dose of 36Gy (range 20-42Gy); 106 patients were not consolidated by RT and observed (OBS). There was higher incidence of bulky disease and B-symptoms in RT group (57% vs 47% and 57% vs 48% resp.) without reaching statistical significance. Median follow up was 5.9 years. OS and PFS probability at 6y were 90.5% and 83.6% resp. for the whole cohort. RT consolidation in PET-negative subgroup led to a significant improvement (p=0.039) in PFS at 6y with 95% (n=68) vs 85.3% in OBS group (n=106). This was, however, not transformed into the OS difference (94.5% vs 92.1% probability at 6y for RT vs OBS; HR 1.64, CI95% 0.52-5.8), figure 1. In subgroup of patients treated by R-CHOP, there was an insignificant trend for better PFS probability in RT group (HR 2.41, 95%CI 0.71-6.92, p=0.17). This was not reflected in any OS difference. The outcome of patients who reached PET negativity by R-CHOEP was the same regardless of the radiotherapy use. Conclusion: Our analysis of retrospectively recorded patients shows that skipping RT in PET-neg PMBL patients at the end of immunochemotherapy does not hamper overall survival. There was borderline improvement of PFS. The patient cohorts with different chemotherapy regimens were not big enough to analyse the RT significance. However, data observed in patient subpopulation treated by CHOEP-like regimen confirm already published observations (Dunleavy et al. 2013) concluding possible RT oblivion after intensified immunochemotherapy. Therefore, the choice between radiotherapy consolidation vs observation in PET negative patients should be discussed with the patient especially when less intensive regimen (R-CHOP) is used. Acknowledgement: This work was supported by Cooperatio Program - research area Oncology and Hematology and by research grant NU21-03-00411 Figure 1. Survival analysis of patients reaching PET negative remission after chemotherapy (n=174) shows improvement in progression free survival (PFS) for patients consolidated with radiotherapy (RT), however without reflection in overall survival (OS). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Venetoclax Plus Intensive Chemotherapy in AML and Advanced MDS: Assessment of Leukemia Stem Cell Eradication By High-Resolution MRD Assay

Background: For the past five decades the standard of care for fit patients with acute myeloid leukemia (AML) has been induction with the "7+3" regimen, using a combination of cytarabine (AraC) and anthracycline (daunorubicin, idarubicin) followed by consolidation high-dose AraC (HiDAC). With this approach, approximately 70% of younger (≤60 years of age) and 60% of older (>60 yrs) fit patients achieve a complete remission, with 30-50% of those patients attaining measurable residual disease (MRD) negative state by multiparameter flow cytometry (MFC). However, even patients with MRD-negative remissions relapse due to remaining chemotherapy-resistant pre-leukemic and leukemic stem cells (LSCs). Eradication of residual disease at the LSC level is therefore the ultimate goal to achieve durable remissions and cure. The combination of Venetoclax (Ven) with chemotherapy can have a synergistic effect; by reducing the apoptotic threshold, Ven can facilitate increased apoptosis induced by genotoxic agents, while at the same time chemotherapy can downregulate MCL-1 that drives Ven resistance. Ven in combination with hypomethylating agents has shown to not only eradicate AML blasts but also target and eliminate LSCs. Early phase trials combining Ven with intensive chemotherapy (IC) have shown encouraging safety and efficacy signals. However, the optimal dose and schedule of Ven that can best synergize with IC to eradicate LSCs remain unknown. Here we present a phase 1b study evaluating the safety and tolerability of Ven in combination with daunorubicin (dauno)/AraC) induction followed by HiDAC consolidation in patients with newly diagnosed AML or high-risk myelodysplastic syndrome (MDS). Objective: The primary objectives of this study are to evaluate the safety, tolerability, and to determine the maximum tolerated dose (MTD) of the combination of Ven plus dauno & AraC, as well as HiDAC IC. Secondary objectives are response per 2017 ELN and revised IWG criteria, survival, event-free survival and duration of response. A key exploratory objective is to comprehensively analyze LSC and assess rates of LSC eradication by means of MFC and single cell sequencing ("high-resolution MRD assay"). Design: This is a Phase 1b, open-label, dose-escalation study, evaluating Ven in combination with IC in previously untreated, adult patients with AML and high-risk MDS (NCT05342584). In Part 1, we are utilizing a 3+3 design to evaluate the safety and tolerability of different Ven doses in combination with IC. In Part 2, we will evaluate the safety and clinical activity in additional 12 patients at the dose determined in Part 1. To evaluate for LSC MRD, bone marrow aspirates obtained at the time of each disease evaluation will be analyzed by high-resolution MRD assays. Specifically, we will perform multicolor flow cytometry assays optimized for primary samples and able to distinguish, quantify, and sort pre-LSCs and LSCs. Furthermore, we will combine this assay with ultra-deep sequencing (1Million x) to detect very low levels of mutant cells, importantly within the LSC compartment. Eligible patients must have a new diagnosis of AML or high-risk MDS (blasts>10% AND R-IPSS>3.5%), be 18-75 yrs of age and deemed fit for intensive chemotherapy. During induction, escalating Ven doses (400 mg x8 -> 11 -> 14 days) will be combined with AraC 100mg/m2 and 2 doses of dauno (60 and 90mg/m2) in patients aged 60yrs or younger, whereas dauno 60 will be used for all patients older than 60yrs. During consolidation, the Ven dose will be escalated (200 -> 400mg) in a similar 3+3 design at a fixed 7-day duration in combination with age-adjusted high dose AraC regimen (1.5g/m2 in ≤60yrs and 1g/m2 in >60yrs, every 12hrs on days 1,3,5). Conclusion: This study will evaluate the optimal dosing of Venetoclax and daunorubicin as part of the Ven plus "7+3" induction regimen. It will also evaluate the optimal dose of Venetoclax in combination with HiDAC consolidation chemotherapy. This trial will utilize a novel highly-sensitive LSC MRD assay to test the efficacy of Venetoclax in eliminating LSCs when combined with conventional chemotherapy.

Abstract 11902: Hypertension Severity Impacts Declines in Left Ventricular Ejection Fraction Among Women Receiving Adjuvant Chemotherapy for Breast Cancer (UPBEAT WF-97415)

Introduction: AHA/ACC hypertension guidelines do not clearly address pharmacological treatment of increases in blood pressure (BP) in women receiving potentially cardiotoxic chemotherapy for treatment of breast cancer. Methods and Results: Magnetic resonance measures of left ventricular ejection fraction (LVEF) were performed in women with stage I-III breast cancer prior to and three months after initiating potentially cardiotoxic chemotherapy. Measurements of brachial BP were collected according to AHA recommendations. Using multivariable analysis, we assessed the association between change in LVEF and pre-existing ACC/AHA stages of hypertension (HTN) after accounting for pre-treatment LVEF, diabetes status, age, and body mass index (BMI). All analyses were performed by those blinded to all participant identifiers. Participants (n=259, female) were aged 56±11 (Mn + SD) years and were 76% white &amp; 19% black (NCT02791581 and NCT01719562). Cancer therapies included combinations of anthracyclines (23%), trastuzumab (10%), paclitaxel (22%) and cyclophosphamide (30%). After accounting for pre-treatment LVEF, diabetes status, age, and BMI, participants with stage 2 HTN experienced a significant decline (p=0.037, Figure) in LVEF relative to individuals with normal blood pressure. Conclusion: Relative to women with normal blood pressure, women with stage 2 HTN experienced a larger decline in LVEF (p=0.037) three months after initiating potentially cardiotoxic chemotherapy for breast cancer. This finding raises the possibility that lower blood pressure targets among women receiving adjuvant treatment for breast cancer may be associated with improved preservation of LVEF.

Network Meta-analysis of traditional Chinese medicine injections against anthracycline-induced cardiac injury

This study aimed to systematically evaluate the effect of traditional Chinese medicine(TCM) injections on anthracycline-induced cardiac injury. The Cochrane Library, PubMed, EMbase, CNKI, and other databases were electronically retrieved to gather randomized controlled trials(RCTs) of TCM injections against anthracycline-induced cardiac injury from their inception to September 2021. After two research fellows independently screened the literature and extracted the data, the risk of bias of included RCTs was assessed and network Meta-analysis was performed by R 4.1.0 and Stata 15.1. A total of 50 RCTs were included, involving eight TCM injections. Network Meta-analysis showed that:(1)the combination of anthracyclines with Huachansu Injection might be the optimal treatment to reduce the abnormal electrocardiogram.(2)The combination with Shenfu Injection might be the optimum treatment to ameliorate the left ventricular ejection fraction(LVEF) decrease.(3)The combination with Shenqi Fuzheng Injection might reduce the incidence of cardiotoxicity most satisfactorily.(4)The combination with Xinmailong Injection might improve the elevated cardiac troponin I(cTnI) optimally.(5)The combination with Shenmai Injection might be optimal to control the rise of creatine kinase MB isoenzyme(CK-MB).(6)The combination with Kushen Injection might be the regimen with the lowest gastrointestinal reactions. TCM injections had desirable effect on anthracycline-induced cardiac injury, with low incidence of adverse reactions, and each TCM injection had its own unique advantages. Due to the limitations in quality and methodological conduct of the included studies, more high-level RCTs are needed to validate the conclusions.

Kleinzelliges Lungenkarzinom – Etablierte Standards und neue Ansätze

Although the treatment and prognosis of many solid tumor types in the metastatic situation could be considerably improved during the last decade, for a long time no significant progress in the treatment of small cell lung cancer (SCLC) could be achieved. The aim of this article is to describe the current treatment standard for SCLC and to discuss potential approaches for further improvement. A selective literature search was carried out in PubMed and abstract lists of relevant conferences. Given the recent approval of two immunochemotherapy regimens based on the combination of anti-PD-L1 antibodies with platinum-etoposide, the therapeutic standard in the first line treatment of metastasized SCLC has finally been improved for the first time in three decades; however, the overall survival benefit has been modest with an improvement of just 2-3months. In advanced lines of treatment no new approaches could so far show improved outcome compared with established chemotherapy protocols, such as topotecan and combinations of anthracycline, cyclophosphamide and vincristine. The slow progress in SCLC compared to non-SCLC, has been attributed to the complex biology, the exceptionally high proliferation rate and rapid development of resistance to chemotherapy. Increasing knowledge on the molecular and immunological principles of SCLC is increasingly opening up novel treatment approaches. There has finally been a slow but clinically meaningful progress in the treatment of SCLC. Patients should be included in clinical trials at the latest after second line treatment, in order to accelerate the speed of the expansion of treatment options.

P443: IMPACT OF PHARMACOGENETIC VARIANTS ON CYTARABINE AND ANTHRACYCLINE EFFECT ON OUTCOMES IN ADULT AML PATIENTS

Background: Acute myeloid leukaemia (AML) is primarily treated with combination of cytarabine and anthracyclines. Despite high remission rates, the 5-year overall survival (OS) is <50% and <20% for<60-year-old a ≥60-year-old patients, respectively. This grim clinical outcome could be partly explained by the patients’ genetic variability of proteins involved in metabolic paths of cytarabine and anthracyclines. Pharmacogenetic variants of the main cytarabine membrane transporter SLC29A1 (solute carrier family 29 member 1), DCK (Deoxycytidine kinase) the first enzyme in cytarabine stepwise activation process, genes coding main anthracycline efflux pump ABCB1 (ATP binding cassette) and genes coding glutathione S-transferases GSTM1 and GSTT1, main cytosolic detoxifiers od anthracycline-induced oxidative stress, are shown to influence clinical outcome in AML patients. Aims: to evaluate: 1) the effects of variants in pharmacogenes SLC29A1, DCK, ABCB1, GSTM1 and GSTT1, on complete remission (CR) and relapse rate (RR), disease free survival (DFS) and overall survival (OS), 2) the influence of demographic, laboratory and AML-related parameters on CR, RR, DFS and OS. Methods: 100 newly-diagnosed consenting adults (18-62 years old) diagnosed with AML, except acute promyelocytic leukaemia in Clinic of Haematology UCCS from January 2015 to January 2018, were included in retrospective cohort. Patients received one or two inductions ‘’3 + 7’’ cycles. In patients achieving CR either three consolidation cycles with high/intermediate doses of cytarabine or allogenic SCT in selected patients were performed. Demographic, standard laboratory and AML-related parameters (blood/bone marrow blast percentage, cytologic, flow cytometry and genetic markers enabling ELN risk stratification were collected from patients’ health records. Variants SLC29A1 rs9394992, DCK rs12648166, ABCB1 rs2032582 and GSTM1 and GSTT1 gene deletions were detected by methodology based on PCR, fragment analysis and direct sequencing. The study was approved by the Ethics Committee of the UCCS. The methods of descriptive and analytic statistics were used, while survival analysis was done by the Kaplan-Meier method using the Log-Rank test. Results: 100 patients (53 males) were included in the study, with the median age of 51 (range 18-62). Median laboratory parameters were: WBC 15.5x109/L (range 1-348.8), Hgb 97g/L (range 20-166), Plt 53.5 (range 1-422), LDH 249U/L (1-4169). CD34 was positive in 56% patients. According to ELN 15, 55 and 30 patients were classified in favorable, intermediate and adverse risk group, respectively. CR was achieved in 57 patients (41 after the first and 16 after the second induction cycle). A total of 34% of patients relapsed. Median DFS was 5.3 months (range 0.25-61.5), while median OS was 6 months (range 0.3-75). There was a significant difference in median DFS between CC, CT and TT genotype of SLC29A1: 13, 8 and 1.75 months, respectively (p=0.00037). Median DFS was significantly decreased in null genotype of GSTM1 (9.5 (null) vs 18 months (non-null); p=0.028). Significant difference in OS within ABCB1 genotypes TT, GG, GT and AG+AT was registered: 13, 7, 6.5 and 3 months, respectively (p=0.0036). Other parameters did not differ significantly. Summary/Conclusion: Our results, regarding impact of variants of SLC29A1, GSTM1 on DFS and impact of variant ABCB1 on OS in AML patients, are in line with previous studies. Although further studies, with larger cohorts, are needed, these pharmacogenetic variants show a potential to become prognostic markers in AML.

Potential Determinants for Radiation-Induced Lymphopenia in Patients With Breast Cancer Using Interpretable Machine Learning Approach.

Radiation-induced lymphopenia is known for its survival significance in patients with breast cancer treated with radiation therapy. This study aimed to evaluate the impact of radiotherapy on lymphocytes by applying machine learning strategies. We used Extreme Gradient Boosting (XGboost) to predict the event of lymphopenia (grade≥1) and conduced an independent validation. Then, we induced feature attribution analysis (Shapley additive explanation, SHAP) in explaining the XGboost models to explore the directional contribution of each feature to lymphopenia. Finally, we implemented the proof-of-concept clinical validation. The results showed that the XGboost models had rigorous generalization performances (accuracies 0.764 and ROC-AUC 0.841, respectively) in the independent cohort. The baseline lymphocyte counts are the most protective feature (SHAP = 5.226, direction of SHAP = -0.964). Baseline platelets and monocytes also played important protective roles. The usage of taxane only chemotherapy was less risk on lymphopenia than the combination of anthracycline and taxane. By the contribution analysis of dose, we identified that firstly lymphocytes were sensitive to a radiation dose less than 4Gy; secondly the irradiation volume was more important in promoting lymphopenia than the irradiation dose; thirdly the irradiation dose promoted the event of lymphopenia when the irradiation volume was fixed. Overall, our findings paved the way to clarifying the radiation dose volume effect. To avoid radiation-induced lymphopenia, irradiation volume should be kept to a minimum during the planning process, as long as the target coverage is not compromised.

Incidence of trastuzumab-induced cardiotoxicity and impact of body mass index in patients with breast cancer: Results from a Saudi tertiary cancer center.

The effect of BMI as a risk factor in trastuzumab-induced cardiotoxicity in Saudi patients with HER2-neu positive breast cancer treated with trastuzumab and anthracyclines is not fully understood. The present study retrospectively evaluated the overall incidence of cardiotoxicity and the effect of BMI as a risk factor for cardiotoxicity. A retrospective study performed between 2011 and 2015 of patients with Her2-neu positive early breast cancer who were treated with either a combination of trastuzumab and anthracycline or a combination of trastuzumab with non-anthracycline or hormonal treatment in the adjuvant settings was carried out. The incidence of cardiotoxicity and the effect of BMI, hypertension and diabetes mellitus as risk factors for cardiotoxicity were assessed. Cardiotoxicity was measured using a drop in the ejection fraction of >10 percentage points to a left ventricular ejection fraction of <50%. The present cohort included 105 patients diagnosed with stage I and II breast cancer. The mean age of the present cohort was 47.5±1.0 years (range, 25-76 years), the mean height was 153.9±14.1 cm (range, 126-170 cm), the mean body weight was 75.7±15.6 kg (range, 40-143 kg) and the mean BMI was 31.3±5.8 (range, 18-49). Cardiotoxicity was detected in 21.9% of the cohort. The BMI was calculated for 81 patients who were treated with a combination of trastuzumab and anthracycline. Cardiotoxicity was detected in 3 out of 9 patients with a BMI <25, in 9 out of 23 patients with a BMI between 25 and 29, and in 6 patients with a BMI >30. There was a significant association between cardiotoxicity and BMI (P=0.03). No significant association between age, hypertension and diabetes and cardiotoxicity was identified. In conclusion, compared with global cohorts, the present results revealed a higher incidence of cardiotoxicity among Saudi patients with HER2-neu positive early breast cancer treated with trastuzumab combinations in adjuvant settings. Increased BMI was significantly associated with cardiotoxicity.

An Unusual Presentation of a Rare Tumor: Primary Renal Synovial Sarcoma

Primary renal synovial sarcomas are very rare and highly aggressive tumors. They are seen at an average age of 35 years. Common symptoms include side pain, abdominal pain, and hematuria. Imaging modalities have no specific findings indicating their presence, and the diagnosis is made based on immunohistochemical methods, which may need to be confirmed by cytogenetic analysis. Radical nephrectomy is the best treatment option currently available, with a combination of anthracyclines and ifosfamidine being administered as adjuvant chemotherapy. In this case report, we present a patient with a primary renal synovial sarcoma presenting with spontaneous massive retroperitoneal bleeding due to tumor rupture. To the best of our knowledge, this is only the second case of such clinical presentation reported in the literature.

Current State of Knowledge on the Immune Checkpoint Inhibitors in Triple-Negative Breast Cancer Treatment: Approaches, Efficacy, and Challenges.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with limited treatment options. Recently, there has been a growing interest in immunotherapy with immune checkpoint inhibitors (ICIs) in TNBC, leading to extensive preclinical and clinical research. This review summarizes the current state of knowledge on ICIs efficacy and their predictive markers in TNBC and highlights the areas where the data are still limited. Currently, the only approved ICI-based regimen for TNBC is pembrolizumab with chemotherapy. Its advantage over chemotherapy alone was confirmed for non-metastatic TNBC regardless of programmed death-ligand 1 (PD-L1) expression (KEYNOTE-522) and for metastatic, PD-L1-positive TNBC (KEYNOTE-355). Pembrolizumab’s efficacy was also evaluated in monotherapy, or in combination with niraparib and radiation therapy, showing potential efficacy and acceptable safety profile in phase 2 clinical trials. Atezolizumab + nab-paclitaxel increased the overall survival (OS) over placebo + nab-paclitaxel in early TNBC, regardless of PD-L1 status (IMpassion031). In IMpassion130 (untreated, advanced TNBC), the OS improvement was not statistically significant in the intention-to-treat population but clinically meaningful in the PD-L1 positive cohort. The durvalumab–anthracycline combination showed an increased response durability over placebo anthracycline in early TNBC (GeparNuevo). Several phase 1 clinical trials also showed a potential efficacy of atezolizumab and avelumab monotherapy in metastatic TNBC. ICIs appear to be applicable in both neoadjuvant and adjuvant settings, and are both pretreated and previously untreated patients. Further research is necessary to determine the most beneficial drug combinations and optimize patient selection. It is essential to identify the predictive markers for ICIs and factors affecting their expression.

Features of response to modern neoadjuvant chemotherapy with dual anti-HER2 blockade (trastuzumab and pertuzumab) in the patients with HER2-positive breast cancer stage II–III

Background. Neoadjuvant chemotherapy (NACT) with dual anti-HER2 blockade has become a priority in the treatment of patients with HER2+ breast cancer (BC) stages IIIII. However, the question of the accordance of various systems for assessing tumor response to NACT, as well as identifying predictor factors for achieving a complete pathomorphological response (pCR) in HER2+ BC remains open.&#x0D; Aim. To assess the accordance of various systems for assessing tumor response to neoadjuvant chemotherapy (NACT) in patients with HER2+ BC and to identify predictor factors for achieving pCR and residual cancer burden.&#x0D; Materials and methods. The study included 49 women with HER2+ BC stage IIIII, who underwent NACT with anti-HER2 blockade, followed by surgical treatment and morphological analysis of the results. The median age of the patients was 47 years; 91.8% had tumor size T2, N+ status 71.4%; tumor grade G3 73.5%, luminal and non-luminal HER2+ subtype 44.9 and 55.1% of patients, respectively. Ki6730% was observed in 93.9% of cases, the level of TILs in the tumor was 10%, 1020% and 20% in 38.1, 9.5 and 52.4% of cases, respectively. The patients received combinations of anthracyclines and taxanes or the anthracycline-free regimen of docetaxel + carboplatin; 87.8% of patients received a dual blockade of trastuzumab + pertuzumab, and 12.2% trastuzumab. After the end of NACT, all patients underwent a radical surgery (mastectomy or breast-conserving) with an assessment of the pathomorphological response, the pathomorphological stage of ypTN, and the residual cancer burden according to the RCB system.&#x0D; Results. The rate of complete pathomorphological response (tpCR/RCB-0/ypT0N0) in HER2+ BC was 61.2%; significant predictors of achieving tpCR were only 3 factors: primary operable BC stages (T13N01) the rate of tpCR was 71.4%, the level of TILs20% the proportion of tpCR reached 95.5%, and the dual anti-HER2 therapy (trastuzumab + pertuzumab) tpCR was 65.1%. Residual tumor was presented by classes RCB-I, RCB-II, RCB-III in 10.2, 24.5, 4.1%. The RCB-I class included of patients with a residual tumor less than 1.0 cm in the absence of regional lymph node involvement (80% of cases); class RCB-II was represented by the presence of a residual tumor less than 2.0 cm in combination with the absence or presence of residual metastases in 13 lymph nodes (83.4%), and class RCB-III was presented the residual tumors 2.0 cm and N12 status in 100% of cases (p0.0001).&#x0D; Conclusion. Modern NACT with dual anti-HER2 blockade (trastuzumab + pertuzumab) are highly effective the rate of tpCR is 61.2%, and in the presence of high TILs20% reaches 95.5%. Residual tumor in most cases was presented by class RCB-I or RCB-II, only 4% of patients had massive residual tumor load (class RCB-III).

Effects of chemotherapy on contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers: A nationwide cohort study

AimBRCA1/2 mutation carriers with primary breast cancer (PBC) are at high risk of contralateral breast cancer (CBC). In a nationwide cohort, we investigated the effects of chemotherapeutic agents given for PBC on CBC risk separately in BRCA1 and BRCA2 mutation carriers. Patients and methodsBRCA1 or BRCA2 mutation carriers with an invasive PBC diagnosis from 1990 to 2017 were selected from a Dutch cohort. We estimated cumulative CBC incidence using competing risks analysis. Hazard ratios (HR) for the effect of neo-adjuvant or adjuvant chemotherapy and different chemotherapeutic agents on CBC risk were estimated using Cox regression. ResultsWe included 1090 BRCA1 and 568 BRCA2 mutation carriers; median follow-up was 8.9 and 8.4 years, respectively. Ten-year cumulative CBC incidence for treatment with and without chemotherapy was 6.7% [95%CI: 5.1–8.6] and 16.7% [95%CI: 10.8–23.7] in BRCA1 and 4.8% [95%CI: 2.7–7.8] and 16.0% [95%CI: 9.3–24.4] in BRCA2 mutation carriers, respectively. Chemotherapy was associated with reduced CBC risk in BRCA1 (multivariable HR: 0.46, 95%CI: 0.29–0.74); a similar trend was observed in BRCA2 mutation carriers (HR: 0.63, 95%CI: 0.29–1.39). In BRCA1, risk reduction was most pronounced in the first 5 years (HR: 0.32, 95%CI: 0.17–0.61). Anthracyclines and the combination of anthracyclines with taxanes were associated with substantial CBC risk reduction in BRCA1 carriers (HR: 0.34, 95%CI: 0.17–0.68 and HR: 0.22, 95%CI: 0.08–0.62, respectively). ConclusionRisk-reducing effects of chemotherapy are substantial for at least 5 years and may be used in personalised CBC risk prediction in any case for BRCA1 mutation carriers.

Abstract 13232: Prokineticin as a Biomarker of Cardiotoxicity in Cancer Patients

Many anticancer drugs are highly effective for cancer treatments. However, they triggerclinically significant cardiovascular morbidity and in some case mortality. Recently,experimental data support an important protective role of prokineticin-2, a cytokine, againstanthracycline-mediated cardiovascular toxicity. The aim of this study was to examine thelevels of plasma prokineticins (PROK1 and PROK2), and clinically used cardiac biomarkers(Troponin-T, Brain Natriuretic peptide) to assess possible correlations of these cytokines withrisk and severity of cardiotoxicity of cancer treatments. 200 patients with different type oftumor (mostly breast cancer, and ovarian cancer, urinarybladder cancer or other types oftumors), were enrolled. They were scheduled for cancer treatments including anthracyclinesalone, monoclonal antibody-based tyrosine kinase inhibitors TKI alone, a combination ofanthracyclines and TKI, and a combination of both anticancer agents and taxanes. Theexclusion criteria were previous anticancer treatments and cardiovascular pathologies suchashypertension, cardiomyopathy, coronary artery disease, life threatening arrhythmias, andongoing cardiovascular treatments. High-sensitive troponin I (TNI), BNP, PROK1 and PROK2were assessed in the plasma and cardiac systolic function (left ventricular ejection fraction,LVEF) were assessed by ECHO atbaseline and at 3, 6, 12 months after the completion of theoncology treatments. 42/142 patients (33%) showed an increase in TNI during or soon afterthe completion of cancer therapy. All patients (except for2) with an elevated TNI received acardioprotective therapy with enalapril. LVEF gradually and significantly decreased frombaseline during the observational period (P&lt;0.001). This was associated with increased levelsof TNI levels during and soon after cancer treatments. BNP levels remained unaltered. PROK1levels (N=63) had slightly, but not significant increased. PROK2 levels significantly increased(N=63) from baseline. This pilot study confirmed the role of TNI in predicting chemotherapy-mediated cardiotoxicity, and identified for the first time PROK2 as potential biomarker thatmay help to identify patients more prone to develop cardiotoxicity.

Therapy-Related Acute Myeloid Leukemia (t-AML) and the Advantage of Intensive Chemotherapy: Real-Life Analysis from Two Regional French Centers

Rational: Patients with t-AML are those previously treated for primary malignancy and are categorized with poor prognosis. t-AML treatment options include intensive chemotherapy (IC), hypomethylating agents (HMA) or low dose cytarabine (LDC). However, survival remains poor and allogeneic hematopoietic cell transplantation (Allo-HCT) could lead to better outcomes. The aim of this analysis is to assess the outcome of all consecutive t-AML pts from two regional centers in France, based on treatment intensity, and to identify prognostic factors.Patients and Methods: between January 2006 and December 2019, 112 adult pts diagnosed with t-AML occurring after treatment of solid tumors (ST; n=72), hematologic malignancies (HM; n=34) or autoimmune diseases (AID; n=6). Pts received chemotherapy and/or radiotherapy or high dose chemotherapy followed by autologous hematopoietic cell transplantation (Auto-HCT) in some. All eligible t-AML pts received intensive chemotherapy (IC, n=55) with the combination of anthracycline and cytarabine in 48 pts and CPX-351 in 7 pts. Unfit pts received non-IC (9 LDC, 24 HMA). The third study group (24 pts) received best supportive care (BSC). Fifteen pts underwent HSCT in first CR.Statistical analysis: We performed a descriptive analysis of the baseline characteristics and each treatment group was compared with a Kruskal-Wallis test and a Pearson's Chi-square test. Survival curves (Kaplan-Meier method) were compared with a log-rank test. Univariate and multivariate analyses on survival, relapse and NRM were done using Cox regression, Gray test, Fine & Gray regression. The bilateral level of significance was set at 5%. All analyses and graphics were made under the R program (v3.5.1). A pair-matched control analysis with de novo AML was performed only on pts who received IC matched for age, cytogenetics and ELN 2010 classification.Results: A total of 112 t-AML pts were identified, 56 were males (50%) with a median age of 68 yrs (19-87) at t-AML diagnosis. Before t-AML, 72 pts had ST (64.5%), 34 HM (30.5%) and 6 AID (5%). Forty-six pts (41%) received chemotherapy alone for their primary cancer, 17 (15%) radiotherapy alone, 49 (44%) radio chemotherapy, 17 (15%) auto-HCT and 6 (5%) long-term methotrexate for AID. Median interval from treatment of previous ST or HM to t-AML diagnosis was 4.7 years in ST, 6.6 years in HM and 21 years in AID (p=0.03). At t-AML diagnosis, 42% of pts presented an unfavorable karyotype and 44% an unfavorable ELN 2010 classification. Regarding molecular alterations, FLT3-ITD, FLT3-TKD, NPM1 and IDH1/2 mutations were observed in 6.9, 2.3, 11.5 and 2.3% of pts respectively. MECOM1 was overexpressed in 25.5% of cases. Among treated pts (n=88), 43 pts (49%) achieved CR: 4 from 33 (12%) in non-IC pts (3 in HMA and 1 in LDC) and 39 from 55 (71%) in IC pts. Fifteen pts (17%) underwent Allo-HCT with a median interval between AML diagnosis and Allo-HCT of 4.7 mo (2.6-17.5). The best response after transplantation was CR in 10 pts; at the last follow up, 4 pts are alive (3 in CR and 1 in relapse) and 11 died (5 from relapse, 5 from TRM causes and 1 from another subsequent malignancy). Overall, with a median follow up of 5.5 mo (0-144), the median OS and DFS were 9 mo (5.9-13.5) and 6.3 mo (5.3-10.3) respectively (Figure). There was a significant difference between the 3 treatment groups concerning OS (p<0.001) and DFS (p<0.001) with a significant difference in OS between IC and non-IC groups (p=0.02). In the 88 treated t-AML pts, with a median follow up of 8.2 mo (0.3-144), the median OS was 13.5 mo (10.3-19.6) and the median DFS was 8.2 mo (7-13.7). Multivariate analysis for total and treated populations showed no impact of all variables related to previous malignancies except for auto-HCT pre-t-AML (significant negative impact on OS, DFS, NRM), WBC at t-AML diagnosis (negative impact on OS, DFS) and chemotherapy (positive in total population on OS, DFS, NRM and negative impact of IC on OS and NRM in treated pts) . In IC treated pts, we showed, in a pair-matched analysis with de novo AML, no difference in term of OS and DFS due to a significant higher CI of NRM (p=0.045) at 24 mo (40% in t-AML versus 27.4% for de novo AML) and a lower CI of relapse (NS) at 24 mo (33% in t-AML versus 47.6% for de novo AML).Conclusion: The prognosis of t-AML remains poor and our study showed the advantage of using intensive chemotherapy whenever possible and, in comparison with de-novo AML, a higher NRM and a lower incidence relapse. [Display omitted] DisclosuresNicolini: Sun Pharma Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kartos Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Research Funding; Incyte Biosciences: Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau; BMS: Honoraria.

Low Intensity Alternative Induction Therapy for Acute Myeloid Leukemia (AML). Real World Experience from Tawam Hospital, United Arab Emirates

Introduction:AML is a heterogenous group of hematological neoplasms with morphological, cytogenetic and molecular abnormalities resulting in maturation arrest of myeloid cell lines. This translates into clinical symptoms and signs resulting from neutropenia, anemia and thrombocytopenia.Although the knowledge of the underlying biology and molecular abnormalities has evolved tremendously, this has not been accompanied as quickly by translational changes in the early management of AML patients. The intensive induction therapy (combination of anthracycline and cytarabine) for young patients with good performance status has remained static since the first description in 1973 (Yates et al, Cancer Chemother Rep. 1973; 57(4):485-8). Older adults and patients with comorbidities had inferior treatment choices limited to hypomethylating (HMA) agents.The activity of Venetoclax R (Ven) with either HMA or Low dose Cytarabine (LDAC) has improved the outcome of patients who are not candidates for intensive induction therapy. In this report we describe our experience with HMA alone or the combination of HMA and Ven in patients not fit for intensive induction therapy in a real-world setting.Method:We conducted a retrospective chart review of AML patients diagnosed between January 2020 and July 2021. Data collected included patient demographics, karyotype, treatment and response to treatment. Older adults were defined as patients greater than 60 years of age. Patients with comorbidities (renal failure, active cardiac, pulmonary and hepatic disease) active opportunistic infections and poor performance status (ECOG >2) were also deemed not suitable for intensive induction therapy.Results:Alternative induction was given with HMA (5 Azacitidine) alone or in combination with Ven. HMA dose (75mg/m 2 was calculated over a period of 7 days and given during workdays of the week. Ven was given 100 mg (with CYP3A4 inhibitor) - 400 mg per day for 21 days. Patients were evaluated for treatment response after 2 - 4 cycles.Between January 2019 and June 2021, 66 patients were diagnosed with AML. The median age was 45 years (range 16-95years). Older adults (>60 years of age) have increased from < 10 % to 28 % (n=19) in the current cohort (Alam A et al Blood 2014; 124 (21).Treatment was as follows: Intensive induction n= 29, alternative induction n=19 and no therapy n=18 (refused treatment, age and poor performance status).The median age of patients given alternative induction was 55 years (range 26-80 years). Karyotype analysis showed good risk n=3, intermediate risk n= 9 poor risk n=3, metaphase failure n=4.Alternative induction reasons included age (n=9), co-morbidities (n=10) (Obesity, respiratory failure, cardiomyopathy, pulmonary embolism, renal failure, acute hepatitis, active infection (mucormycosis) and 2ndry AML).The response to HMA and Ven consisted of CR 60 % (9/15) with 4 patients ineligible for evaluation (2 early death (day + 3 and day + 8), the other 2 < 28 days post induction). The progression free survival is 149 days (range 41-517 days). 3 patients have relapsed after achieving complete remission. The median overall survival (OS) for the cohort is 120 days (range 3 to 517 days) while the median OS for non-responders is 103 days (range 3 to 375 days).Conclusion:The combination of HMA and Ven is an effective treatment modality in newly diagnosed patients with AML who are not eligible for intensive induction. The response to treatment has improved from < 10 % (HMA alone) to 60 % with HMA + Ven in an older cohort or those with comorbidities.The treatment is given in outpatient setting with increased patient satisfaction and minimal toxicities. However, this is complicated by increasing issues with access due to insurance coverage and co pay for Ven.Standardization of HMA and Ven with or without CYP3A4 inhibitors may improve the CR rates. Consolidation strategies in younger patients (especially good risk disease) who are other wise ineligible for intensive induction may improve progression free survival. DisclosuresMcCarthy: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Juno: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Magenta Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees.

MIDOSTAURIN ADDED TO CYTOSINE ARABINOSIDE PLUS IDARUBICIN (“7+3”) IN NEWLY DIAGNOSED FLT3-MUTATED ACUTE MYELOID LEUKEMIA

The combination of an anthracycline and cytosine arabinoside has been the standard induction therapy for acute myeloid leukemia (AML) for more than four decades. Fetal liver tyrosine kinase 3 (FLT3) mutations are among the most frequently found mutations in newly diagnosed AML. According to the results of RATIFY trial, midostaurin was approved for use together with intensive chemotherapy (cytarabine plus daunorubicin). Recently, idarubicin has been more frequently favored over daunorubicin. Report the outcome of patients with AML and FLT3 mutated treated with a combination of cytosine arabinoside plus anthracycline (“7+3”regimen) and midostaurin. Herein, we retrospectively analyzed the treatment outcome of three patients with newly diagnosed AML and confirmed FLT3-ITD were eligible. The treatment consisted induction with “7+3”regimen and midostaurin (administered at a dose of 50 mg orally twice daily on days 8 through 21). All were male with age between 21 and 38 years old. A normal karyotype was found in all cases. Patients received cytarabine, idarubicin and midostaurin for induction and all experienced febrile neutropenia and two necessitated preemptive liposomal amphotericin B. One patient developed neutropenic enterocolitis. A second course of induction chemotherapy was administered to 2 patients. Relapse was observed in 1 patient (after Allo-HCT). One patient died after allo-HCT due to severe acute GVHD and one patient is alive in CR1. We showed that young patients, who had AML and a FLT3-ITD mutation, can be treated with the combination of cytarabine, idarubicin and midostaurin. The RATIFY study (Stone et al., 2017) and the German-Austrian AML Study Group (Schlenk et al., 2019) used daunorubicin 60 mg/m2 for induction, in combination with cytarabine and midostaurin. The complete remission rates in these trials were 59.8% (CR – Ratify) and 77.9% (CR+Cri - German-Austrian trial). In contrast with these two studies, idarubicin was used for induction in 53.5% of cases and was favored over daunorubicin in a more recent trial (Sierra et al. 2020). Of note, the results of FLT3 are necessary before the day 8 of induction. Hence, some patients may have already received the all three planned doses of anthracycline (idarubicin) before the information on results of FLT3 mutation. The recent approvals of new drugs for treating AML will modify the treatment algorithm and our data indicate that the use of idarubicin in combination with cytarabine and midostaurin is feasible in young patients with FLT3-mutated AML.

Evaluation of the changes in Tei-index (myocardial performance index) in Doppler echocardiography before and after treating with anthracycline combinations in children with malignancy

Background: Cardiomyopathy usually causes a cardiac dysfunction resistant to treatment due to anthracycline. This study aimed to evaluate the changes in Tei-Index (myocardial performance index) in patients with malignancies treated with anthracycline. Material and Methods: This case-control study was done on 15 children who were treated with low-dose anthracycline (1-199mg/kg) called group A and 15 children who were treated with high dose (&gt;200mg/kg) anthracycline called group B after acquiring consent from their parents. Children with no abnormality in Echo-Doppler results were included in this study. The patients’ age range between 1- 17 years with a mean age of 6.57 years. Another group of healthy children were assigned to group C as a control group who had not received chemotherapy. The first echo was performed right before the treatment and the second one, two weeks after completing chemotherapy. Data were analyzed by the SPSS statistical software. Results: Changes in mean Tei-index in group A were 0.36 ± 0.04 before treatment and 0.43 ± 0.11 after treatment. Changes in mean Tei-index in group B were 0.37 ± 0.04 before treatment and 0.45 ± 0.06 after treatment. There was no significant difference between the two groups using the independent T-test. (p-value= 0.57). No significant correlation between the changes in mean ejection fraction (EF) and treatment was found in the three groups (p-value=0.45). Conclusion: This study showed a change in the Tei-index (MPI) in patients receiving anthracycline; regardless of the dosage, they got in their regimen. Given the use of anthracycline, any abnormal cardiac finding can alert the physicians to the possibility of cardiomyopathy, hence scheduling routine follow-ups are necessary.

181P Pegylated liposomal doxorubicin (PLD) combined with docetaxel and trastuzumab in neoadjuvant treatment for HER2-positive breast cancer: A multicenter, randomized, phase II, open-label trial

Trastuzumab based chemotherapy is the standard regimen for HER2+ breast cancer (BC) in neoadjuvant trerapy. Combination of trastuzumab and anthracycline is generally avoided clinically due to the cardiotoxicity of the two drugs. PLD is less cardiotoxic compared with traditional anthracyclines. Here, we conducted this prospective study to evaluate the efficacy and safety of PLD (A) + docetaxel (T) + trastuzumab (H) in neoadjuvant treatment for HER2+ BC.

An Exploration of Heart Failure Risk in Breast Cancer Patients Receiving Anthracyclines with or without Trastuzumab in Thailand: A Retrospective Study.

Anthracycline-based regimens with or without anti-human epidermal growth factor receptor (HER) 2 agents such as trastuzumab are effective in breast cancer treatment. Nevertheless, heart failure (HF) has become a significant side effect of these regimens. This study aimed to investigate the incidence and factors associated with HF in breast cancer patients treated with anthracyclines with or without trastuzumab. A retrospective cohort study was performed in patients with breast cancer who were treated with anthracyclines with or without trastuzumab between 1 January 2014 and 31 December 2018. The primary outcome was the incidence of HF. The secondary outcome was the risk factors associated with HF by using the univariable and multivariable cox-proportional hazard model. A total of 475 breast cancer patients were enrolled with a median follow-up time of 2.88 years (interquartile range (IQR), 1.59–3.93). The incidence of HF was 3.2%, corresponding to an incidence rate of 11.1 per 1000 person-years. The increased risk of HF was seen in patients receiving a combination of anthracycline and trastuzumab therapy, patients treated with radiotherapy or palliative-intent chemotherapy, and baseline left ventricular ejection fraction <65%, respectively. There were no statistically significant differences in other risk factors for HF, such as age, cardiovascular comorbidities, and cumulative doxorubicin dose. In conclusion, the incidence of HF was consistently high in patients receiving combination anthracyclines trastuzumab regimens. A reduced baseline left ventricular ejection fraction, radiotherapy, and palliative-intent chemotherapy were associated with an increased risk of HF. Intensive cardiac monitoring in breast cancer patients with an increased risk of HF should be advised to prevent undesired cardiac outcomes.