Chemotherapy-related Toxicity Research Articles

Clinical and genetic predictions of early-onset cardiac toxicity in adjuvant chemotherapy for breast cancer.

Aim: To identify clinical and genetic variants associated with early-onset cardiac toxicity with a low cumulative dose of chemotherapy drugs in breast cancer. Methods: A total of 388 recruited patients completed routine blood, liver and kidney function, D-dimer, troponin T, brain natriuretic peptide (BNP) or N-terminal prohormone of BNP, ECG and echocardiography tests before and after adjuvant chemotherapy. 25 single-nucleotide polymorphisms (SNPs) were tested. Results: A total of 277 adjuvant chemotherapy-related cardiac toxicity events were recorded in 180 patients (46.4%). Anthracycline-containing chemotherapy (odds ratio: 1.848; 95% CI: 1.135-3.008; p=0.014) and the SLC28A3 rs885004 GG genotype (odds ratio: 2.034; 95% CI: 1.189-3.479; p=0.010) were found to be associated with overall cardiac toxicity. The final predictive risk model consisting of clinical risk factors and SNPs was better than SNP alone (p=0.006) or clinical risk factor alone (p=0.065). Conclusion: On the basis of clinical factors, a prediction model with genetic susceptibility factors can better predict early-onset cardiac toxicity.

Biopsychosocial assessment of dental neglect in a pediatric cancer patient from the perspectives of developmental trauma disorder

A nine-year-old male developed severe opportunistic apical periodontitis in maxillary permanent first molars following myeloablative anticancer therapy for T cell lymphoblastic lymphoma . His developmental trajectory was characterized by limited dental care adherence, maltreatment and developmental trauma disorder, suggesting that a complex interplay between premorbid dental neglect and chemotherapy-related toxicity had exacerbated the progression of the dental infection . We would like to stress the importance of biopsychosocial assessment for severe periodontal infection to provide individualized supportive intervention, thereby improving the quality of life of patients with poor oral health literacy.

313 Biobehavioral predictors of dose-limiting toxicities of cancer therapy: Identification of areas for preventative intervention

OBJECTIVES/GOALS: This presentation outlines a novel approach to evaluating multiple risk factors for the development of dose-limiting toxicities in adolescents and young adults with cancer. This is the first to evaluate biobehavioral predictors originally identified in animal models in clinical human studies. METHODS/STUDY POPULATION: Adolescents and young adults (AYAs) have seen the slowest improvements in cancer survival and have some of the highest rates of dose-limiting mucositis (mouth sores). AYAs receiving chemotherapy with a significant chance of dose-limiting mucositis were recruited for a prospective study. Baseline perceived psychologic stress levels and inflammatory markers were collected at the time of chemotherapy administration and participants completed a daily assessment of mucositis for 14 days following chemotherapy. Logistic regression will be used to evaluate stress and inflammation as predictors of mucositis and Sobels testing will evaluate the role of inflammation as mediators in this relationship. RESULTS/ANTICIPATED RESULTS: We anticipate that, as seen in animal models, stress and inflammation will predict mucositis development. First, we hypothesize that stress levels and inflammatory markers will have a direct correlation and that the level of inflammation at the time of chemotherapy administration will predict mucositis incidence and severity. Through mediation testing, we hypothesize that inflammatory markers will explain a significant amount of the variance in mucositis also explained by stress, identifying inflammation as a mediator in this relationship. In all, we expect that stress and inflammation both predict mucositis development and will be identified as important modifiable factors that can be altered to reduce the risk of toxicity development during cancer therapy. DISCUSSION/SIGNIFICANCE: This work intends to evaluate predictors of chemotherapy-related toxicity development in AYAs with cancer and identify areas of intervention that will reduce toxicity profiles and close the gap in cancer survival for AYAs. Findings are applicable to biomedical, nursing, and psychosocial professionals and will inform future, large clinical studies

Prospective comparison of the value of CARG, G8, and VES-13 toxicity tools in predicting chemotherapy-related toxicity in older Turkish patients with cancer

BackgroundIn older patients with cancer, it is very important to choose the appropriate treatment because they are at high risk for chemotherapy toxicity. Our study investigated characteristics of Cancer and Aging Research Group (CARG), Geriatric 8 (G8), and Vulnerable Elders Survey (VES-13) screening tools for predicting chemotherapy-related toxicity (CRT) prospectively. Materials and methods208 patients aged ≥65 years old for whom chemotherapy was planned to treat non-haematological cancer between February 2021–September 2021 were included in the study. The CARG, G8, and VES-13 toxicity tools were completed by the oncologist through face-to-face interviews before starting the first chemotherapy treatment. CRTs during chemotherapy were evaluated according to the National Cancer Institute's Common Terminology Criteria for Adverse Events v4.03. Logistic regression models, the area under the receiver operating characteristic curve (ROC-AUC), and correlation analyses were used for comparing questionnaires. ResultsMedian age was 70.4 (range 65–86) years. Of the participants, 103 (49.5%) participants experienced grade 3–5 CRT (32.2% haematological, 28.4% non-haematological) during chemotherapy. ROC-AUC value of CARG was determined as 0.827 (95% CI [confidence interval]: 0.77–0.88, p < 0.001), it was determined as 0.744 (95% CI: 0.68–0.81, p < 0.001) for G8 and 0.726 (95% CI: 0.66–0.80, p < 0.001) for VES-13. In the univariate regression analysis, CARG (OR [odds ratio] = 13.57, 95% CI: 6.0–30.72, p < 0.001), G8 (OR = 3.19, 95% CI: 1.62–6.29, p = 0.001), and VES-13 (OR = 9.5, 95% CI: 5.01–17.89, p < 0.001) were found to be predictive for CRT. The multivariate analysis (included stage, Eastern Cooperative Oncology Group [ECOG] performance status, presence of comorbid disease, platinum-based treatment regimen, taxane-based treatment regimen, CARG, VES-13, G8) showed that CARG (OR = 12.08, 95% CI: 5.11–28.56, p < 0.001), VES-13 (OR = 10.06, 95% CI: 4.92–22.98, p < 0.001), and G8 (OR = 2.20, 95% CI: 1.04–4.69, p = 0.040) screening tools were strong predictors for CRT. The CARG and VES-13 questionnaires were predictive for reducing the initial treatment dose (p = 0.004, p = 0.004, respectively), interruption of treatment (p < 0.001, p < 0.001, respectively), discontinuing treatment (p = 0.002, p = 0.002, respectively), and unexpected hospitalisation (p = 0.012, p = 0.003, respectively). ConclusionsWe showed that all three CARG, G8, and VES-13 questionnaires are helpful tools in the decision-making process for ideal chemotherapy to predict severe CRT; however, CARG and VES-13 questionnaires appear more useful in daily oncology practice than the G8 questionnaire.

Energy expenditure profiles and the risk of early limiting toxicity in older patients with cancer: The ELCAPA-25 prospective cohort survey

Predicting the risk of early limiting toxicity (ELT) is major challenge for the clinician seeking an effective, safe treatment for older patients with cancer. The Cancer and Aging Research Group (CARG) and CRASH (Chemotherapy Risk Assessment Scale for High-Age Patients) toxicity scores were designed to predict chemotherapy-related toxicity. Elevated resting energy expenditure (REE) may predispose to cachexia and increase ELT and mortality in older patients with cancer. The primary objective was to assess the association between elevated REE and ELT in older patients with cancer. The secondary objectives were to assess the discriminant ability of a predictive model including REE (relative to the CARG and CRASH scores) and the prognostic value of elevated REE. We assessed patients aged 70 or over included in the prospective ELCAPA cohort between 2014 and 2018. The inclusion criteria were a solid tumour, a measurement of REE at baseline (mREE, by indirect calorimetry), and a geriatric assessment prior to cancer treatment in a teaching hospital (Paris, France). The mREE was compared with the predicted REE (pREE), as defined by the Harris-Benedict equation. Depending on the mREE/pREE ratio, study participants were classified as hypermetabolic, hypometabolic or normometabolic. The primary endpoint was 3-month ELT, defined as any unplanned hospitalization or any event leading to dose reduction, a treatment delay of more than 7 days, or treatment discontinuation within 3 months of initiation. The secondary endpoint was the 3-month mortality rate. A total of 179 patients were included. The median age was 80 [interquartile range: 76-84] years, 37% of the patients were female, 81.8% had metastatic disease, 67.6% received chemotherapy, 20.7% received hormone therapy, and 11.7% received targeted therapies. According to the mREE/pREE ratio, 85 patients (47%) were hypermetabolic, 63 (35%) were normometabolic, and 31 (18%) were hypometabolic. Sixty patients (33.5%; 95% confidence interval (CI): 26.7-40.9) experienced ELT. The discriminant ability (as assessed by the C-index) of a multivariate model including REE and adjustment factors was 0.82 [95%CI: 0.73-0.91]. In comparison, the discriminant ability of the CARG and CRASH models was 0.57 [0.45-0.68] and 0.51 [0.40-0.62], respectively. In our model, hypermetabolism was an independent risk factor for ELT (adjusted odds ratio=2.44; 95%CI: 1.02-5.80). Other risk factors were the cancer type and stage, the treatment protocol, a clinical diagnosis of depression, the presence of grade 3 or 4 comorbidities, and the serum lactate dehydrogenase level. Hypermetabolism status is an independent predictor of ELT in older patients with cancer, relative to normometabolic status. Baseline REE measurement might improve the ELT risk assessment and decision-making process.

Outcomes of Ewing sarcoma in adults over 40 years of age from a low-middle income country.

IntroductionThe data on outcomes and toxicity in adult Ewing sarcoma (ES) patients, particularly those aged ≥40 years, is exceedingly scarce around the world, particularly in low- and middle-income countries (LMICs) and mandates research.MethodsThe study involved histologically ascertained ES patients aged ≥40 years who registered at our institute from 2013 to 2018. Prospectively collected data were analysed for overall survival (OS), event-free survival (EFS) and chemotherapy-related toxicities.ResultsThere were 66 patients, of which 34 were non-metastatic, and 32 were denovo metastatic, recurrent or had doubtful metastasis. At presentation, median age was 46 years, and 42 (63.6%) had extra-skeletal primary and 24 (36.3%) had extremity tumours. Curative treatment was offered to 40 (60.6%) patients. Significant grade 3/4 toxicities in non-metastatic and metastatic cohort, respectively, were febrile neutropenia (61.3%, 37.5%), anaemia (58.1%, 37.5%), thrombocytopenia (45.2%, 25.0%), peripheral neuropathy (25.8%, 12.5%) and dyselectrolytemia (25.8%, 6.25%). Chemotherapy-related toxicity led to death in three patients in the metastatic cohort, versus none in the non-metastatic patients. The 5 year EFS and OS for non-metastatic cohort were 53.8% and 67.8%, while the same for metastatic cohort were 20.7% and 27.5%, respectively. On multivariate analysis, Eastern Cooperative Oncology Group-performance status >2 and metastasis at presentation predicted poorer EFS and OS. Additionally, raised lactate dehydrogenase, larger tumours (>8 cm) and palliative intent treatment predicted worse EFS, while extra-skeletal primary and female gender were indicators of worse OS.ConclusionsOlder adult ES patients benefit from aggressive multimodality treatment even in LMIC infrastructure. However, careful patient selection, close monitoring and pertinent dose modifications is imperative due to higher propensity for potential toxicities.

Sporoderm-Broken Spores of Ganoderma lucidum Sensitizes Ovarian Cancer to Cisplatin by ROS/ERK Signaling and Attenuates Chemotherapy-Related Toxicity.

Although platinum-based chemotherapeutics such as cisplatin are the cornerstone of treatment for ovarian cancer, their clinical application is profoundly limited due to chemoresistance and severe adverse effects. Sporoderm-broken spores of Ganoderma lucidum (SBSGL) have been reported to possess antitumor effects. However, the function and mechanism of SBSGL and its essential composition, ganoderic acid D (GAD), in the cisplatin therapy on ovarian cancer have yet to be investigated. Here, we investigated the combined effect of SBSGL and cisplatin in an ovarian tumor xenograft model. The results showed that combining SBSGL with cisplatin reduced tumor growth and ameliorated cisplatin-induced intestinal injury and myelosuppression. We also confirmed that GAD could enhance the therapeutic effect of cisplatin in SKOV3 and cisplatin-resistant SKOV3/DDP cells by increasing the intracellular reactive oxygen species (ROS). Mechanistically, we proved that ROS-mediated ERK signaling inhibition played an important role in the chemo-sensitization effect of GAD on cisplatin in ovarian cancer. Taken together, combining SBSGL with cisplatin provides a novel therapeutic strategy against ovarian cancer.

The PRIMETEST trial: Prospective phase II trial of primary retroperitoneal lymph node dissection (RPLND) in stage II A/B patients with seminoma.

420 Background: Primary retroperitoneal lymph node dissection (RPLND) in patients (pts) with stage II A/B seminoma without adjuvant local or systemic treatment is an experimental treatment to avoid radio- or chemotherapy–related toxicity. The prospective PRIMETEST trial (NCT 2015053664) evaluates recurrence-free (RFS) and overall survival (OS) as well as surgical safety of patients with clinical stage II A/B seminoma undergoing RPLND without adjuvant treatment. Interim results had been presented at ASCO GU 2019. Methods: Primary endpoint of the study is PFS after a median follow-up of 36 months. We performed unilateral open or robotic RPLND in pts with unilateral retroperitoneal lymphnode metastases &lt; 5 cm (stage IIA and IIB) with human chorionic gonadotropin (HCG) &lt; 5 mU/ml. Pts were included with either stage IIA/B at initial diagnosis, at time of recurrence under active surveillance, or after adjuvant carboplatin in clinical stage I. The phase II trial was designed to exclude the upper limit of a 95% confidence interval at 30% recurrences. Results: Trial accrual was completed in a single center from May 2016 to June 2021 with 33 consecutive pts. 13 and 20 pts presented with stage IIA and IIB, respectively. 9 pts had initial stage II, 19 pts presented with recurrence during active surveillance, 5 pts had adjuvant carboplatin. At time of RPLND median HCG was 0.1 mU/ml (range 0 – 2.2 mU/ml). Open and robotic RPLND was performed in 14 (42 %) and 19 (58 %) pts, respectively. One patient had to be converted from robotic to open surgery. Median size of metastasis on histological report was 28 mm (range 11 – 69 mm) with a median OR time of 169 min (range 101 – 351 min). Median estimated blood loss was 50 ml (range 0 – 400 ml). Higher grade complications (Clavien Dindo ≥ III) occurred in 3/ 33 pts (9 %; 2 x pulmonary embolism, 1 x ureteral stricture requiring ileal ureter substitute). Of 33 pts, 2 pts withdrew their consent during follow-up. As of September 1, 2021, the median follow-up is 26 months (range 2 – 56 months). Up to now we observed 10 recurrences (31 %). RFS is 69 % with a median time from RPLND to relapse of 6 months (range 3 – 36 months). The recurrences included infield recurrences in 3/ 10 cases. 5 and 5 recurrences were observed in stage II A and B pts, respectively. Analysis of predictive factors showed vascular invasion present in 5/ 10 recurrences. Half of pts with relapse were treated with robotic RPLND and open RPLND, respectively. All pts with relapse underwent standard chemotherapy and are currently without evidence of disease. Conclusions: Open and minimally invasive surgical resection of small volume, unilateral seminoma metastasis is feasible with acceptable toxicity. Current recurrence-free survival rates suggest this approach as an option to avoid standard treatment (chemotherapy, radiotherapy) in selected patients. Clinical trial information: NCT2015053664.

Survival in total preoperative verus perioperative chemotherapy for patients with metastatic high-grade appendiceal adenocarcinoma undergoing CRS/HIPEC.

90 Background: Due to the relative infrequency of high grade appendiceal adenocarcinoma with peritoneal metastases, there is limited data to guide treatment strategies. Current practices for this disease are largely extrapolated from colon cancer patients with peritoneal metastases, who typically undergo six months of systemic chemotherapy in conjunction with cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). The optimal timing of chemotherapy in relation to CRS/HIPEC remains unknown. In this study, we compare the efficacy of peri-operative chemotherapy to pre-operative chemotherapy alone. Methods: This is a retrospective review of patients who underwent CRS/HIPEC for high grade appendiceal cancers from a tertiary referral center from 2014-2020. Outcomes were compared between patients who underwent planned 6 months of chemotherapy followed by CRS/HIPEC (pre-operative group) versus planned 3 months of chemotherapy both pre- and post-operatively (peri-operative group). Results: 85 patients were treated for metastatic high-grade appendiceal cancers during the study period, of whom24 were eligible for inclusion. Of those included, 16 were in the peri-operative group and 8 in the pre-operative group. Most patients were white (75%), non-Hispanic (96%) and female (54%). Patients in the pre-operative group tended to be older (65 vs. 56 years, p = 0.02). For patients with specified histologic grading, poorly differentiated tumors were common (50%). Signet ring cell histology (42%) and mucinous features (67%) were frequent as well. Median overall survival was similar between the pre-operative and peri-operative groups (32.3 vs. 31.6 months, p = 0.97), although patients undergoing peri-operative treatment received fewer total cycles of chemotherapy on average (14.1 vs. 9.5 cycles, p &lt; 0.01). Half of the patients in the peri-operative group (8/16) did not complete their chemotherapy regimen, with 75% discontinuing therapy due to chemotherapy-related toxicities. Within the peri-operative group, a non-significant decrease in median survival was observed for those who did not complete chemotherapy (27.8 vs &gt; 53.6 months, p = 0.22). Conclusions: Peri-operative and total pre-operative chemotherapy strategies are associated with similar survival in patients with high grade appendiceal cancers undergoing CRS/HIPEC. Peri-operative administration may be limited by chemotherapy-related toxicities.

Managing Side Effects of Cytotoxic Chemotherapy in Patients With High Grade Gliomas.

Cytotoxic chemotherapy has been a mainstay of cancer treatment since the 1940s. In the recent era of emergent targeted therapies and immunotherapies, many cytotoxic chemotherapy agents including temozolomide are still one of main weapons for the treatment of high grade gliomas. However, cytotoxic chemotherapy often causes side effects. Proper management of chemotherapy-induced toxicity can have a significant impact on a patient’s quality of life and clinical outcomes. Many supportive care advances have transformed our ability to give full doses of chemotherapy, which is important for achieving their full efficacy. Prevention and treatment strategies have been developed for many chemotherapy-related toxicities. This review focused on managing gastrointestinal toxicity, chemotherapy-induced nausea and vomiting, and hematologic toxicities such as thrombocytopenia during cytotoxic chemotherapy treatment in high-grade brain tumors.

Cardiac complications of cancer therapies.

The quest of defeating cancer and improving prognosis in survivors has generated remarkable strides forward in research and have advanced the development of new antineoplastic therapies. These achievements, combined with rapid screening and early detection, have considerably extended the life expectancy of patients surviving multiple types of malignancies. Consequently, chemotherapy-related toxicity in several organ systems, especially the cardiovascular system, has surfaced as one of the leading causes of morbidity and mortality among cancer survivors. Recent evidence classifies chemotherapy-induced cardiotoxicity as the second-leading cause of morbidity and mortality, closely comparing with secondary cancer malignancies. While a certain degree of cardiotoxicity has been reported to accompany most chemotherapies, including anthracyclines, anti-metabolites, and alkylating agents, even the latest targeted cancer therapies such as immune checkpoint inhibitors and tyrosine kinase inhibitors have been associated with acute and chronic cardiac sequelae. In this chapter, we focus on describing the principal mechanism(s) for each class of chemotherapeutic agents that lead to cardiotoxicity and the innovative translational research approaches that are currently being explored to prevent or treat cancer therapy-induced cardiotoxicity and related cardiac complications.

Adjuvant Hepatic Arterial Infusion Pump Chemotherapy after Resection of Colorectal Liver Metastases; Surgical Complications, Toxicity, and Survival in a Prospective Study in the Netherlands

Background: Hepatic arterial infusion pump (HAIP) chemotherapy remains a promising treatment for patients with colorectal liver metastases (CRLM). The aim of this study was to investigate surgical complications, toxicity, and survival outcomes of patients who received adjuvant HAIP chemotherapy for CRLM. Methods: A single arm phase II study was performed in four centers. Patients with resectable CRLM without extrahepatic disease were eligible. An infusion pump was implanted after complete local treatment of CRLM followed by a maximum of 6 cycles of HAIP chemotherapy with floxuridine. Outcomes were 90 days pump-related major complications (Clavien Dindo grade ≥III), intra-arterial chemotherapy-related severe toxicity (CTCAE grade ≥III), and overall survival (OS). Results: Twenty-nine patients were included. Four patients (11.8%) had pump-related major complications, all requiring pump replacement; one for pump dysfunction, two for pump dislocation, and one for pump pocket infection. All patients started with HAIP chemotherapy. The median number of cycles was 5 (IQR 4-6), and the median cumulative dosage was 72% (IQR 55-85%). Ten patients (34%) required intra-arterial steroid treatment for biliary toxicity. Seven patients (24%) developed severe toxicity; five patients required stent-placement (three for biliary sclerosis/hyperbilirubinemia, two for persistent increase in liver enzymes without hyperbilirubinemia), one patient developed hepatic artery thrombosis, one patient required endoscopic extraction of an intrahepatic gallstone. Two-year OS was 93% (95%CI: 85-100%). Conclusion: Adjuvant HAIP chemotherapy for CRLM may result in major complications and severe toxicity; 1 in 7 patients required pump replacement and 1 in 6 patients required stent-placement for biliary sclerosis. Two-year OS was 93%.Tabled 1Patient and surgical characteristicsMedian [IQR] / n (%)Age at resection (years)57 [50-64]Clinical Risk Score (Fong score)2 [1-3]Preoperative systemic CTx9 (30)Major hepatectomy6 (21)Synchronous resection with primary CRC3 (10)Open ablation (with or without resection)11 (45)Surgery time (min)247 [204-300]Blood loss (mL)455 [187-762]Postoperative hospital stay (days)8 (6-9) Open table in a new tab

Pharmacogenomics in Cytotoxic Chemotherapy of Cancer.

Pharmacogenetic testing in patients with cancer requiring cytotoxic chemotherapy offers the potential to predict, prevent, and mitigate chemotherapy-related toxicities. While multiple drug-gene pairs have been identified and studied, few drug-gene pairs are currently used routinely in the clinical status. Here we review what is known, theorized, and unknown regarding the use of pharmacogenetic testing in cancer.

Validating an Instrument for Direct Patient Reporting of Distress and Chemotherapy-Related Toxicity among South African Cancer Patients.

Simple SummaryIn the USA and Europe, questionnaires that allow patients to directly report chemotherapy side effects can improve their quality of life and clinical outcomes. No similar tools exist for Africa, so we aimed to design and validate a paper-based tool for use in oncology clinics in South Africa: The Patient Reported Symptoms-South Africa (PRS-SA) survey. The PRS-SA included questions on overall feelings of distress and severity of 11 common chemotherapy side effects. By comparing responses to the PRS-SA to responses to other quality of life questionnaires and to patients’ performance status, we found the PRS-SA to be valid and responsive for measuring all included symptoms. Compared to a standard instrument for measuring depression and anxiety, the PRS-SA’s distress thermometer had 88% sensitivity and 55% specificity for identifying distress. The PRS-SA may be a useful tool for efficiently assessing distress and chemotherapy symptoms in South Africa’s overburdened public oncology clinics.Patient-reported outcome measures (PROM) for monitoring treatment toxicity improve quality of life (QoL) and clinical outcomes. However, no such PROMs exist for sub-Saharan African cancer patients. We aimed to validate the Patient Reported Symptoms-South Africa (PRS-SA) survey, a novel PROM for measuring distress and chemotherapy-related symptoms in South African cancer patients. We enrolled patients at the oncology clinic at Charlotte Maxeke Hospital, Johannesburg. At three separate visits, participants simultaneously completed the PRS-SA survey and several previously validated questionnaires. We constructed a receiver operator characteristics curve for distress levels predicting a Hospital Anxiety and Depression Scale (HADS) score ≥15. We evaluated construct validity for symptom items by comparing severity to the EORTC Core Quality of Life Questionnaire (QLQ-C30) summary score (Pearson correlation tests) and ECOG performance status (Mann–Whitney U tests). We assessed symptom item responsiveness by comparing change in severity to change in QLQ-C30 summary score and comparing standardized mean scores with negative, no, or positive change on the Global Impression of Change (GIC) questionnaire (Jockheere–Terpstra trend test). Overall, 196 participants with solid tumors completed instruments. A distress score of 4 had 82% sensitivity and 55% specificity for clinical depression/anxiety. All symptom items showed construct validity by association with either QLQ-C30 score or performance status (highest p = 0.03). All but cough showed responsiveness to change in QLQ-C30 score (highest p = 0.045). In South African cancer patients, the PRS-SA’s stress scale behaves similarly to the distress thermometer in other populations, and the symptom items demonstrated construct validity and responsiveness. Of note, 46% and 74% of participants who completed the PRS-SA in English or isiZulu, respectively, required assistance reading half or more of the instrument.

An overview of chemotherapy toxicity prediction tools in older adults with cancer: A young international society of geriatric oncology and nursing and allied health initiative

An overview of chemotherapy toxicity prediction tools in older adults with cancer: A young international society of geriatric oncology and nursing and allied health initiative

Pharmacogenetics of induction therapy-related toxicities in childhood acute lymphoblastic leukemia patients treated with UKALL 2003 protocol

Chemotherapy related toxicities have been the major factor limiting the success of acute lymphoblastic leukemia (ALL) induction therapy. Several factors, including the pharmacogenetics of asparaginase and anthracyclines, could contribute to difference in treatment outcome in ALL. We investigated the significance of variations in genes involved in hepatic and cardiac toxicity in acute lymphoblastic leukemia (ALL). Genotyping of SOD2 (rs4880), PNPL3 (rs738409) and ABCC1 (rs4148350), CBR1 (rs9024) and ABCG2 (rs2231142) was performed by Tetra-ARMS PCR-based technique to evaluate the genotype–phenotype correlation. Our results showed only minor allele G of SOD2 rs4880 increase the risk of hepatic toxicity [OR 2.63 (1.42–4.84), P = < 0.05] while minor alleles of other SNPs showed protective impact. However, the genetic contrast analysis showed a recessive form of SOD2 rs4880 [OR 7.82 (3.86–15.85), P = < 0.05] and PNPLA3 I148M [OR 5.82 (3.43–9.87), P = < 0.05] variants whereas dominant genotype of ABCC1 rs4148350 [OR 2.52 (1.55–4.10), P = < 0.05] significantly predisposes hepatotoxicity. Furthermore, heterozygous form of ABCG2 rs2231142 [OR 5.25 (1.84–14.95), P = < 0.05] and recessive genotype of 3′UTR variant CBR1 rs9024 [OR 2.31 (1.31–4.07), P = < 0.05] were strongly associated with cardiotoxicity. The information obtained from these genetic variations could offer biomarkers for individualization of therapeutic intervention in ALL.

HMGN1 expression Predisposes Down Syndrome Patients to Develop P2RY8-CRLF2 acute Lymphoblastic Leukemia

IntroductionChildren with Down Syndrome (DS) frequently develop hematological malignancies including acute lymphoblastic leukemia (ALL), however, the genomic basis for the predisposition to DS-ALL remains unknown. DS-ALL is associated with increased rates of relapse, chemotherapy related toxicity and poor overall survival compared to non-DS patients. The P2RY8-CRLF2 (CRLF2r) gene fusion, the result of deletion of the pseudoautosomal region 1 (PAR1) on the X/Y chromosome (chr), has been identified in 60% of DS-ALL (+21) patients and 30% of iAMP21 (intrachromosomal amplification of chr21) ALL patients compared to only 5-16% of other B-ALL patients. The high mobility group nucleosome binding protein 1, encoded by HMGN1 on chr21 may play a role in DS-ALL leukemogenesis, due to its demethylase activity associated with transcriptional activation.MethodsmRNA seq was performed on the blast cells of 76 ALL patients using the Universal Plus mRNA-seq with NuQuant kit. FusionCatcher, SOAPfuse and JAFFA were used to identify fusions and featureCounts used for mRNA expression of STAR (v2.7.3a) aligned BAM files. CRISPR/Cas9 gRNAs targeting P2RY8 intron 1 or CRLF2 5' UTR created the 320 KB (PAR1) deletion. Cas9/gRNAs were transduced into Jurkat cells ± HMGN1 overexpression, activated with doxycycline and stained with TSLPR (CRLF2/IL-7Rα dimer) for single cell sort and clonal expansion. Phosphorylated proteins were measured by intracellular flow cytometry and SYBR Green RQ-PCR was used for mRNA expression.ResultsSignificantly higher HMGN1 expression was identified in CRLF2r ALL patients, compared to the control (BCR-ABL1+ patients. Fig. 1A; p<0.0001). There was no significant difference in HMGN2 (p=0.7881) or JAK2 (p=0.1171) control genes between groups. Of the CRLF2r ALL patients, 26% harbored +21, and 5% iAMP21, strongly suggesting a relationship between chr21, HMGN1 and the CRLF2r fusion.To further understand the role of HMGN1 in CRLF2r development, HMGN1 was overexpressed (1.5-fold; HMGN1H) in Jurkat Cas9 cells to represent a trisomy level of expression. gRNAs targeting P2RY8 and CRLF2 were activated in cells ± HMGN1H with undirected repair. TSLPR surface and CRLF2 mRNA expression were higher in CRLF2r + HMGN1H cells compared to CRLF2r only cells (Fig. 1B,C; p=0.034 and <0.001 respectively). This suggests higher HMGN1 expression significantly predisposed to PAR1 deletion and formation of CRLF2r fusion after a double stranded DNA break (DSB) versus repair where HMGN1 expression is normal. This is consistent with higher HMGN1 expression observed in patients with CRLF2r. There was also increased gene editing activity in CRLF2r + HMGN1H cells, identified through T7 gene editing assay, compared to CRLF2r only cells.CRLF2r + HMGN1H cells also demonstrated significantly increased pSTAT5 (MFI: 2359 ± 1; Fig. 1D), pAKT (MFI: 2339 ± 6; Fig. 1E) and pERK (MFI: 2478 ± 48; Fig. 1F) compared to CRLF2r only cells (MFI pSTAT5: 1910 ± 10; pAKT: 1727 ± 14; pERK: 1946 ± 6; all p<0.001), consistent with the data observed in CRLF2r patients, and confirming cooperation between CRLF2 and HMGN1. CRLF2r + HMGN1H cells demonstrated reduced H3K27me3 (MFI: 1 ± 0.07) compared to CRLF2r only cells (MFI: 1.6 ± 0.03; p=0.003) and higher expression levels of STAT5 target genes (BCL2, CDKN1,MCL1and MYC).ConclusionThe P2RY8-CRLF2 (CRLF2r) gene fusionis prevalent in DS, +21 and iAMP21 ALL patients. Here, we demonstrate that CRLF2r is associated with high expression of HMGN1 (chr21)in ALL patient cells . Using CRISPR/Cas9 in an in vitro model, we demonstrate that enforced high expression of HMGN1 alters DSB repair mechanism, favoring PAR1 deletion and the subsequent formation of the P2RY8-CRLF2 gene fusion, with attendant higher expression of STAT5 target genes. Understanding the role of HMGN1 in the disproportionate number of DS-ALL patients who are diagnosed with CRLF2r has the potential to lead to novel therapeutic interventions, in this high-risk group of patients where efficacious therapeutic options are currently poor. [Display omitted] DisclosuresYeung: BMS: Honoraria, Research Funding; Amgen: Honoraria; Novartis: Honoraria, Research Funding; Pfizer: Honoraria. White: Novartis: Research Funding; BMS: Honoraria, Research Funding.

Single-Agent Rituximab and Ultra-Low-Dose Adaptive Radiotherapy for the Treatment of Indolent Non-Hodgkin Lymphoma

IntroductionFor indolent non-Hodgkin lymphoma (NHL), there is level 1 evidence (FoRT) demonstrating superior long term local control with 24 Gy radiation treatment (RT) over ultra-low-dose 4 Gy RT (Hoskin et al Lancet 2021). However, it's notable that over 2/3 of those receiving ultra-low-dose RT did achieve durable local control. Further, with RT alone to any dose, the predominant pattern of failure is distal. Thus, the TROG study showed that the addition of systemic therapy (rituximab, cyclophosphamide, vincristine) after RT (30 Gy) significantly improved progression free survival (PFS). However, cytotoxic chemotherapy and higher dose RT can both cause significant, and potentially unnecessary, toxicities. We hypothesize that for indolent NHL, the combination of single-agent rituximab and ultra-low-dose adaptive RT, with repeat treatment as needed, will result in excellent local and systemic disease control with minimal toxicities.MethodsWe conducted an IRB approved, retrospective review of patients with indolent NHL who were treated with both ultra-low-dose RT (2 Gy x 2 or “boom boom”) and single-agent rituximab (4 cycles) either concurrently or within a short interval (median 13 days) at our institution from 2017-2020. 17 treatments [follicular (9), marginal zone (4), mucosal associated lymphoid tissue (3), other (1)] from 15 patients were identified.Treatment sites included pelvis (5), parotid (4), abdomen (4), mediastinum (1), and other (3). The median ECOG performance status was 1 (range: 0-2), the median age was 74 (range: 25-90), and 9/15 patients were male. 7 patients were stage I, 5 stage II, 2 stage III, and 1 stage IV. 3 patients had prior RT with 1 patient having the same spot irradiated twice, and the other 2 both having RT at 2 distal sites. Only 1 patient had prior systemic treatment (ibrutinib) for their low-grade lymphoma.The primary outcomes were rates of complete response (CR), partial response (PR), overall response (defined as CR or PR), stable disease (SD), or progressive disease (PD). Secondary outcomes included PFS, overall survival (OS), symptom relief, and acute and long-term toxicities. Radiographic studies (predominantly PET/CT) were used to determine treatment response and disease control.ResultsIn our cohort with median follow up of 16 months, the PFS and OS at one year was 93% (14/15)and 100% (15/15), respectively. The overall response rate was 94% (16/17), of which 13 sites (76%) achieved CR, 3 (18%) had PR, and 1 (6%) had SD. Of those with PR, 1 had residual disease in the field of RT, 1 outside the field of RT, and 1 both in and out of the field of RT. For the first 2, repeat ultra-low-dose RT was given to sites of PR and both achieved CR. The remaining patient with both in and out of field PR was managed with active surveillance with SD on last follow up.2 patients experienced acute toxicities, 1 with mild diarrhea from pre-sacral RT that resolved within days, and 1 with dysgeusia from parotid RT that resolved within 2 months. Only 1 patient noted long-term toxicity of dry mouth with about 50% reduction in saliva after left parotid gland RT, but of note this patient also had preexisting Sjogren's syndrome.Symptoms were present in 10 patients, of which 9 noted improvement after treatment. The only patient whose symptoms did not improve was the patient with SD. This patient had neuro involvement of the lymphoma with multiple confounding factors.ConclusionCombined modality treatment with single-agent rituximab and ultra-low-dose adaptive RT, with retreatment as needed, in patients with indolent NHL appears to provide effective palliation and disease control with minimal toxicity. For patients with concerns for radiation or chemotherapy related toxicity, this presents an attractive alternate treatment paradigm that warrants further evaluation in larger prospective studies. DisclosuresDesai: Boston Scientific: Consultancy, Research Funding. Awan: ADCT therapeutics: Consultancy; Cardinal Health: Consultancy; Merck: Consultancy; BMS: Consultancy; Dava Oncology: Consultancy; Johnson and Johnson: Consultancy; Beigene: Consultancy; Incyte: Consultancy; Verastem: Consultancy; MEI Pharma: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy; Kite pharma: Consultancy; Gilead sciences: Consultancy; Pharmacyclics: Consultancy; Janssen: Consultancy; Abbvie: Consultancy; Astrazeneca: Consultancy; Genentech: Consultancy.

Evaluating the Carg Chemotherapy Toxicity Calculator Among Older Adults Newly Diagnosed with Hematologic Malignancy

Background: Older adults with hematologic malignancy (HM) are a growing demographic and providing effective treatments that balance toxicity and health related quality-of-life (HRQL) is imperative. The well-studied and utilized chemotherapy toxicity tool, the Cancer and Aging Research Group (CARG) chemotherapy toxicity score, has not been validated in hematologic malignancies.Methods: The primary objective of this study was to validate the predictive ability of the CARG score for grade 3-5 toxicity in newly diagnosed (ND) patients >60 years with HM. This was a prospective longitudinal study with 4 study visits: baseline (pre-therapy), visit 2 (Day 90), visit 3 (Day 180), and end-of-study (EOS) which occurred at the earliest of the following events: progression, transplant, or 1-year from baseline. The CARG score was evaluated at baseline. HRQL (PROMIS-GHS) and physical function measured by short physical performance battery (SPPB) were assessed longitudinally at all visits. Treatment toxicity using the NCI CTCAE (version 5.0) were captured monthly, and the worst grade of each type of chemo-related adverse event (AE) was recorded and summarized for each patient. Wilcoxon signed-rank test was used to test if variables changed significantly across visits. Fine and Gray model was used to associate comprehensive geriatric metrics and CARG score with the development of grade 3-5 chemotherapy-related toxicity with death as the competing risk, and Cox model was used to analyze overall survival (OS).Results: Ninety-seven patients with hematologic malignancy (myeloid n=34, lymphoma n=35, plasma cell n=28) were enrolled. The median age was 70 years (range 60-88) with a median 159 days on study (range 1-435). Baseline evaluations: ECOG PS was 0-1 in 69 (85%), median IADL score was 13 (range 5-14), median MOS physical health score was 44.4 (range 0-100), median self-reported KPS was 80% (50-100%), and median comorbidity score was 6 (range 2-12). PROMIS median scores improved from baseline (32, range: 12-49) to EOS (35, range: 16-47, p=0.05). Median SPPB scores improved significantly from baseline (5, range 0-12) to EOS (9, range 0-12, p=0.005). During the study period, 75 patients had 334 grade 1-2 AEs, and 42 patients had 82 grade 3-5 AEs. Hematologic toxicities were more common with 36 (37%) patients having anemia (30 grade 1-2, and 6 grade 3-5) and 11 (11%) patients having febrile neutropenia (all grade 3-5). In multivariable analysis, significant risk factors associated with grade 3-5 toxicity (p<.05) included living alone (HR 3.11, 95%CI: 1.52-6.34) and social activities score (HR 1.21, 95%CI: 1.02-1.42). Risk factors associated with OS in univariable models (p <0.05) were ECOG PS (HR 4.35, 95%CI 2.43-7.79), physical health score (HR 0.86, 95%CI 0.77-0.97), IADL (HR 0.83, 95%CI 0.73-0.95), comorbidities (HR 1.26, 95%CI 1.07-1.48), number of supplements (HR = 0.76, 95% CI 0.60-0.96), memory score (HR 1.08, 95% CI 1.01-1.14), SPPB score (HR 0.87, 95%CI 0.80-0.95) and CARG score (HR 1.12, 95%CI 1.02-1.23). In multivariable analysis, the SPPB score (HR 0.85, 95%CI 0.78-0.93) remained significant for OS.Conclusions: The CARG chemotoxicity score was not predictive of grade 3-5 toxicities in patients ND with HM, but was univariably associated with OS. Higher SPPB scores were strongly associated with OS. Future studies, evaluating modifications of the CARG score are indicated for patients with HM. Objective measures of function, such as the SPPB, may be a reliable method to stratify treatment intensities for older adults with HM. DisclosuresMims: Glycomemetics: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Aptevo: Research Funding; Leukemia and Lymphoma Society's Beat AML clinical study: Consultancy, Research Funding; Xencor: Research Funding; Kartos Pharmaceuticals: Research Funding; Genentech: Consultancy; Abbvie: Consultancy; BMS: Consultancy; Kura Oncology: Consultancy; Syndax Pharmaceuticals: Consultancy; BMS: Consultancy; Jazz Pharmaceuticals: Consultancy; Aptevo: Research Funding. Woyach: AbbVie Inc, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Research Funding; AbbVie Inc, ArQule Inc, AstraZeneca Pharmaceuticals LP, Janssen Biotech Inc, Pharmacyclics LLC, an AbbVie Company,: Consultancy; Gilead Sciences Inc: Other: Data & Safety; AbbVie Inc, ArQule Inc, Janssen Biotech Inc, AstraZeneca, Beigene: Other: Advisory Committee.

Hematopoietic Stem Cell Transplantation for Acute Lymphoblastic Leukemia: Why Do Adolescents and Young Adults Outcomes Differ from Those of Children? a Study on Behalf of the Francophone Society of Stem Cell Transplantation and Cellular Therapy (SFGM-TC)

Introduction:Adolescents and Young Adults (AYA) represent a specific population in the Acute Lymphoblastic Leukemia (ALL) landscape, often presenting high-risk diseases and increased chemotherapy-related toxicities. Indications of Hematopoietic Stem Cell Transplantation for pediatric patients (HSCT) have been restricted to those with early poor response to chemotherapy. The same trend has led to a decrease of HSCT indications in AYAs, which are nevertheless still more frequent than in younger counterpart. Outcomes of AYAs after HSCT seemed to be worse than the ones of children in two previous studies published in 2013 and 2014. In Minneapolis, the decrease of overall survival in AYA was attributed to an excess of Treatment Related mortality (TRM) (28% versus 14%; p=0.04), but because of small numbers, factors influencing TRM were not identified. Our study aimed to compare, in a large cohort, the outcomes of children and AYA with ALL after HSCT and to determine factors influencing potential differences.Material and Methods:All patients aged between 1 and 25 years, reported in the SFGM-TC (Francophone Society of bone marrow transplantation and cellular therapy) registry, who received a first HSCT in treatment for ALL between 2005 and 2012 were included. The AYA group was defined by age range between 15 and 25 years old, according to European studies and the SFGM-TC. Data about diagnosis and transplantation procedure were prospectively collected in the registry. Before transplant procedure, patients or their parents/guardians provide a signed consent in order to be included in the registry.Results:891 patients were included, 494 children and 397 AYA. Median time of follow up was 45.6 months (0 to 114). HSCT was performed in first CR for 56.8% of the AYAs, whereas 57.5% of children received HSCT in second CR or more advanced phase (p<0.001). HSCT procedures mainly included a Myelo-Ablative Conditioning (MAC) regimen. TBI was used more frequently in AYAs than in children (90.1% versus 83.1%, p=0.003). Bone Marrow (BM) or Cord-Blood (CB) were often used in children 60.2% and 29.4% versus 55.6% and 16.4% in AYA group respectively (p < 0.0001) . Peripheral Blood Stem Cells (PBSC) were more frequently used for AYA (28%) than for children 10.3% (p < 0.0001). Moreover, when being transplanted in an adult center, PBSC were more commonly used for AYA (30% of AYA's HSCT in adult centers versus 21.2% of AYA's HSCT in pediatric centers, p=0.051). BM and PBSC cells were provided by a match sibling donor (MSD) in 40.2% of children and 43.4% of AYAs and from a MUD in 57.2% and 55.1% of cases respectively (p = 0.474). Anti-thymoglobulins (ATG) were used for 336 patients (48% of children and 26% of AYA patients, p<0.001). See patient's characteristics in Table.Five-year OS was lower in AYA 53.1% versus 64% (p = 0.0012) and we confirmed higher 5-years TRM in AYA 19% versus 13% (p=0.04). TRM incidence markedly rose after 10 years of age (from 9% before 10 years old to 20% between 10 and 15 years, and 17% after 15 years).Graft versus host disease and Relapse Free Survival probability (GRFS) was lower in AYA: 36% versus 47% (p=0.007), while Cumulative Incidence of Relapse (CIR) and acute Graft versus Host Disease (GvHD) incidence were both similar in our two groups: 32% and 61% in AYAs versus 27% and 59% in children, (p=0.19 and p=0.62), respectively. Thus, chronic GvHD, which occurred more frequently in AYA than in children (32% versus 19%, p<0.001), mainly impact post-HSCT morbi-mortality in AYA (Figure 1 and 2).In our multivariate analysis, two factors were associated with higher risk of cGvHD: use of PBSC as stem cell source (HR 1.41 [0.96-2.07], p=0.083), and absence of ATG use (HR associated with use of ATG: 0.62 [0.42-0.92], p=0.017) (Figure 3). Of note a subgroup analysis in patients who received a bone marrow transplant after a MAC, showed no TRM difference between AYA and children.Conclusion:AYA or patients aged more than 10 years, compared to ones aged less than 10 years have a worse outcome after HSCT for ALL. Excess of death in this specific population is mainly due cGvHD. Transplantation practices in those patients, particularly choice of stem cells source and GvHD prophylaxis, should be discussed. Their treatment adherence should also be questioned and reinforced by development of multidisciplinary teams. [Display omitted] DisclosuresPeffault De Latour: Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Amgen: Consultancy, Other, Research Funding; Jazz Pharmaceuticals: Honoraria; Alexion, AstraZeneca Rare Disease: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding. Forcade: Novartis: Other: travel grant.