Chemotherapy-related Toxicity Research Articles

Risk Factors of Chemotherapy-Induced Thrombocytopenia After Oxaliplatin-Containing Chemotherapy for Gastrointestinal Malignancies

PurposeThrombocytopenia is among the most common chemotherapy-related hematologic toxicities. We aim to determine the predictors of oxaliplatin chemotherapy-induced thrombocytopenia in patients with gastrointestinal tumors to guide the clinic.MethodsClinical data of 750 patients with a malignant gastrointestinal tumor were included as the primary cohort. Basic clinical data, serological indices, and anthropometric indices of these patients were collected. According to the presence or absence of CIT, univariate analysis was performed to identify significant factors for multivariate analysis. In R language software, nomogram was constructed based on the results of multi-factor analysis, and the calibration curve and ROC curve were drawn.ResultsUnivariate analysis identified 17 factors as closely related to CIT occurrence, namely age, lymph node metastasis (N) stage, metastasis (M) stage, lung metastasis, other site metastasis, chemotherapy regimen, course of treatment, total dose of oxaliplatin, AST, albumin, neutrophils, monocytes, baseline platelets, transferrin, natural killer (NK) cell, phase angle, and SMI (P < 0.10). The binary logistic multivariate regression analysis revealed five independent risk factors for developing CIT (P < 0.05), including the M stage, total dose of oxaliplatin, albumin, baseline thrombocyte count, and NK cell. Based on the results of multivariate logistic regression analysis, R software was used to establish a nomogram model. The calibration curve shows that the combined predictor has good consistency. The area under the ROC curve was 0.877 and the best cut-off value was 0.3579613 (sensitivity, 78.9%; specificity, 81.8%), which showed the better prediction efficiency.ConclusionThe total dose of oxaliplatin, M stage, albumin, baseline platelet count, and NK cell was independent risk factors for CIT. The sequentially constructed histogram model had a good predictive effect on the risk of thrombocytopenia caused by oxaliplatin chemotherapy in patients with gastrointestinal malignancies.

Abstract PO3-03-06: Real-world efficacy and safety of neoadjuvant pembrolizumab plus chemotherapy in Brazilian patients with early-stage triple-negative breast cancer

Abstract Background: Early-stage triple-negative breast cancer (TNBC) is associated with high risk of early recurrence and disease-specific mortality. Studies suggest a sustained clinical benefit in patients with TNBC who have a pathological complete response (PCR) after neoadjuvant chemotherapy (NACT). In TNBC, the combination of immunotherapy based on immune checkpoint inhibitors (anti-PD-1/PD-L1) combined with chemotherapy has been shown to be effective both in the advanced and early. In the early-stage setting, the addition of pembrolizumab to platinum-containing NACT significantly increased pathological complete response (pCR). Methods: We performed a retrospective observational cohort study of patients diagnosed with TNBC, stage II-III, who received NACT with chemotherapy based on paclitaxel and carboplatin (TC) followed by doxorubicin plus cyclophosphamide (AC) associated with pembrolizumab, treated from June 2022 to July 2023, at AC Camargo Cancer Center, São Paulo, Brazil. Objectives: To investigate the real-world pCR rate and safety profile of early-stage TNBC treated with neoadjuvant chemotherapy (weekly TC, ddAC/AC) associated with pembrolizumab and to describe the clinical-pathological characteristics of this population. Results: Eighty patients received neoadjuvant pembrolizumab plus chemotherapy. Around 50.6% of patients were premenopausal, with a median age of 47 years old at diagnosis. About 18% carried a germline mutation in the BRCA1 (50%) .Regarding the pathological characteristics of the tumor, 90.9% were invasive ductal carcinoma (IDC), 80% had histological grade (HG) III, and average Tumor Infiltrating Lymphocytes (TILs) was 18%. In 94.8% of cases, Ki67 was expressed in more 20% of tumor cells. The expression of HER2 was low in 14%, and 5% were ER-low. Regarding the clinical stage of the primary tumor, (64.9%)cT2, (18%) cT3, (10%) cT1c, and (2.5%) cT4. Regarding regional lymph node staging, 48%, 33.7%, 10.3%, and 6.4% were classified as cN0, cN1, cN2a, and cN, respectively. Clinical stage was IIA (42.8%), IIB (24.6%), IIIA (14.2%), IIIB ( 9%), and IIIC (5%). Regarding chemotherapy, 57.1% received dose dense AC, 54% percent had chemotherapy-related toxicity, 35.7% had neutropenic fever, 32.4% required hospitalization, and 31% used antibiotics. 31% received eight cycles of neoadjuvant pembrolizumab and 53.2% of patients completed all NACT, among these patients, 61% had complete .A cutoff date, about 61% of patients have undergone surgery, and 66.6% achieved a complete pathological response (ypT0ypN0). Patients that received eight cycles of neoadjuvant pembrolizumab had a higher chance of pathological complete response rate (61% vs. 45.2%) p=0.073. Immune-related toxicities (IRT) were observed in 16.8% patients, being the most common endocrinologic and cutaneous, being G3 or higher in 46%. About 15.5% used corticosteroids. Fifty percent had already started or completed adjuvant therapy, from which 66.6% received only adjuvant pembrolizumab, 28% had adjuvant pembrolizumab plus capecitabine, 1.2% received adjuvant capecitabine, and 1.2% had adjuvant olaparib. Eight percent of our patients have already completed nine cycles of adjuvant pembrolizumab, 12.7% did not receive adjuvant pembrolizumab due to prior toxicity. In our cohort, we observed greater intercurrences related to ddAC versus conventional AC 61.4% versus 52.4%, p=0.492, therefore, it did not impact whether or not the chemotherapy was completed. Conclusion: Our cohort is composed mostly of pre-menopausal with stage IIA tumors. Most patients received ddAC, Fifty-four percent had chemotherapy-related toxicity. We observed a high rate of pCR (61%) on our patients have already undergone surgery, 66.6% achieved a complete pathological response.Of those who received 8 cycles of neoadjuvant pembrolizumab had a higher chance of pathological complete response rate (61% vs. 45.2%) p=0.073 Citation Format: isadora sousa, Ana Carolina M. Comini, Italo BORGES, Flavia C. Balint, Livia alexandre Martins, Debora G. Sousa, Solange M. Sanches, Marcelle G. Cesca, Vladmir Cordeiro de Lima, Monique Tavares. Real-world efficacy and safety of neoadjuvant pembrolizumab plus chemotherapy in Brazilian patients with early-stage triple-negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-03-06.

Beyond Chemotherapy: Present and Future Perspectives in the Treatment of Lymphoproliferative Disorders.

Over the past three decades, the treatment of lymphoproliferative disorders has undergone profound changes, notably due to the increasing availability of innovative therapies with the potential to redefine clinical management paradigms. A major impact is related to the development of monoclonal antibodies, checkpoint inhibitors, bispecific antibodies, and chimeric antigen receptor T (CAR-T) cell therapies. This review discusses the current landscape of clinical trials targeting various hematological malignancies, highlighting promising early-phase results and strategies to overcome resistance. Lymphoproliferative disorders encompass a range of conditions: while in Hodgkin lymphoma (HL) the goal is to reduce chemotherapy-related toxicity by integrating immunotherapy into the frontline setting, peripheral T cell lymphoma (PTCL) lacks effective targeted therapies. The review emphasizes a shifting therapeutic landscape towards precision medicine and treatment modalities that are less toxic yet more effective.

Synergistic effect of human uterine cervical mesenchymal stem cell secretome and paclitaxel on triple negative breast cancer

BackgroundTriple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer and, despite its adverse effects, chemotherapy is the standard systemic treatment option for TNBC. Since, it is of utmost importance to consider the combination of different agents to achieve greater efficacy and curability potential, MSC secretome is a possible innovative alternative.MethodsIn the present study, we proposed to investigate the anti-tumor effect of the combination of a chemical agent (paclitaxel) with a complex biological product, secretome derived from human Uterine Cervical Stem cells (CM-hUCESC) in TNBC.ResultsThe combination of paclitaxel and CM-hUCESC decreased cell proliferation and invasiveness of tumor cells and induced apoptosis in vitro (MDA-MB-231 and/or primary tumor cells). The anti-tumor effect was confirmed in a mouse tumor xenograft model showing that the combination of both products has a significant effect in reducing tumor growth. Also, pre-conditioning hUCESC with a sub-lethal dose of paclitaxel enhances the effect of its secretome and in combination with paclitaxel reduced significantly tumor growth and even allows to diminish the dose of paclitaxel in vivo. This effect is in part due to the action of extracellular vesicles (EVs) derived from CM-hUCESC and soluble factors, such as TIMP-1 and − 2.ConclusionsIn conclusion, our data demonstrate the synergistic effect of the combination of CM-hUCESC with paclitaxel on TNBC and opens an opportunity to reduce the dose of the chemotherapeutic agents, which may decrease chemotherapy-related toxicity.

Genetic Variations Affect Chemotherapy Outcomes: A Role of the Spindle-assembly Checkpoint.

Cancer patients suffer from complicated chemotoxicity. Pharmacogenomics can help stratify patients by predicting their response to treatment and susceptibility toward severe side effects. The spindle-assembly checkpoint (SAC) is an important pathway that is activated by platinum and taxane compounds and plays a crucial role in their cytotoxic activity. This study investigated a SAC component, Budding Uninhibited by Benzimidazoles 3 (BUB3), its expression, and genetic variants in advanced ovarian cancer patients treated with paclitaxel-carboplatin chemotherapy. Among 80 patients, BUB3 expression correlated with chemosensitivity, suggesting its potential as a predictive marker for chemotherapy response. However, high BUB3 expression was associated with a higher risk of poor survival. In addition, genetic polymorphisms in BUB3 (rs11248416 and rs11248419) were significantly linked to chemotherapy-related toxicities, with rs11248416 showing a negative impact on the patient's physical quality of life.

Racial differences in body composition and survival among older adults with gastrointestinal malignancies

IntroductionMuscle and adipose tissue measures can be quantified from routinely obtained computed tomography (CT) images and are predictors of chemotherapy-related toxicities and survival among patients with gastrointestinal (GI) malignancies. Most studies to date have consisted of predominantly White patients, and the role of body composition among minoritized racial groups is unknown. We examined racial differences in body composition and survival among patients with GI malignancies. Materials and MethodsThis was a prospective cohort study of patients with GI malignancies. Single slices of axial CT images from L3 segments were analyzed using Slice-O-Matic software. The skeletal muscle area (cm2) was divided by height to obtain the skeletal muscle index (SMI, cm2/m2). Skeletal muscle radiodensity (SMD) in Hounsfield units (HU) was used for muscle composition. We compared body composition parameters between non-Hispanic (NH)-White and NH-Black participants. Cox models were used to examine the impact of body composition on survival. We proposed new race-specific cutoffs for body composition using optimal stratification. ResultsFive hundred forty patients were included, of which 24% were NH-Black. In Cox models stratified by race, each 5 cm2/m2 decrease in SMI was associated with increase in risk of all-cause mortality in NH-Black patients (hazard ratio [HR] 1.25; 95% confidence interval [CI] 1.04–1.49 p = 0.02). With the existing cut points, neither sarcopenia nor myosteatosis was associated with worse survival. Using a new cutoff for sarcopenia in NH-Black patients, NH-Black patients with sarcopenia (HR 2.31 95%CI 1.10–4.88 p = 0.03) and myosteatosis (HR 2.63 95% CI 1.25–5.53 p = 0.01) had worse survival. DiscussionNH-Black older patients with GI cancers and sarcopenia or myosteatosis have worse overall survival.

Long-term Musculoskeletal Consequences of Chemotherapy in Pediatric Mice.

Thanks to recent progress in cancer research, most children treated for cancer survive into adulthood. Nevertheless, the long-term consequences of anticancer agents are understudied, especially in the pediatric population. We and others have shown that routinely administered chemotherapeutics drive musculoskeletal alterations, which contribute to increased treatment-related toxicity and long-term morbidity. Yet, the nature and scope of these enduring musculoskeletal defects following anticancer treatments and whether they can potentially impact growth and quality of life in young individuals remain to be elucidated. Here, we aimed at investigating the persistent musculoskeletal consequences of chemotherapy in young (pediatric) mice. Four-week-old male mice were administered a combination of 5-FU, leucovorin, irinotecan (a.k.a., Folfiri) or the vehicle for up to 5 wk. At time of sacrifice, skeletal muscle, bones, and other tissues were collected, processed, and stored for further analyses. In another set of experiments, chemotherapy-treated mice were monitored for up to 4 wk after cessation of treatment. Overall, the growth rate was significantly slower in the chemotherapy-treated animals, resulting in diminished lean and fat mass, as well as significantly smaller skeletal muscles. Interestingly, 4 wk after cessation of the treatment, the animals exposed to chemotherapy showed persistent musculoskeletal defects, including muscle innervation deficits and abnormal mitochondrial homeostasis. Altogether, our data support that anticancer treatments may lead to long-lasting musculoskeletal complications in actively growing pediatric mice and support the need for further studies to determine the mechanisms responsible for these complications, so that new therapies to prevent or diminish chemotherapy-related toxicities can be identified.

Efficacy of oral nutritional supplement in cancer patients receiving chemotherapy: a systematic review and meta-analysis of randomized controlled trials.

The use of oral nutritional supplement (ONS) is one of the modalities employed to manage cancer-associated malnutrition. However, evidence of its efficacy is limited. In 2018, a meta-analysis reported the statistical benefits of increased body weight from ONS. This study aimed to evaluate the efficacy of ONS in cancer patients receiving chemotherapy in more recent trials. All randomized controlled trials (RCTs) of adult cancer patients receiving chemotherapy, which compared ONS with standard of care and reported on body weight, nutritional status, or quality of life (QoL), were included. Eligible RCTs were identified from PubMed, OVID, and the references of previous systematic reviews up until February 2023. The risk of bias was assessed using the Revised Cochrane risk-of-bias tool. The outcomes of interest were pooled and analyzed using the mean difference (MD) with a corresponding 95% confidence interval (CI). This study was registered in PROSPERO, number CRD42023400471. Ten RCTs comprising 1,101 patients were included. ONS did not show a significant impact on final body weight (MD -0.07 kg, 95% CI: -0.99 to 0.84, P=0.88). It tended to increase body weight (MD 0.90 kg, 95% CI: -0.48 to 2.28, P=0.20), and this benefit was particularly noticeable in elderly patients, those with low baseline body weight, females, and non-Asian patients. After adjusting for risk of bias, ONS was found to significantly increase body weight (MD 1.32 kg, 95% CI: 0.12 to 2.52, P=0.03), and it also tended to enhance Patient-Generated Subjective Global Assessment (PG-SGA) score of -2.13 (95% CI: -5.07 to 0.82, P=0.16), global domain QoL score of 4.01 (95% CI: 0.08 to 7.94, P=0.05) and fatigue domain QoL score of -7.63 (95% CI: -13.87 to -1.39, P=0.02). ONS could help to increase body weight in cancer patients receiving chemotherapy. This benefit was especially notable in those at high risk of malnutrition, including elderly patients, those with low baseline body weight, females, and non-Asian patients. It also resulted in improved PG-SGA scores and significantly improved patients' QoL during chemotherapy treatment. Future studies should explore the potential benefit of ONS on oncological outcomes or improvements of chemotherapy-related toxicity.

Targeting MutT Homolog 1 (MTH1) for Breast Cancer Suppression by Using a Novel MTH1 Inhibitor MA-24 with Tumor-Selective Toxicity.

Breast cancer is a commonly diagnosed cancer worldwide. Human MutT homolog 1 (MTH1) is found to be elevated in breast tumors and cancer cells need MTH1 for survival. Pharmacological inhibition of MTH1 may be potentially beneficial in the treatment of breast cancer. MA-24 was screened by malachite green colorimetric assay for MTH1 inhibitors and the kinetic characteristics of MA-24 were assessed. The features of MA-24's binding with MTH1 were ascertained through molecular docking, and the cytotoxic activity of MA-24 was validated in vitro and in vivo. Target engagement assays, comet assay, and Western blot confirmed the intracellular target and mechanism of MA-24. MA-24 shows potent antitumor bioactivity both in vitro and in vivo. MA-24 competitively inhibited the MTH1 and further induced DNA strand breaks, leading to increased apoptosis of cancer cells depending on the upregulation of the cleaved-caspase 3-cleaved-PARP axis. In particular, MA-24 exhibited a powerful efficacy and safety in vivo (tumor growth inhibition rate: 61.8%). MA-24 possesses a broad spectrum of breast cancer cytotoxicity and offered valuable insights for overcoming the challenges of chemotherapy-related toxicity, which holds great potential for the further development MA-24 as an anti-cancer drug.

Stability and consistency of symptom clusters in younger versus older patients receiving chemotherapy

BackgroundBy 2035, the number of newly diagnosed cancer cases will double and over 50% will be in older adults. Given this rapidly growing demographic, a need exists to understand how age influences oncology patients’ symptom burden. The study purposes were to evaluate for differences in the occurrence, severity, and distress of 38 symptoms in younger (< 60 years) versus older (≥ 60 years) oncology patients undergoing chemotherapy and to evaluate for differences in the stability and consistency of symptom clusters across the two age groups.MethodsA total of 1329 patients were dichotomized into the younger and older groups. Patients completed demographic and clinical questionnaires prior to the initiation of their second or third cycle of chemotherapy. A modified version of Memorial Symptom Assessment Scale was used to evaluate the occurrence, severity, and distress of 38 common symptoms associated with cancer and its treatment. Differences between the two age groups in demographic and clinical characteristics and ratings of occurrence, severity, and distress for the 38 symptoms were evaluated using parametric and nonparametric tests. Exploratory factor analyses were done within each age group to identify symptom clusters using symptom occurrence rates.ResultsCompared to the younger group (14.8 (± 7.0)), older adults reported a lower mean number of symptoms (12.9 (± 7.2)). Older patients experienced lower occurrence rates for almost 50% of the symptoms. Regarding symptom clusters, an eight-factor solution was selected for both age groups. Across the two age groups, the eight symptom clusters (i.e., physical and cognitive fatigue, respiratory, psychological, hormonal, chemotherapy-related toxicity, weight gain, gastrointestinal, epithelial) were stable. However, symptoms within the physical and cognitive, chemotherapy-related toxicity, and gastrointestinal clusters were not consistent across the age groups.ConclusionsTo be able to provide tailored and effective symptom management interventions to older oncology patients, routine assessments of the core symptoms unique to the symptom clusters identified for this group warrants consideration. The underlying mechanism(s) for these inconsistencies in symptom burden is an important focus for future studies.

Treatment patterns and outcomes by age in metastatic urothelial carcinoma (mUC): A retrospective tertiary cancer center analysis.

582 Background: Older adults with locally advanced or mUC often do not receive optimal first-line (1L) therapy (Rx) and subsequent treatments (Lara et al. ASCO 2016). There are limited randomized data for age-appropriate Rx in older mUC adults. Through our real-world study, we describe the clinical characteristics, treatment patterns, and outcomes among pts with mUC, comparing older to younger adults receiving 1L systemic Rx. Methods: This retrospective IRB-approved study included pts receiving care between 2014 and 2023 at the University of Utah, Huntsman Cancer Institute, a tertiary care National Cancer Institute-Designated Comprehensive Cancer Center. Eligible pts had a confirmed diagnosis of mUC and received 1L chemotherapy or 1L immunotherapy-based regimens. Based on age at receipt of 1L Rx, pts aged 70 years or above were grouped in the ‘older’ group, while rest were included in the ‘younger’ cohort. Survival and Rx-related outcomes of those enrolled inwere excluded. Overall survival (OS) between the two groups was compared using Kaplan-Meier and Cox Regression analysis. All statistical analyses were implemented in R-Studio (v.4.2). Results: We identified 212 eligible mUC pts (103 older vs. 109 younger). Older pts received more immunotherapy-based Rx in the 1L (52.4% vs 35.7%, p=0.02), were more likely to be (73.6% vs. 45.4%, p&lt;0.001), less likely to receive subsequent lines of Rx (median; range: 0 (0-3) vs 1 (0-5), p=0.005) and had lower clinical trial participation (69.9% vs 81.6%, p=0.04)compared to younger pts. For survival outcomes and treatment-related analysis, 160 patients (72 older vs. 88 younger) undergoing approved standard of care were included. Among mUC treated with 1L chemotherapy (n=108), more pts required dose adjustments in older group (23/43 vs 15/65 younger). Older adults received less number of cycles of chemotherapy (median; range: 4 (0-6) vs 5 (1-12), p= 0.03). Older pts had OS comparable to younger pts (11.2 mos vs. 14 mos, p=0.06). Pts from both age groups had similar rates of Rx-related toxicity and healthcare visits, independent of the type of systemic Rx. Conclusions: Older pts with mUC tend to be cis-ineligible and have lower bone marrow reserve. Nevertheless, select pts can be treated with risk-adjusted regimens of chemotherapy and with immunotherapy with comparable outcomes to younger mUC pts in terms of toxicity and outcomes. Validated tools to predict vulnerabilities and excessive chemotherapy-related toxicity in older adults with mUC are available and may help mitigate toxicity by informing Rx adjustments.

Chemotherapy-related toxicities follow a typical pattern in children treated for acute lymphoblastic leukaemia.

Acute lymphoblastic leukaemia (ALL) therapy has been associated with a significant burden of toxicities. The aim of this study was to describe the full spectrum of toxic effects associated with childhood ALL. Toxicity-related data were collected from the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL-2008 toxicity registry, in which data on 19 clinically relevant toxicities were registered during ALL treatment, and from patient medical records. All patients treated according to the NOPHO ALL-2008 protocol in Oulu University Hospital between 2008 and 2020 were included in the study. The cohort consisted of 73 patients, 38 of whom were male. Mean age at diagnosis was 6.6 ± 4.2 (range 1.4-16.0) years. All but one of the patients developed at least one treatment-related toxicity and more than half had multiple toxicities. Female sex and older age were associated with a higher tendency towards toxicity. The most common toxicity was vincristine-induced peripheral neuropathy, which was observed in 70 patients. Most toxicities were moderate or severe, but even mild toxicities often affected leukaemia treatment. Moderate and severe treatment-related toxicities are common, and most toxicities occur in a typical pattern in relation to the treatment phases.

Decitabine Combined with Low-Dose Chemotherapy Is Effective in the Treatment of Pediatric Refractory/Relapsed Acute Myeloid Leukemia

B ackground : Refractory and relapsed acute myeloid leukemia are usually associated with poor outcomes. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative option for children suffering from refractory/relapsed AML. Complete remission before transplantation can reduce the recurrence rate after transplantation and improve the survival rate. Previous studies have found that low-dose chemotherapy has a complete response rate and long-term survival rate comparable to standard dose chemotherapy, and chemotherapy-related toxicities are lower. Decitabine is active in both initial induction therapy and post-relapse therapy of AML, and has a synergistic effect on apoptosis of leukemia cells when combined with cytarabine. We therefore conducted a prospective study to confirm the efficacy of decitabine combined with low-dose chemotherapy in the treatment of pediatric refractory/relapsed AML. The trial is registered under ChiCTR1800015872(A multicenter clinical study of decitabine combined with low-dose chemotherapy in the treatment of refractory/relapsed AML in children). Methods: We randomized 89 participants &amp;lt; 18 years with refractory/relapsed AML to receive decitabine combined with low-dose chemotherapy. All patients received decitabine 20 mg/ (m 2·d) ×5 days, intravenous; combined with idarubicin 5 mg/ (m 2·d), qod×3 times, intravenous; cytarabine 10 mg/ (m 2·d), q12h×10 days, subcutaneous; granulocyte stimulating factor 5μg/ (kg·d), qd×10 days, intravenous. Subsequently, children received additional intensive chemotherapy or hematopoietic stem cell transplantation (HSCT) as post-remission consolidation. The primary endpoint was overall survival. Results: From June 2018 to June 2022,the trial included 31 children with relapsed AML and 58 children with refractory AML. The male to female ratio was 57:32, median age 100 months (range 59-133months). The most common fusion genes were AML-ETO(17, 19.1%) and MLL-r (17, 19.1%), followed by NUP98- (7, 7.9%),CBFβ-MYH11(5, 5.6%). The most common mutation was WT1(18,20.2%), while FLT3, NRAS, and PTPN11 had the same proportions. (14, 15.7%).After one course of chemotherapy, 48 children (53.9%) achieved CR/CRi, 21 children (23.6%) achieved PR, and 20 children (22.5%) achieved NR, with an overall response rate of 77.5%. Thirty-one of these children received a second course of decitabine combined with low-dose chemotherapy. 11 children (35.5%) achieved CR/CRi, 17 children (54.8%) achieved PR, and 3 children (9.7%) remained NR. Of the 89 children, 66 (74.2%) children eventually received HSCT ,while the remaining 23 did not. The five-year cumulative survival rate was 64.7%. Among them, the five-year survival rate of relapsed AML is 52.6%,while that of refractory AML was 76.1%. The survival rate of refractory AML was better, but there was no statistical difference in P value between the two groups. The five-year survival rate was 82.7% for those who received HSCT, compared with 19.8% for those who only received chemotherapy, the P-value was statistically significant. The survival rate of different fusion genes was shown in figure 1. Conclusions: Decitabine combined with low-dose chemotherapy is a favorable benefit-risk profile and may be a promising option for refractory/relapsed AML in children. Hematopoietic stem cell transplantation after remission can improve survival rate.

Reduced-Dose Chemotherapy Followed By Blinatumomab As Induction Therapy in Treatment of Newly Diagnosed Philadelphia Chromosome-Negative B-Cell Precursor Acute Lymphoblastic Leukemia - Interim Results from a Multicenter, Single-Arm, Phase 2 Study

Introduction: Although intensive pediatric chemotherapeutic regimens have shown good efficacy in the treatment of Philadelphia Chromosome-negative (Ph-negative) B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in adults, the high incidence of chemotherapy-related toxicities limits their use. Blinatumomab, a CD3/CD19 bispecific T-cell antibody, has shown high efficacy in relapsed/refractory or minimal residual disease (MRD) positive BCP-ALL; however, the efficacy of single-agent blinatumomab does not meet the treatment needs of adult patients. Therefore, combining low-intensity chemotherapy with blinatumomab could be a better induction regimen for newly diagnosed adult patients with BCP-ALL. Methods: This multicenter, single-arm, phase 2 trial (NCT05557110) enrolled adult patients (aged 15-59 years) with newly diagnosed Ph-negative BCP-ALL. The induction regimen comprised reduced intensity chemotherapy (idarubicin 8 mg/m 2 on day 1, vindesine 4 mg on day 1, and dexamethasone 9 mg/m 2/day from day 1-7) followed by 2 weeks of blinatumomab (9 ug/day from day 8-14, 28 ug/day from day 15-21). The primary endpoint was to assess the overall response rate (ORR=complete remission [CR] + CR with partial hematologic recovery [CRh] + CR with incomplete hematologic recovery [CRi]) of this induction regimen. Secondary endpoints were MRD negativity (&amp;lt;1x10 -4 by flow cytometry), event-free survival (EFS), overall survival (OS) and safety. Bone marrow evaluation and one intrathecal injection chemotherapy were performed on day 22±2. Patients not achieving ORR continued blinatumomab for another 2 weeks (28 ug/day from day 1-14), followed by bone marrow re-evaluation. Consolidation therapy was given after achieving ORR with recommended multidrug combination chemotherapy (including high-dose methotrexate or cytarabine combined with asparaginase) or alternating with blinatumomab (28 ug/day for 28 days). If allogeneic hematopoietic stem cell transplantation (allo-HSCT) is not performed, consolidation therapy needs at least 4 courses before 2 years of maintenance therapy. Results: Interim results are presented here.By July 6, 2023 (data cut-off), 25 patients were enrolled with a median age of 42 years (range: 15-53); 68% were females. The Eastern Cooperative Oncology Group Performance Status score ranged from 0-1. Eight (32.0%) patients had poor cytogenetic risk factors, including 3 with P2RY8::CRLF2, 2 with hypodiploidy, 2 with KMT2A rearranged and 1 with alterations of IKZF1 (Table 1). The bone marrow evaluation done in 19 patients on day 8 prior to blinatumomab treatment showed that none of the patients had got ORR. All 21 (100%) patients evaluable for the primary endpoint attained CR/Cri - 19 at the end of 2 weeks of blinatumomab and the remaining 2 after another 2 weeks of blinatumomab (Table 2). The MRD negativity rate was 90.5% (19/21) after 2 weeks of blinatumomab which increased to 95.5% (20/21) after another 2 weeks of treatment with blinatumomab. In 21 patients evaluated for safety, blinatumomab-related cytokine release syndrome was reported in 10 (47.6%) patients (grade 1: n=6, grade 2: n=3 and grade 3: n=1). No incidence of neurotoxicity was reported. Febrile neutropenia was reported in 4 (19%) patients (all ≥grade 3). The non-hematological AEs reported were fever in 7 (33.3%) patients (any grade), increased ALT in 10 (47.6%) patients (any grade) and infections in 4 (19%) patients, including pneumonia in 2 and sepsis in 2 (all ≥grade 3). The median duration of neutrophil deficiency (&amp;lt;0.5×10 9/L) and platelet deficiency (&amp;lt;20×10 9/L) during induction therapy was 9 days (range: 0-20) and 1 day (range: 0-18), respectively. The median follow-up time was 4 months and no relapse or leukemia-related deaths were observed. The median EFS and OS were not yet reached. All enrolled patients are alive except one who died of infection after multidrug combination consolidation chemotherapy. The median cycles for consolidation were 2 (range: 1-5) with 3 patients undergoing allo-HSCT. Conclusion: Thesepreliminary results indicate that the reduced intensity chemotherapy followed by blinatumomab is an effective regimen in adults with newly diagnosed Ph-negative BCP-ALL, resulting in favorable response rates, deep remission, and low-grade treatment-related AEs. These promising findings may provide a rationale for integrating blinatumomab into future induction therapy recommendations.

Down Syndrome with Acute Myeloid Leukemia in an Adolescent Male Successfully Treated with Low Dose Ara-C in Combination with Hypomethylating Agent

Introduction Patients with Down syndrome (DS) are prone to developing hematological malignancies, with risk of acute myeloid leukemia (AML) being 150 -fold higher compared to the general population. DS patients with leukemia are likely to experience significant chemotherapy related toxicities, hence require dose modifications. The myeloid leukemia of Down Syndrome (ML-DS) typically reflects acute megakaryoblastic leukemia (AMKL) a rare subtype of AML. ML-DS typically evolves from transient aberrant/abnormal myelopoiesis (TAM), aka transient myeloproliferative disorder (TMD), a pre-leukemic syndrome that almost always precedes myeloid leukemia in Down syndrome. GATA1, the hallmark driver mutation of TAM, is found in all TMD/TAM cases. AML in DS can occur de-novo which represents a different entity, appears immunophenotypically as (non-AMKL) AML, but differs morphologically from the classical ML-DS. The de-novo type AML in DS is reported to have worse prognosis. Poor outcomes are due to increased chemosensitivity and resulting chemotherapy-related toxicities when treated on standard high dose Ara-C based AML regimens. There is currently a lack of consensus on standard-of-care AML therapy applicable to this population. Methods Case report, retrospective electronic medical record review with institutional board review exemption Results We report a case of a 25-year-old male with trisomy 21, presenting with a one-month history of low-grade fevers, fatigue, and upper back pain. Initial laboratories showed a white cell count of 6.6 K/uL, hemoglobin 11.9 gm/dL, platelets 352 K/uL. CT chest showed a large right-sided pleural effusion, pleural thickening and multiple sclerotic bone lesions concerning for malignancy. Positron emission tomography (PET) CT revealed multiple hypermetabolic foci in the pelvis, spine, ribs, and cervical lymph nodes. Thoracocentesis was completed and pleural fluid pathology revealed atypical cells, flow cytometry showed 18% blasts positive for CD38, CD45, CD117 and negative for CD34 and HLA DR indicative of a myeloid neoplasm. Bone marrow aspirate and biopsy showed 10% CD117 positive immature myeloid cells. Morphology was not megakaryoblastic. Bone marrow flow cytometry results were consistent with that of pleural fluid with CD117 and myeloperoxidase (MPO) positive blasts. Fluorescent in-situ hybridization was negative for fusions/rearrangements. Next generation sequencing (NGS) detected NPM1 mutation and also a low level (variant allelic frequency &amp;lt;3%) FLT3 p.Y599C mutation (not internal tandem duplication or tyrosine kinase domain). GATA1 mutation was absent. A diagnosis of AML with NPM1 mutation and staging CNS1 was confirmed. Our patient was defined as DS and AML. Given innate fragility and higher chemo sensitivity in patients with DS, we elected to treat him off protocol with Cladribine and low dose Ara-C alternating with Decitabine. This regime was derived from an adult leukemia protocol. Cycle 1 was complicated by central line related occlusive thrombus requiring anticoagulation, slow count recovery, and a brief episode of febrile neutropenia managed with antibiotics. End of induction marrow evaluation was negative for minimal residual disease (MRD). Flow cytometry on pleural fluid was also negative for abnormal blasts that were previously detected. Repeat molecular testing with NGS was negative for NPM1, DNMT3A, and FLT3 mutations. The patient received a total of 8 cycles of chemotherapy. On subsequent bone marrow evaluations, blasts remained &amp;lt;5% and MRD was negative. Interval PET scan showed significant improvement. Patient is currently more than a year off therapy and remains in remission. Conclusion Patients with DS and AML have a higher mortality due to increased risk of cardiotoxicity and infection from chemotherapy. There is a risk of either undertreatment or less commonly overtreatment leading to early mortality. Our case describes an adolescent male with DS and AML with pulmonary comorbidity who was successfully treated with a low-dose Ara-C regimen adapted from an adult protocol and had great clinical outcome. AML treatment in DS remains a challenge and further research is warranted to develop tailored regimens effectively balancing curative intent and reduced toxicity. This regimen could be considered in pediatric patients with Down Syndrome and other comorbidities.

Impact of Daratumumab on Hematopoietic Stem Cell Mobilization with G-CSF and on-Demand Plerixafor in Newly-Diagnosed Multiple Myeloma Patients

Introduction Autologous stem cell transplantation (ASCT) is a standard of care for transplant eligible (TE) patients with newly diagnosed (ND) multiple myeloma (MM); therefore, an adequate hematopoietic stem cell (HSC) collection is crucial to allow patients to proceed to ASCT and ensure optimal hematologic recovery. A more frequent use of plerixafor (PLX) and lower HSC yields have been reported in patients treated with daratumumab, a backbone of induction therapy for NDMM patients. Chemotherapy-free mobilization with G-CSF and on-demand PLX is an effective mobilization strategy lacking chemotherapy-related toxicities. Here we present the results of a multicenter, retroprospective and prospective, observational study, aiming to compare the impact of daratumumab on HSC mobilization with G-CSF + on-demand PLX in patients with NDMM treated with bortezomib-thalidomide-dexamethasone (VTd) or VTd plus daratumumab (D-VTd). Methods NDMM patients undergoing a first HSC mobilization attempt with G-CSF (10 mcg/kg/day) were enrolled and observed up to 30 days after ASCT. According to its label, on-demand PLX was administered in patients with &amp;lt;20 CD34 + cells/µL after ≥ 4 days of G-CSF or in case &amp;lt;1×10 6 CD34 + cells/kg were collected on the first day of apheresis. The primary endpoint of the study was the rate of poor mobilizing patients (≤2x10 6 CD34 + cells/Kg collected or need for PLX to reach an adequate HSC harvest). Key secondary endpoints included: the rate of suboptimal (2 to 4 CD34 + cells/kg) and optimal (≥4 CD34 + cells/Kg) collection; the median number of apheresis required to obtain ≥2x10 6 CD34 + cells/Kg; the impact of daratumumab on HSC engraftment. Results A total of 190 NDMM patients (median age, 62 years) were enrolled in 2 Italian centres (IRCSS Istituto Clinico Humanitas and Città della Salute e della Scienza di Torino) and analyzed; of these, 70% (133/190) were treated with VTd and 30% (57/190) with D-VTd. The median number of induction cycles was 4 in both groups. Best response after the induction phase was at least very good partial response (VGPR) in 87/133 (65%) and 41/57 (72%) of patients treated with VTd or D-VTd, respectively (p=0.4). The median time from the end of induction to G-SCF administration was 24 days in the VTd group and 29 days in the D-VTd group (p=0.5). The rate of poor mobilizing patients was 31% (41/133) in the VTd group and 54% (31/57) in the D-VTd group (p=0.002), mainly due to a higher rate of PLX use in the D-VTd as compared to the VTd group (53% vs. 28%; p=0.001), while the rate of patients who failed HSC mobilization (≤2x10 6 CD34 + cells/kg collected) was similar in the two groups (2% vs. 3%; p=1). Despite a numerically higher median number of CD34 + cells collected in the VTd group (7.9) as compared to the D-VTd group (7.1; p=0.009), no difference in the rate of patients who collected 2-4 (5% vs. 5%; p=1) and ≥4 CD34 + cells/Kg (95% vs. 95%; p=1) was observed in the VTd and D-VTd groups, respectively. A higher median number of CD34 +/µL on the first day of count was observed in the VTd as compared to the D-VTd group (24.5 vs. 19, p=&amp;lt;0.001). Among patients who had &amp;lt;20 CD34 +/µL [32% (43/133) vs. 51% (29/57)] on the first day of count, a similar increase in the CD34 +/µL (48.5 vs. 55) was observed in the two groups after PLX administration. The median number of apheresis session needed to complete the harvestwas 1 fo the VTd group and 2 in the D-VTd group (p=0.1). Neutrophil and platelet recovery were achieved in 100% of patients with a median time to neutrophil recovery of 15 and 13 days in the VTd and D-VTd groups, respectively (p=&amp;lt;0.001) and a median time to platelet recovery of 16 and 14 days in the VTd and D-VTd groups, respectively (p=0.001). Conclusion G-CSF plus on-demand PLX for HSC mobilization demonstrated to be an effective strategy in NDMM patients treated with VTd with or without daratumumab, resulting in very low rates of mobilization failures irrespective of the use of daratumumab during induction. Despite a higher rate of patients requiring PLX for HSC collection and lower CD34 + yields, the incorporation of daratumumab as part of the induction treatment did not negatively impact the possibility to achieve an optimal HSC collection. Our results, along with the lack of chemotherapy-associated toxicity, support the use of a chemotherapy-free HSC mobilization with G-CSF and on-demand plerixafor also in patients receiving daratumumab upfront.

SIOG2023-5-OA-116 - Association between chemotherapy-related toxicity and QoL/ physical functioning in older patients

SIOG2023-5-OA-116 - Association between chemotherapy-related toxicity and QoL/ physical functioning in older patients

Chemo-Toxicity Calculator use in shared decision-making for chemotherapy treatment planning.

403 Background: Chemotherapy related symptoms and toxicities are frequent among cancer patients, especially those ≥ 65 years old. These symptoms and toxicities can contribute to patients having a decreased quality of life and unmet treatment outcomes. The modified CARG, Chemo-Toxicity Calculator, is an assessment of function, comorbidity, cognition, psychological state, social activity/support and nutrition. The goal of using the calculator, was to improve shared decision-making between the physician, patient and caregiver. Discussions focused on treatment, modifying treatment regimens and other alternatives such as palliative or hospice. Methods: Rocky Mountain Cancer Centers introduced the modified CARG, Chemo-Toxicity Calculator, in 2022 as part of cancer patient workflow for 10 physicians. In 2022, 156 patients completed the Chemo-Toxicity Calculator to identify and predict the risk of initiation or continuation of chemotherapy treatment in patients ≥ 65 years old. Using the CARG assessment allowed the physician and patient to have open discussions about the pros and cons of initiation or continuation of chemotherapy treatment or if they should pursue alternative treatment. 27 of these patients (17.3%) elected to receive hospice care in lieu of traditional treatment. The Chemo-Toxicity Calculator link was added in the electronic health record (EHR) for access at the point of care. Process: 1. Review patients at the time of initial treatment and subsequent lines of therapy. 2. CARG assessment completed for patients ≥ 65 years old. 3. Shared decision-making discussion including the voice of the patient. 4. Psychosocial interventions and care coordination. Results: As of May 2023,10 providers administered the modified CARG assessment on 244 patients. The tool identified patients that would not benefit from treatment and instances where cycle one dose reduction would be appropriate to reduce toxicity risk. Of the 244 patients who completed the assessment, 47 (19.2%) elected alternative treatment. Conclusions: The Chemo-Toxicity Calculator is a functional, practical first step toward the inclusion of a geriatric assessment for all patients ≥ 65 years old. Patients understand it, and it sets the stage for shared decision-making discussions. This valued intervention aids subsequent discussions about dose reduction and ongoing risks of treatment. Actions taken based on the results of the Chemo-Toxicity Calculator, reduced toxicity by dose reductions and helped patients choose an alternative to chemotherapy.

S-1 maintenance therapy in advanced gastric cancer without disease progression after first-line chemotherapy: A retrospective analysis.

For patients with advanced gastric cancer after chemotherapy, the optimal mode of maintenance therapy is not yet clear. This research aimed to compare the efficacy and adverse effects of S-1 maintenance therapy and follow-up observation in patients with advanced gastric cancer without disease progression after first-line combined chemotherapy. This study retrospectively analyzed 106 patients from January 2018 to December 2021. The primary endpoints were overall survival and progression-free survival, the secondary endpoint was chemotherapy-related toxicity, and the curative effects and baseline characteristics of the patients were analyzed. Longer progression-free survival and overall survival were observed in the S-1 maintenance treatment group than in the follow-up observation group (p < 0.001). No obvious differences existed in the subgroup results regarding progression-free survival or overall survival (p > 0.05). In the maintenance treatment group, the occurrence of thrombocytopenia and hand-foot syndrome was significantly increased (p < 0.001). No toxicity-related deaths occurred. The included patients without disease progression after first-line combined chemotherapy can achieve significant survival benefits by receiving S-1 maintenance therapy. The patient's tolerance to S-1 maintenance therapy was good.

2159P Machine learning algorithms to predict the risk of chemotherapy-related toxicity in older Asians

2159P Machine learning algorithms to predict the risk of chemotherapy-related toxicity in older Asians