Severe Hematologic Toxicity Research Articles

Efficacy and Safety of Ino Combined with Reduce Dose R-GDP Regimen in Patients with Relapsed/Refractory B-Cell NHL in China

Background: The combination of immunochemotherapy resulted in satisfactory efficacy and survival for B-cell Non-Hodgkin Lymphoma (NHL). But many patients face no response to combination therapy or the disease progression again. This study aimed to investigate the efficacy and safety of Inotuzumab Ozogamicin (InO) combined with reduce dose R-GDP as a salvage therapy in patients with relapsed/refractory (R/R) B-NLH. Patients and methods: Seven patients with R/R B-NLH or even failure of anti-CD19 and CD22 chimeric antigen receptor (CAR) T cell therapy received InO combined with reduce dose R-GDP combination therapy. All patients received Rituximab (R) 375mg/m 2 intravenously (IV) on day -1, and InO 0.8 mg/m 2 (IV) on day 0. Then Gemcitabine (G) 500-1000mg/m 2(IV), Dexamethasone (D) 40 mg/day (IV) on day 1-4 and Cisplatin (P) 40-75mg/m 2 (IV) on day 1 of each 21-day cycle (±2 days). Treatment was continued for up to two cycles unless progressive disease (PD) or intolerable toxicity occurred. The primary endpoint of this study was the Complete remission (CR) and Overall response rate (ORR). The secondary endpoint of this study was Progression-free survival (PFS), Overall survival (OS) and Adverse events (AE), particularly hematological toxicity. In our study, the response evaluation was detected using computed tomography (CT) or PET-CT. Results: Seven patients with R/R B-NLH received 1-2 cycles of InO combined with reduce dose R-GDP therapy. Three patients did not respond to anti-CD19 and CD22 CAR-T cell therapy or their disease progressed again. The other four patients did not respond to more than 3 lines of combined immunochemotherapy and never achieved Partial response (PR) or CR. Four patients with R/R B-NLH who received 1-2cycles of InO combined with reduce dose R-GDP therapy achieved CR and survived to this day. Three of the four patients had previously received anti-CD19 and CD22 CAR-T cell therapy. Two patients with R/R B-NLH achieved PR after one cycle of InO combined with reduce dose R-GDP therapy, the other one patient achieved Stable disease (SD) only. One R/R B-NLH patient who achieved CR after one cycle of this salvage therapy had a PFS of one year to date without any other treatments. The other three R/R B-NLH patients who achieved CR after 1-2 cycles of this salvage therapy had a PFS of 3-6 months without any other treatments. The other two patients who achieved PR after 1 cycle of this salvage therapy survived 7 months and 2 months, while the only one patient who achieved SD survived one month without any other treatment. The main AE of this study was hematological toxicity. Three patients were defined as 3-4 grade of neutropenia, four patients were defined as 3-4 grade of anemia and three patients were defined as 3-4 grade of thrombocytopenia in this study. Except for one patient who was defined as grade 3 of thrombocytopenia recovered nine months after this salvage therapy, all other patients recovered two to three months after this study. There have been no deaths from severe infections due to hematological toxicity. Conclusions Ino combined with reduce dose R-GDP therapy in patients with R/R B-NLH could be an effective and safety therapy. However, the GDP regimen needs to be reduced appropriately to avoid severe hematological toxicity.

Adjuvant Concurrent Chemoradiotherapy vs. Radiotherapy Alone in Cervical Cancer Patients with Intermediate-Risk Factors after Radical Surgery

For early-stage cervical cancer patients with intermediate-risk factors, there is no consensus about whether postoperative concurrent chemoradiotherapy (CCRT) is superior to radiotherapy (RT) alone. We retrospectively reviewed medical records of stage I-IIA cervical cancer patients underwent radical surgery and postoperative RT or CCRT from June 2012 to December 2017. Patients with any of the high-risk factors including positive pelvic lymph node, positive resection margin, and parametrial invasion were excluded. Patients with any of the intermediate-risk factors including large tumor size (≥4cm), deep stromal invasion (≥1/2), and lymphovascular space involvement were included. 1:1 propensity score matching was performed to balance baseline variables between patients receiving RT and CCRT. A total of 350 patients were enrolled (84 underwent RT alone and 266 underwent CCRT). The median follow-up period was 50.4 months. For patients underwent RT alone and CCRT, the 5-year overall survival (OS) rates were 93.4% and 93.8% (p = 0.741), the 5-year disease-free survival (DFS) rates were 90.6% and 91.4% (p = 0.733), respectively. 83 pairs of patients were enrolled based on propensity score matching. Similarly, there was no significant difference between OS or DFS rates of those matched patients. For patients with single intermediate-risk factor who received RT alone (n = 58) and CCRT (n = 132), the 5-year OS rates were 94.2% and 95.7% (p = 0.636), the 5-year DFS rates were 92.8% and 94.1% (p = 0.637). For patients with multiple intermediate-risk factors who received RT alone (n = 26) and CCRT (n = 134), the 5-year OS rates were 91.8% and 91.7% (p = 0.761), the 5-year DFS rates were 85.4% and 88.4% (p = 0.717). The cox regression analysis also indicated that adjuvant CCRT or RT was not an independent prognostic factor for OS or DFS. Otherwise, patients underwent CCRT seemed to develop a higher proportion of grade 3 or higher acute hematologic toxicities than RT group (45.5% and 14.3%, p<0.001). There was no significant difference in OS and DFS between cervical cancer patients with intermediate-risk factors receiving postoperative CCRT and RT alone. Patients underwent CCRT seemed to develop a higher proportion of severe hematologic toxicities than RT alone. To a certain extent, CCRT is not superior to RT alone for intermediate-risk patients.

A Dosimetric Study Indicates the Spinal Cord Irradiation Contributes to Acute Hematologic Toxicities in Non-Small Cell Lung Cancer Patients Receiving Radiotherapy Combined with Immunotherapy

To assess the radiation therapy (RT) dose to radiation-associated hematologic toxicities (HTs) in patients with non-small cell lung cancer (NSCLC) after RT combined with immunotherapy. Cases of NSCLC treated with RT combined with immunotherapy at Shandong Cancer Hospital in China were identified. The mean dose and the volume of the spinal cord receiving at least 5 to 40 Gy (V5-V40) were retrospectively recorded. Logistic regression was used to estimate associations between grade ≥3 HT (HT3+) and dosimetric/clinical parameters. Receiver operating characteristic analysis was used to determine dosimetric cut-points. Ninety-nine patients were analyzed. The majority were male (n = 78, 78.8%) and received chemotherapy (n = 83, 83.9%). All patients received either anti-PD-1 immune checkpoint (n = 89, 89.9%) or anti-PD-L1 immune checkpoint (n = 10, 10.1%) therapy. The rate of HT3+ was 24.2% (n = 24). Spinal cord mean dose, V5 to V40 and BMI parameters associated with HT3+ were included in the multivariate analysis. On multivariate analysis, increasing mean spinal cord dose (per Gy) was associated with higher odds of developing HT3+ (odds ratio 1.053, 95% confidence interval 1.002-1.105, P = .041), as were increasing spinal cord V5 to V20 (As show in the Table below). The optimal cut-points identified were V5 = 52.5%, V10 = 47.5%, V20 = 39.4%, and mean dose = 23.3 Gy. Patients with values above these cut-points had an approximately 2-fold increased risk of HT3+. We found that mean spinal cord dose and low-dose parameters (V5-V20) were associated with HT3+ in NSCLC patients after RT and immunotherapy. The mean dose of the spinal cord should be kept lower than 23.3 Gy for these patients. These data suggested that efforts to spare doses to the spinal cord might reduce rates of severe HT.

Predicting Severe Haematological Toxicity in Gastrointestinal Cancer Patients Undergoing 5-FU-Based Chemotherapy: A Bayesian Network Approach.

Severe toxicity is reported in about 30% of gastrointestinal cancer patients receiving 5-Fluorouracil (5-FU)-based chemotherapy. To date, limited tools exist to identify at risk patients in this setting. The objective of this study was to address this need by designing a predictive model using a Bayesian network, a probabilistic graphical model offering robust, explainable predictions. We utilized a dataset of 267 gastrointestinal cancer patients, conducting preprocessing, and splitting it into TRAIN and TEST sets (80%:20% ratio). The RandomForest algorithm assessed variable importance based on MeanDecreaseGini coefficient. The bnlearn R library helped design a Bayesian network model using a 10-fold cross-validation on the TRAIN set and the aic-cg method for network structure optimization. The model's performance was gauged based on accuracy, sensitivity, and specificity, using cross-validation on the TRAIN set and independent validation on the TEST set. The model demonstrated satisfactory performance with an average accuracy of 0.85 (±0.05) and 0.80 on TRAIN and TEST datasets, respectively. The sensitivity and specificity were 0.82 (±0.14) and 0.87 (±0.07) for the TRAIN dataset, and 0.71 and 0.83 for the TEST dataset, respectively. A user-friendly tool was developed for clinical implementation. Despite several limitations, our Bayesian network model demonstrated a high level of accuracy in predicting the risk of developing severe haematological toxicity in gastrointestinal cancer patients receiving 5-FU-based chemotherapy. Future research should aim at model validation in larger cohorts of patients and different clinical settings.

A prediction model for severe hematological toxicity of BTK inhibitors.

Bruton's tyrosine kinase inhibitor (BTKi) has revolutionized the treatment of B-cell lymphomas. However, BTKi-related hematological toxicity hinders treatment continuity and may further affect clinical efficacy. To identify risk factors and predict the likelihood of BTKi-related hematological toxicities, we constructed and validated a prediction model for severe hematological toxicity of BTKi. Approved by the hospital medical science research ethics committee (No. M2022427), we collected real-world data in patients treated with BTKi from a Lymphoma Research Center in China. The outcome of interest was severe hematological toxicity caused by BTKi. 36 candidate variables were categorized into demographics, diagnostic and treatment information, laboratory data, and medical history. The study sample was randomly divided into training (70%) and validation (30%) sets. We developed and compared the performance of various modelling methods, including decision tree (DT), random forest (RF), gradient boosting decision tree (GBDT), extreme gradient boosting (XGBoost), light gradient boosting machine (LightGBM), and logistic regression (LR). Finally, we constructed a Web-calculator of the optimal model to estimate the risk of hematological toxicity. This study was designed, conducted and reported strictly in compliance with the TRIPOD checklist. Data from a total 121 patients were included [median age, 65years (range, 56-73years); 74 (61.15%) men; 47 (38.84%) severe hematological toxicity]. The XGBoost model demonstrated better overall properties than other models, achieving high discrimination (AUC: 0.671; accuracy: 0.730; specificity: 0.913) and clinical benefit. The following 10 variables were used to develop the XGBoost model: white blood cell count (WBC), neutrophil count (Neut), red blood cell count (RBC), platelet count (PLT), fibrinogen (Fib), total protein (TP), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), gender and type of BTKi. SHAP values demonstrated insightful associations between these variables and hematological toxicity. Finally, to facilitate clinical and research use, we also deploy the XGBoost model on a web-calculator for free access. The XGBoost model with promising accuracy was developed to predict the severe hematological toxicity of BTKi. It helps to strengthen the proactive monitoring and management of patients with hematological toxicity, and thus achieve long-term continuous BTKi treatment.

Iminosugar-Based Nicotinamide Phosphoribosyltransferase (NAMPT) Inhibitors as Potential Anti-Pancreatic Cancer Agents.

The nicotinamide phosphoribosyltransferase (NAMPT) is considered a very promising therapeutic target because it is overexpressed in pancreatic cancer. Although many inhibitors have been prepared and tested, clinical trials have shown that NAMPT inhibition may result in severe haematological toxicity. Therefore, the development of conceptually new inhibitors is an important and challenging task. We synthesized ten β-d-iminoribofuranosides bearing various heterocycle-based chains carbon-linked to the anomeric position starting from non-carbohydrate derivatives. They were then submitted to NAMPT inhibition assays, as well as to pancreatic tumor cells viability and intracellular NAD+ depletion evaluation. The biological activity of the compounds was compared to that of the corresponding analogues lacking the carbohydrate unit to assess, for the first time, the contribution of the iminosugar moiety to the properties of these potential antitumor agents.

Predictive factors associated with pemetrexed acute toxicity

Pemetrexed has shown efficacy as monotherapy or in combination with platinum salts in the treatment of non-small cell lung cancer and mesothelioma. However, severe hematological toxicities induced by pemetrexed-based chemotherapy have been observed. Some studies have suggested that drug interactions may be associated with pemetrexed toxicity. The objective of this study was to determine predictive factors, including drug interactions, associated with pemetrexed toxicity. This retrospective open monocentric study included patients consecutively treated with pemetrexed after a multidisciplinary risk assessment. Patients who experienced toxicity of grade 3 or 4 according to the Common Terminology Criteria for Adverse Events v5.0, or a grade 2 leading to a change in management, during the first four courses of pemetrexed, were assigned to the early limiting toxicities (ELT) group. Univariate and multivariable logistic regression models were used to test the association variables with the occurrence of ELT. Seventy-four patients were included in this study (median age: 67years, with non-small cell lung cancer adenocarcinoma (88%), mesothelioma (7%), or others (5%). Thirty-six patients (49%) were assigned to the ELT group (27 grades 3 and 4; 9 grade 2 with management modification). Three baseline factors were associated with pemetrexed ELT in univariate and multivariate analysis: cystatin clearance (p = 0.0135), albumin level (p = 0.0333), and proton pump inhibitors use (p = 0.035). To conclude, ELT induced by pemetrexed-based treatments occur frequently in cancer patients in a real-world setting. A pretherapeutic assessment before pemetrexed initiation should include three major checkpoints: use of proton pump inhibitors, sarcopenia, and denutrition evaluation.

A Pharmacokinetic-Pharmacodynamic Model Predicts Uracil-tegafur Effect on Tumor Shrinkage and Myelosuppression in a Colorectal Cancer Rat Model.

Oral 5-fluorouracil (5-FU)-based prodrugs, used in cancer chemotherapeutic regimens, exhibit large inter- and intra-patient variability in plasma 5-FU concentrations, contributing to treatment failure. Although dosage determination criteria according to plasma drug concentrations are required, the relationship between pharmacokinetics and drug response after multiple oral 5-FU derivative administrations remain unknown. We evaluated the pharmacokinetics and pharmacodynamics/toxicodynamics of uracil-tegafur (UFT) after multiple administrations in colorectal cancer (CRC) model rats, and applied a pharmacometric approach to describe the time-course alterations of plasma 5-FU concentrations and tumor shrinkage. CRC was induced in rats using 1,2-dimethylhydrazine and dextran sulfate sodium. UFT (30 mg/kg as tegafur) was administered to CRC rats for 14 days. Plasma 5-FU exposure levels increased with the dosing time, and large variations were observed in tumor 5-FU concentrations (32.0-125.8% with coefficient of variation). Although severe hematological toxicities were not observed, a weak correlation was observed between blood platelet count and the plasma 5-FU concentration (r=0.439, p=0.176). A simple pharmacokinetic-pharmacodynamic model was developed comprising of a small number of parameters and successfully describing plasma 5-FU levels and tumor shrinkage after multiple UFT administrations. A pharmacometric model approach can help establish the dose-determination criteria based on plasma 5-FU concentration of UFT-based regimens, and contribute to improvement of clinical outcomes.

Influence of Genetic Variations in miRNA and Genes Encoding Proteins in the miRNA Synthesis Complex on Toxicity of the Treatment of Pediatric B-Cell ALL in the Brazilian Amazon

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer in the world. Single nucleotide variants (SNVs) in miRNA and genes encoding proteins of the miRNA synthesis complex (SC) may affect the processing of drugs used in the treatment of ALL, resulting in treatment-related toxicities (TRTs). We investigated the role of 25 SNVs in microRNA genes and genes encoding proteins of the miRNA SC, in 77 patients treated for ALL-B from the Brazilian Amazon. The 25 SNVs were investigated using the TaqMan® OpenArray™ Genotyping System. SNVs rs2292832 (MIR149), rs2043556 (MIR605), and rs10505168 (MIR2053) were associated with an increased risk of developing Neurological Toxicity, while rs2505901 (MIR938) was associated with protection from this toxicity. MIR2053 (rs10505168) and MIR323B (rs56103835) were associated with protection from gastrointestinal toxicity, while DROSHA (rs639174) increased the risk of development. The rs2043556 (MIR605) variant was related to protection from infectious toxicity. SNVs rs12904 (MIR200C), rs3746444 (MIR499A), and rs10739971 (MIRLET7A1) were associated with a lower risk for severe hematologic toxicity during ALL treatment. These findings reveal the potential for the use of these genetic variants to understand the development of toxicities related to the treatment of ALL in patients from the Brazilian Amazon region.

Imatinib-induced severe hematological toxicity: Prolonged myelosuppression resulting from extraordinary sensitivity in an old age

The advent of tyrosine kinase inhibitors (TKIs) has profoundly changed the therapeutic landscape of chronic myeloid leukemia (CML) in the chronic phase (CML-CP). Imatinib is the first-generation, and the first and as yet the most widely used TKI, and the recommended dose is 400 mg/day for treating CML-CP. Most patients tolerate this treatment well, and prolonged hematological toxicities have rarely been reported. In this manuscript, we report a newly diagnosed CML-CP patient who developed prolonged myelosuppression (lasting for more than three months) following only one week of imatinib at 400 mg/day as the solitary treatment. Imatinib was discontinued, and pancytopenia persisted, with a continuous decrease in hemoglobulin levels. After restoration of autologous hematopoiesis, reintroduction of imatinib at 100 mg/day resulted in recurrent myelosuppression, and subsequent treatment with imatinib at 50 mg/day achieved good hematological homeostasis. We hypothesized that extraordinary sensitivity resulted in severe and prolonged myelosuppression.

Efficacy and survival analysis of nimotuzumab combined with concurrent chemoradiotherapy in the treatment of locally advanced nasopharyngeal carcinoma.

This study investigated the curative effect of adding nimotuzumab (NTZ) in patients with locally advanced nasopharyngeal carcinoma (NPC) who were treated with concurrent chemoradiotherapy (CCRT) and explored significant prognostic factors of NPC. The clinical data of 307 patients with NPC treated in the First Affiliated Hospital of Soochow University from January 2013 to December 2018 were retrospectively analyzed. The patients were divided into the NTZ-CCRT group and the CCRT group according to whether they were associated with NTZ. We applied propensity score matching to reduce the interference of biases and compared the short-term efficacy and long-term survival rate of the two groups. Moreover, univariate and multivariate analyses were performed for all patients, and subgroup analysis was used to compare the efficacy of therapy combined with NTZ in different subgroups. In primary nasopharyngeal tumors, the objective response rates in the NTZ-CCRT group and CCRT group were 95.8% and 85.7%, respectively (P =0.007). In cervical positive lymph nodes, the objective response rates in the NTZ-CCRT group and CCRT group were 98.3% and 87.4%, respectively (P =0.001). Compared with CCRT alone, the addition of NTZ significantly improved the 5-year OS (94.1% vs. 81.8%, P=0.014) and the 5-year DFS (84.2% vs. 75.5%, P=0.031) of NPC patients; however, the addition of NTZ was accompanied by more severe hematologic toxicity and acute oral mucositis. Multivariate analysis demonstrated that the addition of NTZ was an important prognostic factor for OS and DFS (HR 0.367, 95% CI 0.167-0.808, P=0.013 for OS and HR 0.536, 95% CI 0.312-0.919, P=0.023 for DFS) and the level of pretreatment LDH (HR 5.170, 95% CI 2.125-12.580, P<0.001 for OS and HR 2.421, 95% CI 1.027-5.707, P=0.043 for DFS). Moreover, patients with high levels of hsCRP before treatment (HR 0.389, 95% CI 0.177-0.853, P=0.018) may gain more benefits from combined treatment with NTZ. For locally advanced NPC patients treated with concurrent chemoradiotherapy, the addition of NTZ can significantly improve their survival outcome. However, it is necessary to guard against the associated increase in hematological toxicity and acute oral mucositis.

A radiomics approach for predicting acute hematologic toxicity in patients with cervical or endometrial cancer undergoing external-beam radiotherapy

PurposeThis study is purposed to establish a predictive model for acute severe hematologic toxicity (HT) during radiotherapy in patients with cervical or endometrial cancer and investigate whether the integration of clinical features and computed tomography (CT) radiomics features of the pelvic bone marrow (BM) could define a more precise model. MethodsA total of 207 patients with cervical or endometrial cancer from three cohorts were retrospectively included in this study. Forty-one clinical variables and 2226 pelvic BM radiomic features that were extracted from planning CT scans were included in the model construction. Following feature selection, model training was performed on the clinical and radiomics features via machine learning, respectively. The radiomics score, which was the output of the final radiomics model, was integrated with the variables that were selected by the clinical model to construct a combined model. The performance of the models was evaluated using the area under the receiver operating characteristic curve (AUC). ResultsThe best-performing prediction model comprised two clinical features (FIGO stage and cycles of postoperative chemotherapy) and radiomics score and achieved an AUC of 0.88 (95% CI, 0.81–0.93) in the training set, 0.80 (95% CI, 0.62–0.92) in the internal-test set and 0.85 (95% CI, 0.71–0.94) in the external-test dataset. ConclusionThe proposed model which incorporates radiomics signature and clinical factors outperforms the models based on clinical or radiomics features alone in terms of the AUC. The value of the pelvic BM radiomics in chemoradiotherapy-induced HT is worthy of further investigation.

DNA-PKcs inhibitors sensitize neuroendocrine tumor cells to peptide receptor radionuclide therapy in vitro and in vivo.

Background: Peptide receptor radionuclide therapy (PRRT) increases progression-free survival and quality of life of neuroendocrine tumor (NET) patients, however complete cures are rare and dose-limiting toxicity has been reported. PRRT induces DNA damage of which DNA double strand breaks (DSBs) are the most cytotoxic. DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a key player in DSB repair and its inhibition therefore is a potential way to enhance PRRT efficacy without increasing the dosage. Methods: We analyzed effects of combining PRRT and DNA-PKcs inhibitor AZD7648 on viability, cell death and clonogenic survival on SSTR2-expressing cell lines BON1-SSTR2, GOT1 and NCI-H69. Therapy-induced DNA damage response was assessed by analyzing DSB foci levels and cell cycle distributions. In vivo efficacy was investigated in BON1-SSTR2 and NCI-H69 xenografted mice and hematologic and renal toxicity were monitored by blood counts, creatinine levels and analyzing renal morphology. Results: Combining PRRT and AZD7648 significantly decreased viability of BON1-SSTR2, GOT1 and NCI-H69 cells and induced cell death in GOT1 and BON1-SSTR2 cells. A strong effect of AZD7648 on PRRT-induced DSB repair was found. In GOT1 cells, this was accompanied by induction of cell cycle blocks. However, BON1-SSTR2 cells were unable to fully arrest their cell cycle and polyploid cells with high DNA damage levels were detected. In vivo, AZD7648 significantly sensitized BON1-SSTR2 and NCI-H69 xenograft models to PRRT. In addition, combination therapy did not induce significant changes in body weight, blood composition, plasma creatinine levels and renal morphology, indicating the absence of severe acute hematologic and renal toxicity. Conclusion: These results highlight that the potentiation of the therapeutic effect of PRRT by DNA-PKcs inhibition is a highly effective and well-tolerated therapeutic strategy. Based on our findings, we recommend initiation of phase I/II studies in patients to find a safe and effective combination regimen.

Association of Hypometilating Agents (HMA) + Venetoclax (VEN) in the Treatment of Myeloproliferative Neoplasms in Blastic Phase (MPN-BP) and Acute Leukemias Evolved from Myelodysplastic Syndromes (AML-MDS) Already Treated with Azacytidine

Background Association of hypometilating agents (HMA) and venetoclax (VEN) is widely used in the treatment of elderly patients with de novo Acute Myeloid Leukemia (AML) not eligible for intensive chemotherapy, with improvement of survival. However, very few data are available about the use of this combined regimen in patients with Myeloproliferative Neoplasms evolved in blastic phase (MPN-BP) and in patients with AML secondary to Myelodysplastic Syndrome (AML-MDS) previously treated with HMA during the dysplastic phase. In both these settings the survival is dismal and at present no therapy seems to have a role. Methods Data of patients with MPN-BP and AML-MDS treated frontline with HMA+VEN in 20 hematological Italian Centers outside clinical trials were retrospectively collected and analysed. Patients treated with HMA + VEN as salvage therapy after induction failure/relapse were excluded. Composite overall response rate [ORR; complete remission (CR) + CR with incomplete hematologic recovery (iCR) + partial remission (PR) + hematological improvement (HI)], duration of response and overall survival (OS) were assessed. Results: A total of 64 patients (41 MPN-BP and 23 AML-MDS) treated between 11/2018 and 5/2022 were included. Baseline characteristics at evolution and starting treatment for the whole cohort and according to previous disease are reported in the Table 1. Median interval from initial MPN/MDS diagnosis to evolution was 31.5 months [interquartile range (IQR) 16.0 - 108.1] in the entire cohort [42.0 months (IQR 22.0 - 124.9) in MPN-BP and 18.8 months (IQR 10.9 - 39.8) in AML-MDS]. Patients were treated for a median of 2 courses (IQR 2-6): HMA were administered at standard dosage, VEN daily dose in the 1st cycle was 50 mg in 6 patients (9.4%), 100 mg in 27 patients (42.2%), 200 mg in 8 patients (12.5%) and 400 mg in 23 patients (35.9%), respectively. On the whole, 50/64 patients (78.1%) had at least one hematological toxicity of grade 3-4: in particular, severe neutropenia (PMN < 0.5 x 109/l) was reported in 46 patients (71.8%). Twenty-nine patients (45.3%) had at least one infective episode during the treatment: pulmonary infections were reported in 18 patients (28.1%). Response to treatment is shown in the Table 1: ORR was 60.0% (60.5% in MPN-BP and 59.1% in AML-MDS, respectively). Median response duration of the whole cohort was 5.3 months (95%CI 2.2-8.4), without significant differences in MPN-BP and AML-MDS patients [4.8 (95%CI 3.2 - 6.5) and 7.8 (95%CI 2.8 - 12.8) months, respectively (p=0.467)]. After a median follow-up of 6.1 months (IQR xx - xx) from the start of combined regimen, 37 patients (57.8%) died, 2 (3.1%) were lost to follow-up and 25 (39.1%) were alive. Median overall survival (OS) of the whole cohort was 7.2 months (95%CI 4.8-9.7), without differences between MPN-BP and AML-MDS groups [8.0 (95%CI 5.0 - 10.9) and 6.8 (95%CI 4.3 - 9.3) months, respectively (p=0.717, Figure 1)]. Patients with any type of response to the combination regimen had a significantly longer OS compared to patients with progressive/stable disease [11.6 (95%CI 8.2 - 14.9) and 5.4 (95%CI 2.8 - 7.9) months, respectively (p=0.006)]. Conclusions: Our real-life data confirm that HMA + VEN combination could have a role in these two very challenging subsets of secondary AML, with achievement of ORR > 50% in patients unfit for intensive approaches: however, this treatment is affected by severe hematological and infective toxicities and the response duration is short, leading to a persistently poor median OS. Larger cohorts of patients and a longer follow-up are needed to assess factors predictive of CR/iCR achievement, while the addition of other targeted therapies should be explored. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

High-Dose Idarubicin Plus Busulfan As Conditioning Regimen to Autologous Stem Cell Transplantation Improves Prognosis in Patients with Favorable and Intermediate-Risk AML

Introduction: The optimal post-remission therapy (PRT) for patients with favorable and intermediate-risk acute myeloid leukemia (AML) remains uncertain. We retrospectively analyzed and compared the efficacy of high-dose idarubicin plus busulfan conditioning regimen combined with autologous stem cell transplantation (ASCT) and intermediate- to high-dose cytarabine consolidation chemotherapy for post-remission treatment (PRT) in patients with favorable- and intermediate-risk AML. Methods: A total of 116 patients with favorable- and intermediate-risk AML according to 2022 ELN risk stratification who were treated with ASCT (n=58) or intermediate- to high-dose cytarabine regimen (n=58) were enrolled in this study. All the patients received IA regimen (idarubicin 10-12 mg/m2 on days 1 to 3 and cytarabine 100 mg/m2/d on days 1 to 7) as induction and complete remission (CR) was obtained in all the patients after one course of induction. Fifty-eight patients were subjected to 2-4 courses of intermediate- to high-dose cytarabine (cytarabine 2-3 g/m2 twice daily on days 1-3). High-dose idarubicin plus busulfan conditioning regimen (I-Bu; idarubicin 20 mg/m2 continuous i.v. from days -13 to -11, busulfan in intravenous formulation: 3.2 mg/m2 or oral formulation: 4.0 mg/m2 from day -5 to -2) combined with ASCT was given to the other 58 patients 2-3 courses of intermediate- to high-dose cytarabine and mobilization and collection of peripheral blood stem cells. Clinical outcomes were retrospectively analyzed for patients belonging to the two treatment arms. Results: The median age was 38 (14-60 years) and 32 years (14-59 years) in ASCT and chemotherapy cohort, respectively. After a median follow-up of 68 months (1-200 months), and the median overall survival (OS) has not been reached in both groups. The 5-year and 10-year OS in the ASCT group was 77.5% and 71.5%, and 5-year and 10-year disease-free survival (DFS) was 73.9% and 71.1%, respectively. The 5-year OS and DFS in the chemotherapy group were 53.5% and 52.4%, respectively. The median OS and DFS of the patients in ASCT group were significantly better than those in chemotherapy group (OS: p=0.009, HR=0.444, CI 0.237 to 0.831; DFS：p=0.018, HR=0.494,CI 0.268 to 0.911). No treatment-related early death (death within 8 weeks after treatment) was observed in the ASCT group. All the patients experienced severe bone marrow suppression and severe (grade 3 or 4) hematological toxicity, and we did not observe severe (grade 3 or 4) cardiotoxic complications during or after ASCT in all the patients. Conclusions: ASCT with I-Bu regimen is possibly a promising PRT for patients with favorable- and intermediate-risk AML in the first CR, improving prognosis of these patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Chemotherapy-Induced Toxicities and Their Associations with Clinical and Non-Clinical Factors among Breast Cancer Patients in Vietnam.

Understanding the burden and factors related to chemotherapy-induced toxicity is important in treatment planning for breast cancer patients. We conducted a prospective study among 396 newly diagnosed and chemotherapy-treated breast cancer patients recruited in two major cancer hospitals in northern Vietnam. Toxicities were captured through medical chart reviews and patient self-reports and graded using NCI CTCAE classification. Associations for sociodemographic and clinical factors with chemotherapy-induced toxicities during first-line chemotherapy were evaluated via multivariable logistic regression. Severe (i.e., grade ≥ 3) hematological (38.6%), and gastrointestinal (12.9%) toxicities were common. A pre-existing nephrological condition was significantly associated with the risk of severe hematological toxicity with adjusted odds ratios (OR) and 95% confidence intervals (CIs) of 2.30 (1.32-4.01). Patients living in rural areas had a lower risk of severe hematological toxicity (OR = 0.48; 95% CI, 0.30-0.77). Patients diagnosed with stage II and stage III-IV had a lower risk of severe gastrointestinal toxicity with ORs and 95% CIs of 0.26 (0.12-0.59) and 0.47 (0.20-1.10), respectively. Triple-negative/basal-like subtype was associated with a higher risk of severe hematological (OR = 3.15; 95% CI, 1.56-6.34) and gastrointestinal toxicities (OR = 3.60; 95% CI, 1.45-8.95) comparing to hormone receptor (HR)-positive HER2-negative subtype. Further research investigating underlying mechanisms would facilitate the development and delivery of personalized treatment and care plans.

Intravenous route for folate supplementation in a patient with celiac disease treated by pemetrexed-based chemotherapy for non-small-cell lung cancer.

Oral folic acid supplementation is essential for patients treated with pemetrexed, to prevent the risk of severe hematologic toxicity. In case of intestinal absorption disorder, no recommendations exist for intravenous folic acid supplementation. We describe a 74-year-old patient with multimetastatic non-small-cell lung adenocarcinoma, receiving first-line chemotherapy with carboplatin AUC5, pemetrexed 500 mg/m2 and pembrolizumab 200 mg intravenously every 3 weeks. The patient presented neglected celiac disease, resulting in malabsorption syndrome with iron and folic acid deficiency. The question was how to administer folic acid supplementation during the pemetrexed-based chemotherapy. Intravenous injection of 200 mg levoleucovorin on day 1 of cycle 1 of pemetrexed-based chemotherapy was administered and well tolerated. During the second cycle, the levoleucovorin perfusion was not renewed by omission. The patient was hospitalized for 7 days because of febrile aplasia. Piperacillin-tazobactam was started, and then switched to amoxicillin-clavulanate plus ciprofloxacin. After this episode of post-chemotherapy febrile aplasia, it was decided to systematically supplement the patient with intravenous levoleucovorin, with blood folate concentration monitoring at each cycle. At 16 months after start of treatment, the patient was in complete remission, indicating that the immune-chemotherapy was effective, with no further febrile neutropenia. This case report highlights intravenous levoleucovorin supplementation as an alternative to oral folic acid if needed during pemetrexed-antifolate-based chemotherapy.

FRI237 - FIB-4 predicts severe hematological toxicity and 6-month mortality in older patients with cancer: ELCAPA-LIVER.

FRI237 - FIB-4 predicts severe hematological toxicity and 6-month mortality in older patients with cancer: ELCAPA-LIVER.

Pelvic bones ADC could help to predict severe hematologic toxicity in patients undergoing concurrent chemoradiotherapy for cervical cancer

BackgroundHematologic toxicity (HT) during concurrent chemoradiotherapy (CCRT) for cervical cancer can lead to treatment breaks and compromise efficacy. PurposeTo evaluate the association between severe hematologic toxicity (HT) and clinical factors and pelvic apparent diffusion coefficient (ADC) during CCRT of cervical cancer patients. MethodsData from 120 patients with cervical cancer who were treated with CCRT from January 2016 and December 2018 were retrospectively analyzed. The clinical data (age, menopausal status, clinical stage, body mass index, chemotherapy regimen and chemotherapy cycle) of the patients were collected, and the cohort were divided into two groups based on the HT grade: HT3+ group (HT grade ≥ 3; 66 patients) and HT3- group (HT grade<3; 54 patients). All patients performed MRI before CCRT, and pelvic (ilium, pubis, ischium) ADC value was measured on ADC map. The correlation between severe HT and clinical parameters and pelvic ADC value were analyzed by univariate analysis, and the diagnostic performance was further assessed by receiver operating characteristic (ROC) analysis. ResultsIn univariate analysis, the menopausal status (p = 0.012) and chemotherapy regimen (p = 0.011) were significantly correlated with severe HT in overall patients, and menopausal patients or patients receiving paclitaxel plus cisplatin (TP) regimen were more likely to develop severe HT. HT3+ group showed a significantly lower pelvic ADC value than HT3- group. The ADC value cut-offs derived from our study for predicting severe HT was 0.317 × 10−3 mm2/s in overall patients. Neither clinical parameters nor pelvic ADCs were associated with severe HT in menopausal patients when analyzed separately (p > 0.05). ConclusionsSevere HT was significantly associated with menopausal status and chemotherapy regimen in patients with cervical cancer treated with CCRT, and HT3+ group showed a lower pelvic ADC value.

Baseline predictors of hematological toxicity in patients with advanced cancer treated with ATR inhibitors in phase I/II clinical trials.

3111 Background: Ongoing trials are exploring ATR inhibitors (ATRi) in genomically selected contexts. However, myelosuppression, particularly anemia, has limited the therapeutic window of this class of drugs. We sought to discover clinical biomarkers predicting severe hematological toxicity from ATRi. Methods: We retrospectively analyzed clinical parameters and peripheral blood cell indices retrieved from complete blood count (CBC) reports of patients (pts) pre- and during treatment with an oral ATRi on phase I/II trials at our center. Pts received ATRi monotherapy or in combination with a PD1 inhibitor (PD1i) or a PARP inhibitor (ATRi+PARPi) in dose-escalation and expansion cohorts, which included ATRi at potentially toxic doses. Results: 37553 indices from 2209 CBC reports of 141 pts treated with an ATRi from 10/2017 to 1/2022 were analyzed. 132 (93.6%) pts received ATRi +/- PD1i; 9 (6.4%) pts received ATRi+PARPi. The incidences of ≥ grade (G) 3 anemia, neutropenia and thrombocytopenia were 47.5%, 31.9% and 11.4%. 73/141 (51.8%) pts received red cell transfusion. Baseline risk factors predicting ≥G3 anemia on univariate analysis included: lower median (med) hematocrit (Hct) (hazard ratio (HR) (95% confidence interval) = 3.05 (1.82, 5.13) ≤med vs &gt; med; p &lt; 0.0001), hemoglobin (Hb) (HR = 2.74 (1.64,4.57) ≤med vs &gt; med; p = 0.0001), mean corpuscular Hb concentration (HR = 1.85 (1.11,3.10) ≤med vs &gt; med; p = 0.019); and higher median immature reticulocyte fraction (HR = 0.43 (0.25,0.71) ≤med vs &gt; med; p = 0.0012), reticulocyte count (ct) (HR = 0.59 (0.35,0.97) ≤med vs &gt; med; p = 0.037) and red cell distribution width (RDW) (HR = 0.54 (0.33,0.88) ≤med vs &gt; med; p = 0.015). On multivariate analysis, lower median Hct (HR = 3.76 (2.15, 6.6) ≤med vs &gt; med; p &lt; 0.0001), higher immature granulocyte ct (HR = 1.71 (1.30, 2.25) per 1 fold increase; p = 0.0001), higher RDW (HR = 7.83 (1.70, 36.03) per 1 fold increase; p = 0.0082) and higher ATRi starting dose (HR = 1.40 (1.05, 1.86) per 1 fold increase; p = 0.022) significantly predicted ≥G3 anemia risk. Baseline risk factors for ≥G3 neutropenia on univariate analysis included: lower median absolute neutrophil ct (ANC) (HR = 2.26 (1.18, 4.33) ≤med vs &gt; med; p = 0.015) or white blood cell ct (WBC) (HR = 2.73 (1.40, 5.33) ≤med vs &gt; med; p = 0.0032). On multivariate analysis, lower median WBC (HR = 2.85 (1.45, 5.59) ≤med vs &gt; med; p = 0.0024) was associated with higher risk of neutropenia, while ATRi+PARPi increased risk of neutropenia (ANC &lt; 0.75) (HR = 4.15 (1.40, 12.3); p = 0.01) and thrombocytopenia (HR = 3.90 (1.47, 10.4); p = 0.0064). Conclusions: ≥G3 anemia was frequent in pts receiving ATRi. At baseline, lower median Hct and higher RDW predict severe anemia, while lower WBC predicts neutropenia from ATRi. ATRi+PARPi has increased risk of neutropenia and thrombocytopenia vs ATRi +/- PD1i. These indices may inform patient selection and CBC monitoring for future ATRi trials.