Incidence Of Hematologic Toxicity Research Articles

Effects of bone marrow sparing radiotherapy on acute hematologic toxicity for patients with locoregionally advanced cervical cancer: a prospective phase II randomized controlled study

ObjectiveTo evaluate effects of bone marrow sparing (BMS) radiotherapy on decreasing the incidence of acute hematologic toxicity (HT) for locoregionally advanced cervical cancer (LACC) patients treated by pelvic irradiation.Materials and methodsLACC patients were recruited prospectively from May 2021 to May 2022 at a single center and were evenly randomized into the BMS group and the control group. All patients received pelvic irradiation with concurrent cisplatin (40 mg/m2 weekly), followed by brachytherapy and BM V40 < 25% in the BMS group was additionally prescribed. Acute HT was assessed weekly. Binary logistic regression model and receiver operating characteristic (ROC) curve were used for predictive value analysis. The trial was registered with Chinese clinical trial registry (ChiCTR2200066485).ResultsA total of 242 patients were included in the analysis. Baseline demographic, disease and treatment characteristics were balanced between the two groups. In the intention-to-treat population, BMS was associated with a lower incidence of grade ≥ 2 and grade ≥ 3 acute HT, leukopenia and neutropenia s(72.70% v 90.90%, P < 0.001*; 16.50% vs. 65.30%, P < 0.001*; 66.10% vs. 85.10%, P = 0.001*; 13.20% vs. 54.50%, P < 0.001*; 37.20% vs. 66.10%, P < 0.001*; 10.70% vs. 43.80%, P < 0.001*). BMS also resulted in decreased dose delivered to the organs at risk (OARs) including rectum, bladder and left and right femoral head. Univariate and multivariate analyses showed that BM V40 was an independent risk factor for grade ≥ 3 acute HT (odds ratio [OR] = 2.734, 95% confidence interval [CI] = 1.959–3.815, P < 0.001*). Cutoff value was 25.036% and area under the curve (AUC) was 0.786. The nomogram was constructed, which was rigorously evaluated and internally cross-validated, showing good predictive performance.ConclusionsReceiving BMS pelvic irradiation could reduce the incidence of acute HT in LACC patients, and BM V40 < 25% may be a significant factor in reducing the risks of acute HT.

Tislelizumab plus chemotherapy is an optimal option for second-line treatment for advanced gastroesophageal junction adenocarcinoma.

The development of programmed cell death receptor-1 and its ligand (PD-L1) have offered new treatment options for several cancers, but the clinical benefit of tislelizumab in the gastroesophageal junction (GEJ) adenocarcinoma is still murky. Thus, we aim to investigate the efficacy and safety of tislelizumab combined with chemotherapy in patients with GEJ cancer. In this study, 90 GEJ patients were retrospectively enrolled including 45 patients who received chemotherapy plus tislelizumab while 45 underwent chemotherapy only. Overall response rate (ORR), overall survival (OS), and progression-free survival (PFS) were estimated and safety was assessed by treatment-related adverse events between two arms. The ORR was significantly higher in the tislelizumab group than in patients with chemotherapy alone (71.1 vs. 44.4%). The PFS [54.7% (47.2-62.2) vs. 33.3% (26.3-40.3), P = 0.047] and OS [62.1% (54.5-69.7) vs. 40.0% (32.5-47.5), P = 0.031] were also significantly improved in patients with concomitant use of tislelizumab. When stratified by PD-L1 combined positive score (CPS), patients with PD-L1 CPS ≥ 1 also with significantly higher PFS and OS when taking tislelizumab (P = 0.015 and P = 0.038). The incidence of hematologic toxicity was similar in the combination arm compared to the chemotherapy alone arm and the number of adverse events was not significantly increased by adding tislelizumab (all P > 0.05). Concomitant use of tislelizumab and chemotherapy in GEJ patients may be with optimal therapeutic effect and similar incidence of adverse events than chemotherapy alone. Further studies with larger number of patients are warranted to confirm it.

Effects of intensity-modulated radiotherapy combined with chemotherapy and prognostic factors in patients with locally advanced oesophageal cancer

PurposeWe explored the efficacy and influencing factors of chemoradiotherapy and radiotherapy alone in patients with locally advanced oesophageal squamous cell carcinoma. MethodsWe retrospectively analysed 226 locally advanced oesophageal squamous cell carcinoma patients who underwent chemoradiotherapy and radiotherapy alone. Univariate and multivariate Cox regression analyses were used to analyse the impact of relevant factors. The endpoint was overall survival and progression-free survival. ResultsCompared with the radiotherapy group, the chemoradiotherapy group had a significant difference in the overall survival rate and the progression-free survival rate between 3 and 5 years (both p ​< ​0.05). The incidences of radiation pneumonitis and radiation oesophagitis were analysed, and the differences were not significant (all p ​> ​0.05). The incidence of haematological toxicity in the chemoradiotherapy group was significantly higher than that in the radiotherapy group (p ​= ​0.001). There was a significant difference in the incidence of haematological toxicity between the ≤65 and the >65 age groups (p ​< ​0.05). Tumour location, T stage, tumour length, tumour target volume, and short-term curative effect were the main factors affecting the prognosis (all p ​< ​0.05). T stage, gross tumour volume, and short-term curative effect were all independent factors affecting the prognosis (all p ​< ​0.05). ConclusionsPatients with locally advanced oesophageal cancer who received intensity-modulated radiotherapy (IMRT) combined with chemotherapy had significant survival benefits compared with radiotherapy alone. Haematological toxicity was the main adverse reaction. T-stage, gross tumour volume and short-term curative effect were independent factors influencing the prognosis.

Induction chemoimmunotherapy may improve outcomes of chemoradiotherapy in patients with unresectable stage III NSCLC.

Currently, the value of induction chemoimmunotherapy before chemoradiotherapy (CRT) in unresectable stage III non-small cell lung cancer (NSCLC) has not been explored. This study was designed to explore the efficacy and safety of induction chemoimmunotherapy in patients with unresectable stage III NSCLC. Unresectable stage III NSCLC patients who received CRT with or without induction chemoimmunotherapy between August 2014 and December 2021 were retrospectively enrolled. Progression-free survival (PFS) and overall survival (OS) were assessed from the initiation of treatment and estimated by the Kaplan-Meier method. The potential factors affecting PFS and OS were analyzed by univariate and multivariate Cox regression models. One-to-one propensity score matching (PSM) was used to further minimize confounding. A total of 279 consecutive patients were enrolled, with 53 (19.0%) receiving induction chemoimmunotherapy followed by CRT (I-CRT group), and the remaining 226 (81.0%) receiving CRT alone (CRT group). After PSM, the median PFS was 24.8 months in the I-CRT group vs. 13.3 months in the CRT group (P=0.035). The median OS was not reached (NR) vs. 36.6 months ((P=0.142). The incidence of treatment-related adverse events (TRAEs) was similar in both groups, except that the incidence of hematological toxicity was higher in the I-CRT group (77.1% vs. 58.3%, P=0.049). Compared to induction chemotherapy, induction chemoimmunotherapy demonstrated a superior objective response rate (60.4% vs. 22.2%, P<0.001) and further prolonged PFS (median NR vs. 13.2 months, P=0.009) and OS (median NR vs. 25.9 months, P=0.106) without increasing the incidence of TRAEs in patients receiving concurrent chemoradiotherapy. Induction chemoimmunotherapy is safe and may improve outcomes of CRT in patients with unresectable stage III NSCLC. Moreover, induction chemoimmunotherapy may further improve treatment response and survival outcomes compared to induction chemotherapy before cCRT.

Linezolid-induced haematological toxicity

Objectiveto determine the incidence of linezolid-induced haematological toxicity and study the influence of renal clearance on its appearance and the preventive effect of pyridoxine. Methoda retrospective observational study was conducted. Every patient treated with linezolid in a university hospital during 6 months was included. Haematological toxicity was defined as a decrease of 25% in hemoglobin, of 25% in platelets and/or 50% in neutrophils from baseline. The incidence of haematological toxicity and the percentage decrease in analytical variables were compared in patients with and without renal failure (creatinine clearance lower than 50 mL/min), using the 30 mL/min threshold, and with or without pyridoxine; using Chi -Square and U Mann-Whitney tests, respectively. Resultsthirty-eight patients were evaluated. Sixteen (42%) presented haematological toxicity (2 due to a decrease in haemoglobin, 9 in platelets and 8 in neutrophils). Two patients (5%) discontinued treatment due to thrombocytopenia. Toxi-city incidence was similar in patients with and without renal failure, 42% vs 42%, p = 0.970, with more or less than 30 ml/min, 67% vs 40%, p = 0.369, or with or without pyridoxine, 47.8% vs 33%, p = 0.376. Patients with renal failure had a significantly greater reduction in platelet count, p = 0.0185. Conclusionsforty-two percent of patients had haematological toxicity, being more frequent platelets and neutrophils reduction. This was not significantly higher in patients with renal failure or in those without pyridoxine. Greater reduction in platelet count was observed in patients with renal failure.

Evaluating the Effects of Bone Marrow Sparing Radiotherapy on Acute Hematologic Toxicity for Patients with Locoregionally Advanced Cervical Cancer: A Prospective Phase II Randomized Controlled Trial

Bone marrow sparing intensity modulated radiotherapy (BMS-IMRT) can reduce the incidence of acute hematologic toxicity (HT) for locoregionally advanced cervical cancer (LACC) patients receiving concurrent chemoradiotherapy (CCRT), but the norm has been controversial. The purpose of the study was to evaluate the effects of bone marrow (BM) V40 <25% on decreasing the incidence of acute HT in a prospective clinical trial. A total of 242 LACC patients were recruited from May 2021 to May 2022, who were evenly randomized into BMS-IMRT group and standard IMRT group according to a computer-generated random number list. All patients received pelvic irradiation with concurrent cisplatin (40 mg/m2 weekly), followed by brachytherapy. For patients in BMS-IMRT group, the outer contour of pelvic bone, lumbar spine and left and right femur heads were additionally delineated as a surrogate for BM, and V40 <25% was prescribed. Blood counts were tested weekly, of which nadirs during external beam radiotherapy (EBRT) were graded to assess acute HT as primary observation index. Second observation index were dosimetric parameters of EBRT plan from the dose volume histograms (DVHs). Binary logistic regression model and receiver operating characteristic (ROC) curve were used for predictive value analysis. Baseline demographic, disease and treatment characteristics were all balanced between BMS-IMRT group and standard IMRT group. BMS-IMRT was associated with a lower incidence of grade ≥2 and grade ≥3 acute HT, leukopenia and neutropenia (72.70% vs 90.90%, P <0.001*; 16.50% vs 65.30%, P <0.001*; 66.10% vs 85.10%, P = 0.001*; 13.20% vs 54.50%, P <0.001*; 37.20% vs 66.10%, P <0.001*; 10.70% vs 43.80%, P <0.001*). Plan target volume (PTV) for all patients satisfied the clinical requirement of V(100%) ≥95%, and conformity and homogeneity were both comparable between 2 groups. BMS also decreased dose delivered to the organs at risk (OARs) including rectum, bladder and left and right femur head. Univariate and multivariate analyses showed that BM V40 was an independent risk factor for grade ≥3 acute HT (odds ratio [OR] = 2.734, 95% confidence interval [CI] = 1.959-3.815, P <0.001*). Cutoff value was 25.036% and area under the curve (AUC) was 0.786. The nomogram was constructed, which was rigorously evaluated and internally cross-validated, showing good predictive performance. BM V40 <25% can reduce the risks of acute HT for LACC patients receiving CCRT while the dose delivery of target volume and other normal tissues were not compromised. With great practicality and applicability, BM V40 <25% is a promising strategy, making BMS-IMRT widespread especially in the area where application of image guided radiotherapy (IGRT) such as 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET)/CT is not popularized. Chinese clinical trial registry (ChiCTR2200066485).

Translated article] Influence of augmented renal clearance in the lower incidence of linezolid-related haematological toxicity

ObjectivesLinezolid is an oxazolidin commonly related to the development of haematological toxicity, being renal clearance the major factor involved in the drug clearance. The aim of this study is to evaluate the influence of increased filtration rates in the incidence of linezolid-induced haematological toxicity by comparing augmented renal clearance (ARC) patients versus normal renal function patients. Material and methodsA retrospective, observational study was conducted on hospitalized patients treated with linezolid for 5 days or more during 2014–2019 period. Patients with a filtration rate of ≥130 mL/min versus reference patients (60–90 mL/min) were compared. Haematological toxicity was defined as a decrease of 25% in platelets, of 25% in haemoglobin, and/or 50% in neutrophils from baseline. Toxicity relevance was classified according to Common Terminology Criteria for Adverse Events v5. Incidence of haematological toxicity between groups was studied by chi-square and Fisher test. Furthermore, percentage diminution of all 3 parameters was calculated and compared by Mann–Whitney test and treatment interruption and transfusion requirements were registered. Results30 ARC patients and 38 reference patients were included. Haematological toxicity was observed in 16.66% of ARC patients vs 44.74% of reference patients (P=.014); thrombocytopenia in 13.33% vs 36.84% (P=.051), anaemia in 3.3% vs 10.52% (P=.374) and neutropenia in 10% vs 23.68% (P=.204). Median percentage of platelets decrease in ARC patients was −10.36 (−193.33–62.03) vs 2.68 (−163.16–82.71) in reference patients (P=.333), while haemoglobin decrease was 2.50 (−12.12–25.93) vs 9.09 (−17.72–30.63) (P=.047) and neutrophils decrease was 9.14 (−73.91–76.47) vs 27.33 (−86.66–90.90) (P=.093). 10.5% of normal renal function patients reported at least 1 adverse event grade 3 or superior while 2.6% of them interrupted treatment and 5.2% had transfusion requirements. No major events or interruptions were reported in ARC patients. ConclusionOur findings suggest a lower incidence and clinical relevance of haematological toxicity in augmented renal clearance patients. Thrombocytopenia was the major event in both populations. This might be related to a lower exposure to the drug due to the higher clearance and likely lower therapeutic efficiency. These results suggest a potential benefit of therapeutic drug monitoring on high risk patients.

Influencia de la hiperfiltración glomerular en la menor toxicidad hematológica inducida por linezolid

ObjectivesLinezolid is an oxazolidin commonly related to the development of hematological toxicity, being renal clearance the major factor involved in the drug clearance. The aim of this study is to evaluate the influence of increased filtration rates in the incidence of linezolid-induced hematological toxicity by comparing augmented renal clearance (ARC) patients versus normal renal function patients. Material and methodsA retrospective, observational study was conducted on hospitalized patients treated with linezolid for 5 days or more during 2014–2019 period. Patients with a filtration rate of ≥130 mL/min versus reference patients (60–90 mL/min) were compared. Hematological toxicity was defined as a decrease of 25% in platelets, of 25% in hemoglobin and/or 50% in neutrophils from baseline. Toxicity relevance was classified according to Common Terminology Criteria for Adverse Events v5. Incidence of hematological toxicity between groups was studied by chi-square and Fisher test. Furthermore, percentaje disminution of all three parameters was calculated and compared by Mann–Whitney test and treatment interruption and tranfusion requirements were registered. Results30 ARC patients and 38 reference patients were included. Hematological toxicity was observed in 16.66% of ARC patients vs 44.74% of reference patients (p = 0.014); thrombocytopenia in 13.33% vs 36.84% (p = 0.051), anemia in 3.3% vs 10.52% (p = 0.374) and neutropenia in 10% vs 23.68% (p = 0.204). Median percentaje of platelets decrease in ARC patients was −10.36 (−193.33–62.03) vs 2.68 (−163.16–82.71) in reference patients (p = 0.333), while hemoglobin decrease was 2.50 (−12.12–25.93) vs 9.09 (−17.72–30.63) (p = 0.047) and neutrophils decrease was 9.14 (−73.91–76.47) vs 27.33 (−86.66–90.90) (p = 0.093). 10.5% of normal renal function patients reported at least one adverse event grade 3 or superior while 2.6% of them interrupted treatment and 5.2% had tranfusion requirements. No major events or interruptions were reported in ARC patients. ConclusionOur findings suggest a lower incidence and clinical relevance of hematological toxicity in augmented renal clearance patients. Thrombocytopenia was the major event in both populations. This might be related to a lower exposure to the drug due to the higher clearance and likely lower therapeutic efficiency. These results suggest a potential benefit of therapeutic drug monitoring on high risk patients.

Safety of linezolid in patients with decreased renal function and trough monitoring: a systematic review and meta-analysis

BackgroundLinezolid causes hematological toxicity, mostly thrombocytopenia, which leads to treatment discontinuation and failure. Recent studies revealed that during linezolid therapy, the incidence of treatment-related hematological toxicity is significantly higher in patients with decreased renal function (DRF) than in those with normal renal function. Linezolid monitoring is necessary due to the high frequency of hematological toxicity in patients with DRF and the relationship between blood concentration and safety. We performed a systematic review and meta-analysis to evaluate the safety correlation between DRF and trough monitoring.MethodsArticles published before June 24, 2022, on MEDLINE, Web of Sciences, Cochrane Register of Controlled Trials, and ClinicalTrials.gov were systematically analyzed. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using the Mantel–Haenszel method and the variable effects model.ResultsThe incidence of hematological toxicity was significantly higher in patients with DRF than in those without DRF (OR = 2.37; p < 0.001). Subgroup analysis, performed according to hematotoxicity classification, including thrombocytopenia, anemia, and pancytopenia, revealed a significantly higher incidence of thrombocytopenia (OR = 2.45; p < 0.001) and anemia (OR = 2.31; p = 0.006) in patients with DRF than in those without; pancytopenia (OR = 1.41; p = 0.80) incidences were not significantly higher. Based on a systematic review, linezolid trough concentrations > 6–7 μg/mL may be associated with an increased incidence of thrombocytopenia. However, no confidential threshold values for the development of thrombocytopenia were found in the area under the concentration curve values for children or adults.ConclusionWe observed a high frequency of hematological toxicity during linezolid therapy in patients with DRF. To ensure safety, linezolid trough concentrations should be ≤6–7 μg/mL.

Efficacy of the combination of venetoclax and hypomethylating agents in the treatment of patients with primary, relapsed and/or refractory acute myeloid leukemia

Relevance and goals. Treatment of patients with acute myeloid leukemia has traditionally been highly intensive and includes induction therapy using cytarabine and anathracyclines. In addition to new opportunities in the treatment of acute myeloid leukemia, the problem of toxicity of high-intensity therapy in elderly and young somatically burdened patients is quite acute. International clinical trials of phases I-III demonstrated a combination of high efficacy and acceptable hematological toxicity of combinations of hypomethylating agents and venetoclax in the first line of therapy, as well as in the treatment of resistant forms and relapses of acute myeloid leukemia in the older age group, which contributed to the study of the effectiveness of combinations of hypomethylating agents and venetoclax in the treatment of similar groups of young comorbid patients. In this work, we evaluated the efficiency of a combination of hypomethylating agents and venetoclax and overall and disease-free survival in patients with acute myeloid leukemia in routine practice.Methods. In the period from October 2017 to December 2021 on the basis of the Department of Hematology No. 11 and the Department of Bone Marrow and Hematopoietic Stem Cell Transplantation No. 56 of the Botkin Hospital (Moscow, Russia) 33 patients with acute myeloid leukemia received venetoclax therapy in combination with decitabine or azacitidine: 14 (42%) men and 19 (58%) women, median age was 60 years (23–83 years). In 42% (14 of 33) of cases, the regimen was prescribed for resistant course or relapse of acute myeloid leukemia and in 61% (20 of 33) as induction therapy. Three patients (15%) out of 19 from the group of newly diagnosed acute myeloid leukemia received this treatment regimen in the first line, taking into account the ECOG status 3-4. By August 2022, 13 (39%) patients are alive, 20 (61%) people have died. Overall survival, the rate of complete remission and complete remission with incomplete recovery, the rate of achieving negativity of minimal residual disease, the frequency of hematological toxicity and infectious complications were assessed. Statistical data processing used: frequency analysis using contingency tables (Fisher's exact test), survival analysis using the Kaplan-Meier method.Results. Complete remission and complete remission with incomplete recovery were achieved in 72.72% (24 of 33) of patients. In the group of primary acute myeloid leukemia, remissions were observed in 80% (16 out of 20) of cases, in the group with resistant course or recurrence of acute myeloid leukemia in 67% (8 out of 12) (p = 0.3). Determination of minimal residual disease by flow cytometry after the 1st course was performed for 54.54% (18 of 33) patients, while negativity was stated in 84.2% (14 of 18 patients) cases. In both groups, the incidence of hematological toxicity and infectious complications are comparable to those according to the literature data. The median follow-up was 9.5 months (1–47). Median overall survival was 39 months, 2-year overall survival was 63%, and overall 4-year survival was 39%. The disease-free survival rate was 33%.Conclusion. The combination of hypomethylating agents and venetoclax showed good efficacy and fairly high overall survival in patients of all age groups, both for primary acute myeloid leukemia and for relapses and resistant forms, regardless of previous therapy. Given the moderate hematological toxicity, as well as the relatively low rates of infectious complications during therapy, including the rather low mortality rates in case of COVID-19 infection in comparison with those on the background of high-intensity courses of therapy for acute myeloid leukemia, this scheme can be widely used not only in patients of the older age group, but also in young comorbid patients.

Comparison of the Efficacy and Safety of Pegylated Interferon Alpha-2b and Common Interferon Alpha in Patients with Myeloproliferative Neoplasms

Objective: To compare the efficacy and safety of pegylated interferon alpha-2b (PEG-IFN-α2b) and common interferon alfa (IFN-α) in the treatment of myeloproliferative neoplasms (MPNs). Methodology: This study was designed as a prospective clinical study. Patients with MPN who visited the Second Hospital of Tianjin Medical University from August 1, 2019 to June 30, 2022 were enrolled in this study. There were 30 patients in the PEG-IFN-α2b group and 60 patients in the common IFN-α group, and the median follow-up period was 24 (9 - 32) months. The differences in the clinical characteristics, efficacy and safety indicators between the two groups were compared. Results: ①The baseline clinical characteristics of patients in the PEG-IFN-α2b group and the common IFN-α group were well balanced and comparable. ②Efficacy: There was no significant difference in hematological objective response rate (ORR) at month 6, 12 and 24 between the PEG-IFN-α2b group and the common IFN-α group (68.2% vs 60%, 86.4% vs 68.3%, 84.6% vs 68.3%, P > 0.05); the ORR of molecular response at month 12 in the PEG-IFN-α2b group was higher than that in the common IFN-α group (81% vs 47.1%, P = 0.022); the proportion of patients with decreased V617F%and scores for MPN-10 symptoms in the PEG-IFN-α2b group was significantly higher than that in the common IFN-α group (80% vs 46.4%, 82.4% vs 44.2%, P < 0.05); Interleukin-6 (IL-6), Tumor necrosis factor alpha (TNFα) and Interferon gamma (IFNγ) in the PEG-IFN-α2b group after treatment were significantly lower than those before treatment (P < 0.05); the event-free survival (EFS) in the PEG-IFN-α2b group tended to be longer than that in the common IFN-α2b group, and for patients with essential thrombocythemia (ET), the EFS in the PEG-IFN-α2b group was significantly longer than that in the common IFN-α group (P < 0.05). ③Safety: There was no significant difference in the incidence of hematological toxicity between the two groups, and the incidence of grade 3-4 adverse events of fever and influenza-like symptoms as non-hematological toxicity was significantly lower than that in the common IFN-α group (6.6% vs 23.3%, 6.6% vs 15%, P < 0.05). Conclusion: Compared with common IFN-α group, PEG-IFN-α2b group showed significantly superior results for molecular response rate, V617F% reduction, physical symptoms improvement, and IL-6, TNFα and IFNγ reduction, as well as prolong EFS in ET patients with better safety profile. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Hematologic toxicities of sunitinib in patients with gastrointestinal stromal tumors: a systematic review and meta-analysis.

Sunitinib offers a significant survival benefit to patients with imatinib-resistant gastrointestinal stromal tumors (GIST). However, the incidence and risk of sunitinib-induced hematologic toxicities in such a population are often overlooked and have not been well characterized. This meta-analysis was performed to assess the summary incidence and risk of hematologic toxicities secondary to sunitinib in patients with GIST. Searches were performed in PubMed, Embase, Cochrane Library, and Web of Science as well as ClinicalTrials.gov to identify relevant studies up to April 2022. Studies with adequate safety profile, including anemia, neutropenia, and thrombocytopenia, were included to calculate the pooled incidence, relative risk (RR), and corresponding 95% confidence intervals (CIs). This study was registered with PROSPERO under number CRD42022328202. A total of 2593 patients from 13 studies were included in the present meta-analysis. For patients with GIST assigned to sunitinib, the overall incidences of all-grade anemia, neutropenia, and thrombocytopenia were 26.2% (95% CI, 14.9-39.4%), 41.8% (95% CI, 29.0-55.1%), and 36.4% (95% CI, 22.8-51.1%), respectively. Regarding high-grade (grades 3 and 4) events, there were 4.7% (95% CI, 3.8-5.6%) for anemia, 9.3% (95% CI, 5.6-13.7%) for neutropenia and 5.0% (95% CI, 2.9-7.3%) for thrombocytopenia. Compared to placebo arms, sunitinib was related to an increased risk of high-grade neutropenia with an RR of 10.39 (95% CI, 1.53-70.72; p = 0.017). Sunitinib carries a relatively high incidence of hematologic toxicities and a substantial increased risk of high-grade neutropenia in patients with GIST. Appropriate prevention and management seem to be inevitable.

Investigation of the optimal platinum-based regimen in the postoperative adjuvant chemotherapy setting for early-stage resected non-small lung cancer: a Bayesian network meta-analysis

ObjectiveThis study aimed to compare the efficacy and safety of different platinum adjuvant chemotherapy regimens for early-stage resected non-small-cell lung cancer (NSCLC).DesignSystematic review with network meta-analysis of randomised trials.Data sourcesPubMed,...

Toxicity of concurrent and adjuvant temozolomide in patients with glioblastoma multiforme (GBM).

e14037 Background: (MGMT) promotor is prognostic and predictive of temozolomide (TMZ) benefit in newly diagnosed GBM. It has been suggested that MGMT methylation is associated with TMZ toxicity in some cancers such as melanoma but is not clearly defined in GBM. Methods: To investigate this, a retrospective electronic chart review of patients (pts) with resected GBM in a tertiary neurosurgical referral center from 1 July 2017 – 31 Dec 2020 was conducted. Hematological toxicities during TMZ with RT (concurrent) and subsequent TMZ (adjuvant) were assessed and graded by CTCAE V5.0. Toxicity was compared by MGMT methylation status. Results: In a 3.5 year period, 417 GBM resections were performed. Of these, 186 (45%) patients received at least 1 dose of TMZ in our institution: 180 pts received concurrent TMZ, 6 pts received adjuvant only. MGMT was methylated, unmethylated and unknown in 72, 97 and 17 pts respectively. In the concurrent and adjuvant phases respectively, thrombocytopenia incidence was 20%(N=14) and 52%(N=25) in the methylated group and 15%(N=15) and 51%(N=37) in the unmethylated group. In the adjuvant phase, incidence of ≥ grade 3 thrombocytopenia was 8%(N=4), in the methylated patients and 9%(N=7) for those unmethylated. Neutropenia incidence was low in the concurrent phase, however in the adjuvant phase was 29%(N=14) in the methylated group and 23%(N=17) in the unmethylated group. ≥G3 incidence was 10%(N=5) and 3%(N=2) respectively. Conclusions: In this retrospective study, a higher incidence of hematological toxicity was not seen in pts with MGMT methylated tumors. Methylation of the DNA repair enzyme O(6)-methylguanine-DNA methyltransferase.[Table: see text]

Dosimetric predictors and Lyman normal tissue complication probability model of hematological toxicity in cervical cancer patients with treated with pelvic irradiation.

PurposeTo identify dosimetric parameters associated with acute hematological toxicity (HT) and identify the corresponding normal tissue complication probability (NTCP) model in cervical cancer patients receiving helical tomotherapy (Tomo) or fixed‐field intensity‐modulated radiation therapy (ff‐IMRT) in combination with chemotherapy, that is, concurrent chemoradiotherapy (CCRT) using the Lyman–Kutcher–Burman normal tissue complication probability (LKB‐NTCP) model.MethodsData were collected from 232 cervical cancer patients who received Tomo or ff‐IMRT from 2015 to 2018. The pelvic bone marrow (PBM) (including the ilium, pubes, ischia, acetabula, proximal femora, and lumbosacral spine) was contoured from the superior boundary (usually the lumbar 5 vertebra) of the planning target volume (PTV) to the proximal end of the femoral head (the lower edge of the ischial tubercle). The parameters of the LKB model predicting ≥grade 2 hematological toxicity (Radiation Therapy Oncology Group [RTOG] grading criteria) (TD 50(1), m, and n) were determined using maximum likelihood analyses. Univariate and multivariate logistic regression analyses were used to identify correlations between dose–volume parameters and the clinical factors of HT.ResultsIn total, 212 (91.37%) patients experienced ≥grade 2 hematological toxicity. The fitted normal tissue complication probability model parameters were TD 50(1) = 38.90 Gy (95%CI, [36.94, 40.96]), m = 0.13 (95%CI [0.12, 0.16]), and n = 0.04 (95%CI [0.02, 0.05]). Per the univariate analysis, the NTCP (the use of LKB‐NTCP with the set of model parameters found, p = 0.023), maximal PBM dose (p = 0.01), mean PBM dose (p = 0.021), radiation dose (p = 0.001), and V 16–53 (p < 0. 05) were associated with ≥grade 2 HT. The NTCP (the use of LKB‐NTCP with the set of model parameters found, p = 0.023; AUC = 0.87), V 16, V 17, and V 18 ≥ 79.65%, 75.68%, and 72.65%, respectively (p < 0.01, AUC = 0.66∼0.68), V 35 and V 36 ≥ 30.35% and 28.56%, respectively (p < 0.05; AUC = 0.71), and V 47 ≥ 13.43% (p = 0.045; AUC = 0.80) were significant predictors of ≥grade 2 hematological toxicity from the multivariate logistic regression analysis.ConclusionsThe volume of the PBM of patients treated with concurrent chemoradiotherapy and subjected to both low‐dose (V 16–18) and high‐dose (V 35,36 and V 47) irradiation was associated with hematological toxicity, depending on the fractional volumes receiving the variable degree of dosage. The NTCP were stronger predictors of toxicity than V 16–18, V 35, 36, and V 47. Hence, avoiding radiation hot spots on the PBM could reduce the incidence of severe HT.

The Efficacy and Safety of Trifluridine/Tipiracil Treatment for Elderly Patients With Metastatic Colorectal Cancer in a Real-world Setting.

Recently, trifluridine/tipiracil (FTD/TPI) treatment was established as a later-line treatment for metastatic colorectal cancer (mCRC). However, FTD/TPI treatment is frequently associated with hematological toxicity. The aim of this study was to evaluate the efficacy and safety of FTD/TPI in elderly patients with mCRC in a real-world setting. We retrospectively reviewed the medical records of 74 patients with mCRC who were treated with FTD/TPI. The treatment effect of the elderly patient group was not inferior to that of the younger patient group. Although the incidence of hematological toxicity in the elderly patient group was higher than that in the younger patient group, there were no significant differences in the rate of treatment discontinuation due to adverse events between the two groups. In elderly patients with mCRC, FTD/TPI treatment was effective for prolonging survival. However, it should be noted that elderly patients showed a higher rate of hematological toxicity than younger patients.

Mechanisms, Management and Prevention of Pemetrexed-Related Toxicity.

Pemetrexed is a cytostatic antifolate drug and a cornerstone in the treatment of lung cancer. Although generally well tolerated, a substantial part of the patient population experiences dose-limiting or even treatment-limiting toxicities. These include mucositis, skin problems, fatigue, renal toxicity, and neutropenia. Several studies confirmed that pemetrexed pharmacokinetics can serve as a prognostic factor for the development of toxicity, especially for neutropenia. Preventing and managing toxicity of pemetrexed can help to ensure durable treatment. Several evidence-based strategies are already implemented in clinical care. With the introduction of standard vitamin supplementation and dexamethasone, the incidence of hematological toxicity and skin reactions substantially decreased. In the case of high risk for toxicity, granulocyte colony-stimulating factor can be used to prevent severe hematological toxicity. Moreover, high-dose folinic acid can resolve severe pemetrexed-induced toxicity. There are several experimental options to prevent or manage pemetrexed-related toxicity, such as the use of standard folinic acid, hemodialysis, antidotes such as thymidine, hypoxanthine, and glucarpidase, and the use of therapeutic drug monitoring. These strategies still need clinical evaluation before implementation, but could enable treatment with pemetrexed for patients who are at risk for toxicity, such as in renal impairment.

Association of O6-Methylguanine Methyltransferase (MGMT) Promotor Methylation Status and the Incidence of Hematologic Toxicities after Treatment with Temozolomide

Introduction:MGMT is a key enzyme in DNA repair. Epigenetic silencing of the MGMT gene plays a critical role in carcinogenesis and confers increased sensitivity of tumor cells to alkylators. MGMT methylation status is known to be prognostic and predictive of treatment response to Temozolomide in patients with Glioblastoma Multiforme (GBM). Despite advancing knowledge about the clinical implication of MGMT in GBM, there is limited information about the association between tumor MGMT status and hematologic tolerance to Temozolomide. The objective of this study was to evaluate the association of MGMT status and hematologic toxicities after treatment with Temozolomide.Methods:A single institutional retrospective case control study was performed for patients with biopsy proven diagnosis of GBM within the years 2015 to 2020. We collected tumor specific information such as patients MGMT status and treatment specific information including the timing of hematologic adverse events, dose exposure, incidence, and severity of hematologic toxicities. To evaluate the association between tumor MGMT status and hematologic toxicities to Temozolomide we used the Fisher's exact test as well as odds ratio with 95% confidence interval.Results:A total of 74 patients with biopsy proven glioblastoma were evaluated. 44 were MGMT negative while 30 were MGMT positive. All hematologic adverse events occurred within six weeks of exposure to Temozolomide. At the time of the study completion, the number of high grade (grade 3-4) hematologic toxicity events including leukopenia, anemia, thrombocytopenia, or neutropenia were evaluated. There were 2 out of a possible 176 events for nonmethylated MGMT vs 10 out of a possible 120 events for methylated MGMT. This association was determined to be statistically significant with a P value of 0.0051 by Fisher's exact test. Odds ratio (OR) was also calculated with a OR of 7.9, P value of 0.0041 and 95% confidence interval of [1.701- 36.776]. Statistical difference was also noted in the incidence of grade 2-4 thrombocytopenia with 5 events occurring in the methylated group and 0 events occurring in the nonmethylated group with a P value of 0.0088 by Fisher's exact test.Conclusion:Studies have shown the importance of MGMT status in predicting response to treatment with alkylators in patients with GBM. Our study shows that the patients with MGMT methylated GBM tend to develop more hematologic toxicities compared to patients with MGMT non-methylated GBM early in their treatment course, leading to early discontinuation of Temozolomide. This implies these patients need to have close monitoring for hematological toxicity from the initiation of treatment. Further research is warranted to investigate the effect of tumor MGMT status on the DNA repair network in host hematopoietic system after exposure to alkylators. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Effect of Pelvic Bone Marrow Sparing Intensity Modulated Radiation Therapy on Acute Hematologic Toxicity in Rectal Cancer Patients Undergoing Chemo-Radiotherapy.

BackgroundWhile chemo-radiotherapy improves local control in patients with locally advanced rectal cancer, it can also increase acute hematological toxicity (HT), which leads to poor outcomes. Patients receiving bone marrow radiation have been shown to develop acute HT. However, the safety and efficacy of bone marrow sparing is undetermined. The aim of our study was to explore the feasible dosimetric constraints for pelvic bone marrow (PBM) that can be widely used in rectal cancer patients undergoing chemo-radiotherapy.Methods112 rectal cancer patients were selected and divided into the PBM sparing IMRT group (60 cases) and the non-PBM sparing IMRT group (52 cases). All patients underwent pelvic radiotherapy with concurrent capecitabine-based chemotherapy. The PBM dosimetric constraints in the PBM sparing IMRT group were set to:V10 ≤ 85%, V20 ≤ 65% and V30 ≤ 45%. An independent sample t test was applied for the dose-volume parameters, and Chi-squared analysis was applied for clinical parameters and adverse events.ResultsThe radiation dose to PBM (V5~V45, Dmean, P<0.05), PBM sub-regions (V10~V35, Dmean, P<0.05) and both femoral heads (V5~V40, Dmean, P<0.05) decreased significantly in the PBM sparing IMRT group compared with that of the non-PBM sparing IMRT group (P<0.05). There was no significant difference in any dose-volume parameters of the bladder and small bowel in either groups, and none in the planning target volume (PTV) dose homogeneity and conformity (P>0.05). For acute HT observation, the incidence of grade 3 acute HT (χ2 = 7.094, P=0.008) was significantly reduced in patients treated with PBM sparing IMRT compared with patients treated with non-PBM sparing IMRT. There was no statistical difference in the incidence of vomiting, diarrhea, fatigue, anorexia, nausea, hand-foot syndrome, cystitis, perianal pain and perianal dermatitis in patients of both groups (P >0.05).ConclusionsApplying PBM dosimetric constraints (V10 ≤ 85%, V20 ≤ 65% and V30 ≤ 45%) can significantly reduce the radiation dose to PBM. The patients treated with PBM sparing IMRT had a lower incidence of acute HT compared with those treated with non-PBM sparing IMRT. Applying the PBM dosimetric constraints proposed by our study can benefits the patients with rectal cancer undergoing capecitabine-based chemo-radiotherapy.

Quadruplet regimen with capecitabine, irinotecan, oxaliplatin, and bevacizumab in chemo-naive patients with metastatic colorectal cancer: Results from the safety lead-in of QUATTRO-II study.

57 Background: FOLFOXIRI plus bevacizumab (BEV) is regarded as the standard of care for selected patients (pts) with metastatic colorectal cancer (mCRC), despite the high incidence of neutropenia and diarrhea. The AXEPT phase III study showed that the modified capecitabine (CAP) + irinotecan (IRI) + BEV (CAPIRI+BEV) [CAP 1600 mg/m2, IRI 200 mg/m2, and BEV 7.5 mg/kg q3wk] treatment was non-inferior to FOLFIRI+BEV, with a lower incidence of hematologic toxicity. We hypothesized that the modified CAPIRI combined with oxaliplatin (OX) and BEV (CAPOXIRI+BEV) would be more feasible than FOLFOXIRI+BEV, without compromising efficacy. Methods: The QUATTRO-II study is an open-label, multicenter, randomized phase II study. In Step 1, the recommended doses (RD) of OX and IRI were investigated as a safety lead-in. In Step 2, pts are randomized to either the RD of CAPOXIRI+BEV or FOLFOXIRI+BEV. In Step 1, four dose levels of CAPOXIRI (fixed dose of CAP 1600 mg/m2 and BEV 7.5 mg/kg plus escalated or de-escalated doses of OX and IRI, q3wk) were investigated in a 3+3 manner. A dose level of ≤ 2/6 of dose-limiting toxicity (DLT) cases was expected as the RD. Results: A total of 9 pts (3 at Level 0, 6 at Level 1) were included in Step 1. The baseline characteristics were as follows: the median age was 62 years; 6 were male; 6 presented with a left-sided tumor; 8 had a performance status of 0; all wild type/ RAS mutant/ BRAF V600E mutant were 8/1/0; and UGT1A1 wild type/*6 single hetero/*28 single hetero were 7/0/2. In Level 0 (IRI 200 mg/m2, OX 100 mg/m2), one grade 4 neutropenia and one grade 3 anorexia were observed, but without DLT. In Level 1 (IRI 200 mg/m2, OX 130 mg/m2), two grade 4 neutropenia and one grade 3 colitis were observed, with 1 DLT (febrile neutropenia) case, fully recovered without G-CSF administration. No treatment-related deaths were observed. Although dose modifications were needed in 4 of the 6 pts, no further safety concerns related to treatment continuity were observed in the 2nd or subsequent cycles. Thus, we determined that the dose administered in Level 1 is the RD for Step 2. According to the preliminary efficacy results at 8 weeks after initiating study treatment, 6 pts achieved a partial response (2 in Level 0 and 4 in Level 1). Conclusions: The RD of CAPOXIRI+BEV was 200 mg/m2 IRI, 130 mg/m2 OX, 1600 mg/m2 CAP, and 7.5mg/kg BEV. The randomized phase II Step (Step 2) of QUATTRO-II is ongoing. Clinical trial information: NCT04097444.