Rates Of Neutropenia Research Articles

FOOTPATH: A randomized, open-label phase-2 study of liposomal irinotecan + 5-FU and folinic acid (NAPOLI) versus sequential NAPOLI and mFOLFOX6 versus gemcitabine/nab-paclitaxel in treatment-naïve metastatic pancreatic cancer (mPDAC).

4021 Background: The optimal first-line regimen in the treatment of mPDAC remains unknown. Recent data demonstrated superiority of 5-FU/liposomal irinotecan/oxaliplatin (NALIRIFOX) over gemcitabine/nab-paclitaxel. However, the question remains open if both irinotecan and oxaliplatin are required in first-line treatment and whether these agents can be given sequentially. Methods: Eligible patients with histologically confirmed diagnosis of mPDAC were randomized 1:1:1 to receive in Arm A standard treatment (gemcitabine 1000 mg/m2 + nab-paclitaxel 125 mg/m2) or investigational therapy applying in Arm B the NAPOLI regimen (liposomal irinotecan 80 mg/m2 + folinic acid 400 mg/m2 + 5-FU 2400 mg/m2) or in Arm C a sequence of NAPOLI and mFOLFOX6 (oxaliplatin 85mg/m2 + folinic acid 400mg/m2 + 5-FU 2400 mg/m2). Overall, 274 patients were enrolled at 48 sites in Germany. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate, disease control rate, duration of study treatment and safety. Results: In the full analysis set (n=265), neither treatment with NAPOLI (3.1 months, HR 1.224, p= 0.2123) nor the sequence of NAPOLI and mFOLFOX6 (6.0 months, HR 0.864 p= 0.0720) lead to a statistically significant improvement of PFS over gemcitabine/nab-paclitaxel (4.3 months). Median duration of treatment was 3.5 months in Arm A, 2.0 months in Arm B and 3.7 months in Arm C, respectively. In a first analysis of overall survival, OS in Arm A was 8.7 months (95% CI, 7.1-11.9 months) versus 7.9 months in Arm B (95% CI, 6.6-12.3 months; HR 1.178, P= 0.348) and 11.0 months in Arm C (95% CI, 8.4-13.6 months; HR 0.879, P=0.154). Overall, safety was comparable with published data, with higher rates of neutropenia and peripheral neuropathy in Arm A, while diarrhea was more frequent in Arms B and C. Conclusions: The study did not show superiority of either NAPOLI or the sequence of NAPOLI/mFOLFOX6 over standard therapy with gemcitabine/nab-paclitaxel. In view of the published evidence, the present data supports the hypothesis that sequential NAPOLI/mFOLFOX6 may be equally effective with regard to OS, but less toxic, compared to mFOLFIRINOX. Clinical trial information: NCT03487016 . [Table: see text]

Trimethoprim-Sulfamethoxazole-associated early neutropenia in Mexican adults living with HIV: A cohort study.

Trimethoprim/sulfamethoxazole (TMP/SMX) is the antimicrobial of first choice in the treatment and prophylaxis of Pneumocystis jirovecii pneumonia (PCP) in immunocompromised patients, particularly in people living with human immunodeficiency virus (HIV). TMP/SMX use entails different adverse effects, and its association with early neutropenia is minimally documented. This study aimed to identify the risk of early neutropenia associated with TMP/SMX use in adults living with HIV in Mexico. A prospective cohort study was conducted in TMP/SMX-naïve adults living with HIV admitted to a third-level hospital between August 2019 and March 2020. Socio-demographic, clinical, and laboratory data were collected. According to patients' diagnostic, if they required treatment or prophylaxis against PCP, medical staff decided to prescribe TMP/SMX, as it is the first-line treatment. The risk of TMP/SMX induced early neutropenia, as well as associated factors were analyzed through a bivariate model and a multivariate Poisson regression model. The strength of association was measured by incidence rate ratio (IRR) with 95% confidence interval. 57 patients were enrolled in the study, of whom 40 patients were in the TMP/SMX treatment-group for treatment or prophylaxis of PCP (204.8 person-years of observation, median 26.5 days) and 17 patients were in the non-treatment group because they did not need the drug for treatment or prophylaxis of PCP (87.0 person-years of observation, median 21 days). The incidence rate of early neutropenia in the TMP/SMX-treatment group versus non-treatment group was 7.81 and 1.15 cases per 100 person-years, respectively. After adjusting for stage 3 of HIV infection and neutrophil count <1,500 cells/mm3 at hospital admission, the current use of TMP/SMX was not associated with an increase in the incidence rate ratio of early neutropenia (adjusted IRR: 3.46; 95% CI: 0.25-47.55; p = 0.352). The current use of TMP/SMX in Mexican adults living with HIV was not associated with an increase in the incidence rate ratio of early neutropenia.

Toxicity and feasibility of vincristine, etoposide, and carboplatin alternating with vincristine, doxorubicin, and cyclophosphamide in children with advanced retinoblastoma in Guatemala.

Retinoblastoma is highly curable, with event-free survival (EFS) of greater than 95% in high-income countries. However, in lower middle-income countries, outcomes of EFS are 30%-60% due to delayed diagnosis and lack of resources resulting in extra-ocular disease. We report the toxicity profile and outcomes of intensified therapy for advanced retinoblastoma: vincristine, etoposide, carboplatin (VEC) alternating with vincristine, doxorubicin, and cyclophosphamide (VDoCx) in Guatemala. Compared to VEC alone, similar rates of neutropenia, anemia, and thrombocytopenia were seen, with no toxic deaths. Although survival was not a primary objective, a modest survival benefit supports further investigation of VEC+VDoCx for advanced retinoblastoma.

Impact of neoadjuvant FLOT treatment of advanced gastric and gastroesophageal junction cancer following surgical therapy.

Therapeutic treatment for advanced-stage (T2-T4) gastroesophageal junction (GEJ) and gastric cancer involves neoadjuvant chemotherapy with subsequent surgical intervention. Neoadjuvant oncological treatment for GEJ and gastric cancer previously consisted of the intravenous administration of epirubicin, cisplatin and fluorouracil (ECF) or epirubicin, cisplatin and capecitabine (ECX) combination (Group 1). The new protocol (FLOT, F: 5-FU, L: leucovorin, O: oxaliplatin, T: docetaxel), included patients with resectable GEJ and gastric cancer who had a clinical stage cT2 or higher nodal positive cN+ disease (Group 2). Between 31 December 2008 and 31 October 2022, the effect of different oncological protocols in terms of surgical outcomes in cases of T2-T4 tumours were retrospectively evaluated. Results of randomly assigned patients from the earlier ECF/ECX protocol (n = 36) (Group 1) and the new FLOT protocol (n = 52) (Group 2) were compared. Effect of different neoadjuvant therapies on tumour regression, types of possible side effects, type of surgery, and oncological radicality of surgical procedures were analysed. When comparing the two groups, we found that in case of the FLOT neoadjuvant chemotherapy (Group 2, n = 52), complete regression was achieved in 13.95% of patients, whereas in the case of ECF/ECX (Group 1, n = 36), complete regression occurred in only 9.10% of patients. Furthermore, in the FLOT group, the mean number of lymph nodes removed was slightly higher (24.69 vs. 20.13 in the ECF/ECX group). In terms of the safety resection margin (proximal), no significant difference was found between the two treatment groups. Nausea and vomiting were the most common side effects. The occurrence of diarrhea was significantly higher in the FLOT group (p = 0.006). Leukopenia and nausea occurred more commonly with the old protocol (Group 1). The rate of neutropenia was lower following FLOT treatment (p = 0.294), with the lack of grade II and III cases. Anaemia occured at a significantly higher rate (p = 0.036) after the ECF/ECX protocol. As a result of the FLOT neoadjuvant oncological protocol for advanced gastro-esophageal junction and gastric cancer, the rate of complete tumour regression increased significantly. The rate of side effects was also appreciably lower following the FLOT protocol. These results strongly suggest a significant advantage of the FLOT neoadjuvant treatment used before surgery.

Predictors of hypogammaglobulinemia and serious infections among patients receiving ocrelizumab or rituximab for treatment of MS and NMOSD.

Ocrelizumab and rituximab are monoclonal antibodies targeting the CD20 marker on B lymphocytes. The enhanced efficacy of B lymphocyte depleting therapies poses a greater risk of decreased immunoglobulin (Ig) levels. The rate and risk factors of hypogammaglobulinemia in MS and NMOSD patients treated with anti-CD20 therapies are unknown. A retrospective study was conducted among patients who received anti-CD20 therapy for the treatment of MS, NMOSD, and other related neurological disorders. The goal was to determine the incidence and risk factors of hypogammaglobulinemia and serious infections in patients receiving ocrelizumab versus rituximab. The secondary goals were to determine the rates of lymphopenia, neutropenia, and early B cell repopulation among patients on anti-CD20 therapy. Overall, 184 patients (mean age 48.4±13.7, 66.8% female) met inclusion criteria; 152 patients received ocrelizumab and 32 patients received rituximab. A total of 22 patients (12%) developed hypogammaglobulinemia. Patients who developed hypogammaglobulinemia were more likely to have been ≥50years of age (p=.0275) with lower baseline IgG (p=.001) and IgA (p=.0038) levels. Serious infections were observed in 21 patients (11%) and seen more commonly in those that developed total lymphopenia (<1.0×109/L) and had longer duration of B-cell therapy. Multivariate analysis identified age≥50years, white race, and rituximab as independent predictors of hypogammaglobulinemia, and absolute lymphopenia as an independent risk factor for serious infections. Among patients receiving anti-CD20 therapy, 12% of patients experienced hypogammaglobulinemia which was seen more commonly in white patients, at least 50years old, with lower baseline IgG and IgA levels and in those treated with rituximab. Serious infections were seen more commonly in patients with total lymphopenia and longer exposure to anti-CD20 therapy.

Abstract P3-06-06: Real-world analysis of adverse events of patients with triple negative breast cancer receiving therapy per KEYNOTE-522

Abstract Background: KEYNOTE-522 was a randomized, double-blind, placebo-controlled phase 3 trial which resulted in the FDA approval of pembrolizumab with neoadjuvant chemotherapy for patients (pts) with newly diagnosed, high-risk, early-stage triple negative breast cancer (TNBC). Given the improvement in pathological complete response (pCR) and event-free survival rates, this regimen has emerged as standard-of-care (SOC) therapy. Adverse events in pts on this treatment regimen in clinical practice is unknown and understanding the real-world toxicity of this regimen is critical. Methods: In this IRB approved retrospective, single-center study we examined pts with early-stage TNBC who received planned treatment per KEYNOTE-522 per SOC from 2021-present. This regimen includes a year of pembrolizumab combined with 4 cycles of neoadjuvant carboplatin/paclitaxel followed by 4 cycles of doxorubicin/cyclophosphamide. Number and length of treatment delays, treatment related toxicities of all grades, and pCR rate were collected from the electronic medical record. Results: Of the 87 identified pts, 2 were excluded due to locally recurrent or metastatic disease and 6 did not receive immunotherapy due to concerns for toxicity or patient preference. Of the 79 pts who initiated treatment with chemotherapy and immunotherapy, median age of the cohort was 52 (27-77). 9 pts had a BRCA1 mutation and 1 pt had a BRCA2 mutation. 41 (51.9%) had T1-2 disease and 38 (48.1%) had T3-4 disease. 37 (46.8%) pts had N0 disease and 42 (53.2%) had N1-3 disease. 15 pts had baseline comorbidities, including heart disease, kidney disease, type II DM, and/or peripheral neuropathy. 68 pts (86.1%) had baseline ECOG 0, 9 (11.4%) had ECOG 1, and 2 (2.5%) had ECOG 2. At the time of analysis, 70 pts (88.6%) were receiving active treatment, of which 47 (67.1%) had completed ≥50% of the planned neoadjuvant therapy. Of pts completing ≥50% of planned neoadjuvant therapy and pts off therapy (N=56), 31 (55.4%) had 1 or more hospitalizations and 23 (41.1%) had 1 or more emergency room visits. 30 pts had treatment delays (53.6%) and 21 pts (37.5%) had dose reductions. Rates of adverse events are presented in Table 1. Of the 79 analyzed pts, 35 have undergone surgery. pCR rate was 45.7% (N=16). 8 (22.9%) pts had RCB-I, 4 (11.4%) pts had RCB-II, 3 (8.6%) pts had RCB-III, and 4 (11.4%) pts had residual disease without RCB calculation. Updated analysis will be included at time of presentation. Conclusions: In this single-center retrospective study of pts receiving chemoimmunotherapy for TNBC, we found higher rates of grade 3 toxicity, including nausea, fatigue, neutropenia, diarrhea, peripheral neuropathy, and hypothyroidism, and lower pCR rate than was reported in the KEYNOTE-522 trial. This may reflect a more heterogeneous population of pts treated in routine clinical practice who are typically less fit than pts on clinical trials. Additionally, pts in this study had higher T stages (48.1% with T3-4 disease vs 26.0% in trial) and node positive disease (53.7% with N1-3 disease vs 48.8% in trial). Limitations include immaturity of data and small sample size; however, these data warrant validation through longer-term follow-up and multicenter validation. Adverse Events in pts receiving Keynote-522 regimen as SOC and on clinical trial Citation Format: Mara Hofherr, Jennifer Hedgecorth, Foluso O. Ademuyiwa, Lindsay L. Peterson, Nusayba A. Bagegni, Rama Suresh, Ashley Frith, Ron Bose, Katherine Weilbaecher, Cynthia Ma, Andrew A. Davis, Katherine K. Clifton. Real-world analysis of adverse events of patients with triple negative breast cancer receiving therapy per KEYNOTE-522 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-06-06.

Abstract P4-01-31: High Incidence of Palbociclib Related Neutropenia in Asian Patients Associated with Genetic Polymorphisms

Abstract CDK4/6 inhibitors (CDK4/6i) is well established as the current standard of care for hormone positive (HR(+)) metastatic breast cancer (mBC), in combination with endocrine therapy. CDK4/6i extend a chemotherapy-free, progression free survival (PFS) that preserves quality of life in patients. The most common side effect of CDK4/6i is myelosuppression, with neutropenia the most prevalent adverse effect, especially for palbociclib and ribociclib. In PALOMA-2 and MONALEESA-2, where neutropenia was prevalent (any grade neutropenia 79.5%, grade 3/4 neutropenia 66.5% in PALOMA-2, and any grade neutropenia: 74.3%, grade 3/4 55.3% in MONALEESA-2), although febrile neutropenia seldom occurred (1.8%). Several studies have proposed different genetic factors predisposing to CDK4/6 inhibitor induced neutropenia, including Duffy antigen polymorphisms, ABCB1 and ERCC1 polymorphisms (ABCB1_rs1128503, ABCB1_rs1045642, ERCC1_rs11615, ERCC1_rs3212986), CDK6 polymorphisms, and others. Subgroup studies from the PALOMA trials have suggested that Asian patients receiving palbociclib have higher rates of neutropenia, although the exact explanation is unknown. We conducted a retrospective analysis of 102 Taiwanese patients who received palbociclib for HR(+) mBC at the Taipei Veterans General Hospital for the clinical features, incidence and time course of neutropenia were analyzed. Significant neutropenia incidence was observed (&amp;gt; 95% of all grade neutropenia, 74.5% grade 3/4 neutropenia). In addition, in our clinical cohort, one of the patients was a long term peritoneal dialysis patient newly diagnosed of HR(+) mBC and started on Palbociclib, initially 125mg, later decreased dosage to 100mg after neutropenia occurrence. By Liquid chromatography–mass spectrometry (LC–MS), we quantified the levels of palbociclib in her serum and peritoneal fluid at various time points, while on different dosage use. To our knowledge, this is the first pharmacokinetics analysis on a peritoneal dialysis patient receiving CDK4/6i. To investigate a possible genetic association for the high prevalence of neutropenia, we queried the Taiwan biobank, a nationwide biospecimen repository with 129,586 healthy individual genome wide DNA sequencing data deposited. We investigated the prevalence of the 4 SNPs previously reported to be related to neutropenia in the PALOMA studies. By comparing the Taiwan biobank data to SNP databases from different ethnicities, we observed interesting findings on ethnicity differences of SNP distribution and higher prevalence of neutropenia SNPs. Collectively, in this study we report real world data, biobank genome wide analysis, and a novel report of pharmacokinetic study in a peritoneal dialysis patient, providing novel insights into the real world use of palbociclib and CDKi. Table 1. Median TTF of each subsequent therapy after PAL+ET Characteristics of the clinical cohort treated with palbociclib at TVGH Citation Format: Kuan-Jung Huang, Ting-Hao Kuo, Ta-Chung Chao, Chun-Yu Liu, Yi-Fang Tsai, Chi-Cheng Huang, Ling-Ming Tseng, Cheng-Chih Richard Hsu, Jiun-I Lai. High Incidence of Palbociclib Related Neutropenia in Asian Patients Associated with Genetic Polymorphisms [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-31.

A retrospective review of primary prophylaxis with granulocyte-colony stimulating factor (G-CSF) for patients with genitourinary malignancies receiving chemotherapy during the COVID-19 pandemic and implications for the future.

115 Background: To mitigate the risks of chemotherapy associated neutropenia, during the COVID-19 pandemic, all genitourinary (GU) cancer patients treated with chemotherapy at the Princess Margaret Cancer Centre (PMCC) were offered primary prophylaxis with GCSF. We hypothesize that this reduced rates of febrile neutropenia, hospitalizations, healthcare costs and improved overall outcomes, compared to GU cancer patients treated with chemotherapy without GCSF in the 2 years prior to the pandemic. Methods: We performed a retrospective review of GU cancer patients, receiving curative or palliative intent chemotherapy, with or without primary GCSF prophylaxis between January 2018 and June 2022. GCSF was given either as a single dose or as consecutive doses post chemotherapy. Main outcomes were incidence of febrile neutropenia, hospitalization, health care expenditures as well as disease specific outcomes. Results: Overall, 248 patients with prostate cancer (44%), urothelial cancers (33%) germ cell (21%), and rare GU cancers (4%) were identified. Median age was 70 (range 19-91), 92% were male, 65% were ECOG 0/1. Treatment intent was neoadjuvant (13%), adjuvant (20%), or palliative (67%). Main regimens used were docetaxel, cabazitaxel, carboplatin, cisplatin/etoposide, gemcitabine/cisplatin and BEP. Median follow-up was 10.5 months (0.23-52.3 months). A total of 206/248 received primary GCSF prophylaxis. During chemotherapy, the median white blood cell levels were higher in the GCSF group compared to the non-GCSF group (14.1*10*9/L vs 2.90*10*9/L, p&lt;0.0001); and neutropenia rates were markedly lower (2% vs. 93%, P=&lt;0.0001). Hospital admission rates were significantly lower in G-CSF users compared to non-users (19% vs. 69%, P&lt;0.0001). Symptomatic disease progression 13% was the leading cause of admission in the G-CSF group. Infectious causes such as UTI, pneumonia, COVID-19, and sepsis were seen in only 12% of the G-CSF group compared to 31% in the non-users. G-CSF was generally well tolerated with just 0.97% discontinuing G-CSF. Conclusions: During the COVID-19 pandemic, primary prophylactic G-CSF use in GU cancer patients, undergoing chemotherapy significantly lowered rates of both febrile neutropenia and hospitalizations and could be a cost-effective strategy in this patient population that warrants further study.

An observational study of dose dense chemotherapy with lipegfilgrastim support in early breast cancer

PurposeBreast cancer is one of the most prevalent malignant diseases in women. The development of dose dense chemotherapy regimens has improved clinical outcomes but has been associated with increased hematological toxicity. Currently there is a paucity of data on the use of lipegfilgrastim in dose dense AC treatment in early breast cancer. The purpose of this study was to assess the use of lipegfilgrastim in the treatment of early breast cancer and to examine the incidence of treatment-related neutropenia during the dose dense AC phase and subsequent paclitaxel treatment.MethodsThis was a single arm, non-interventional, prospective study. The primary endpoint was to determine the rate of neutropenia defined as ANC of < 1.0 × 109/L, during four cycles of dose dense AC with lipegfilgrastim support. The secondary endpoints were the incidence of febrile neutropenia, (temperature > 38 °C and ANC < 1.0 × 109/L), treatment delays, premature treatment cessation and toxicity.ResultsForty-one participants were included in the study. Of the 160 planned dose dense AC treatments, 157 were administered, and 95% (152/160) of these were given on time. The rate of treatment delay was 5% (95% CI 2.2 to 9.9%) due to infection (4) and mucositis (1). Four (10%) patients developed febrile neutropenia. The most frequently occurring adverse event was grade 1 bone pain.ConclusionLipegfilgrastim is an effective option in the prophylaxis of chemotherapy-induced neutropenia, and its use in everyday anti-cancer treatment can be considered.

Does ferritin level affect the outcomes of autologous stem cell transplantation equally in all diseases?

BackgroundIn this retrospective study, we evaluated the effect of ferritin levels on the outcomes of autologous stem cell transplantation in patients with MM or lymphoma. MethodsIn this study, 170 patients with measured ferritin levels within one month before transplantation who underwent ASCT with the diagnosis of MM or lymphoma were evaluated. The cut-off value of ferritin was determined as 500 ng/mL to evaluate the transplant outcomes in both groups. The hematological recovery status/duration, febrile neutropenia rate, hospitalization time, transplant-related mortality (TRM) in the first 100 days, and OS were evaluated according to the ferritin level ResultsOf all patients, 105 (61,8%) were diagnosed with MM and 65 (38.2%) with lymphoma. Ferritin levels had no statistically significant effect on the engraftment status/times, the febrile neutropenia rates, and hospitalization times of both lymphoma and myeloma patients (p > .05). Ferritin level was not significantly associated with TRM in MM (p = .224). However, in lymphoma, ferritin level was significantly associated with TRM (33.3% for ferritin level ≥500 ng/L vs. 5.3% for ferritin level ng/mL, p = .005). There was no statistically significant correlation between ferritin value and OS in MM group [ferritin level ≥ 500 ng/L: 39.9 months (95% CI: 33.7–46.1) and ferritin level 500 ng/mL: 39.4 months (95% CI: 36.5–42.2), p = .446]. Ferritin level was significantly associated with OS in patients with lymphoma [ferritin level ≥ 500 ng/L: 22.1 months 95% CI: 14.7–29.5), ferritin level 500 ng/mL: 27.3 months (95% CI: 22.4–32.2), p = .038] ConclusionHigh ferritin level is important prognostic factor on survival after ASCT in patients with lymphoma.

Pegfilgrastim on febrile neutropenia in pediatric and adolescent cancer patients: a systematic review and meta-analysis

ABSTRACTObjectivesThere is no meta-analysis about the effects of pegfilgrastim on the occurrence of febrile neutropenia (FN) in pediatric/adolescent cancer patients. The study explored the efficacy of prophylactic pegfilgrastim in preventing FN in children/adolescents with cancer.MethodsPubMed, Embase, and the Cochrane Library were searched for studies published before April 7, 2020. The primary outcome was the rate of FN. Effect size (ES) and odds ratio (OR) with 95% confidence intervals (CIs) were used to evaluate the outcome. The ES represented the rate of FN, and the STATA ‘metaprop’ command was used to synthesize the rate.ResultsEight studies were included, comprising 167 patients and 550 courses of treatment. There was no difference between pegfilgrastim and filgrastim for the rate of FN in children receiving chemotherapy (OR = 0.68, 95% CI: 0.20–2.23, P = 0.520). In patients receiving pegfilgrastim, the rate of FN was 25.6% (95% CI: 14.9%−36.3%), the rate of grade 4 FN was 38.3% (95% CI: 19.2%−59.5%), the rate of severe neutropenia (SN) was 40.5% (95% CI: 35.1%−46.1%), and the rate of treatment delays due to FN was 4.8% (95% CI: 0.8%−11.3%).DiscussionThe number of studies that could be included was small; therefore, a specific type of cancer or a specific treatment could be studied. Heterogeneity was high.ConclusionThere was no difference between pegfilgrastim and filgrastim for the rate of FN. The use of pegfilgrastim was still associated with rates of FN, grade 4 FN, severe neutropenia, and treatment delays due to FN in pediatric cancer patients.

Rates of Neutropenia following the Introduction of G-CSF to Upfront Docetaxel

Rates of Neutropenia following the Introduction of G-CSF to Upfront Docetaxel

Trifluridine/tipiracil with or without bevacizumab in metastatic colorectal cancer: results of a systematic review and meta-analysis.

Trifluridine/tipiracil plus bevacizumab (FTD/TPI + BEV) has shown efficacy and tolerability in refractory metastatic colorectal cancer (mCRC). Because randomized controlled trial (RCT) data comparing FTD/TPI + BEV with FTD/TPI are lacking, this meta-analysis evaluated outcomes with both regimens. Electronic databases, congress proceedings (past 3 years), trial registries, systematic review bibliographies, gray literature, and guidelines through June 2021 were searched for RCTs, non-RCTs, and prospective observational studies involving >20 previously treated patients with mCRC receiving FTD/TPI + BEV or FTD/TPI. Absolute and relative disease control rate (DCR), progression-free survival (PFS), overall survival (OS), adverse event (AE) rates, and discontinuation rates due to AEs were evaluated using fixed-effects and random-effects models. Study quality, heterogeneity, and publication bias were assessed. In all, 29 of 875 screened publications were selected (26 studies: 5 RCTs, 11 non-RCTs, and 10 prospective observational studies). One RCT compared FTD/TPI + BEV with FTD/TPI. FTD/TPI + BEV versus FTD/TPI had a higher absolute DCR [64% (6 studies; n = 289) versus 43% (10 studies; n = 2809)], median PFS [4.2 (5 studies; n = 244) versus 2.6 (6 studies; n = 1781) months], 12-month PFS [9% (5 studies; n = 244) versus 3% (6 studies; n = 1781)], median OS [9.8 (5 studies; n = 244) versus 8.1 (6 studies; n = 1814) months], and 12-month OS [38% (5 studies; n = 244) versus 32% (6 studies; n = 1814)]. Grade ⩾3 febrile neutropenia, asthenia/fatigue, diarrhea, nausea, and vomiting rates were similar (1%-7%). Grade ⩾3 neutropenia rate was higher with FTD/TPI + BEV than with FTD/TPI [43% (6 studies; n = 294) versus 29% (12 studies; n = 7139)]. Discontinuation rates due to AEs were similar [8% (5 studies; n = 244) and 7% (10 studies; n = 3724)]. Low study quality, heterogeneity, and/or publication bias were detected in certain instances. Despite fewer patients treated with the combination, this meta-analysis consistently suggested that FTD/TPI + BEV provides benefits over FTD/TPI in refractory mCRC and has similar safety, except for more frequent grade ⩾3 neutropenia.

Veliparib with frontline chemotherapy and as maintenance in Japanese women with ovarian cancer: a subanalysis of efficacy, safety, and antiemetic use in the phase 3 VELIA trial

BackgroundThe phase 3 VELIA trial evaluated veliparib with carboplatin/paclitaxel and as maintenance in patients with high-grade serous ovarian carcinoma.MethodsPatients with previously untreated stage III–IV high-grade serous ovarian carcinoma were randomized 1:1:1 to control (placebo with carboplatin/paclitaxel and placebo maintenance), veliparib-combination-only (veliparib with carboplatin/paclitaxel and placebo maintenance), or veliparib-throughout (veliparib with carboplatin/paclitaxel and veliparib maintenance). Randomization stratification factors included geographic region (Japan versus North America or rest of the world). Primary end point was investigator-assessed median progression-free survival. Efficacy, safety, and pharmacokinetics were evaluated in a subgroup of Japanese patients.ResultsSeventy-eight Japanese patients were randomized to control (n = 23), veliparib-combination-only (n = 30), and veliparib-throughout (n = 25) arms. In the Japanese subgroup, median progression-free survival for veliparib-throughout versus control was 27.4 and 19.1 months (hazard ratio, 0.46; 95% confidence interval, 0.18–1.16; p = 0.1 [not significant]). In the veliparib-throughout arm, grade 3/4 leukopenia, neutropenia, and thrombocytopenia rates were higher for Japanese (32%/88%/32%) versus non-Japanese (17%/56%/28%) patients. Grade 3/4 anemia rates were higher in non-Japanese (65%) versus Japanese (48%) patients. Early introduction of olanzapine during veliparib monotherapy maintenance phase may help prevent premature discontinuation of veliparib, via its potent antiemetic efficacy.ConclusionsMedian progression-free survival was numerically longer in Japanese patients in the veliparib-throughout versus control arm, consistent with results in the overall study population. Pharmacokinetics were comparable between Japanese and non-Japanese patients. Data for the subgroup of Japanese patients were not powered to show statistical significance but to guide further investigation.

210. Neutropenia and Associated Infectious Complications Among Kidney Transplant Recipients Receiving Valganciclovir Prophylaxis in the United States: An Administrative Claims Database Study

Abstract Background Valganciclovir (VGCV) prophylaxis is commonly utilized to prevent cytomegalovirus (CMV) infection among high (D+/R-) and intermediate (R+) risk kidney transplant recipients (KTRs). Due to the myelosuppressive effects of VGCV, KTRs may be at an increased risk of opportunistic infections (OIs) resulting in interruptions to VGCV therapy. Therefore, we aimed to quantify the clinical burden of neutropenia among adult KTRs receiving VGCV prophylaxis. Methods A retrospective cohort design was utilized to identify adult KTRs who received VGCV prophylaxis using the IBM MarketScan Commercial and Medicare Supplemental claims databases. First-time KTRs between 1/1/2012 - 12/31/2018 with 1 year of continuous pharmacy and medical coverage before (baseline period) and after (follow-up period) were included. KTRs with a History of other solid organ transplantation were excluded. Fills of ≥ 1 prescription of VGCV (either 450 mg or 900 mg/day) within 30 days of the kidney transplant (KT). Neutropenia events were identified as either ≥ 1 inpatient, or ≥ 2 outpatient ICD-9/ICD-10 diagnoses codes within 14 days. Results Of the 4,965 adults KTRs with baseline and follow-up enrollment, 3,258 (66%) used VGCV prophylaxis. 311/3256 (9.5%) developed neutropenia within 1-year post KT. Baseline characteristics were similar between those with and without neutropenia (table 1). The majority received the following pre-transplant immunosuppression: tacrolimus (78.9%), mycophenolate mofetil (62.8%) and steroids (prednisone, 79.3%, methylprednisolone 10.6%). KTRs with neutropenia had a nearly two-fold increase in the development of CMV infection compared to those without neutropenia. In addition, KTRs with neutropenia had significantly higher rate of bacterial or fungal infections compared to those without neutropenia (Table 2). Interruptions in VGCV prophylaxis (gap &amp;gt;15 days) were more common in KTRs with neutropenia (P&amp;lt; 0.001). Conclusion Our findings showed that neutropenia was associated viral, bacterial, and fungal OIs among adults KT receiving VGCV prophylaxis. The findings highlight the needs for interventions to reduce neutropenia and its associated OIs. These results suggest that clinical management steps to reduce rates of neutropenia among KT recipients may warrant further study. Disclosures Vladimir Turzhitsky, PhD, Merck &amp; Co., Inc.,: Employee|Merck &amp; Co., Inc.,: Stocks/Bonds Amit D. Raval, PhD, Merck and Co., Inc.: Employee of Merck|Merck and Co., Inc.: Stocks/Bonds Pamela Moise, PharmD, Merck &amp; Co., Inc: Employee &amp; Shareholder Sanjay Merchant, PhD, Merck &amp; Co., Inc.: Stocks/Bonds.

Influence of a biliary stent in patients with advanced pancreatic cancer treated with modified FOLFIRINOX.

Endoscopic biliary drainage is the recommended 1st-line treatment for malignant biliary obstruction. Although a high incidence of febrile neutropenia has been reported in patients treated with FOLFIRINOX and a biliary stent, it remains unknown whether the biliary stent contributes to patient survival. Thus, we aimed to elucidate the effects of biliary stents on the survival of patients with advanced pancreatic cancer treated with modified FOLFIRINOX (mFFX). We retrospectively reviewed medical charts of patients with advanced pancreatic cancer treated with mFFX between January 2014 and April 2020. We compared the overall survival (OS) of patients with and without biliary stent during mFFX treatment and examined the independent effect on mortality using propensity score matching. Overall, we included 89 patients (stent group, n = 24; non-stent group, n = 65). The proportion of patients with pancreatic head cancer was significantly higher in the stent group than in the non-stent group (P < .01). Stratification analysis in patients with pancreatic head cancer revealed that OS was significantly shorter in the stent group than in the non-stent group (P = .03). After propensity score matching, 19 pairs of patients in each group were analyzed. The stent group revealed a significantly shorter survival than the non-stent group (median OS, 10.3 vs 24.9 months; P < .01). The incidences of febrile neutropenia (P = .01) and biliary tract-related events that required biliary stenting or stent replacement (P < .01) were significantly higher in the stent group than in the non-stent group. Stent insertion was an independent risk factor for overall mortality. Biliary stents may reduce survival in patients with advanced pancreatic cancer. The rate of febrile neutropenia was higher in the stent group than in the non-stent group. There is a need to assess the patient's condition with discretion and develop a treatment strategy with short prognosis in mind after stent insertion.

Antiviral toxicities in pediatric solid organ transplant recipients

Prophylaxis with valganciclovir (VGCV) is used routinely to prevent cytomegalovirus (CMV) infections in at-risk pediatric solid organ transplant (SOT) recipients. However, the rate and factors associated with toxicities in this population are not well-described. We conducted a retrospective cohort study of children undergoing SOT at our hospital from January 2012-June 2018. We evaluated the frequency of hematologic and renal toxicities from day 15 through 1-year post-SOT in relation to antiviral exposures, focused on VGCV prophylaxis. Marginal rate models were used to determine the risk of kidney injury and neutropenia in relation to VGCV prophylaxis. Among 281 SOTs, VGCV prophylaxis was administered on 20.1% of all follow-up days. The incidence rates of kidney injury, leukopenia, and neutropenia were significantly higher during VGCV prophylaxis compared to when no antiviral agents were given. Using multivariable marginal rate models, receipt of VGCV prophylaxis was associated with development of kidney injury (rate ratio [RR] 1.79, 95% confidence interval [CI]: 1.22-2.65) and neutropenia (RR 4.82, 95% CI: 3.08-7.55). VGCV dosing did not impact the development of kidney injury or neutropenia. Toxicities are common with VGCV prophylaxis in pediatric SOT recipients.

The adverse effects of trastuzumab-containing regimes as a therapy in breast cancer: A piggy-back systematic review and meta-analysis.

Trastuzumab is a valuable therapy option for women with ERBB2(HER2)+ breast cancer tumours, often used in combination with chemotherapy and alongside other therapies. It is known to have adverse effects, but these have proved difficult to separate from the effects of other concurrent therapies patients are usually taking. This study aims to assess the adverse effects specifically attributable to trastuzumab, and whether they vary by patient subgroup or concurrent therapies. As registered on PROSPERO (CRD42019146541), we used previous systematic reviews as well as the clinicaltrials.gov registry to identify randomised controlled trials in breast cancer which compared treatment regimes with and without trastuzumab. Neoadjuvant, adjuvant and metastatic settings were examined. Data was extracted from those which had, as of July 2022, reported adverse events. Risk of bias was assessed using ROB2. Primary outcomes were adverse events of any type or severity (excluding death). A standard random-effects meta-analysis was performed for each outcome independently. In order to ascertain whether adverse effects differed by individual factors such as age or tumour characteristics, or by use of trastuzumab concurrently with hormone therapy, we examined individual-level patient data for one large trial, HERA. 79 relevant trials were found, of which 20 contained comparable arms of trastuzumab-containing therapy and corresponding matched therapy without trastuzumab. This allowed a comparison of 8669 patients receiving trastuzumab versus 9556 receiving no trastuzumab, which gave a list of 25 statistically and clinically significant adverse effects related to trastuzumab alone: unspecified pain, asthenia, nasopharyngitis, skin disorders (mainly rash), dyspepsia, paraesthesia, infections (often respiratory), increased lacrimation, diarrhoea, myalgia, oedema (limb/peripheral), fever, nose bleeds, cardiac events, insomnia, cough, back pain, dyspnoea, chills, dizziness or vertigo, hypertension, congestive heart failure, increased levels of aspartate aminotransferase, gastrointestinal issues and dehydration. Analysis of individual patient-level data from 5102 patients suggested that nausea is slightly more likely for women taking trastuzumab who are ER+ /also taking hormone therapy than for those who are ER-/not taking hormone therapy; no other potential treatment-subgroup interactions were detected. We found no evidence for significantly increased rates of neutropenia, anaemia or lymphopenia in patients on trastuzumab-containing regimes compared to those on comparable regimes without trastuzumab. This meta-analysis should allow clinicians and patients to better identify and quantify the potential adverse effects of adding trastuzumab to their treatment regime for breast cancer, and hence inform their decision-making. However, limitations include serious risk of bias due to heterogeneity in reporting of the outcomes and the open-label nature of the trials.

The effectiveness of consolidation chemotherapy in high-risk early-stage cervical cancer patients following concurrent chemoradiation after radical surgery.

Studies determining which early-stage cervical cancer patients with high-risk factors benefit from consolidation chemotherapy after postoperative concurrent chemoradiotherapy (CCRT) are limited and inconsistent. The aim of this study was to evaluate the value of consolidation chemotherapy in early-stage cervical cancer. From 2010 to 2019, a retrospective review was conducted among high-risk early-stage cervical cancer patients who were treated with postoperative CCRT or consolidation chemotherapy after postoperative CCRT. Disease-free survival (DFS) and overall survival (OS) were calculated using the Kaplan-Meier method and compared using the log-rank test. A total of 293 patients with early-stage cervical cancer were included in this study. A total of 188 patients were in the consolidation chemotherapy group, and 105 patients were in the postoperative CCRT alone group. The median follow-up was 48.3months (range: 3-123months). In the survival analyses, no significant differences in DFS (P=0.21) or OS (P=0.15) were observed between the groups. The grade 3-4 leukopenia and neutropenia rates in the consolidation group were higher than those in the concurrent chemoradiotherapy alone group (54.8% vs. 28.6%, P=0.02; 49.4% vs. 10.5%, P=0.001, respectively). For patients with ≥2 positive lymph nodes or ≥2 high-risk factors, consolidation chemotherapy significantly improved DFS (P=0.013 and P=0.002) and OS (P<0.001 and P<0.001) compared with CCRT alone. For early-stage cervical cancer, consolidation chemotherapy after postoperative CCRT improved survival outcomes in patients with ≥2 positive lymph nodes or ≥2 high-risk factors.

A Phase 1b Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of an Investigational Microbiome Therapeutic, SER-155, in Adults Undergoing Hematopoietic Stem Cell Transplantation

Background: In patients undergoing allogeneic hematopoietic cell transplantation (HCT), loss of gastrointestinal microbial diversity is associated with risk of bloodstream infections (BSI), acute graft-versus-host disease (aGvHD), and death. SER-155 is an investigational cultivated microbiome therapeutic rationally designed to improve clinical outcomes in HCT by restoring colonization resistance to potential pathogens, promoting epithelial barrier integrity, and reducing colonic inflammation. SER-155-001 is a Phase 1b study to evaluate the efficacy, safety, and pharmacokinetics (PK) of SER-155 in adults undergoing HCT that is currently enrolling at 4 sites. Study Design and Methods: This study will enroll approximately 70 subjects ≥ 18 years in an open-label Cohort 1 (n = 10) followed by a double-blind, placebo-controlled Cohort 2 (n = 60) randomized 1:1 to SER-155 or placebo and stratified by conditioning regimen intensity. Exclusion criteria include history of severe colitis or active inflammatory bowel disease or total colectomy, umbilical cord blood or ex vivo T-cell depletion, exposure to fecal microbiota transplant or any live microbial therapeutic within 3 months prior to screening, and evidence of relapse or progression of hematologic malignancy (minimal residual disease is allowed). Following screening, subjects in both cohorts will receive 2 treatment courses (before and after HCT), each comprised of microbiome conditioning with oral vancomycin or placebo followed by SER-155 or placebo, and a conditional 3rd treatment course if the subject receives antibiotics (Table 1; Figure 1). Safety outcomes will be followed through 52 weeks post HCT. The primary endpoint is to evaluate the incidence and severity of adverse events, serious adverse events, and adverse events of special interest. Secondary endpoints include rates of BSI, gastrointestinal infections, aGvHD, febrile neutropenia and overall survival in placebo vs SER-155 arms. Microbiome related endpoints include engraftment of SER-155 bacterial strains in the gastrointestinal tract (PK endpoint) and fecal microbiome diversity, composition and metabolites. In April 2022, the SER-155 Data and Safety Monitoring Committee met as part of a planned review of available safety data from Cohort 1 and supported continuation of Cohort 1 enrollment. Summary: In this Phase 1b study, the feasibility, safety, and clinical efficacy of SER-155 is being assessed in the setting of allogeneic HCT. This trial will add to the expanding clinical experience of microbiome-directed interventions in allogeneic HCT recipients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal