Gemcitabine Plus Vinorelbine for Refractory or Relapsing Non-Hodgkin Lymphoma: Response Rate and Survival

Background: Two chemotherapeutic agents, vinorelbine and gemcitabine, have shown encouraging early results in the treatment of heavily pre-treated relapsed or refractory lymphoma when used as single agents, with responses of between 20 and 47%. This work aimed to evaluate the role of gemcitabine and vinorelbine in the treatment of relapsed and /or refractory aggressive Non-Hodgkin Lymphoma (NHL) as regard response rate, survival analysis. Methods: This prospective study was conducted on 20 patients who had relapsed and /or refractory NHL and treated with a minimum follow of 6 months. All patients were subjected to full clinical examination, laboratory and radiological study. Vinorelbine, Gemcitabine, dexamethasone, filgrastim (VGF) was administrated, On days 1 and 8, patients received vinorelbine 25 mg/m2, Gemcitabine 1000 mg/m2 and Dexamethasone 16mg/m2 I.V, On day 9, they received peg-filgrastim 6 mg subcutaneously, Patients received 4 cycles of VGF, Assessment was performed after 4th cycle of treatment and according to response during follow up period, the patient received 2 more cycles with minimum follow up 6 months and/or PET-CT was done in all patients to evaluate response rate. Results: Regarding status; 60 % of patients were relapsed and 40% of them were refractory. Regarding line therapy: all patients were treated with 1st line protocol of Rituxan/Rituximab-Cyclophosphamide-Hydroxydaunorubicin-Oncovin-Prednisone regimen (R-CHOP), and 4 of them had been treated with 2nd line chemotherapy of Ifosfamide, Cisplatin or Carboplatin, and Etoposide (ICE). So 80% of patients received VGF chemotherapy as 2nd line, while 20% of them received it as the 3rd line. And there was no statistical difference between relapsed and refractory groups regarding lines of VGF chemotherapy. Regarding the toxicity of VGF (toxicity criteria as defined by Chesson and WHO); 50% of patients complicated with grade III anaemia, 50% of patients complicated with grade III neutropenia, 60% of patients complicated with grade III thrombocytopenia, 20% of patients complicated with grade II GIT upset, 40% of patients complicated grade II thrombophlebitis and 40% of patients complicated with grade II neurotoxicity. Conclusions: VGF shows substantial activity in relapsed or refractory aggressive NHL. The regimen is generally well-tolerated, but haematological toxicity is common.

Novel longitudinal Multiple Overall Toxicity (MOTox) score to quantify adverse events experienced by patients during chemotherapy treatment: a retrospective analysis of the MRC BO06 trial in osteosarcoma

ObjectivesThis study aims at exploring and quantifying multiple types of adverse events (AEs) experienced by patients during cancer treatment. A novel longitudinal score to evaluate the Multiple Overall Toxicity (MOTox) burden is proposed. The MOTox approach investigates the personalised evolution of high overall toxicity (high-MOTox) during the treatment.DesignRetrospective analysis of the MRC-BO06/EORTC-80931 randomised controlled trial for osteosarcoma.SettingInternational multicentre population-based study.ParticipantsA total of 377 patients with resectable high-grade osteosarcoma, who completed treatment within 180 days after randomisation without abnormal dosages (+25% higher than planned).InterventionsPatients were randomised to six cycles of conventional versus dose-intense regimens of doxorubicin and cisplatin. Non-haematological toxicity data were collected prospectively and graded according to the Common Terminology Criteria for Adverse Events (CTCAE).Main outcome measuresThe MOTox score described the overall toxicity burden in terms of multiple toxic AEs, maximum-severity episode and cycle time-dimension. Evolution of high-MOTox was assessed through multivariable models, that investigated the impact of personalised characteristics (eg, achieved chemotherapy dose, previous AEs or biochemical factors) cycle-by-cycle.ResultsA cycle-by-cycle analysis identifies different evolutions of MOTox levels during treatment, detecting differences in patients’ health. Mean MOTox values and percentages of patients with high-MOTox decreased cycle-by-cycle from 2.626 to 1.953 and from 57.8% to 36.6%, respectively. High-MOTox conditions during previous cycles were prognostic risk factors for a new occurrence (ORs range from 1.522 to 4.439), showing that patient’s history of toxicities played an important role in the evolution of overall toxicity burden during therapy. Conventional regimen may be preferred to dose-intense in terms of AEs at cycles 2–3 (p<0.05).ConclusionsThe novel longitudinal method developed can be applied to any cancer studies with CTCAE-graded toxicity data. After validation in other studies, the MOTox approach may lead to improvements in healthcare assessment and treatment planning.Trial registration numberISRCTN86294690; Post-results.

Cardiotoxic Effects of Yew Tree and Pink Periwinkle Alkaloids

Antitumour herbal medicines based on pink periwinkle and yew tree alkaloids are included in combination therapies for many types of cancer. The use of these classes of products may entail cardiotoxic effects leading to life-threatening conditions. The aim of the study was to analyse scientific literature on cardiotoxic effects of anticancer drugs based on yew tree alkaloids (taxanes) and pink periwinkle alkaloids (vinca alkaloids). The results of the analysis demonstrated that the main manifestations of taxane-induced cardiotoxicity were bradycardia, atrioventricular block, atrial and ventricular arrhythmias. Concomitant use of taxanes and anthracycline antibiotics exacerbated cardiotoxic effects of both drug classes. The use of vinca alkaloids was associated with haematological toxicity in the form of neutropenia, while cardiotoxic effect was rarely observed during monotherapy. Raising awareness among oncologists, cardiologists, and other specialists involved in the management of cancer patients about potential cardiac complications of antitumour therapy contributes to early detection of adverse reactions and allows for individual correction of treatment regimens, especially in patients with predisposition to cardiovascular disease.

Mesenchymal Stromal Cells Plus Anti-CD25 Antibody and Calcineurin Inhibitors for Steroid-Resistant Acute Graft-Versus-Host Disease: A Multicenter, Randomized, Phase 3 Trial

INTRODUCTION Steroid-resistant (SR) acute graft-versus-host disease (aGVHD) lacks standard second-line treatment. Mesenchymal stromal cells (MSCs) have potential efficacy in SR aGVHD. To assess efficacy and safety of MSCs combined with anti-CD25 antibody and calcineurin inhibitors as second-line therapy for SR aGVHD. METHORDS A randomized phase 3 trial involved 203 SR aGVHD patients at 10 centers in China (September 2014-March 2019). Final follow-up was on June 30, 2020. Participants were randomized in a 1:1 ratio to receive second-line therapy (anti-CD25 antibody combined with calcineurin inhibitors) with MSCs (n=101) or without MSCs (n=102). The primary endpoint was overall response (OR) at day 28 with a predefined threshold of -20%. Secondary and safety endpoints included durable OR at day 56, failure-free survival, overall survival (OS), chronic GVHD (cGVHD), infection, haematological toxicity and relapse. RESULTS Of 203 patients, 198 (97.5%; mean age, 30.1years; 40.4% women) completed the study. OR at day 28 was higher in the MSCs group than in the control group (82.8% [82 patients] vs 70.7% [70]; odds ratio, 2.00; 95% confidence interval [CI], 1.01-3.94; P=.043). Durable OR at day 56 was also higher in the MSCs group (78.8% [78 patients] vs. 64.6% [64]; odds ratio, 2.02; 95% CI, 1.08-3.83; P=.027). The median failure-free survival was longer in the MSCs group compared with control group (11.3 months vs. 6.0 month; hazard ratio (HR) 0.68; 95% CI, 0.48-0.95, P=.024). The 2-year cumulative incidence of cGVHD was 39.5% (95% CI, 29.3%-49.4%) and 62.7% (51.4%-72.1%) in the MSCs and control groups (HR 0·55, 95% CI, 0·36-0·84; P=0·005). Within 180 days after study treatments, the most common grade 3 and 4 adverse events were infections (65 [65.7%] in the MSCs group vs 78 [78.8%] in the control group), haematological toxicity (37 [37.4%] vs 53 [53.5%]). CONCLLUSIONS MSCs plus second-line treatments may increase the efficacy of SR aGVHD, decrease drug toxicity of second-line therapy and cGVHD development, and are well tolerated. Disclosures No relevant conflicts of interest to declare.

Role of Pegfilgrastim in the Supportive Care of Heavily Pretreated Multiple Myeloma in Treatment with Pomalidomide-Dexamethasone

Pegfilgrastim is a pegylated long-acting recombinant form of G-CSF that extends the half-life and allows for once-per-cycle dosing, requiring less frequent dosing than nonpegylated G-CSF. The objective of this study was to compare the efficacy and safety of pegfilgrastim in patients affected by heavily pretreated MM, treated with pomalidomide-dexamethasone, in order to determine whether a single subcutaneous injection of pegfilgrastim is as effective as daily injections of standard filgrastim, in terms of haematological toxicity, febrile neutropenic episodes, antibiotic usage and hospedalization duration. 57 patients (31 M and 26 F) were enrolled, median age at diagnosis 69 years (r. 52-84), and median age at start of treatment 76 years (r.56-90) treated with several lines of treatments (median 7, r. 2-12), every refractory to all the drugs previously received, received Pomalidomide-Dexamethasone (P 4 mg for 21 days, D 40 mg days 1,8,15,22, pegfilgrastim day +8) every 28 days, until progression. Since first course, received in domestic setting, with a very good compliance, patients performed blood counts once weekly and received, from day +8 to day +19, prophylactic oral chinolonic antibiotics and anti-fungal drugs. During neutropenia after first cycle, Filgrastim (5 μgr/kg/day for 3 days) was given if neutrophils count was &lt;1500 x 10^9 cells/L. Median number of filgrastim administrations was 4.6 (r. 3-6); nadir neutropenia was registered after a median of 10.4 days (r. 7-14); median of nadir neutrophil count was 1.13 x 10^9 cells/L (r.0.3 - 1.5), with maximum duration of 14 days. From the second course, all patients switched to prophylaxis with pegfilgrastim (6 mg), injected subcutaneously with a single administration on day +3 independently from the neutrophil count at that time. During pegfilgrastim, neutropenia was never longer than 8 days, with a consequent reduction of neutropenia-related infections. Median nadir neutrophil count, evaluated for every patients for at least three courses of therapy (r. 3-6) registered at day +11, was 1.28 (r.0.9-2.2). Only 4 patients needed a supplement of 3 administrations of filgrastim. Pegfilgrastim was well tolerated in all patients: main side effects in our patients were mild fever and bone pain (21.2%). In patients affected by heavily pretreated MM treated with pomalidomide-dexamethasone, pegfilgrastim seems to reduce the incidence of severe neutropenia and infections and may increase the possibility to maintain the scheduled time of treatment. Disclosures Pane: AbbVie; Amgen; Novartis, GSK , Incyte: Consultancy; AbbVie; Amgen; Novartis, GSK, Incyte: Speakers Bureau; Novartis Pharma SAS;: Research Funding; AbbVie; Amgen; Novartis: Other: Travel, accommodation, expenses. Martinelli: Jazz Pharmaceuticals: Consultancy; Stemline Therapeutics: Consultancy; Astellas: Consultancy, Speakers Bureau; Roche: Consultancy; Incyte: Consultancy; Pfizer: Consultancy, Speakers Bureau; Abbvie: Consultancy; Celgene /BMS: Consultancy, Speakers Bureau; Daichii Sankyo: Consultancy.

Evaluation of Treatment Outcome and Acute Toxicity in Patients Undergoing Adjuvant Therapy in Ductal Carcinoma Pancreas: A Prospective Observational Study

Ductal adenocarcinoma of the pancreas is one of the commonly diagnosed cancers and is a leading cause of cancer mortality in the population. The prognosis of patients even after undergoing a complete resection is generally poor, with a median survival of 13–20 months and a 3-year survival of 30%. Therefore, adjuvant therapies including adjuvant chemoradiation and adjuvant chemotherapy are given in an effort to improve survival. In the authors’ centre, all patients undergoing resection are given adjuvant chemoradiation followed by adjuvant chemotherapy. This study was conducted to evaluate the acute toxicity and treatment outcome (patterns of failure, overall and disease-free survival) of patients undergoing adjuvant therapy in resected carcinoma pancreas. Adjuvant chemoradiation was well tolerated by most patients with resected carcinoma pancreas and all patients completed chemoradiation. Adjuvant chemotherapy was associated with high haematological toxicity, similar to previously published literature. However, treatment interruptions were higher and only 77% patients completed adjuvant chemotherapy. The adjuvant gemcitabine, given on Days 1, 8, and 15, for a 4-weekly schedule was poorly tolerated by the authors’ patient population and there were only fewer interruptions in patients who were switched to the 3-weekly schedule. Inclusion of a greater number of patients and longer follow-up of this study is required to clearly assess the patterns of failure and survival outcomes.

Toxicity And Surface Modification Of Dendrimers: A Critical Review

: As compared to other nano polymers, dendrimers have novel three dimensional, synthetic hyperbranched, nano-polymeric structures. The characteristic of these supramolecular dendritic structures has a high degree of significant surface as well as core functionality in the transportation of drugs for targeted therapy, specifically in host-guest response, gene transfer therapy and imaging of biological systems. However, there are conflicting shreds of evidence regarding biological safety and dendrimers toxicity due to their positive charge at the surface. It includes cytotoxicity, hemolytic toxicity, haematological toxicity, immunogenicity and in vivo toxicity. Therefore to resolve these problems surface modification of the dendrimer group is one of the methods. From that point, this review involves different strategies which reduce the toxicity and improve the biocompatibility of different types of dendrimers. From that viewpoint, we broaden the structural and safe characteristics of the dendrimers in the biomedical and pharmaceutical fields.

P14.13 Severe hematological toxicity during chemoradiation for glioblastoma: Identification of clinical and pharmacological risk factors and consequences for the individual patient

BACKGROUND Besides early tumour progression, standard first-line radiation with concurrent and adjuvant temozolomide in de novo glioblastoma patients is abrogated frequently by severe haematological toxicity. This leads to treatment delays with unknown effect on efficacy and to more hospital visits with increased disease burden. In the present study, we identified clinical and pharmacological risk factors for temozolomide induced severe hematological toxicity. Furthermore, we describe the burden of toxicity for patients and evaluate the effect of severe toxicity on prognosis. METHODS A retrospective cohort study of adult patients with a histological confirmed glioblastoma (n=363), treated with standard treatment regimen at the Brain Tumor Center Amsterdam between 2000 and -2020. Severe haematological toxicity was defined as a CTCAE (version 5.0) grade ≥3. We used Pearson Chi-Square test to analyze differences in patient characteristics between the groups (no vs. severe toxicity) and paired samples T- Test to analyze fluctuations in cell counts. Univariate and multivariate logistic regression were used to identify patient- and treatment characteristics associated with severe hematological toxicity. Cox Proportional Hazards models were used to estimate Hazard Ratio’s for the association between survival and severe hematological toxicity. RESULTS Female gender (OR 8.05, 95%CI 2.96–21.89, p&lt;0.001) and older age (age &gt; 70 years; OR 2.44, 95%CI 1.12–5.31, p=0.025) were independent risk factors for severe toxicity. Concurrent and adjuvant temozolomide was discontinued in respectively 56% and 35% of the patients. In general, patients with severe hematological toxicity had a treatment delay of 22 ± 48 days. Of all patients with severe hematological toxicity during chemoradiation, 96% developed toxicity after ≥4 weeks of treatment (p&lt;0.001). Females who received highest temozolomide-doses (4th quartile) had a longer survival than females with low cumulative temozolomide doses (1st quartile). Patients, who developed severe toxicity had much more hospital visits (20; range 12–26), and were admitted more frequently to the hospital. Severe haematological toxicity was not related to survival (HR 1.04; 95%CI 0.74–1.45). CONCLUSION Female gender and age &gt;70 years are risk factors for severe hematological toxicity. Severe hematological toxicity relates to temozolomide exposure and results in a significant treatment burden for patients. Low temozolomide exposure results in decreased survival. Patient tailored therapy may result in better treatment outcomes.

UPLC-MS/MS Determination of Linezolid and Heme in Plasma of Infected Patients and Correlation Analysis

Linezolid can cause serious haematological toxicity, such as thrombocytopenia and aneamia. Heme, composed of iron and porphyrin, is an important component of hemoglobin. In order to investigate the relationship between the concentration of linezolid and heme in the plasma of infected patients, a UPLC-MS/MS method that can determine the concentrations of linezolid and heme simultaneously was developed and validated. A total of 96 healthy subjects and 81 infected patients, who received blood routine blood tests, were included and determined by the UPLC-MS/MS method. The results showed that the concentration of linezolid was 5.08 ± 3.46 μ g / mL in infected patients who were treated with linezolid. The heme in healthy subjects was 7.05 ± 8.68 μ g / mL , and it was significantly decreased to 0.88 ± 0.79 μ g / mL in infected patients ( P < 0.01 ). Spearman correlation analysis showed that linezolid had a high negative correlation with platelet (PLT) ( R = − 0.309 ). Heme had a high positive correlation with hemoglobin (Hb) ( R = 0.249 ) in healthy subjects and infected patients. The ROC analysis showed that heme had diagnostic value to distinguish low Hb (110 g/L). In conclusion, there was a positive correlation between heme and Hb, and this correlation was also observed in infected patients. A high concentration of linezolid was inclined to decrease PLT. Monitoring of heme and linezolid helps in the early diagnose of low Hb and PLT.

Neoadjuvant chemotherapy for locally advanced colon cancer patients: Long-term results from a single institutional experience.

e15598 Background: Neoadjuvant chemotherapy (NAC) is an emerging alternative in the management of patients with locally advanced colorectal cancer (LACRC), with promising results in terms of R0 resection rates, compliance, postoperative morbidity and a trend towards reduced risk of relapse. However, more mature data are required. We evaluated the long-term outcome of this strategy in our institution. Methods: We retrospectively analysed LACRC patients treated preoperatively with either biweekly FOLFOX or XELOX at standard doses as a follow-up of our previous experience with this neoadjuvant approach. Patients were identified from a prospectively collected tumor registry database from our institution. Clinical staging was based on colonoscopy and CT-scan. Only patients with radiological signs of lymph node involvement and/or extramural invasion > 5 mm were included. The uracil/dihidrouracil ratio was calculated at baseline as a surrogate marker of DPD deficiency. Pathological tumor regression was graded according to the MSKCC and toxicity with the NCI-CTCAE 4.0. Results: From February 2006 to November 2019 91 pts with MSS LACRC (M/F: 62/29; median age 66. Clinical stage; T3: 60.4%, T4: 37.4%, N+: 75.8%; Sideness: 82.4% left located were analysed. Preoperative chemo was FOLFOX in 46 pts and CAPOX in 45 pts. Median number of preoperative cycles was 4 (range 1-10). Side effects profile included G3-4 diarrhea (3.3%), G2 sensitive neuropathy (12.1%) and G2 neutropenia (4.4%). 9 pts had a treatment delay due to haematological toxicity. No progressive disease was noted during neoadjuvant chemotherapy. All patients underwent surgery, most of them (63.7%) by a laparoscopic approach. pCR was found in 11 pts (12.1%). Grade 3, 3+ and 4 tumor regression according to MSKCC score was reached in 50.5% of the patients (Median number of harvested nodes was 17 (range 7-51), with 75.8% being ypN0. Lymphovascular and perineural invasion were found in 7.7% and 6.6% of the patients, respectively. The median hospital stay was 7 days (3-36) and 13 pts develop any surgical complication. 37.4% received adjuvant treatment. After a median follow-up of 63 months, median progression-free (PFS) and overall survival (OS) have not been reached. 5-year actuarial PFS for right and left LACRC was 77 and 87%, respectively. Conclusions: Our data add to the growing evidence suggesting that NAC may play a meaningful role in LACRC patients