Rate Of Hematologic Toxicity Research Articles

A single institution retrospective study of the effect of starting doses in patients with ER-positive metastatic breast cancer on CDK 4/6 inhibitors.

e13056 Background: CDK4/6 inhibitors (CDKi) have become part of standard of care in the treatment ER-positive, Her2Neu negative of metastatic breast cancer (MBC). Hematologic toxicity from CDKi are common which can lead to dose interruption or dose reduction. There is limited data to compare those who started on full dose and those who started on a reduced dose CDKi. We sought to investigate the impact of reduced starting dose of CDKis. Methods: We conducted a single institution retrospective study on patients (pts) who were treated with CDKi from 2015 to 2019. In this subgroup analysis, we sought to determine the percentage of pts that started on reduced dose CDKi. Pts who were started on reduced dose were compared to those started on standard FDA dose CDKi. Rates of hematologic toxicities, dose interruptions, further dose reductions, progression-free survival and overall survival were compared between the two groups. Data from absolute neutrophil count, hemoglobin and platelet count on Days 1 and 15 of the first 2 cycles were graded for hematologic toxicity according to CTCAE v 5.0. Results: Out of 220 pts, 175 (79.6%) pts started on standard starting dose CDKi and 45 (20.5%) pts started on reduced dose CDKi. 30.86% of pts on the standard dosing group and 28.9% of pts on the reduced starting dose group had a dose interruption. The association between starting dose and dose interruption is not statistically significant (p < 0.86). The estimated 12-month survival rate is 95% (95% CI: 89% - 97%) for the pts on standard dose CDKi and 85% (95% CI: 67% - 93%) for the group reduced dose group. The estimated 12-month progression-free survival rate is 72% (95% CI: 64% - 78%) for the standard dosing group and 35% (95% CI: 21% - 50%) for the reduced dose group. Conclusions: Our study showed a significant survival rate and progression-free survival rate difference between patients who were started on standard FDA starting dose compared to those started on reduced dose CDKi.

Immune-related adverse events (irAEs) among urothelial carcinoma (UC) patients treated with PD-1 VS PD-L1 inhibitors: A real-world observational study.

e17017 Background: Anti-PD-1/PD-L1 agents are US FDA-approved for patients with advanced or metastatic UC, but limited information exists on real world irAEs among this patient population. We examined the rates and time to onset of select irAEs in UC patients receiving PD-L1s vs PD-1s in the real world. Methods: This observational study included US commercial and Medicare Advantage health plan members from Optum Research Database with UC and treated with a PD-1 or PD-L1 agent between 01-Sep-14 and 30-Apr-19. Baseline characteristics were assessed ≤ 6-months prior to the first claim for anti-PD-1/PD-L1. 21 irAEs were chosen a priori based on the ASCO clinical guideline on irAE management, clinical input, frequency, and cost of treatment. Patients were followed for newly occurring irAEs, based on claims ICD codes, during the PD-1/PD-L1 therapy and up to 180 days after if no new treatment, study period end, death, or disenrollment. Kaplan-Meier method was utilized to calculate time to onset of irAEs. Results: The study included 240 patients receiving PD-L1s and 317 receiving PD-1s. Baseline demographics were similar (Table). The most common irAEs were 1) thyroid disorders, 2) impaired ventricular function with heart failure and vasculitis, 3) rash, and 4) nephritis. UC patients receiving PD-L1s had a lower rate of irAEs vs PD-1s, mainly driven by lower rates of hematologic and endocrine toxicities (Table). UC patients receiving a PD-L1 also had longer time to irAE onset (p-value = 0.05). Conclusions: UC patients receiving PD-L1s had a lower incidence rate of irAEs and longer time to irAE onset than patients on PD-1s. Findings suggest patients receiving PD-1s may require more intense monitoring for irAEs than patients taking PD-L1s. [Table: see text]

Efficacy and tolerance of carboplatin-cetuximab in patients with metastatic or recurrent head and neck squamous cell carcinoma unfit for extreme regimen.

6539 Background: Head and neck squamous cell carcinoma (HNSCC) is the fourth cause of death by cancer in France. For metastatic patients, the standard first line treatment is the EXTREME regimen. However, a lot of these patients have a poor performance status (PS) and/or several comorbidities making them unfit for this regimen. We have treated them with carboplatin and cetuximab (simplified EXTREME regimen) since 2007. The aim of this study is to assess the efficacy and tolerance of this regimen in this frail population. Methods: We retrospectively reviewed the medical charts of all patients treated with simplified EXTREME regimen for recurrent or metastatic HNSCC in three French academic hospitals between 2007 and 2017. The primary endpoint was overall survival (OS) and secondary endpoints were progression free survival (PFS), overall response rate (ORR), identification of prognostic factors, and toxicity. Results: 103 patients were included with a median age of 63 y.o., 60% had a PS 0-1 and 40% a PS 2-3. With a median follow-up of 30.2 months, median OS was 7.2 months and median PFS 3.7 months. ORR was 39% and 24% of patients had disease stabilization. On univariate analysis, a PS of 2 or more was significantly associated with a worse OS (median OS 10.1 months if PS 0-1 versus 4.6 months if PS 2-3; HR = 1.68; 95%CI = 1.11-2.57; p = 0.01). Acute grade 3-4 hematologic and non-hematologic toxicity rates were 25.2% and 27.2%, respectively, with 11.8% of thrombopenia, 9.7% of neutropenia, 10% of skin toxicity, and 12.6% of asthenia. Patients with grade 1 or more skin toxicity had a higher ORR (HR = 3.44; 95%CI = 1.16-10.23; p = 0.03) and a prolonged OS (HR = 0.37; 95%CI = 0.23-0.58; p < 0.0001) and PFS (HR0.29; 95%CI = 0.19-0.47; p < 0.0001). During treatment, 29% of patients had a pain decrease, 13.5% a gain of weight, and 17.2% an improvement in PS. Conclusions: This is the largest cohort of patients treated with simplified EXTREME for HNSCC. Simplified EXTREME was well tolerated in this frail population with a high ORR. Patients with a good PS had prolonged survival. Interestingly, skin toxicity of any grade was significantly correlated with treatment efficacy.

Daratumumab (Dara) and hyperfractionated cyclophosphamide (HyperCy)/dexamethasone (Dex) with and without carfilzomib (Car) for the treatment of relapsed/refractory multiple myeloma (RRMM).

e20528 Background: RRMM can be associated with high disease burden and/or end organ damage requiring rapid disease control. Our group has previously published data with hyperCy-bortezomib (bor)-doxorubicin-dex (Tabchi et al. 2019) for such patients (pts). Dara, a monoclonal antibody targeting CD38, has limited overlapping toxicities with cytotoxic chemotherapy, making it an attractive partner for hyperCy-dex. We report our retrospective experience of pts treated with dara-hyperCy-dex ± car. Methods: Between 5/2016-8/2019, 53 pts were treated with dara (16 mg/kg IV d1,8,15,22)-hyperCy (300-350 mg/m2 IV q12h x 6-8 doses d1-3/4)-dex (20-40 mg IV/PO d1-4, 8-11, 15-18, 22-23) alone (27 records), or with car (20 mg/m2 IV d1-2, 27-36 mg/m2 IV d8-9, 15-16) (32 records) on 28 day cycles. Pts received growth factor, anti-fungal, anti-bacterial, anti-viral, and peptic ulcer prophylaxis. High-risk MM (HRMM) was defined by t(4;14), t(14;16), and/or del 17p. Response was assessed by International Myeloma Working Group Uniform Criteria. Overall response rate (ORR) and disease control rate (DCR) were defined as ≥ partial response and ≥ stable disease, respectively. Each instance of treatment (tx) started > 60 days from the previous cycle start date was counted as a separate record. Patient characteristics, progression-free survival (PFS) and overall survival (OS) were assessed per pt, based on earliest administration date. Results: Median age of pts was 61 (26-77) years. Median number of prior therapies was 4 (1-18). Previous exposure to both lenalidomide and pomalidomide (93%), both bor and car (83%), and dara (64%) was frequent. HRMM was present in 20/42 evaluable pts. After a median of 1 cycle (1-5), ORR was 63%, with ≥ very good partial response in 24%. DCR was 86%. Median PFS was 4.3 months. Median OS was 9.7 months. Grade 3-4 hematologic toxicities included 66% neutropenia, 66% anemia, and 68% thrombocytopenia. Grade 3-4 non-hematologic toxicities included 42% febrile neutropenia, 19% bacteremia, and 15% pneumonia. Within 60 days of tx, 7 pts underwent autologous stem cell transplant (ASCT), and 7 pts died. Conclusions: Dara-hyperCy-dex ± car demonstrates a high ORR and DCR in heavily treated and HRMM, allowing bridging of some pts to ASCT. High rates of hematologic toxicity and risk of infection are manageable with twice weekly monitoring for transfusion support, as well as early detection and intervention for infections. Rates of end organ damage reversal will be presented.

Toxicity burden in older patients with chronic lymphocytic leukemia (CLL) receiving bendamustine with rituximab (BR) or ibrutinib (IB) regimens: Alliance A041202.

e20004 Background: IB is a Bruton’s tyrosine kinase inhibitor that showed superior progression-free survival compared with BR in CLL patients (pts) 65 years or older in a randomized phase 3 trial (Woyach et al, NEJM 2018). Pts receiving IB had higher rates of atrial fibrillation (AFIB) and hypertension (HTN); BR pts had higher rates of hematologic toxicity. Differences in treatment duration for BR (6 cycles) and IB (until progression) complicated adverse event (AE) comparisons. Here we use an exploratory approach to compare toxicity burden between arms and provide assessment of AFIB, HTN and infections (INF). Methods: AEs were reported for each of cycles 1-6 and then every 3 cycles until progression or nonprotocol CLL therapy. Only grade (gr) 3-4 AEs were reported thereafter until death. A simple global AE score was calculated for each pt by summing grades of all gr 1-4 AEs and dividing by the number of cycles over which AEs were submitted. Results: 537 pts began therapy (176 BR, 361 IB). 68% on BR completed all 6 cycles. At a median follow-up of 38 months, 64% remained on IB. Treatment discontinuation for AE occurred in 10% and 14% of BR and IB pts. Overall, median AE score was 1.8 (interquartile range (IQR) 0.9-3.3) and 3.8 (IQR 2.3-5.9) in BR and IB arms (p < 0.01). For cycles 1-6, median AE score was 6.2 (IQR 3.8-9.0) and 4.8 (IQR 3.0-7.2) in BR and IB arms (p < 0.01). In the IB arm, median AE score post 6 cycles decreased significantly to 3.4 (IQR 1.9-5.6) (p < 0.01). Gr 3 or higher cumulative rates of AFIB, HTN, and INF over time appear in the table. 100 pts (26/176 BR, 74/361 IB) had 137 severe INF (39% respiratory: 16 BR, 37 IB; 25% skin: 3 BR, 31 IB; 12% GU: 3 BR, 13 IB; 25% other: 12 BR, 22 IB). There were 7 gr 5 INF (3 BR, 4 IB), none confirmed fungal. Conclusions: There was no difference in treatment discontinuation rates for AE. Overall toxicity burden was significantly higher for IB, although IB toxicity burden decreased after 6 cycles. Toxicity burden was significantly higher in cycles 1-6 for pts receiving BR. Risk of severe AFIB, HTN, and INF is highest in the first year of IB. A simple AE score provides valuable information, especially when evaluating regimens of varying length. Clinical trial information: NCT01886872 . Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org ; Pharmacyclics; ClinicalTrials.gov Identifier: NCT01886872. [Table: see text]

When It Comes to Snakebites, Kids Are Little Adults: a Comparison of Adults and Children with Rattlesnake Bites

Rattlesnake envenomations are a significant cause of morbidity in the USA. While pediatric rattlesnake envenomations are relatively common, data comparing adult and pediatric patients with rattlesnake envenomationsremain limited. This multi-center retrospective study used the North American Snakebite Registry (NASBR), a sub-registry of the Toxicology Investigator's Consortium (ToxIC). All cases of rattlesnake envenomations between January 1, 2013, and December 31, 2017, which were entered into the NASBR, were reviewed. Clinical and laboratory parameters, as well as treatment and outcome measurements, were compared between adult and pediatric patients. A total of 420 unique cases were identified, including 94 pediatric patients. Adult patients were more likely to be male(76% vs. 62%; OR 1.98) and sustain upper extremity envenomations(57% vs. 25%; OR 4.4). After adjusting for bite location, adults were more likely to exhibit edema compared with pediatric patients. After controlling for envenomation location, there was no difference in rates of necrosis between adult and pediatric patients. Adults exhibited early hematologic toxicity less frequently than pediatric patients, but there was no difference in the rates of late hematologic toxicity. There were no differences in the rates of hypotension or intubation. While adult and pediatric patients have some differences in envenomation characteristics and laboratory parameters, adults and pediatric patients had similar rates of systemic toxicity, severity, length of stay, and late hematologic toxicity.

Impact of Diabetes Mellitus on Head and Neck Cancer Patients Undergoing Concurrent Chemoradiotherapy

In this retrospective study, we investigated the impact of diabetes mellitus (DM) on patients with head and neck cancer (HNC) undergoing concurrent chemoradiotherapy (CCRT). We analyzed the demographic and clinical characteristics, treatment tolerance, and toxicities of patients with HNC undergoing primary or adjuvant CCRT with or without DM between 2007 and 2016. Of the 556 patients undergoing CCRT, 84 (15.1%) had DM. Compared with patients without DM, patients with DM were significantly older (56.2 ± 11.2 vs. 51.9 ± 9.5 years, P < 0.001), received lower doses of cisplatin (adjuvant CCRT: 175.30 ± 84.03 vs. 214.88 ± 68.25, P = 0.014; primary CCRT: 142.84 ± 79.49 vs. 187.83 ± 76.19, P < 0.001), and experienced higher rates of infection (adjuvant CCRT: 52% vs. 30.5%, P = 0.042; primary CCRT: 45.8% vs. 22.9%, P < 0.001). Among patients undergoing primary CCRT, compared with those without DM, the patients with DM experienced significantly higher rates of hematologic toxicity (65.7% vs. 39.3%, P = 0.004) and treatment-related deaths (10.2% vs. 3.5%, P = 0.051); and a greater weight loss (−6.17 ± 9.27% vs. −4.49 ± 6.84, P = 0.078). Patients with HNC and DM undergoing CCRT, compared with patients without DM, experienced higher rates of infection and hematotoxicity, loss of body weight, and higher treatment-related mortality.

FOLFOXIRI vs FOLFIRINOX as first-line chemotherapy in patients with advanced pancreatic cancer: A population-based cohort study.

BACKGROUNDFOLFIRINOX regimen is the first-line reference chemotherapy (L1) in advanced pancreatic ductal adenocarcinoma (aPDAC). FOLFOXIRI, a schedule with a lower dose of irinotecan and no bolus 5-fluorouracil, has demonstrated efficacy and feasibility in colorectal cancer.AIMTo investigate the potential clinical value of FOLFOXIRI in patients with aPDAC in routine clinical practice.METHODSAnalyses were derived from all consecutive aPDAC patients treated in L1 between January 2011 and December 2017 in two French institutions, with either FOLFOXIRI (n = 165) or FOLFIRINOX (n = 124) regimens. FOLFOXIRI consisted of irinotecan (165 mg/m2), oxaliplatin (85 mg/m2), leucovorin (200 mg/m2) and 5-fluorouracil (3200 mg/m2 as a 48-h continuous infusion) every 2 wk. Ninety-six pairs of patients were selected through propensity score matching, and clinical outcomes of the two treatment regimens were compared.RESULTSMedian overall survival was 11.1 mo in the FOLFOXIRI and 11.6 mo in the FOLFIRINOX cohorts, respectively. After propensity score matching, survival rates remained similar between the two regimens in terms of overall survival (hazard ratio = 1.22; P = 0.219) and progression-free survival (hazard ratio = 1.27; P = 0.120). The objective response rate was 37.1% in the FOLFOXIRI group vs 47.8% in the FOLFIRINOX group (P = 0.187). Grade 3/4 toxicities occurred in 28.7% of patients in the FOLFOXIRI cohort vs 19.5% in the FOLFIRINOX cohort (P = 0.079). FOLFOXIRI was associated with a higher incidence of grade 3/4 digestive adverse events. Hematopoietic growth factors were used after each chemotherapy cycle and the low hematological toxicity rates were below 5% with both regimens.CONCLUSIONFOLFOXIRI is feasible in L1 in patients with aPDAC but does not confer any therapeutic benefit as compared with FOLFIRINOX. The low hematological toxicity rates strengthened the relevance of primary prophylaxis with hematopoietic growth factors.

Abstract P6-10-03: Germline (g)BRCA1/2 mutations (m) and hematological toxicities in patients (pts) with triple negative breast cancer (TNBC) treated with neoadjuvant chemotherapy (NACT)

Abstract Background: BRCA1/2 genes play a central role in DNA repair. Therefore, pts harboring gBRCA1/2m treated with chemotherapy might be at higher risk of acute hematological toxicities due to the lower level of functional BRCA1/2 protein potentially resulting in more toxicity. Published results are discordant, further data are needed. Methods: Pts with early TNBC and known gBRCA1/2m treated with anthracycline-taxane based NACT in the GeparQuinto (n=487), GeparSixto (n=291) and GeparOcto (n=393) studies were included. Primary G-CSF prophylaxis was foreseen only for the iddETC arm in GeparOcto. Primary objective was the rate of neutropenia grade (G)3-4 after cycle 1; secondary objectives were the rate of other hematological toxicities G3-4 and the overall toxicity rate after cycle 1 as well as hematological toxicities in gBRCA1/2 pts during the taxane part of chemotherapy. Results: 209/1171 evaluated pts (17.8%) had a gBRCA1/2m (177 gBRCA1m, 33 gBRCA2m). Median age was 48yrs [21-78]. The rate of neutropenia G3-4 after cycle 1 in gBRCA1/2 wildtype (wt) pts was 35.7% vs 37.4% in gBRCA1/2m (p=0.683), 35.9% in gBRCA1m (p=1.000), 44.8% in gBRCA2m (p=0.330). gBRCA1/2 mutational status did not predict neutropenia G3-4 at univariate (OR=1.08, 95%CI 0.78-1.48 p=0.658) or multivariate analysis adjusted for age, BMI and treatment (OR=1.26, 95%CI 0.87-1.82 p=0.226). The overall rate and the rates of other hematological toxicities are shown in the table. gBRCA1/2 mutational status did also not predict for any other hematological toxicities G3-4 (univariate OR=0.94, 95%CI 0.64-1.40 p=0.773; multivariate OR=0.94, 95%CI 0.62-1.43 p=0.779). gBRCA1/2 mutational status predicted for hematological toxicities G3-4 under taxane treatment (univariate OR=1.94, 95%CI 1.35-2.77 p&amp;lt;0.001; multivariate OR=2.91, 95%CI 1.55-5.45 p=0.001). During taxane treatment, the overall rate of hematological toxicities G3-4 in wt pts was 43.1% (n=270) vs 59.5% (n=91) in gBRCA1/2m, p&amp;lt;0.001; anemia G3-4 2.6% (n=16) vs 3.3% (n=5), p=0.584; leucopenia G3-4 32.7% (n=203) vs 47.1% (n=72), p=0.001; neutropenia G3-4 35.8% (n=219) vs 49.3% (n=73), p=0.003; thrombopenia G3-4 1.4% (n=9) vs 4.6% (n=7), p=0.024; febrile neutropenia 5.9% (n=37) vs 4.6% (n=7), p=0.696. Conclusions: Overall, gBRCA1/2 mutation is not associated with a significantly higher risk of severe hematological toxicities. Under taxane therapy, pts with gBRCA1/2 demonstrate a higher rate of hematological toxicities G3-4, especially neutropenia, compared to wildtype pts, and should therefore be carefully monitored. Hematological toxicities after cycle 1wildtypegBRCA1/2mp-valuegBRCA1mp-valuegBRCA2mp-valueN%N%N%N%neutropenia G3-432635.77437.40.6836135.91.0001344.80.330febrile neutropenia171.831.41.00010.60.33726.10.130leucopenia G3-424425.83818.20.0212815.80.0041030.30.548anemia G3-420.200.01.00000.01.00000.01.000thrombopenia G3-4111.210.50.70510.60.70400.01.000any hematological toxicities G1-477782.617081.70.76314180.10.4533090.90.344any hematological toxicities G3-442846.38843.60.5337241.90.3171651.60.587 Citation Format: Jenny Furlanetto, Volker Möbus, Andreas Schneeweiss, Kerstin Rhiem, Hans Tesch, Jens-Uwe Blohmer, Kristina Lübbe, Michael Untch, Christoph Salat, Jens Huober, Peter Klare, Rita Schmutzler, Fergus J Couch, Bianca Lederer, Bernd Gerber, Dirk-Michael Zahm, Ingo Bauerfeind, Valentina Nekljudova, Claus Hanusch, Christian Jackisch, Theresa Link, Sibylle Loibl, Peter A Fasching. Germline (g)BRCA1/2 mutations (m) and hematological toxicities in patients (pts) with triple negative breast cancer (TNBC) treated with neoadjuvant chemotherapy (NACT) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-10-03.

Abstract P1-17-09: Cardiotoxicity and overall safety profile of adjuvant chemotherapy in elderly breast cancer patients: A cohort study

Abstract Background: around 40% of breast cancers are diagnosed in patients over 65-years old and more than one third of them receive indication to adjuvant chemotherapy. This population has, generally, more comorbidities, worst performance status and is more likely to suffer chemotherapy side effects compared to younger patients. The higher rate of toxicities, including cardiologic toxicity straight related to chemo-immunotherapy, often leads clinicians to reduce doses, delay schedules or even prematurely interrupt treatments, which negatively affect survival. The aim of this study was to evaluate the rate of main toxicities in this specific setting, the rate of discontinuation and eventually their correlation with outcomes.Methods: we conducted a retrospective cohort study enrolling consecutive out-setting breast cancer patients treated at the medical oncology unit of ICS Maugeri Hospital, University of Pavia, from 01/2010 to 12/2017. Inclusion criteria were female sex, age ≥ 65 years, ECOG PS 0-2 and indication to adjuvant chemotherapy after multidisciplinary tumor board evaluation. Regimens and adherence to chemotherapy, intended as dose reductions or early interruptions have been collected for each patient by review of electronic medical records, as well as side effects (cardiologic, hematologic and gastrointestinal) occurred during the treatment period. Cardiologic toxicity was defined as a reduction &amp;gt;10% in EF without symptoms or &amp;gt;5% when associated with clinical manifestation, below the threshold of 55%. Rates of hematologic and cardiologic toxicity and rate of chemotherapy dose reduction/ discontinuation have been calculated. Progression free survival (PFS) were performed by Kaplan-Meier and evaluated for its association with chemotherapy reduction/suspension and toxicities occurrence using Log-rank test. Results: the study population included 128 women, with a median age of 71 years (range 65-81). The most used chemotherapy regimen was sequential antracyclines plus taxanes (61/128, 47.7%) followed by antracyclines monotherapy in 33 patients (25.8%) and taxanes monotherapy in 22 (17.2%). In our cohort, 19 patients experienced cardiologic toxicity (14.8 %) and almost one third of the study population hematologic one (38/128, 29.7%). Dosage of chemotherapy, compared to first cycle, was reduced in 23 patients (18.0%), while 14 of the total (10.9%) prematurely interrupted the adjuvant treatment. Median PFS in the whole cohort was 92 months (95% CI 86.6 - 99.1). Dose reduction or premature interruption of the treatment for any reasons were associated with numerically worse PFS [78.2 months (95% CI 61.2 - 95.1) vs 94.8 months (95% CI 88.4 - 101.3) p = 0.10). In addition, similarly, patients who experienced cardiologic toxicity had worst PFS [75.6 months (95% CI 52.5 - 98.6) vs 93.5 months (95% CI 87.1 - 99.9) p = 0.41). Conclusion: cardiologic toxicity affected 15% of patients in our over 65-years population and reduction or discontinuation of adjuvant chemotherapy due to side effects happened in nearly 30%, both potentially worsening outcomes. Further work is required to improve patient selection and identify early cardiac damage biomarkers in order to successfully complete adjuvant treatment and minimize side effects. Citation Format: Lorenzo Gervaso, Valentina Zanuso, Marco Cefalì, Vittorio Fregoni, Camillo Porta. Cardiotoxicity and overall safety profile of adjuvant chemotherapy in elderly breast cancer patients: A cohort study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-17-09.

Supervised, Multimodal Exercise: The Chemotherapy Supportive Therapy That Almost Does It All.

This commentary describes and places the results into context for the recent OptiTrain trial, a three‐arm randomized trial of two different exercise interventions versus usual care on rates of chemotherapy completion, hospitalization, and hematological toxicity.

Ruxolitinib Is an Effective Salvage Treatment for Multidrug-Resistant Graft-Versus-Host Disease after Allogeneic Hematopoietic Transplantation

Aim: Graft-versus-host disease (GVHD), particularly the multidrug-resistant (MDR) GVHD, is one of the most important complications for allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. The purpose of our study is to identify the efficacy of ruxolitinib in allo-HSCT recipients with MDR-GVHD. Methods: A total of 44 patients who received ruxolitinib treatment for MDR-GVHD after allo-HSCT between 2017 and 2019 were enrolled in this study (HLA-identical sibling donors: n=10; HLA-haploidentical related donors: n=34). MDR-GVHD was defined as GVHD showing no improvement after at least 3 types of treatments. Patients were treated with ruxolitinib as an add-on immunosuppression therapy at a dose of 5 mg orally twice daily, and it could be increased to 10mg twice daily if hematologic parameters were stable and no treatment-related toxicities were observed after the first 7 days of treatment. This work was supported by the Capital's Funds for Health Improvement and Research (grant number 2018-4-4089). Results: The median number of previous GVHD-therapies was 4 for both MDR-aGVHD and MDR-cGVHD. For MDR-aGVHD (n=16), the median time to response was 10 days (range, 2 to 65), and the overall response rate (ORR) was 62.5% (10/16) in, including 37.5% (6/16) complete response (CR) and 25.0% (4/16) partial response (PR). Patients with 3 organs involvement had a lower ORR compared to that of those with 1-2 organs involvements (88.9% vs 28.6%, P=0.035). The 1-year probability of overall survival after ruxolitinib was 62.1%. The rates of hematologic and infectious toxicities were 75.0% and 50.0% after ruxolitinib treatment. For MDR-cGVHD (n=28), the median time to response was 30 days (range, 6 to 270), and the ORR was 78.6% (22/28), including 28.6% (8/28) CR and 50% (14/28) PR. The 1-year probability of overall survival after ruxolitinib was 90.0%. The rates of hematologic and infectious toxicities were 46.4% and 42.9% after ruxolitinib treatment. Conclusions: Ruxolitinib is an effective and safe salvage treatment for both MDR-aGVHD and MDR-cGVHD in allo-HSCT recipients. Disclosures No relevant conflicts of interest to declare.

ABVD Versus Escalated Beacopp in Advanced Stage Hodgkin's Lymphoma: Results from a Retrospective, Multicenter European Study

ABVD Versus Escalated Beacopp in Advanced Stage Hodgkin's Lymphoma: Results from a Retrospective, Multicenter European Study

Hematologic Toxicity of Single Posterior Pencil-Beam Scanning Versus IMRT Approaches for Esophageal Cancer

Proton beam therapy has been shown to decrease heart and lung dose in esophageal cancers. Our group has previously published on the feasibility and safety of a single posterior field pencil-beam scanning (SPF-PBS) approach that has the advantage of maximally sparing heart and lung, but potentially at the cost of increased dose to the vertebral bodies (VBs). In this single-institution retrospective study, we assessed the hematologic toxicity and associated dosimetric factors with SPF-PBS as compared with IMRT. Twenty-one patients treated with SFP-PBS and seventeen patients treated with IMRT for locally advanced esophageal cancer between 2011-2017 were analyzed. All patients were treated concurrently with paclitaxel and platinum-based chemotherapy. Lymphocyte, neutrophil and total leukocyte values while under treatment were recorded and graded per the CTCAE v4.03 toxicity scale, and the neutrophil-to-lymphocyte ratio (NLR) was also computed. VBs were contoured 4 cm superior and inferior to the volume receiving at least 45 Gy (PTV45). The spleen was also contoured if present within the fields. Mean dose and volumes (cc) receiving at least 5, 10, 20, 30, 40 and 50 Gy were calculated (V5-V50) for both VB and spleen contours. A receiver-operator characteristic (ROC) analysis was performed for univariate correlation between incidence of grade ≥3 neutropenia, lymphopenia and dose-volume parameters. The mean VB dose was higher in the proton group than in the IMRT group (30.7Gy vs 24.5Gy, p < 0.00001). The rates of grade 3 or 4 toxicity in the proton group were 33.3% (leukopenia), 19.0% (neutropenia), and 80.0% (lymphopenia); grade 3-4 toxicity rates for the IMRT group were 47.1%, 17.6% and 93.3%, respectively. There was a significant correlation between neutropenia and VB mean dose in proton patients (AUC=0.85, p=0.031); in IMRT patients, neutropenia showed a significant correlation with D5-50 as well as V30-50. NLR values were significantly higher in the IMRT group (12.62 vs 4.69 with protons, p = 0.0038). No statistically significant correlations were seen between lymphopenia or neutropenia and splenic dose parameters. The SPF-PBS approach for esophageal cancer yields hematologic toxicity rates comparable with or superior to patients treated with IMRT at the same institution despite delivering higher mean VB doses. The use of SPF-PBS technique remains a safe method of approach for locally advanced esophageal patients that maximally spares heart and lung tissue without compromising hematologic toxicity.

Avoiding peg-filgrastim (Peg-F) prophylaxis during the paclitaxel (T) portion of the dose-dense (DD) doxorubicin-cyclophosphamide (AC)-T regimen: A prospective study.

517 Background: Use of growth factors (GF) adds considerable expense and some toxicity to adjuvant breast cancer chemotherapy. We tested the feasibility and safety of omitting routine GF use during the T portion of DD AC-T. Methods: This is a prospective, single-arm study in which patients (pts) who completed 4 cycles of DD-AC proceeded to DD-T 175 mg/m2 every two weeks (wks) without routine GF (NCT02698891). Key inclusion: age≤ 65, ECOG PS≤1, absolute neutrophil count (ANC) ≥1500/mm3, and no febrile neutropenia (FN) during DD-AC. Criteria to treat for T included ANC ≥1000/mm3. Peg-F was given only if pts had FN in a prior cycle, or at investigator discretion if infection or treatment delay &gt; 1 wk. Once Peg-F was given, pts received it in all future cycles. The primary endpoint was the rate of T completion ≤ 7 wks from cycle 1 day 1 (C1D1) to C4D1. Secondary endpoints included total use of Peg-F, rates of hematologic toxicity and FN, reasons for dose modification or hold. If ≥85% of pts completed T on time, the regimen would be considered feasible. If the true on-time completion rate is 75%, the chance the regimen would be declared infeasible is 91%, and if it is 85% the chance that the regimen is falsely declared infeasible is 10% (power = 0.899). ≥100/125 pts had to complete T on time for the regimen to be deemed successful. Results: Among 127 pts enrolled, 125 received ≥1 dose of protocol therapy and are included in the analysis. Median age at registration was 46 (range 21-65). Median C1D1 ANC was 7500/mm3 (range 1500-20500). 112 (90%) (95% CI 83-94%) pts completed DD-T ≤ 7 wks, and 3 (2%) completed within &gt; 7 wks (2 due to neutropenia); 10 (8%) did not complete all cycles of T. Omission of Peg-F was not causally related to non-completion of T in any pts. The most common reasons for dose reduction or delays were non-hematologic. One pt had FN but was able to complete T on time. Eight (6.4%) pts received Peg-F during the trial. Conclusions: Omission of routine GF use during DD-T according to a pre-specified algorithm appears safe, feasible, and was associated with a 95.7% reduction in use of Peg-F, relative to the current standard of care. Additional analyses including cost implications are ongoing. Clinical trial information: NCT02698891.

Toxicities in B‑cell non-Hodgkin lymphoma—new agents, new pitfalls

Immunochemotherapy has long been the backbone of all treatment for B‑cell non-Hodgkin lymphoma. These therapies led to long-term disease control or even cure for some patients. However, these treatments also caused—sometimes severe—toxicities and deterioration of the quality of life. Novel agents targeting the B‑cell-receptor pathway and bcl2 have made great inroads in the treatment of mature lymphoid neoplasms. These new agents present themselves with a wide variety of new toxicities, which have to be taken into account when being administered to our patients. Hematological toxicities are very common. All new agents lead to various levels of immune suppression or immune modulation, which is often not easily quantifiable. Opportunistic infections such as progressive multifocal leukoencephalopathy, pneumocystis pneumonia, other mycotic infections, cytomegalovirus infections and pneumocystis pneumonia have been described, sometimes with fatal outcome. Ibrutinib shows increased risk of atrial fibrillation. It also increases the risk of bleeding, making the proper anticoagulatory management of patients developing atrial fibrillation under treatment a challenge. Idelalisib causes severe, sometimes fatal immune-mediated end-organ toxicities, especially colitis, pneumonitis, and transaminitis. Copanlisib leads to metabolic changes, namely episodes of hyperglycemia and arterial hypertension. Venetoclax has caused clinically significant tumor lysis syndrome. The introduction of a prolonged ramp-up phase of step wise dose escalation has decreased the rate of clinically significant tumor lysis syndrome. The drug also causes high rates of hematological toxicities, especially neutropenia.

Cost-Effectiveness and Cost-Utility Analysis of ABVD Versus Beacopp in the Treatment of Advanced-Stage Hodgkin Lymphoma

Background:Treatment options for advanced-stage Hodgkin lymphoma include ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) or combinations of BEACOPPbaseline and BEACOPPescalated (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone, hereinafter referred to as BEACOPP). There remains clinical equipoise over the best initial treatment strategy, as both strategies have similar 10-year overall survival in long-term clinical trial follow-up. There is a trade-off that occurs with inferior progression-free survival in the ABVD strategy, but higher rates of hematologic toxicity, infertility, and second malignancy in the BEACOPP strategy. The overall lifetime cost of each strategy is also unknown.Methods:We developed a Markov decision-analytic model to compare ABVD versus BEACOPP for a hypothetical cohort of transplant-eligible patients with newly-diagnosed advanced-stage Hodgkin lymphoma. The model simulates their clinical course over a 20-year time horizon. Baseline probability estimates and utilities were derived from a systematic review of published studies. Direct medical costs were obtained from publicly available administrative databases or from the literature and applied to the health states. All costs and benefits were discounted by 1.5%. A Canadian public health payer's perspective was considered and costs are presented in 2018 Canadian dollars (Table 1). Sensitivity analyses were performed for key variables.Results:Based on a 20-year model, life expectancy was 12.6 years with ABVD and 13.6 years with BEACOPP, yielding an expected survival benefit with BEACOPP of 1.0 years. The quality-adjusted life expectancy (QALY) was 10.4 years with ABVD and 11.4 years with BEACOPP, leading to an expected quality-adjusted survival benefit with BEACOPP of 1.0 QALYs. The direct costs were $98,081 for ABVD and $81,296 for BEACOPP, making BEACOPP the cost-saving strategy with a net benefit of $16,785. In the base-case analysis, BEACOPP was associated with both cost-savings and improved quality-adjusted outcomes over ABVD, making it the dominant treatment strategy. Sensitivity analyses demonstrated that the model was robust to key variables including probability of death from secondary malignancy, probability of relapse post-primary and salvage therapy, and probability of infertility secondary to BEACOPP. In sensitivity analysis of treatment-related mortality secondary to BEACOPP, the threshold value was found to be 6.5% mortality over the 6-month treatment period, a value much greater than that reported in the literature. The threshold utility of infertility was found to be 0.72 for ABVD to have a greater QALY than BEACOPP, a value lower than the utility derived from a systemic review of the literature (0.87). We assumed all infertile patients underwent a cycle of fertility preservation or IVF, which is a conservative approach, and likely overestimates BEACOPP costs. In sensitivity analysis of costs, the BEACOPP strategy was non-dominant if the cost of three months of brentuximab was decreased to $19,360 (compared to its current price of $59,110 per three months), or if the cost of fertility preservation was greater than $37,615 per patient, which is higher than the average amount for this treatment in Canada. In these scenarios, BEACOPP was still more effective, but more expensive; however, the maximum ICER was still less than $10,000 per QALY for both costs, considerably lower than conventional willingness to pay (WTP) thresholds of $50,000. Probabilistic sensitivity analyses (10,000 simulations) were performed. For the WTP threshold of $50,000, BEACOPP was the dominant strategy 72% of the time, and overall the most cost-effective strategy 87.5% of the time (Figure 2).Conclusions:The preferred treatment strategy for patients with newly diagnosed advanced-stage Hodgkin lymphoma is a BEACOPP regimen. This strategy maximizes life expectancy, quality-adjusted life years, and is the most cost-effective strategy, accounting for increased rates of hematologic toxicity, secondary malignancy, and infertility in patients receiving the BEACOPP strategy. The model was robust to sensitivity analyses of key variables tested through plausible ranges obtained from the published literature. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

R-CHOP with or without Lenalidomide/Bortezomib As a First Line Treatment for Patients with Non-Germinal Center Diffuse Large B Cell Lymphoma (DLBCL) Subtype: Son Espases University Hospital Experience

INTRODUCTIONThe standard first line treatment for patients with diffuse large B-cell lymphoma (DLBCL) is rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) independently of cell origin subtype. Retrospective studies have shown that non-germinal center (NGC) subtype is associated with a worse progression free survival (PFS) and overall survival (OS) compared to germinal center subtype. In phase II studies the combination of lenalidomide (lena) or bortezomib (bor) with R-CHOP in this lymphoma subtype has shown better results in comparison to R-CHOP alone. For this reason, the aim of our study is to analyze the efficacy and toxicity of R-CHOP plus lena/bor in comparison with R-CHOP alone in patients with NGC DLBCL.PATIENTS AND METHODSIn order to avoid selection bias, all patients with NGC DLBCL (confirmed by immunohistochemistry with Hans algorithm) who received R-CHOP or R-CHOP-lena/bor (25mg lenalidomide daily from day 1 to 10 / bortezomib 1.3mg/m2 days 1 and 4) were retrospectively selected from the Pharmacy Registry. Patients in our center received R-CHOP from March 2002 to June 2013, R-CHOP-bor from June 2013 to July 2015 and R-CHOP-lena from November 2014 until now. Cheson and Lugano criteria were used to confirm response rates. Toxicity was checked with CTCAE v4-5 criteria.RESULTSFifty-five patients with NGC DLBCL were identified from 2002 to 2018, 18 of whom were treated with R-CHOP-lena/bor and 33 with R-CHOP. Baseline characteristics are specified in Table 1. Overall response rate was similar in both treatment regimens, 94% versus 87%, respectively. 12.5% progression/stable disease cases were identified with R-CHOP alone compared to 5.3% with R-CHOP-lena/bor. With a median follow-up of 45 months (6-126) for R-CHOP and 22 months (6-59) for R-CHOP-lena/bor, the median PFS was 65 months for R-CHOP and was not reached for R-CHOP-lena/bor. 47% versus 9% of progressions were observed in R-CHOP and R-CHOP-lena/bor, respectively (p=0.006). Regarding OS, the death rate in the R-CHOP group was 45% in comparison with 23% in R-CHOP-lena/bor group (p=0.015). Higher hematological toxicity was observed in the R-CHOP-lena/bor group comparing with R-CHOP: neutropenia (95% versus 68%), grade 3-4 neutropenia (81% versus 37%) and anemia (81% vs 56%) (p<0.05) (Table 2) being manageable in all cases.CONCLUSIONSThe addition of lenalidomide or bortezomib to R-CHOP seems to be a good option in NGC DLBCL, with a lower progression rate, refractoriness and less mortality in comparison with R-CHOP alone. R-CHOP-lena/bor is associated to higher rates of hematological toxicity but manageable in all cases. These retrospective data should be confirmed in ongoing phase III clinical trials. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Phase 2 Study of Radiation Therapy Plus Low-Dose Temozolomide Followed by Temozolomide and Irinotecan for Glioblastoma: NRG Oncology RTOG Trial 0420

To evaluate the toxicity and efficacy of adjuvant temozolomide (TMZ) and irinotecan (CPT-11) for 12months after concurrent chemoradiation in patients with newly diagnosed glioblastoma (GBM). Trial RTOG 04-20, a single-arm, multi-institutional phase 2 trial, was designed to determine the efficacy and toxicity of concomitant TMZ and radiation therapy (RT) followed by adjuvant TMZ combined with CPT-11 given for 12 cycles compared with historical controls of adjuvant TMZ alone given for 6 cycles. A total of 170 patients were enrolled, 152 of whom were eligible. Adjuvant CPT-11 combined with TMZ was more toxic than expected. A higher rate of hematologic and gastrointestinal toxicities was more frequently noted with the combination regimen compared with adjuvant TMZ alone. Grade 3/4 hematologic toxicity was 38% compared with 14% reported in the Stupp trial. After an early interim analysis, the adjuvant CPT-11 dose was reduced to 100mg/m2 on days 1 and 5 for the first cycle. CPT-11 dose escalation proceeded over the first 3 cycles if tolerated. Median overall survival for all eligible patients was 16.9months compared with 13.7months of the historical control (P=.03). Post hoc subgroup analysis suggested an improvement in overall survival for patients with Radiation Therapy Oncology Group recursive partitioning analysis class 3, although improvement was limited to 22 patients (14% of eligible patients). Although irinotecan and TMZ for 12 cycles given after chemoradiation for patients with newly diagnosed glioblastoma significantly improved median survival compared with historical control data at the time the study was conducted, the historical control median survival time of 13.7months does not represent the current benchmark for this patient population. Treatment intensification does prolong overall survival compared with the current standard.

Hematologic Toxicity of Single Posterior Pencil-Beam Scanning Approach for Esophageal Cancer

Proton beam therapy has been shown to decrease heart and lung dose in esophageal cancers. Our group has previously published on the feasibility and safety of a single posterior field pencil-beam scanning (SPF-PBS) approach that has the advantage of maximally sparing heart and lung, but potentially at the cost of increased dose to the vertebral bodies (VBs). In this single-institution retrospective study, we assessed the hematologic toxicity and associated dosimetric factors with SPF-PBS. Eighteen patients treated with SFP-PBS and concurrent carboplatin and paclitaxel for locally advanced esophageal cancer between 2015 and 2016 were analyzed. Lymphocyte, neutrophil, and total leukocyte values while under treatment were recorded and graded per the CTCAE v4.03 toxicity scale, and the neutrophil-to-lymphocyte ratio (NLR) were also recorded. VBs were contoured 4 cm superior and inferior to the volume receiving at least 45 Gy (PTV45). VB mean dose and VB volumes (cc) receiving at least 5, 10, 20, 30, 40 and 50 Gy were calculated (V5-V50). A receiver-operator characteristic (ROC) analysis was performed for univariate correlation between incidence of grade ≥3 neutropenia / lymphopenia and VB dose-volume parameters. Spearman rank correlations were computed between NLR and dose variables. The rates of grade 3 toxicity were 38.9% (leukopenia), 22.2% (neutropenia), and 62.5% (lymphopenia); grade 4 toxicity rates for the same groups were 0%, 5.6%, and 18.8%, respectively. There were no cases of grade 3 or 4 anemia or thrombocytopenia. There was a significant correlation between neutropenia and VB mean dose (AUC = 0.83, p = 0.034). No statistically significant correlations were seen between lymphopenia and VB mean dose or V5-V50 (p > 0.069), nor were there correlations between NLR and VB dose (p > 0.067). The SPF-PBS approach for esophageal cancer yields hematologic toxicity rates comparable with previously published studies of IMRT and multiple field proton beam therapy. The possible increase in dose to the VBs in this setting may not be clinically relevant to hematologic toxicity, or may be balanced by the potential to spare more heart and lung tissue.