High Rate Of Febrile Neutropenia Research Articles

Hypomethylating Agents Are Associated with High Rates of Hematologic Toxicity in Patients with Secondary MDS/AML That Develops after Acquired Aplastic Anemia

Acquired aplastic anemia (AA) is an autoimmune bone marrow failure (BMF) associated with depletion of hematopoietic stem and progenitor cells. Approximately 15-20% of AA patients treated with immunosuppressive therapy (IST) develop late complications of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Little is known about managing patients with post-AA myeloid neoplasms (MN). We hypothesized that patients with post-AA MN may be particularly susceptible to hematologic toxicities from cytotoxic therapy because of stem cell deficits. To investigate our hypothesis, we retrospectively analyzed post-AA MN patients treated at our 2 institutions over the past 15 years. Fourteen post-AA MN patients were identified: 11 with MDS, 1 with AML, and 2 with clonal cytopenia of undetermined significance (CCUS). Patients with inherited BMF or allogeneic stem cell transplant (SCT) prior to MN diagnosis were excluded. The median age at MN was 56.5 years (range 5-75) with a median time of 5 years (range 0.25-30) between AA diagnosis and MN. At MN diagnosis, 12 of 14 patients (86%) had a partial or complete response of AA with 5 receiving cyclosporine (CSA) maintenance. Two patients (14%) were on CSA within 6 months of IST without response. After MN diagnosis, CSA was discontinued. Ten adults received hypomethylating agents (HMA) as first-line treatment in preparation for SCT. Three pediatric patients were treated with SCT with no prior HMA. One patient died before receiving treatment. The 10 post-AA patients who received HMA were matched in a 3:1 ratio with a similarly aged, randomly selected non-AA MDS cohort treated with HMA at our center during the same period (Table 1). Compared to patients with non-AA MDS, post-AA MN patients tolerated HMA poorly with frequent, severe complications. Their median per-cycle duration of grade 4 neutropenia was longer (9 v. 1.5 days, p = 0.044), as was median duration of grade 4 thrombocytopenia (13 v. 0 days, p = 0.003). Post-AA patients notably had lower baseline platelets prior to HMA (median 36.5 v. 115 k/mL, p =0.007). Following HMA, the post-AA cohort had higher rates of febrile neutropenia (80% v. 17%, RR 4.8, p < 0.001) and infections ≥ grade 3 (90% v. 13%, RR 6.8, p < 0.001). They also had higher rates of ≥ grade 3 bleeding (40% v. 7%, RR 6.0, p = 0.026) with 2 patients (20%) experiencing intracranial hemorrhage on HMA; no such events occurred in the non-AA cohort. Post-AA patients had more hospital admissions - 18 in 25 total chemotherapy cycles (72%) compared to 12 in 207 cycles (6%) in the matched cohort (RR 12.4, p < 0.001). Post-AA MN patients had more treatment delays >2 weeks (28% v. 8% of planned treatment cycles, RR 3.4, p = 0.01) and dose reductions (40% v. 13%, RR 3.0, p = 0.089). HMA was discontinued due to treatment-emergent adverse events (TEAEs) in 70% of post-AA cases v. 3% of non-AA patients (RR 21.0, p < 0.001). Consequently, post-AA MN patients received fewer cycles of HMA compared to non-AA patients (median 2.5 v. 6, p = 0.021). Death occurred following TEAEs in 20% of post-AA MN patients; no deaths on HMA occurred in the non-AA cohort (RR 14.1, p = 0.058). Among surviving patients, SCT was delayed in 20% of the non-AA cohort due to TEAEs, while no delays occurred in the matched cohort. The median months from final chemotherapy cycle to SCT were 4 (range 1-12) in post-AA v. 1 (1-3) in non-AA, while median months from MN diagnosis to SCT were 8.5 (4-21) in post-AA v. 5 (4-15) in non-AA. For all 14 post-AA MN patients, including those not treated with HMA, overall survival (OS) from MN diagnosis was 71% (95% CI 51-99) at 1 year and 56% (95% CI 34-90) at 3 years. OS of post-AA MN patients differed significantly (p = 0.011) based on treatment with SCT. Among the 5 who did not receive SCT, 4 died within 3 years of MN, while 1 patient is alive 13 months from diagnosis receiving supportive care after intracranial hemorrhage during the first cycle of HMA. In contrast, 7 of 9 (78%) patients who received SCT were alive 3 years after MN diagnosis. Of the 6 patients treated with SCT after HMA, 5 stopped HMA due to toxicity, all had morphologic dysplasia at SCT, and 2 were transplanted with ≥ 5% marrow blasts. Our study shows that patients with MN following antecedent autoimmune AA are at high risk of severe toxicities with standard HMA regimens and have difficulty tolerating repeated cycles. Our results do not support routine use of HMA prior to SCT in this patient population and suggest that early SCT may be the most suitable strategy.

A territory-wide real-world efficacy and toxicity analysis of abiraterone acetate versus docetaxel in 574 Asian patients with metastatic hormone-sensitive prostate cancer

IntroductionAbiraterone acetate (ABI) or docetaxel (DOC), in addition to androgen-deprivation therapy (ADT), are current treatment options for metastatic hormone-sensitive prostate cancer (mHSPC). No randomized head-to-head trial has compared these 2 mHSPC treatments, and real-world data regarding their outcomes in Asian patients are lacking. Patients and MethodsThe medical records of mHSPC patients who began upfront ABI or DOC treatment in addition to ADT at seven public oncology centers in Hong Kong between 2015 and 2021 were reviewed. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), prostate-specific antigen (PSA) response, and toxicities. Kaplan-Meier and multivariate Cox regression analyses were performed. ResultsA total of 574 patients were included, of whom 419 received DOC and 155 received ABI. The median follow-up duration was 22.4 (DOC group: 23.8; ABI group: 17.3) months. The ABI group demonstrated significantly better PFS than the DOC group (not reached vs. 15.1 months: hazard ratio = 0.37; 95% confidence interval = 0.28-0.50; P < .001). No significant OS difference was observed (P = .58). Failure to achieve a ≥ 90% decline in PSA level at 3 months and failure to achieve an undetectable PSA nadir were each associated with unfavorable PFS and OS. Patients who received DOC had a higher rate of febrile neutropenia, whereas those who received ABI had higher rates of grade ≥ 3 hypokalemia and elevated alanine transaminase. Treatment discontinuation due to toxicities was more common in the DOC (3.6%) than the ABI (0.6%) group. ConclusionIn Asian mHSPC patients, upfront ABI + ADT was associated with better PFS than DOC + ADT, with no significant OS difference. PSA kinetics may help stratify the prognosis for treatment intensification. Toxicity profiles were different, with a higher rate of toxicity-related treatment discontinuation in the DOC group.

A phase II study of FOLFIRINOX with primary prophylactic pegfilgrastim for chemotherapy-na\xefve Japanese patients with metastatic pancreatic cancer

BackgroundAlthough FOLFIRINOX is currently one of the standard therapies for chemotherapy-naïve patients with metastatic pancreatic cancer (MPC), the high rate of febrile neutropenia (FN) presents a clinical problem. This study aimed to evaluate the safety and efficacy of primary prophylactic pegfilgrastim with FOLFIRINOX in Japanese MPC patients.MethodsFOLFIRINOX (intravenous oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, levofolinate 200 mg/m2, 5-fluorouracil (5-FU) bolus 400 mg/m2 and 5-FU 46 h infusion 2400 mg/m2) and pegfilgrastim 3.6 mg on day 4 or 5, every 2 weeks was administered to previously untreated MPC patients. The primary endpoint was the incidence of FN during the first 3 cycles. The planned sample size was 35 patients, but the trial was predefined to discontinue enrollment for safety if 4 patients developed FN.ResultsAt the enrollment of 22 patients, 4 patients developed FN in the first cycle, resulting in an incidence of FN of 18% {95% confidence interval [CI], 0.5–40.3%}, and enrollment was discontinued early. The incidence of grade 3 or higher neutropenia was 36.4%. Median relative dose intensities during the initial 3 cycles of oxaliplatin, irinotecan, bolus 5-FU, infusional 5-FU, and levofolinate maintained high (100%, 89.0%, 100%, 66.0%, and 100%, respectively). Response rate and median overall survival were 54.5% (95% CI 32.7–74.9) and 15.7 months (95% CI 7.9–18.8), respectively.ConclusionsThis phase II study could not demonstrate any reduction in the incidence of FN, nevertheless some patients experience benefits for efficacy by maintaining dose intensity using prophylactic pegfilgrastim.Trial registrationhttp://www.umin.ac.jp/ctr/index-j.htm, UMIN000017538. Date of registration: May/13/2015

A randomized phase 2 trial of first-line docetaxel, carboplatin, capecitabine (CTX) and epirubicin, oxaliplatin, capecitabine (EOX) in advanced esophagogastric adenocarcinoma

Background No preferred first-line chemotherapy regimen exists for advanced esophagogastric adenocarcinoma. Addition of docetaxel to cisplatin and 5-fluorouracil (DCF) has been shown to improve survival but is associated with increased toxicity. In this randomized, non-comparative phase 2 trial, we tested carboplatin, docetaxel, and capecitabine (CTX), a potentially useful modification of DCF (NCT02177552). Patients and methods Patients with advanced HER2-negative esophagogastric adenocarcinoma not previously treated in the first-line setting were randomized to intravenous docetaxel 60 mg/m2 and carboplatin AUC5 plus oral capecitabine 1000 mg/m2 bd days 1–14, q4w (CTX) or intravenous epirubicin 50 mg/m2 and oxaliplatin 130 mg/m2 on day 1 plus oral capecitabine 625 mg/m2 bd days 1–21, q3w (epirubicin, oxaliplatin and capecitabine [EOX]). Treatment continued until progression, intolerance or for a maximum of nine cycles. The primary endpoint was 1-year survival for patients treated with CTX. Results Between June 2014 and January 2019, a total of 98 eligible patients were randomized. The 1-year survival rate was 34.7% (95% CI 21.8 − 47.9) with CTX and 36.7% (95% CI 23.6 − 50.0) with EOX. Progression-free survival and overall survival were 6.1 months (95% CI 5.5 − 7.1) and 9.8 months (95% CI 8.2 − 11.0) with CTX and 5.1 months (95% CI 4.3 − 7.0) and 10.2 months (95% CI 8.0 − 11.9) with EOX, respectively. Related grade 3 or 4 treatment-emergent adverse events (AEs) occurred in 86% of patients on CTX and 69% on EOX. Febrile neutropenia occurred in 31.4% of patients on CTX and 13.7% on EOX. Conclusions First-line CTX showed insufficient efficacy and caused a high rate of febrile neutropenia. CTX could not, therefore, be recommended for further study. This trial adds to current knowledge of docetaxel combined with platinum and 5-FU: that the combination is associated with increased toxicity and its use should be limited to fit patients in need of a response.

Haematological Toxicities Following Treatment of Childhood Hepatoblastoma with Intensive Multiagent Chemotherapy

Background: Hepatoblastoma is a rare malignant liver tumour that occurs almost exclusively in childhood. Although surgical resection is the foundation of curative therapy, with the use of effective neoadjuvant and adjuvant chemotherapy the 5 years overall survival of patient with hepatoblastoma had recently reached up to 80% to 90 %. But the frequency and severity of haematological toxicity is one of the major concerns of intensive chemotherapy. Objective: To evaluate the frequency and severity of haematological toxicities following treatment of childhood hepatoblastoma with two different regimens of multi-agent chemotherapy. Methodology: This was a comparative observational study conducted at Bangabandhu Sheikh Mujib Medical university in 24 childhood hepatoblastoma patients who received either cisplatin/carboplatin /doxorubicin (Group A; n=14) or cisplatin/ vincristine/5- fluorouracil (Group B; n= 10) to between March 2010 and July 2014. Results: Grade 3 or 4 anaemia and thrombocytopenia, and Grade 4 neutropenia were observed in 64.3% vs 60%, 35.7% vs 20% and 57.1% vs 20% respectively in group A and Group B. Febrile neutropenia occurred in 100% vs 70% and septicaemia developed in 92.9% vs 70%. Red cell concentrates and Platelet transfusions were required in 35.7% vs 50% and 14.3% vs 10% respectively in two groups. Deaths due to haematological toxicities occurred in 21.4% in Group A and 21% in Group B. Conclusion: We found similar toxicity profiles for two chemotherapy regimens except for higher rates of febrile neutropenia and septicaemia in patients treated with cisplatin/carboplatin /doxorubicin compared to cisplatin/ vincristine/5- fluorouracil.

Are We Choosing Mobilization Regimens for Autologous Stem Cell Transplantation in Multiple Myeloma Wisely?: A Single Centre Comparison of GCSF+/-Plerixafor Vs Cyclophosphamide/GCSF+/- Plerixafor

Background: Autologous stem cell transplantation (ASCT) as consolidation post induction is standard of care for eligible multiple myeloma patients. Multiple strategies are employed for mobilization of stem cells in ASCT. Cyclophosphamide/GCSF is an effective standard regimen. However there are reported toxicities associated with cyclophosphamide including risk of febrile neutropenia. Since plerixafor was introduced in Canada, this mobilization agent has been increasingly used as needed with GCSF at Kingston Health Science Centre (KHSC), with elimination of cyclophosphamide. There is however high cost associated with plerixafor. To date, there is no standard mobilization regimen across Canada. This retrospective study evaluates mobilization and ASCT outcomes of multiple myeloma patients who had undergone stem cell mobilization with GCSF+/-plerixafor (GP) vs cyclophosphamide/GCSF+/-plerixafor (CyGP) at KHSC. The goal is to analyze the efficacy of each regimen balanced with adverse events to guide optimal mobilization regimen choice. Method: Patient with multiple myeloma who had ASCT at KHSC were selected consecutively based on date of ASCT in a reverse chronological order starting from Jan 2019. From Oct 2015 to March 2018, CyGP was the mobilization regimen used at KHSC. From March 2017 to January 2019, cyclophosphamide was eliminated and GP was used. Both groups could have received plerixafor as needed based on Cancer Care Ontario funding criteria such as failure to achieve target CD34+ cell count. Retrospective chart review was conducted to collect data on demographics, plerixafor use, days of apheresis, total cell collected, rate of febrile neutropenia, length of transplant hospital stay, time to engraftment, and transfusion requirement. Chi-Square, t-test, or Mann Whitney methods were used for test of statistical significance where appropriate. Results: Total 97 patients were included with 47 in the GP group and 50 in the CyGP group (Table 1). Average age was 64 and 63 respectively. 32% of patients in GP group and 36% of CyGP group required plerixafor rescue. No difference in the number of apheresis days were noted in the two groups. Total cell collection was significantly higher in the CyGP group (P&lt;0.001). Day 1 and 2 cell collections were also significantly higher in the CyGP group (P&lt;0.05) (Fig 1). The cell dose target varied in the CyGP group due to changing practices over time which is a confounding factor. There were no cases of febrile neutropenia in the GP group and 3 cases in the CyGP group (P=0.243). All 3 febrile neutropenia patients required hospitalization with 1 requiring ICU. There was no clinically significant difference in transfusion requirement during ASCT (Fig 2). Median time to engraftment of neutrophil and platelet after ASCT were less by 1 day in the CyGP group (P&lt;0.05) (Fig 3), although there was no difference in length of transplant hospital stay. Conclusions: Stem cell mobilization with CyGP resulted in significantly higher total collection cell count, and more efficient collection with higher yield on the first 2 days of apheresis. However, there was no difference in the total number of apheresis days. It also did not lead to less plerixafor usage and was associated with possibly higher rate of febrile neutropenia. There was no clinically significant difference in transplant outcomes in terms of transfusion support required, days to engraftment, or length of hospitalization for ASCT. Mobilization with GCSF+/-plerixafor without cyclophosphamide is a non-inferior regimen. Disclosures Bhella: Celgene: Consultancy, Honoraria.

796P - Randomised phase II trial of first-line docetaxel, carboplatin, capecitabine (CTX) and epirubicin, oxaliplatin, capecitabine (EOX) in advanced esophagogastric adenocarcinoma (SEED)

BackgroundChemotherapy is associated with a survival benefit in advanced gastric cancer. Several options exist, including EOX. The regimen docetaxel, cisplatin and 5-fluorouracil (DCF) is toxic and modifications have been developed. In our institution CTX was a standard treatment from 2004 to 2012 when it was replaced by EOX. Afterwards, a randomised trial with CTX was conducted. MethodsSEED was a prospective, single-center, phase 2 trial in unresectable HER2-negative esophagogastric adenocarcinoma. Patients were randomised to either docetaxel 60mg/m2, carboplatin AUC5 and capecitabine 1000mg/m2 bd for 14 days q4w (CTX) or epirubicin 50mg/m2, oxaliplatin 130mg/m2 and capecitabine 625mg/m2 bd for 21 days q3w (EOX). Treatment continued until progression, intolerance or a maximum of 9 cycles. The primary endpoint was 1-year-survival for patients treated with CTX. The trial sought to accept (lower boundary 55%) or reject (higher boundary 40%) CTX for further study without making direct comparisons to EOX. Secondary endpoints included OS, PFS and grade 3/4 toxicities. ResultsFrom 2014 to 2019 a total of 98 patients were randomised (49 in each arm). The median age was 63 (36 - 79). Male/female: 79/19; ECOG PS (0/1): 46/52; oesophageal/GEJ/gastric: 29/44/25; metastatic/non-metastatic: 96/2. As of 26 April 2019, 85 patients had died. The estimated 1-year survival was 32% (95% CI 19 - 46) for CTX and 39% (95% CI 25 - 52) for EOX. The median PFS and OS was 6.2 months (95% CI 5.2 - 7.2) and 9.2 months (95% CI 7.2 - 11.2), respectively, for CTX, and 5.2 months (95% CI 3.5 - 7.0) and 10.2 months (95% CI 7.9 - 12.4), respectively, for EOX. Grade 3/4 related toxicities in>5% were neutropenia (78%), febrile neutropenia (25%), diarrhoea (8%) and fatigue (6%) for CTX, and neutropenia (49%), febrile neutropenia (10%), peripheral neuropathy (8%) and nausea (8%) for EOX. There were no treatment-related deaths. ConclusionsCTX resulted in a 1-year-survival rate of 32% and so is rejected for further study. Also, CTX had a high rate of febrile neutropenia. CTX is not recommended for patients with esophagogastric cancer, except selected patients intolerant of other standard therapies, and then only with G-CSF support. Clinical trial identificationNCT02177552. Legal entity responsible for the studyLene Baeksgaard. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Phase II trial of single agent amrubicin in patients with previously treated advanced thymic malignancies

ObjectivesThere are limited treatment options for patients with thymic malignancies. Here we present data supporting treatment with single agent amrubicin, a third generation anthracycline and topoisomerase II inhibitor. Materials and methodsThis was a phase 2 open-label, single arm trial of amrubicin in patients with thymoma (T) or thymic carcinoma (TC), conducted at two academic institutions. Patients were included if they had received at least one prior chemotherapy regimen. The first 18 patients received amrubicin at 40 mg/m2 IV days 1–3 repeated every 3-weeks. Due to the high incidence of febrile neutropenia, dosing was subsequently amended to 35 mg/m2 for the final 15 patients. ResultsA total of 33 patients (14 T/19 TC) were enrolled from 2011 to 2014. Median number of prior therapies was 2. Best response included 6 partial responses, 21 stable disease, and 6 progressive disease (all TC). Objective response rate was 18% (90% exact binomial CI 8.2%–32.8%; T = 4/14 (29%), TC = 2/19 (11%)). Median progression-free survival was 7.7 months (T: 8.3 months; TC: 7.3) and median overall survival was 29.7 months (T: 54.1 months; TC: 18 months). There was a high rate of febrile neutropenia (7 patients) that occurred despite a reduction in amrubicin dose and one related death. Five patients had reduction in LVEF below 50% during the course of treatment resulting in treatment discontinuation in one patient. ConclusionAmrubicin shows promise as a single agent in heavily pre-treated patients with thymic malignancies. Notable side effects include febrile neutropenia and the use of growth factor support is essential. Further investigation of this agent is warranted.

Radium-223 in combination with docetaxel in patients with castration-resistant prostate cancer and bone metastases: a phase 1 dose escalation/randomised phase 2a trial

PurposeRadium 223 dichloride (radium-223) is an alpha particle–emitting bone-directed therapy that prolongs overall survival in men with bone-predominant metastatic castration-resistant prostate cancer (mCRPC). Docetaxel is an antimicrotubule cytotoxic agent that improves survival in mCRPC. We investigated whether combining these potentially cross-sensitising agents to dually target tumour and bone would be safe and effective. Patients and methodsPhase 1 was a dose escalation study to define a recommended phase 2 dose (RP2D) of docetaxel and radium-223. In phase 2a, patients were randomised 2:1 to the recommended combination regimen or docetaxel at a dose of 75 mg/m2 every 3 weeks (q3w). Patients with bone-predominant mCRPC were eligible. End-points were safety, efficacy and treatment-related changes in serum and imaging biomarkers. ResultsTwenty patients were enrolled in phase 1; 53 patients were randomised in phase 2a: 36 to combination treatment and 17 to docetaxel alone. The RP2D for the combination was radium-223 55 kBq/kg every six weeks × 5 doses, plus docetaxel 60 mg/m2 q3w × 10 doses. Febrile neutropenia was dose limiting. A higher rate of febrile neutropenia was seen in the docetaxel monotherapy arm (15% vs 0%); the safety profile of the treatment groups was otherwise similar. The combination arm had more durable suppression of prostate-specific antigen (median time to progression, 6.6 vs 4.8 months, respectively), alkaline phosphatase (9 vs 7 months) and osteoblastic bone deposition markers. ConclusionsRadium-223 in combination with docetaxel at the RP2D was well tolerated. Exploratory efficacy data suggested enhanced antitumour activity for the combination relative to docetaxel alone. Comparative studies with end-points of clinical benefit are warranted. ClinicalTrials.gov number: NCT01106352.

Incidence of febrile neutropenia with use of docetaxel plus cyclophosphamide (TC) for breast cancer.

e12073 Background: Incidence of febrile neutropenia (FN) is reported as 5% in breast cancer patients receiving TC (Jones et al., JCO 2006), which would not justify the usage of prophylactic granulocyte colony stimulating factors (G-CSF). We previously showed that the incidence of FN may be as high as 23% in a small study. (N = 130, Soni et al., ASCO 2011). In the current study, we determined the incidence of FN in a larger cohort (N = 415), and evaluated the usage of G-CSF and its relation to FN, age, stage, and hormonal status. Methods: We retrospectively reviewed the electronic medical records from patients diagnosed with breast cancer who received at least one standard dose cycle of adjuvant TC between 2010-2016 at a university-based breast oncology practice. Chi-square or Fisher’s exact tests were used to assess differences between groups. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using multiple logistic regression models. Results: We identified in total 415 patients who received adjuvant TC. Median age at diagnosis was 58 (range: 25-86), the majority had stage I or II (N = 382; 92.1%) disease, and 315 (75.9%) were ER+, 277 (66.8%) PR+, 42 (10.1%) HER2+, 22 (5.3%) triple-positive, and 81 (19.5%) triple-negative. Prophylactic G-CSF was utilized in 247 patients (59.5%), and unknown for 43 (10.4%). Overall 39 (9.4%) patients experienced febrile neutropenia. Incidence of FN among those receiving G-CSF was 4.5% versus 17.6% among those who did not (p &lt; 0.001). Use of G-CSF significantly lowered risk of FN, OR (95%CI): 0.20 (0.10-0.43) adjusted for age at diagnosis and stage. Use of G-CSF on incidence of FN did not differ significantly by age, stage, or hormonal status. Conclusions: Our data confirms a high rate of FN in patients receiving TC without G-CSF prophylaxis. Our institutional high rate of G-CSF use ( &gt; 50%) reduced the incidence of FN to 4.5% and the observed significant difference in FN incidence between the non G-CSF group and G-CSF group suggests that prophylaxis may be considered when administering TC. Age, stage, and hormonal status do not seem to affect the usage of G-CSF or incidence of FN in our population.

Febrile Neutropenia Risk with Adjuvant Docetaxel and Cyclophosphamide (TC) Chemotherapy Regimen in Two Brazilians Cancer Centers

Introduction: In selected patients diagnosed with Breast Cancer (BC), adjuvant chemotherapy might reduce local and systemic recurrence risk, as well as cancer death rate. The combination of Docetaxel and Cyclophosphamide (TC) is a well-recognized effective adjuvant chemotherapy regimen. Nonetheless, a considerable high rate of febrile neutropenia (FN) is associated with this regimen. We sought to investigate hematologic toxicity associated with adjuvant TC in a non-selected, “real world” cohort of BC patients. Methods: We reviewed the electronic medical records of patients who presented to the Oncology Center from Hospital Sirio-Libanes (HSL) and Instituto do Câncer do Estado de Sao Paulo (ICESP). Patients included in the analysis received adjuvant chemotherapy with TC regimen after definitive breast surgery. Results: 95 patients with were included in our analysis. Median age was 55.5 years. All patients had a good performance status (either ECOG 0 or 1), and the great majority had no comorbidities. Most patients received 4 cycles of chemotherapy (80%). Data on granulocyte colony stimulating factor (G-CSF) administration was available in 85 patients from our cohort. G-CSF was used as primary prophylaxis in 31 patients, and as secondary prophylaxis in 13 patients, following a prior episode of febrile neutropenia. Overall, fifteen women (15.8%) had a documented FN episode. Among women who received G-CSF as primary prophylaxis, the rate of FN was 6.45% (2 patients). In contrast, among patients who did not receive primary prophylaxis with G-CSF, FN rate was considerably higher, namely 24.07% (13 patients). Patients who received primary prophylaxis with G-CSF had a statistically significant lower risk of experiencing a FN episode (p=0.049). Conclusion: Febrile Neutropenia rate in this group of non-selected BC patients was higher than previous reported on randomized controlled trials that evaluated adjuvant TC regimen in the same dosing and schedule as used in our cohort. Primary prophylaxis with G-CSF was associated with a statistically significant lower risk of FN and should be considered in the management of patients who receive this chemotherapy combination.

Systematic Review of Emerging Models of Cancer Care: Implications for the Health Industry

In selected patients diagnosed with Breast Cancer (BC), adjuvant chemotherapy might reduce local and systemic recurrence risk, as well as cancer death rate. The combination of Docetaxel and Cyclophosphamide (TC) is a wellrecognized effective adjuvant chemotherapy regimen. Nonetheless, a considerable high rate of febrile neutropenia (FN) is associated with this regimen. We sought to investigate hematologic toxicity associated with adjuvant TC in a non-selected, “real world” cohort of BC patients. Methods: We reviewed the electronic medical records of patients who presented to the Oncology Center from Hospital Sirio-Libanes (HSL) and Instituto do Câncer do Estado de Sao Paulo (ICESP). Patients included in the analysis received adjuvant chemotherapy with TC regimen after definitive breast surgery. Results: 95 patients with were included in our analysis. Median age was 55.5 years. All patients had a good performance status (either ECOG 0 or 1), and the great majority had no comorbidities. Most patients received 4 cycles of chemotherapy (80%). Data on granulocyte colony stimulating factor (G-CSF) administration was available in 85 patients from our cohort. G-CSF was used as primary prophylaxis in 31 patients, and as secondary prophylaxis in 13 patients, following a prior episode of febrile neutropenia. Overall, fifteen women (15.8%) had a documented FN episode. Among women who received G-CSF as primary prophylaxis, the rate of FN was 6.45% (2 patients). In contrast, among patients who did not receive primary prophylaxis with G-CSF, FN rate was considerably higher, namely 24.07% (13 patients). Patients who received primary prophylaxis with G-CSF had a statistically significant lower risk of experiencing a FN episode (p=0.049). Conclusion: Febrile Neutropenia rate in this group of non-selected BC patients was higher than previous reported on randomized controlled trials that evaluated adjuvant TC regimen in the same dosing and schedule as used in our cohort. Primary prophylaxis with G-CSF was associated with a statistically significant lower risk of FN and should be considered in the management of patients who receive this chemotherapy combination.

Optimal primary febrile neutropenia prophylaxis for patients receiving docetaxel-cyclophosphamide chemotherapy for breast cancer: a systematic review.

Due to the high rate of febrile neutropenia (FN) with docetaxel-cyclophosphamide (DC) chemotherapy, primary FN prophylaxis is recommended. However, the optimal choice of prophylaxis [i.e., granulocyte-colony stimulating factors (G-CSF) or antibiotics] is unknown. A systematic review was performed to address this knowledge gap. Embase, Ovid Medline, Pubmed, the Cochrane database of systematic reviews, and Cochrane register of controlled trials were searched from 1946 to April 2016 for studies evaluating primary prophylactic FN treatments in breast cancer patients receiving DC chemotherapy. Outcome measures evaluated included: incidence of FN and treatment-related hospitalizations, chemotherapy dose reduction/delays/discontinuations, and adverse events. Screening and data collection were performed by two independent reviewers. Of 2105 identified records, 7 studies (n=2535) met the pre-specified eligibility criteria. Seven additional studies (n=621) were identified from prior systematic reviews. There were 3 randomized controlled trials (RCTs) (n=2256) and 11 retrospective studies (n=900). Study sample sizes ranged from 30 to 982 patients (median 99.5), evaluating pegfilgrastim (n=1274), filgrastim (n=1758), and oral ciprofloxacin (n=108). Given the heterogeneity of patients and study design, a narrative synthesis of results was performed. Median FN rates with and without primary prophylaxis were 6.6% (IQR 3.9-10.6%) and 31.3% (IQR 25-33%), respectively. No FN-related deaths were reported. No RCT directly compared G-CSF with antibiotic interventions. Primary FN prophylaxis reduces the incidence of FN. Despite considerable cost and toxicity differences between G-CSF and antibiotics, there is insufficient data to make a recommendation of one strategy over another.

Long-term outcomes after adjuvant treatment of sequential versus combination docetaxel with doxorubicin and cyclophosphamide in node-positive breast cancer: BCIRG-005 randomized trial

The optimal regimen for adjuvant breast cancer chemotherapy is undefined. We compared sequential to concurrent combination of doxorubicin and cyclophosphamide with docetaxel chemotherapy in women with node-positive non-metastatic breast cancer. We report the final, 10-year analysis of disease-free survival (DFS), overall survival (OS), and long-term safety. A total of 3298 women with HER2 nonamplified breast cancer were randomized to doxorubicin and cyclophosphamide every 3 weeks for four cycles followed by docetaxel (AC → T) every 3 weeks for four cycles or docetaxel, doxorubicin, and cyclophosphamide (TAC) every 3 weeks for six cycles. The patients received standard radiotherapy and endocrine therapy and were followed up for 10 years with annual clinical evaluation and mammography. The 10-year DFS rates were 66.5% in the AC → T arm and 66.3% in the TAC arm (P = 0.749). OS was 79.9% in the AC → T arm and 78.9% in the TAC arm (P = 0.506). TAC was associated with higher rates of febrile neutropenia, although G-CSF primary prophylaxis greatly reduced this risk. AC → T was associated with a higher rate of myalgia, hand-foot syndrome, fluid retention, and sensory neuropathy. This 10-year analysis of the BCIRG-005 trial confirmed that the efficacy of TAC was not superior to AC → T in women with node-positive early breast cancer. The toxicity profiles differ between arms and were consistent with previous reports. The TAC regimen with G-CSF support provides shorter adjuvant treatment duration with less toxicity. ClinicalTrials.gov Identifier NCT00312208.

Report of ITMIG 2015 Meeting.

Background: Limited treatment options exist for patients with thymic malignancies (TM), and chemotherapy efficacy is often restricted by cumulative toxicity such as neuropathy (taxanes) and cardiomyopathy (anthracyclines). Single agent amrubicin, a third generation anthracycline and topoisomerase II inhibitor with minimal cardiac toxicity, was investigated in TM patients in this trial. Methods: This was an open-label single drug trial at two institutions in the United States (Stanford University and Indiana University). Eligible patients had TM [thymoma (T) or thymic carcinoma (TC)] with progression or relapse after at least one prior chemotherapy regimen, and adequate organ function including left ventricular ejection fraction (LVEF) of >50%. The initial treatment plan consisted of amrubicin at 40 mg/m 2 IV days 1–3 repeated in 3-week cycles. Results: From July 2011 to April 2014, a total of 33 patients (14T/19TC) were enrolled. There were 14 women and 19 men; age range of 30–81 years; 9 Asian, 1 African-American, 1 Hispanic and 22 non-Hispanic White patients. A high rate of febrile neutropenia (FN) led to an amended starting dose of 35 mg/m 2 days 1–3 repeated in 3-week cycles. In total, 7 patients experienced FN with 1 related death. Other grade 3/4 related events included: thrombocytopenia (n=2), neutropenia without fever (n=3), hyponatremia (n=2), hypokalemia (n=2), anemia (n=7), lethargy/fatigue (n=7), perirectal abscess (n=2), palmar-plantar erythrodysesthesia (n=3), syncope (n=2), venous embolism (n=2), and 1 patient each with sepsis, oral abscess, mucositis, chest pain, and epigastric pain. Other toxicities were generally mild and well tolerated. No significant changes in LVEF were noted on serial echocardiograms. There were 6 partial responses (4T/2TC), 21 with stable disease, and 4 with progressive disease (PD) or death at or before first assessment for a response rate (RR) of 18% and a disease control rate (DCR) of 88% (29%/11% RR in T vs . TC and 100%/78% DCR in T vs. TC). All but 5 patients received at least 4 cycles, and 15 tolerated >10 cycles, with 38 cycles as the highest number to date. Three patients remain on therapy. Conclusions: Amrubicin, at 35 mg/m 2 IV days 1–3 on a 3-week cycle, shows promise as a single agent in pre-treated patients with T and TC with an 18% RR (29% T/11% TC) and no unexpected toxicity. DCRs of 100% in the T patients and 78% in the TC patients were observed. RR and DCR were higher in the T patients compared to the TC patients. Further exploration of amrubicin as a single drug or in combination is warranted in TM.

Febrile neutropenia risk with adjuvant TC (docetaxel and cyclophosphamide) regimen: Experience of Brazilian cancer centers.

e12002 Background: In patients diagnosed with Breast Cancer (BC), adjuvant chemotherapy is an important treatment strategy toreduce risk of breast and systemic recurrence, as well as cancer death. The combination of Docetaxel and Cyclophosphamide (TC) is a well-recognized effective regimen. Nonetheless, a considerable high rate of febrile neutropenia (FN) may be associated with this regimen. We sought to investigate hematologic toxicity associated with adjuvant TC in a non-selected cohort of BC patients. Methods: We reviewed the electronic medical records of patients who presented to the Oncology Center from Hospital Sirio-Libanes (HSL) and Instituto do Cancer do Estado de Sao Paulo (ICESP) after definitive breast surgery to initiate adjuvant chemotherapy with TC. Results: 95 patients with early BC were included in our analysis. Median age was 55.5 years. All patients had a good performance status (Ecog 0 or 1) and the great majority of them had no comorbidities. Four chemotherapy cycles were given for mo...

A phase III randomized trial of high‐dose CEOP + filgrastim versus standard‐dose CEOP in patients with non‐Hodgkin lymphoma: 10‐year follow‐up data: Australasian Leukaemia and Lymphoma Group (ALLG) NHL07 trial

Increasing dose intensity (DI) of chemotherapy for patients with aggressive non-Hodgkin lymphoma (NHL) may improve outcomes at the cost of increased toxicity. This issue was addressed in a randomized trial aiming to double the DI of myelosuppressive drugs. Between 1994 and 1999, 250 patients with previously untreated aggressive NHL were randomized to treatment with six cycles of 3-weekly standard (s) or intensive (i) chemotherapy: s-CEOP-cyclophosphamide 750, epirubicin 75, vincristine 1.4 mg/m(2) all on day 1, and prednisolone 100 mg days 1-5; i-CEOP-cyclophosphamide 1,500, epirubicin 150, vincristine 1.4 mg/m(2) all on day 1, and prednisolone 100 mg days 1-5. Primary endpoint was 5-year overall survival (OS). Relative to s-CEOP patients, i-CEOP patients achieved a 78% increase in the DI of cyclophosphamide and epirubicin. Despite this, there was no significant difference in any outcome: 5-year OS (56.7% i-CEOP; 55.1% s-CEOP; P = 0.80), 5-year progression free survival (PFS; 41% i-CEOP; 43% s-CEOP; P = 0.73), 5-year time to progression (TTP; 44% i-CEOP; 47% s-CEOP; P = 0.72), or complete remission (CR) + unconfirmed CR (CRu) rates (53% i-CEOP; 59% s-CEOP; P = 0.64). Long-term follow up at 10 years also showed no significant differences in OS, PFS, or TTP. The i-CEOP arm had higher rates of febrile neutropenia (70 vs. 26%), hospitalisations, blood product utilisation, haematological and gastrointestinal toxicities, and lower quality of life scores during treatment, although without significant differences 6-month later. In the treatment of aggressive NHL in the prerituximab era, increasing DI did not result in improved outcomes, while at the same time lead to increased toxicity.

Similar Incidence Of Febrile Neutropenia With Same-Day Versus Subsequent Day G-CSF Administration In Non-Hodgkin Lymphoma Patients Receiving R-CHOP Chemotherapy

▪ BackgroundThe chemotherapy regimen of Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) every 21 days remains a standard first line treatment for many subtypes of B-cell non-Hodgkin lymphoma (NHL). R-CHOP chemotherapy carries a significant risk of febrile neutropenia (FN). FN is a potentially life threatening complication which typically requires hospital admission and empiric administration of broad spectrum antibiotics. FN can also cause delays and dose reductions with treatment, which are associated with poorer outcomes. Granulocyte colony stimulating factors (G-CSF) are indicated for primary prophylaxis with high risk patients to ameliorate this serious complication of treatment. Prescribing guidelines recommend that G-CSF's not be given until 24 hours after receiving chemotherapy. However, due to logistical issues of outpatient insurance coverage, travel, and patient convenience, it is not always practical to delay G-CSF administration until the day after chemotherapy. Therefore, some patients at our institution received G-CSF on the same day as chemotherapy. Patients and MethodsWe identified 113 lymphoma patients treated with R-CHOP who also received G-CSF primary prophylaxis at our institution from 6/21/04-1/12/12. G-CSF primary prophylaxis with daily filgrastim or a single dose of pegfilgrastim was administered within the first six days of starting R-CHOP, categorized as either same day (D1) or later (D2+). We retrospectively analyzed FN incidence and associated outcomes in patients receiving growth factor as primary prophylaxis administered the same day compared with >24 hours after chemotherapy. FN was estimated using the cumulative incidence method and compared between groups with the Pepe-Mori test. Cox analysis was used to identify prognostic factors for survival and relapse-free survival. ResultsIn our study, 113 patients received R-CHOP and G-CSF as primary prophylaxis (31 D1, 82 D2+). FN occurred in 8 out of 31 D1 patients (25.8%), and in 21 out of 82 patients in the D2+ group (25.6%). FN incidence did not differ between the two groups (P=0.91). No significant differences in relapse-free or overall survival were observed. Risk factors associated with mortality in multivariable analysis included development of FN (hazard ratio 4.33, 95% CI 1.88-10.0, P<0.001) and receiving R-CHOP while hospitalized as an inpatient (hazard ratio 7.16, 95% CI 3.08-16.6, P<0.001). ConclusionsAmong patients receiving G-CSF as primary prophylaxis with R-CHOP, we observed no difference in FN between G-CSF administered the same day and D2+. Not surprisingly, the development of FN and receiving R-CHOP while hospitalized, were both found to be significant risk factors associated with mortality. Previous prospective studies showed more severe and prolonged level of neutropenia, with higher rates of FN with same day versus next day administration in a small cohort of R-CHOP treated NHL patients (Burris et al, 2010). In our retrospective study, we were not able to evaluate neutrophil levels at multiple time points throughout each cycle, and longer follow-up is necessary to evaluate other long-term endpoints of potential interest, such as the incidence of secondary myeloid malignancies after same-day versus next-day G-CSF treatment. For patients who require G-CSF support, next day administration remains the recommended schedule. However, same day administration may be a reasonable alternative if access to care and patient compliance are concerns. Disclosures:Hill:Celgene: Honoraria, Research Funding.

Outcomes and costs of autologous stem cell mobilization with chemotherapy plus G-CSF vs G-CSF alone

Chemotherapy plus granulocyte colony stimulating factor (G-CSF) (C+G) and G-CSF alone are two of the most common methods of mobilizing CD34+ cells for autologous hematopoietic stem cell transplantation (AHSCT). In order to compare and determine real-world outcomes and costs of these strategies, we performed a retrospective study of 226 consecutive patients at 11 medical centers (64 lymphoma, 162 multiple myeloma), of whom 55% and 66% received C+G. Patients with C+G collected more CD34+ cells/day than G-CSF alone (lymphoma: average 5.51x106 cells/kg on day 1 vs. 2.92x106 cells/kg, p=0.0231; myeloma: 4.16x106 cells/kg vs. 3.69x106 cells/kg, p<0.00001) and required fewer days of apheresis (lymphoma: average 2.11 days vs. 2.96, p=0.012; myeloma: 2.02 vs. 2.83 days, p=0.0015), though nearly all patients ultimately reached the goal of 2x106 cells/kg. With the exception of higher rates of febrile neutropenia in myeloma patients with C+G (17% vs. 2%, p<0.05), toxicities and other outcomes were similar. Mobilization with C+G cost significantly more (lymphoma: median $10,300 vs. $7,300, p<0.0001; myeloma: $8,800 vs. $5,600, p<0.0001), though re-mobilization adds $6,700 for drugs alone. Our results suggest that while both C+G and G-CSF alone are effective mobilization strategies, C+G may be more cost-effective for patients at high risk of insufficient mobilization.

Review of practice patterns of primary granulocyte-colony stimulating factor prophylaxis and impact on febrile neutropenia rate and chemotherapy delivery in patients with early breast cancer treated with modern adjuvant chemotherapy.

e19541 Background: Febrile neutropenia (FN) is a major complication of chemotherapy and is associated with substantial morbidity and mortality. Primary prophylaxis with granulocyte colony-stimulating factors (PP-G-CSF) is recommended for regimens with FN risk above 20%. We undertook a review of practice patterns of PP-G-CSF and impact on febrile neutropenia rate and chemotherapy delivery in patients with early breast cancer (EBC) treated with modern adjuvant chemotherapy (ACT) at the Cancer Centre of Southeastern Ontario. Methods: Women with EBC receiving at least one cycle of modern ACT (taxane containing regimens with or without anthracyclines) between January 2009 and December 2011 were included in our review. We collected demographic, disease-related, treatment-related, and outcome variables for each patient. Results: 239 women were treated with modern ACT during the specified period and were included in our analysis. Median age was 55 (32-80); 197 (82%) were &lt;65 years and 148 (62%) were postmenopausal. 212 (89%) patients were treated with an anthracycline-taxane (A-T) regimen and 27 (11%) with a taxane (T) regimen. 145 patients (61%) received PP-G-CSF: 47 (32%) with filgrastim (F) and 98 (68%) with pegfilgrastim (PF). Of all patients 50 (21%) developed at least one FN episode. PP-G-CSF led to lower FN rate (15% vs 31%; p=0.002), reduced dose delay (17% vs 27%; p=0.060) and dose reduction (19% vs 25%; p=0.28) of planned ACT. In women receiving PP-G-CSF higher rate of FN was associated with age ≥ 65 years (27% vs 12% if &lt; 65 years; OR 2.8, p=0.053); T regimen (30% vs 12% for A-T; OR 3.1, p=0.041) and F use (28% [n=13] vs 8% [n=8] with PF; OR 4.3, p=0.003). Conclusions: In this single-centre retrospective cohort study patients with EBC treated with modern ACT had a high rate of FN (31%) without PP-G-CSF. More than half (61%) of the patients received PP-G-CSF which led to fewer FN episodes and increased delivery of planned ACT; however, the risk of FN remained high at 15%. Factors linked to higher rate of FN despite PP-G-CSF were older age, taxane-based chemotherapy and use of filgrastim.