Rate Of Febrile Neutropenia Research Articles

Preadmission Penicillin Allergy Evaluation Before Hematopoietic Stem Cell Transplantation Optimizes Febrile Neutropenia Treatment and Inpatient Resource Utilization

Febrile neutropenia is a common complication of conditioning chemotherapy for hematopoietic stem cell transplant (HSCT), but a major barrier for optimal treatment of febrile neutropenia is historical penicillin allergies. Our group recently published a development of a clinical pipeline for delabeling penicillin allergies in adult patients planned to undergo hematopoietic stem cell transplant (HSCT). In this retrospective cohort study, we followed patients to evaluate their outcomes during inpatient admission for HSCT. We hypothesized that, among patients planned for HSCT with a self-reported penicillin allergy, completing penicillin allergy testing (amoxicillin ingestion challenge with or without concomitant penicillin skin testing) prior to HSCT admission would be associated with differences in inpatient treatment for febrile neutropenia (including antibiotic selection and timing of antibiotic administration) and improved inpatient resource utilization (including nursing and inpatient physician consults). We identified patients with a self-reported penicillin allergy who answered a penicillin allergy questionnaire and were subsequently admitted to our institution for HSCT. We divided the cohort into 2 groups: patients whose penicillin allergy was evaluated prior to admission (EPTA) and patients whose penicillin allergy was not evaluated prior to admission (NEPTA). We then performed comparison between the 2 groups for general clinical outcomes of HSCT admission (duration of admission, need for ICU transfer, readmission rate, etc.), febrile neutropenia treatment, and inpatient resource utilization. Statistics were calculated using the non-parametric two-tailed Fisher exact test for categorical outcomes and the non-parametric two-tailed Mann-Whitney U test for numerical outcomes RESULTS: Within our cohort, 35 patients completed penicillin allergy testing prior to HSCT admission (EPTA) and 44 patients did not (NEPTA). Demographics were similar between these groups, and there was no significant difference in the rate of febrile neutropenia during HSCT admission (EPTA 64% vs NEPTA 66%, p=1.00). EPTA patients were significantly more likely to receive standard first-line antibiotics (cefepime or ceftazidime) for febrile neutropenia (EPTA 95% vs NEPTA 65%, p=0.015) and time between febrile neutropenia onset and antibiotic administration was shorter (EPTA mean 66 mins vs NEPTA mean 121 mins, p=0.0058). No patients in the EPTA group experienced an immediate hypersensitivity reaction (hives, anaphylaxis, etc.) or severe cutaneous adverse reaction (SCAR) during HSCT admission. EPTA patients were also significantly less likely to require 1:1 nursing for antibiotic test doses, challenges, and desensitizations (EPTA 0% vs NEPTA 49%, p<0.0001); less likely to require inpatient allergy consult (EPTA 0% vs NEPTA 12%, p=0.031); and less likely to require inpatient antimicrobial stewardship consult (EPTA 0% vs NEPTA 13%, p=0.013) during their HSCT admission. In summary, patients who completed penicillin allergy testing prior to HSCT admission were more likely to receive first-line antibiotics and received antibiotics more rapidly for treatment of febrile neutropenia. Furthermore, patients who completed penicillin allergy testing prior to HSCT admission were less likely to require 1:1 nursing, inpatient allergy consults, and inpatient antimicrobial stewardship consults during HSCT admission.

Mecapegfilgrastim for prophylaxis of febrile neutropenia in children and adolescents with rhabdomyosarcoma or Ewing sarcoma: a prospective, single-arm, pilot study

BackgroundThe chemotherapy regimens recommended for both rhabdomyosarcoma (RMS) and Ewing sarcoma (ES) patients are myelosuppressive and can reduce the absolute neutrophil count (ANC) and subsequently increase the risk of febrile neutropenia (FN). However, only a few studies have focused on the efficacy and safety of granulocyte-colony stimulating factor (G-CSF) drugs in pediatric and adolescent patients with RMS and ES. Our objective was to investigate the efficacy and safety of mecapegfilgrastim, a biosimilar of pegfilgrastim, in prophylaxis of FN for pediatric and adolescent patients with RMS or ES.MethodsIn this single-arm, single-center, prospective study, pediatric and adolescent patients with RMS or ES were enrolled to receive either VAC (vincristine, cyclophosphamide, dactinomycin) regimen or VDC (vincristine, cyclophosphamide, doxorubicin) regimen in a 3-week cycle, followed by treatment with mecapegfilgrastim (100 μg/kg, maximum 6 mg) given at 24 h after completing chemotherapy. The primary endpoint was the incidence rate of FN. Secondary endpoints included the incidence rate of grade 4 neutropenia, duration of ANC ≤ 0.5 × 109/L, incidence rate of chemotherapy delay or reduction, use of antibiotics, and safety profile.ResultsIn total, 2 of the 30 (6.7%, 95% CI: 0.82–22.07) patients experienced FN after the first cycle of chemotherapy. Eight (26.7%, 95% CI: 12.28–45.89) patients experienced grade 4 neutropenia after receiving prophylactic mecapegfilgrastim. Eight patients experienced ANC ≤ 0.5 × 109/L with a median duration of 4.5 days; among them, 6 patients reached the lowest point of their ANC level on day 7, and 5 of them recovered by day 10. No dose reductions, delays, or discontinuation of chemotherapy was reported. Twenty-one (70.0%) patients received antibiotics during the treatment period. No patient experienced FN in the 0–5 years and the 13–18 years groups, and 2 patients experienced FN in the 6–12 years group. Two patients, 6 patients, and no patient experienced grade 4 neutropenia in the 0–5 years, 6–12 years, and 13–18 years groups, respectively.ConclusionMecapegfilgrastim showed acceptable efficacy and safety profile in pediatric and adolescent patients with RMS or ES. Further randomized studies with large sample size are warranted.Trial registrationThis clinical trial was registered at Chictr.org.cn (No.ChiCTR1900022249). Registered on March 31, 2019.

Pegylated recombinant human granulocyte colony-stimulating factor for primary prophylaxis of neutropenia in patients with cervical cancer receiving concurrent chemoradiotherapy: a prospective study

BackgroundThis study aimed to investigate the efficacy and safety of pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) for primary prophylaxis of neutropenia in patients with cervical cancer receiving concurrent chemoradiotherapy.MethodsIn this prospective, single-center, single-arm study, we enrolled patients (18–70 years) with 2018 International Federation of Gynecology and Obstetrics (FIGO) stage IIIC1r-IVA and IVB (distant metastasis only with inguinal lymph node metastasis) cervical cancer. Eligible patients should have normal function of the bone marrow (absolute neutrophil count (ANC) ≥ 2.0 × 109/L) and adequate hepatic and renal functions. Key exclusion criteria included: previous chemotherapy and/or radiotherapy; a history of bone marrow dysplasia or other hematopoietic abnormalities. All patients underwent radical radiotherapy (pelvic radiotherapy or extended-field irradiation) plus brachytherapy. The chemotherapy regimen included four cycles of 3-weekly paclitaxel and cisplatin. PEG-rhG-CSF was administered 48–72 h after each treatment cycle. Salvage granulocyte colony-stimulating factor (G-CSF) was only permitted in certain circumstances. The primary endpoint was the incidence of grade 3–4 neutropenia. The secondary endpoints included frequency of febrile neutropenia (FN), chemotherapy completion rate in cycles 2–4, time to complete radiotherapy, and safety.ResultsOverall, 52 patients were enrolled in this study from July 2019 to October 2020. The incidence of grade 3–4 neutropenia was 28.8%, with an average duration of grade 3–4 neutropenia persistence of 3.85 days (1–7 days). The incidence rate of FN was 3.8%. The chemotherapy completion rate was 94.2%, 82.7%, and 75.0% for cycles 2–4, respectively. The incidences of grade 3–4 neutropenia for cycles 1–4 were 9.6% (5/52), 8.2% (4/49), 14.0% (6/43), and 2.6% (1/39), respectively. All patients completed radiotherapy within 8 weeks (median, 48 days; range: 41–56 days), except one patient who withdrew consent and did not receive radiotherapy. Severe non-hematologic toxicity was not observed in any patient.ConclusionPEG-rhG-CSF is an effective and safe prophylactic treatment for neutropenia in patients with cervical cancer undergoing concurrent chemoradiotherapy.Trial registrationChinese Clinical Trial Registry, ChiCTR1900024494. Date of Registration:13/July/2019.

Rates of febrile neutropenia and its causes in the real world.

Aim: Characterize febrile neutropenia in the real-world and explore potentially modifiable risk factors.Patients & methods: Characteristics of patient presenting with febrile neutropenia after systemic cancer treatment were investigated, with a thorough evaluation of potential risk factors.Results: The rate of febrile neutropenia requiring hospitalization was comparable with clinical trials (mean absolute difference 2%, 95% CI: -1-4%;p=0.29). The in-hospital mortality rate was 6%. Most cases resulted from low-risk regimens (50%) and 18.2% presented no apparent risk factors. 42.4% of patients presented modifiable factors potentially involved in the occurrence of febrile neutropenia.Conclusion: Febrile neutropenia rate in contemporary real-world evidence is comparable with clinical trials. Appropriate G-CSF administration and avoidance of potentially harmful drug-interactions represent potential areas for improvement.

MDB-20. TOXICITY PROFILE OF TWO CHEMOTHERAPEUTIC REGIMENS ADOPTED FROM COG A9961 AND ACNS0331 FOR STANDARD-RISK MEDULLOBLASTOMA, A COMPARATIVE STUDY

Abstract BACKGROUND Medulloblastoma (MB) is classically treated with surgery, irradiation, and chemotherapy (CTH). Cisplatin-based CTH regimens for standard-risk (SR) MB entail significant toxicities particularly ototoxicity which adversely affect patients’ quality of life. We compared the toxicity profile of two regimens in terms of grade 3 or 4 ototoxicity, hematologic toxicity, hepatotoxicity, nephrotoxicity, and neurotoxicity. METHODS SR-MB patients enrolled at Children Cancer Hospital-Egypt (57357) between January 2016 and December 2019 (cohort A) received adjuvant CTH adopted from COG-A9961 protocol (regimen A; 8 cycles of vincristine, cisplatin, and CCNU; cumulative cisplatin dose 600 mg/m2). Starting from January 2020 (cohort B), patients received CTH adopted from ACNS0331 protocol (9 cycles; 2 cycles of vincristine, cisplatin, CCNU followed by 1 cycle of cyclophosphamide and vincristine, for 3 rounds; cumulative cisplatin dose 450 mg/m2). Toxicity grading was done using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. RESULTS enrolled patients (n=168; cohort A = 112; 67% and cohort B = 56; 33%). Cohort A had significantly higher rate of grade ≥3 ototoxicity at some point during treatment (27% vs 3.6%, p &amp;lt;0.001). Similarly, cohort A had higher grade ≥3 neurotoxicity (26% vs 12%, p =0.046), anaemia and thrombocytopenia (72% vs 56%, p =0.04). Cumulative rate of leukopenia was very high in both cohorts, 98% of all patients, while the rate of febrile neutropenia was much lower in cohort A (38% vs 67%, p &amp;lt;0.001). No toxic deaths were observed in both cohorts. There was no difference in grade ≥3 nephrotoxicity nor hepatotoxicity between the 2 cohorts. The 2-year OS for cohort A and B were 96.4% and 86.6%, respectively, p=0.11. Similarly, the 2-year EFS were 92.9% and 86.8%, p=0.29. CONCLUSION adjuvant CTH from ACNS0331 protocol showed a better toxicity profile particularly for ototoxicity compared to A9961 CTH regimen, while maintaining comparable survival.

Abstract PO2-12-12: REaCT 5G: A randomized study comparing bone pain after 5 days of filgrastim or one day of pegfilgrastim for primary febrile neutropenia prophylaxis during neo-/adjuvant chemotherapy for early breast cancer

Abstract Background: Granulocyte colony stimulating factor (G-CSF) such as filgrastim (FIL) or pegfilgrastim (PEG) significantly reduces the risk of febrile neutropenia (FN) and treatment-related hospitalization in patients with early breast cancer receiving chemotherapy. However, patients receiving G-CSF can experience clinically significant bone pain. Previous studies examining post-GCSF bone pain were mostly based on physician pain assessment and compared mixed doses (30/60/100 μg/kg) of PEG vs. FIL (5μg/kg/day or 300 μg/day) given for 7 to 14 days. Based on a randomized non-inferiority study, 5 days of FIL is considered non-inferior to 10 days of FIL to prevent FN and hospitalizations and is frequently used in patients receiving chemotherapy for breast cancer. Patient-reported bone pain after 5 days of FIL vs. single dose of PEG has never been compared in a prospective randomized study and has important implications for patient and physician treatment preferences. Methods: In this multicenter, open-label trial, patients receiving neo-/adjuvant chemotherapy for early-stage breast cancer requiring primary FN prophylaxis with G-CSF were randomized 1:1 to either 5 days of FIL (300 μg or 480μg if ≥ 90 kg) or 1 day of PEG (6 mg) with each cycle of chemotherapy. The primary endpoint was bone pain using area under the curve (AUC) of the daily pain score from days 1-5 (AUC score 0 to 40) during cycle 1. We used linear regression adjusting for stratification factors [cancer center (2 centers) and chemotherapy regimen (taxane (TAX) or anthracycline (ANTH)-based during cycle 1] and prespecified baseline covariates: age, pain, and use of pain medications pre-chemotherapy. Supportive analysis of bone pain across cycles 1 to 4 was conducted using repeated linear regression. Key secondary endpoints included incidence of FN, hospitalizations, chemotherapy delay, dose-reduction or discontinuation, and chemotherapy-related deaths. Results: From June 2021 to March 2023, 233 patients were enrolled, with 217 patients (108 FIL/109 PEG) in the intention-to-treat analysis; 16 (7.4%) patients were excluded because of incomplete follow-up. Participants were mean age 55.6 years; almost exclusively female (99.1%), on chemotherapy regimen TAX 57% vs. ANTH 43%, had mean baseline pain score 1.12, and prevalence of pain medication use pre-chemotherapy was acetaminophen 14.7%, non-steroidal anti-inflammatory drugs (NSAIDs) 6.0% and opioids 3.2%. Characteristics were balanced between arms (Table 1). After repeated measures linear regression adjusted for age, chemotherapy regimen, baseline pain, and use of pain medications pre-chemotherapy, mean AUC for bone pain at cycle 1 was 10.94 for FIL and 10.12 for PEG (mean difference 0.82; 95% CI: -1.59, 3.23; p = 0.516). There was no significant difference between arms across treatment cycles (interaction p = 0.785; mean time-averaged difference 0.28; 95% CI: -1.75, 2.32). Across cycles 1 to 4, mean peak pain over 5 days post-GCSF was 3.27 vs. 3.41 (p=0.700); frequency of bone pain during first 8 days (pain score &amp;gt; 0) was 52.5% vs. 51.3%; p=0.358, and mean frequency of severe pain (pain score ≥ 5) was 17.5% vs. 15.2%; p=0.014 for FIL vs. PEG, respectively. The incidence of FN [4.6% vs. 0%, absolute difference 4.6% (95% CI: -0.3%, 9.5%; p=0.069)] and hospitalization [FN and non-FN related: 10.2% vs. 1.8%, absolute difference of 8.4% (95% CI: 1.2%, 15.5%; p=0.021)] was higher in the FIL group. There were no significant differences in chemotherapy delay (13% vs. 11%; p=0.815), dose reduction (14.8% vs. 14.7%; p=0.999), early discontinuation (8.3% vs. 5.5%; p=0.580), or chemotherapy-related death (0.9% vs. 0%; p=0.996) in the FIL vs. PEG groups, respectively. Conclusion: There was no difference in patient-reported bone pain after 5 days of FIL or PEG, even after controlling for important clinical factors. Importantly, the study observed higher rates of FN and hospitalizations in patients receiving FIL for 5 days only. Table 1 Baseline Characteristics Citation Format: Terry Ng, Yuxin Zhang, Carol Stober, Jennifer Shamess, Natalie Mills, Stuart Nicholls, Mohammed Ibrahim, Daniel Davoudpour, Christopher Armiento, Marie-France Savard, Moira Rushton, Arif Awan, Sandeep Sehdev, John Hilton, Xinni Song, Rakesh Goel, Fiona Macdonald, Kelly Daigle, Lisa Vandermeer, Monica Taljaard, Mark Clemons. REaCT 5G: A randomized study comparing bone pain after 5 days of filgrastim or one day of pegfilgrastim for primary febrile neutropenia prophylaxis during neo-/adjuvant chemotherapy for early breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-12-12.

Clinical characteristics and survival outcomes of elderly patients with de novo metastatic germ cell tumors.

To determine the outcomes for elderly patients with de novo metastatic germ cell tumors and the influence of patient age on adherence to standard chemotherapy. A total of 150 patients who were initially diagnosed with metastatic germ cell tumors and treated at our institution between 2007 and 2021 were included. Patients were classified according to three age groups: aged <40, 40-49, and ≥50 years. Clinicopathological features, adherence to standard first-line chemotherapy, overall survival, and disease-free survival were compared between these groups. We also analyzed the outcomes of patients who received low-intensity induction chemotherapy due to adverse events and/or comorbidities. There was no significant difference in any of the survival outcomes and in the rate of adherence to standard first-line chemotherapy between the three age groups, although elderly patients with intermediate/poor prognosis group tended to receive less-intense chemotherapies. The rate of febrile neutropenia as a chemotherapy-related adverse event was significantly higher in patients aged ≥50 years. No statistical significance in survival outcomes was detected between the group of patients who received relatively low-intensity induction chemotherapy and those who received adequately intensive planned chemotherapy. The adherence rate of standard fist-line chemotherapy of elderly patients is almost comparable to that of younger patients, although some adverse events should be carefully managed. Even elderly patients with metastatic germ cell tumors can aim for equivalently good survival outcome like younger populations, with effort to adhere to standard chemotherapy.

Efficacy of delayed pegfilgrastim administration following consolidation therapy with high-dose cytarabine (HiDAC) in acute myeloid leukemia (AML) patients.

To study the effects of delaying pegfilgrastim administration following high-dose cytarabine (HiDAC) consolidation in AML patients on time to neutrophil count recovery, infectious complications, and survival. Single-center retrospective chart review of 55 patients receiving pegfilgrastim as early administration (within 72h) or delayed administration (after 72h) of HiDAC. The difference in neutrophil recovery time was similar between the early and delayed groups (18days versus 19days, p < 0.28). Infections were seen in four patients in the early administration group following chemotherapy compared to none in the delayed group (p = 0.04). Febrile neutropenia rates were also decreased in the delayed administration group (23.1% versus 10.3%, p = 0.28) as well as a trend towards longer median survival (16months versus 19months, p = 0.69) and overall survival (21months versus 31months, p = 0.47). A difference in time to neutrophil recovery was not observed between the early and delayed administration groups yet decreased infectious complications may support the delayed administration of pegfilgrastim in these patients.

Effectiveness of G-CSF in chemotherapy for digestive system tumors: a systematic review of the Clinical Practice Guidelines for the Use of G-CSF 2022 delineated by the Japan Society of Clinical Oncology.

Granulocyte colony-stimulating factor (G-CSF) reportedly reduces the risk of neutropenia and subsequent infections caused by cancer chemotherapy. Although several guidelines recommend using G-CSF in primary prophylaxis according to the incidence rate of chemotherapy-induced febrile neutropenia (FN), the effectiveness of G-CSF in digestive system tumor chemotherapy remains unclear. To address these clinical questions, we conducted a systematic review as part of revising the Clinical Practice Guidelines for the Use of G-CSF 2022 published by the Japan Society of Clinical Oncology. This systematic review addressed two main clinical questions (CQ): CQ1: "Is primary prophylaxis with G-CSF effective in chemotherapy?", and CQ2: "Is increasing the intensity of chemotherapy with G-CSF effective?" We reviewed different types of digestive system tumors, including esophageal, gastric, pancreatic, biliary tract, colorectal, and neuroendocrine carcinomas. PubMed, Cochrane Library, and Ichushi-Web databases were searched for information sources. Independent systematic reviewers conducted two rounds of screening and selected relevant records for each CQ. Finally, the working group members synthesized the strength of evidence and recommendations. After two rounds of screening, 5/0/3/0/2/0 records were extracted for CQ1 of esophageal/gastric/pancreatic/biliary tract/colorectal/ and neuroendocrine carcinoma, respectively. Additionally, a total of 2/6/1 records were extracted for CQ2 of esophageal/pancreatic/colorectal cancer, respectively. The strength of evidence and recommendations were evaluated for CQ1 of colorectal cancer; however, we could not synthesize recommendations for other CQs owing to the lack of records. The use of G-CSF for primary prophylaxis in chemotherapy for colorectal cancer is inappropriate.

In vitro activity of cefepime/taniborbactam and comparator agents against Gram-negative bacterial bloodstream pathogens recovered from patients with cancer.

Taniborbactam is a β-lactamase inhibitor that, when combined with cefepime, may offer a potential treatment option for patients with serious and resistant Gram-negative bacterial (GNB) pathogens. This study evaluated in vitro activity of cefepime/taniborbactam and comparator agents against GNB pathogens isolated from patients with cancer at our institution. A total of 270 GNB pathogens (2019-23) isolated from patients with cancer were tested against cefepime/taniborbactam and comparator agents commonly used for these patients. CLSI-approved broth microdilution methods were used. MIC50, MIC90, MIC range and percentage of susceptibility calculations were made using FDA breakpoints when available. Cefepime/taniborbactam showed highly potent activity against tested Enterobacterales, including isolates producing ESBLs and carbapenem-resistant Enterobacterales. At a provisional breakpoint of ≤16/4 mg/L, cefepime/taniborbactam inhibited most tested species of GNB pathogens, with overall 98.9% susceptibility, which was significantly (P < 0.0001) higher than the susceptibility of the GNB isolates to all other tested comparator agents, ranging from 39.6% for cefepime to 86.3% for ceftazidime/avibactam. Our results showed that taniborbactam in combination with cefepime improved in vitro activity against GNB pathogens isolated from patients with cancer, including MDR Pseudomonas aeruginosa, carbapenem-resistant Enterobacterales, ESBL-producing Enterobacterales and Stenotrophomonas maltophilia isolates, with highest activity compared with all tested comparator agents, including other β-lactam/β-lactamase inhibitor combinations. Further studies are warranted to explore the efficacy of cefepime/taniborbactam for empirical initial treatment of GNB infections in cancer patients with high rates of febrile neutropenia requiring hospitalization.

Effectiveness and safety of primary prophylaxis with G-CSF for lung cancer: a systematic review and meta-analysis to develop clinical practice guidelines for the use of G-CSF 2022.

Granulocyte colony-stimulating factor (G-CSF) is commonly administered to cancer patients undergoing myelosuppressive chemotherapy, especially when incidence rate of febrile neutropenia (FN) surpasses 20%. While primary prophylaxis with G-CSF has been proven effective in preventing FN in patients with cancer, there is limited evidence regarding its efficacy in specifically, lung cancer. Our systematic review focused on the efficacy of G-CSF primary prophylaxis in lung cancer. We extracted studies on non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) using the PubMed, Ichushi Web, and Cochrane Library databases. Two reviewers assessed the extracted studies for each type of lung cancer and conducted quantitative and meta-analyses of preplanned outcomes, including overall survival, FN incidence, infection-related mortality, quality of life, and musculoskeletal pain. A limited number of studies were extracted: two on NSCLC and six on SCLC. A meta-analysis was not conducted owing to insufficient data on NSCLC. Two case-control studies explored the efficacy of primary prophylaxis with G-CSF in patients with NSCLC (on docetaxel and ramucirumab therapy) and indicated a lower FN frequency with G-CSF. For SCLC, meta-analysis of five studies showed no significant reduction in FN incidence, with an odds ratio of 0.38 (95% confidence interval 0.03-5.56, P = 0.48). Outcomes other than FN incidence could not be evaluated due to low data availability. Limited data are available on G-CSF prophylaxis in lung cancer. Primary prophylaxis with G-CSF may be weakly recommended in Japanese patients with NSCLC undergoing docetaxel and ramucirumab combination therapy.

Impact of primary prophylaxis (PP) with granulocyte colony-stimulating factor on the outcomes of patients with locally advanced gastric cancer treated with FLOT: A single-center retrospective analysis.

414 Background: The role of primary prophylaxis (PP) with granulocyte colony-stimulating factor (G-CSF) for patients with locally advanced gastric cancer (LAGC) treated with FLOT is currently unknown. Although original FLOT4 study did not recommend PP, the use of G-CSF is common in clinical practice to avoid serious complications. However, its use is associated with increased financial costs. Methods: This is a retrospective, single-institution study. We included patients with pathologically confirmed LAGC who received perioperative FLOT4. Patients were categorized in two groups: PP versus no- PP. Our objectives were to compare frequency of grades 3 or 4 neutropenia (G3/4N) and febrile neutropenia (FN) between PP and non-PP patients. We also evaluate the association between pathological complete response (pCR) and disease-free survival (DFS) and overall survival (OS) according to the use of PP. Binomial variables were compared using Fisher's exact test. Kaplan-Meier method was used to calculate median DFS and OS and respective 95% confidence intervals [95%CI] and any difference assessed by the log-rank test. Results: From January 2019 until December 2022, 122 LAGC patients were treated with perioperative FLOT. Median age was 56 years, 53.2% were female and 84.4% were ECOG 0. Primary prophylaxis (PP) was used by 58 patients (47.5%); there was no difference between clinical and tumor features between both groups regarding age, sex, ECOG, T and N staging and Lauren’s subtype. PP costs raised treatment costs up to 15%. Grade 3 or 4 neutropenia occurred more frequently among patients without PP (65.6 vs. 1.7%; p &lt; 0.001). There was no difference in the frequency of FN between groups (7.8 vs. 0%; p = 0.06). Overall patients, pCR occurred in 11.8% os patients. Regarding the influence of PP in pathological response after FLOT chemotherapy, there was no difference between PP vs non-PP patients with pCR (14.3% vs 9.5%, p = 0.57). Median follow-up was 27.4 (range 2.8 – 70.6 months). Twenty-six patients (21.3%) died during follow-up. Median OS was 52.5 months (95% CI: 47.1-57.8). Median OS for patients in PP and no PP groups were 44.5 and 56.2 months (log-rank P =0.06), respectively. Median DFS was 43.1 months (95% CI: 37.2-48.9). Median DFS for patients in PP and no PP groups were 39.6 and 43.5 months (log-rank P =0.80), respectively. Conclusions: Despite the reduction in the frequency of G3/4N, rates of FN among patients treated with FLOT with G-CSF are too low to justify its use in a routine basis. Furthermore, PP is not associated with relevant clinical endpoints such as pCR neither OS or DFS. Based on this, PP in such situations should not be routinely used due to its financial costs.

A Pilot Study to Determine the Safety and Efficacy of Repeated Hyperbaric Oxygen Therapy in Multiple Myeloma Patients Undergoing High-Dose Therapy and Autologous Stem/Progenitor Cell Transplantation

Background Serum erythropoietin (EPO) negatively impacts hematopoietic stem cell homing and engraftment. Hyperbaric oxygen (HBO) therapy can reduce serum EPO in healthy volunteers and when given prior to stem cell infusion may improve engraftment after hematopoietic stem cell transplant (HSCT). We previously performed a phase II trial randomizing patients with multiple myeloma undergoing high dose melphalan and autologous HSCT 1:1 between a single HBO treatment and no HBO. HBO was given as 100% oxygen, 2.5 ATA for a total of 90 min, in a single treatment on Day 0 prior to the transplant. A total of 99 patients were enrolled with 52 randomized to HBO. HBO significantly reduced EPO levels for the first 24 hours after auto transplant, but EPO levels quickly rebounded by 48 hours after transplant. We hypothesized multiple HBO treatments will keep EPO levels low during the duration of stem cell homing (i.e: the first 72 hours after HSCT) and may improve neutrophil and NK cell recovery. Methods We performed a pilot study to evaluate the safety and tolerability of multiple HBO treatments during autologous HSCT. Patients with multiple myeloma undergoing autologous HSCT were eligible. Patients received HBO therapy, consisting of hyperbaric oxygen at 2.5 ATA for a total of 90 minutes breathing 100% oxygen on days 0 (prior to HSCT), 1, and 2 of transplant. The primary objective of this pilot study was to determine the safety of repeated HBO therapy in the setting, as defined by treatment limiting toxicity (TLT) including occurrence of seizure disorder, pneumothorax, death, or any irreversible grade Ill or any grade IV toxicity within 24 hours of HBO therapy. Secondary objectives were to determine the effects of multiple HBO therapy on neutrophil count recovery and the effect of multiple HBO on serum EPO. Results 10 patients have been enrolled that are evaluable for the primary objective. All patients had multiple myeloma and 4 were female. 9/10 patients successfully completed all 3 HBO treatments and 1/10 completed HBO on days 1 and 2 only because of ear pain on day 0. No patients experienced treatment limiting toxicity. The median times to neutrophil and platelet engraftment was 12 days (range 11-14) and 16 days (range 14-28), respectively. The median length of hospitalization was 13 days (range 12-16). Febrile neutropenia occurred in 3/10 patients with just one incidence of documented infection. This was significantly less than the rate of febrile neutropenia in patients receiving a single treatment of HBO or no HBO (81% and 47%, respectively, p&amp;lt;0.05). 3 patients required red blood cell transfusion and 5 platelet transfusion. Conclusions Multiple HBO treatment were well tolerated without treatment limiting toxicity during autologous HSCT for multiple myeloma.

Gimema Seifem Real-Life Study VS Randomized CPX-351 Registrative Trial for Older Patients with Secondary ACUTE Myeloid Leukemia: An Unanchored Matching-Adjusted Indirect Comparison of Infection Rates and Survival Outcomes

Background: Unanchored MAIC (Matching-Adjusted Indirect Comparison) is an ITC (Indirect Treatment Comparison) method adjusting for cross-trial heterogeneity in patient demographic or disease that are believed to be either prognostic or treatment effect modifiers. In this analysis, two trials for adults with secondary acute myeloid leukemia (AML) were compared by an unanchored MAIC. Aims: The GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto)-SEIFEM (Sorveglianza Epidemiologica Infezioni nelle Emopatie) real-life study on the use of CPX-351 (Fianchi et al- Cancers 2023) was weighted for the aggregated patients characteristics from the standard arm(“7+3”) of the CPX-351 trial (cytarabine and daunorubicin Liposome for Injection Versus Conventional Cytarabine Plus Daunorubicin in Older Patients With Newly Diagnosed Secondary Acute Myeloid Leukemia, Lancet et al - JCO 2018). This analysis aimed to test the feasibility to compare individual patients' data with aggregated published results and evaluate the rate of infections of CPX-351 in real life vs the “3+7” regimen and their impact on the survival outcomes. Methods: Patients-level data from GIMEMA-SEIFEM on the use of CPX-351 (n=202) and aggregated data from CPX-351 (“3+7” arm, n=156) trials were used to conduct an unanchored MAIC. GIMEMA-SEIFEM study included included all consecutive patients with AMLfrom 30 Italian hematologic centers who received at least 1 course of CPX-351 from July 2018 to June 2021 according to clinical practice. Patients from the GIMEMA-SEIFEM study were weighted to balance with baseline characteristics from the USA and Canada cohoort. Accordingly, weighted Overall and Event-free survival (w-OS, w-EFS) estimates, as well as rates of febrile neutropenia, pneumonia, CR, and the interval of PMN recovery, were computed. Results: Four potential effect modifiers were identified and used for adjustment: age, sex, AML subtype (tAML, sAML, MRC), and prior HMA exposure. Median w-OS and w-EFS were 14.2 (95%CI: 11.6-18.7) and 7.4 (95%CI: 3.0-10.6) months, respectively. These estimates were slightly lower than those documented in the most recent report of the GIMEMA-SEIFEM trial (median OS 17.7 months and median EFS 9.8 months) and higher than the results obtained by the standard arm of the CPX-351 trial (median OS 5.9 months, median EFS 1.3 months). Weighted rates of febrile neutropenia, pneumonia, CR, and interval of PMN recovery were comparable to the observed values and better than observed in the standard arm of the CPX-351 trial for all considered variables, except for febrile neutropenia (Table 1). Conclusions: The MAIC method allowed a robust comparison of two clinical trials for the treatment of AML patients. After adjustment, survival outcomes of the real-life cohort were slightly lower than the observed estimates and higher than the observed in the standard arm of the CPX-351 trial. Pneumonia risk was confirmed lower in GIMEMA-SEIFEM CPX-351 matched group than in “3+7” arm. This pilot analysis underlined the potentiality of this statistical method. Indeed, it could be useful to compare with high accuracy studies with strong differences in the selection of patients.

Comparison of different plerixafor-based strategies for adequate hematopoietic stem cell collection in poor mobilizers

Objectives: The main objective of the present study was to evaluate whether the use of plerixafor in combination with granulocyte colony-stimulating factor (G-CSF) or subsequent use of isolated G-CSF and then plerixafor following disease-specific chemotherapy, and whether it would allow for adequate peripheral stem cell collection in patients. Methods: The retrospective study evaluated 54 patients with previous mobilization failure who were administered plerixafor in 2 centers. In patients without any side effects, CD 34+ cell counts, the percentage of patients who were found eligible for autologous transplantation, the engraftment kinetics of the patients who underwent transplantation, and their overall survival results were compared between the two groups where G-CSF was used with plerixafor, or where plerixafor was used after isolated G-CSF following chemotherapy. Results: The median age of the patients was 49 years (range: 17-70), and 64.8% (n = 35) were males. It was identified that 31 (57.4%) patients underwent mobilization treatment with isolated G-CSF and plerixafor, and 23 (42.6%) patients underwent mobilization treatment with chemotherapy plus G-CSF and plerixafor. In all patients, mean hemoglobin level (11.3 ± 1.5 g/dL vs. 9.3 ± 1.3 g/dL; p &amp;lt; 0.001) and median platelet level (129.2 ×103/µL vs. 58.4 ×103/µL) were found to be higher, while febrile neutropenia rate (3.3% vs. 60.9%), the percentage of replacement patients (6.7% vs. 65.2%), and median days of G-CSF (6 vs. 9) were found to be lower on the day of plerixafor administration in the isolated G-CSF and plerixafor group compared to the chemotherapy and G-CSF and plerixafor group. Conclusions: In conclusion, our study demonstrated that administration of plerixafor is generally safe and well-tolerated. Regardless of the underlying disease, it offers an effective alternative for patients with previous failed mobilization attempts using conventional regimens, and allows stem cell collection with fewer apheresis sessions.

Autologous STEM Cell Collection after Daratumumab, Bortezomib, Thalidomide and Dexamethasone Versus Bortezomib, Thalidomide and Dexamethasone in NEWLY Diagnosed Multiple Myeloma: A Real-Life Monocentric Italian Experience

Introduction In newly diagnosed multiple myeloma (NDMM) patients (pts), induction followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT) remains the standard of care. The addition of an anti-CD38 antibody, daratumumab, to an established frontline protocol based on bortezomib, thalidomide and dexamethasone (D-VTd), improves efficacy but could hamper peripheral blood stem cell collection (PBCS). Methods The aim of our study is to evaluate the possible impact of the addition of daratumumab to induction therapy prior to ASCT on PBCS and hospitalization parameters a real-world population with NDMM. We hereby, retrospectively analyzed 28 NDMM pts who received 6 cycles of D-VTd as induction therapy before ASCT and compared them with a consecutive series of 32 VTD-treated NDMM pts who were matched for cytogenetic abnormalities and age, managed at the Hematology Department of Sapienza University in Rome. Results Patient baseline characteristics were equally distributed among both groups, as summarized in Table 1. After induction therapy, a combination of cyclophosphamide (CTX) with granulocyte colony stimulating factor (G-CSF) at standard dose of 10 mg/sqm/day was used as the first mobilizing regimen attempt in both groups. The median time between the last day of induction therapy and the first day of mobilization therapy was 30 days for D-VTd groups and 22 days for VTD groups (p=0.041). Overall, 94% of pts treated with VTd met the desired collection goal after first mobilization therapy, compared to 68% of pts treated with D-VTd (p=0.01). In the VTd arm, 1 pts required a second mobilization attempt, and 1 pts required a further one. In the D-VTd arm, 5 pts required a second mobilization attempt, and 4 pts also required a further one. Overall, 3 pts in the D-VTd arm did not meet the collection goal. In pts with impaired mobilization, plerixafor was used in 4/32 pts in the VTd arm (13%), compared to 29% of pts treated with D-VTd (p=0.195). In the D-VTd arm, 12/28 pts (43%) had received a higher dose of CTX as mobilization therapy (3 g/m 2) compared to the standard dose of 2.4 g/m 2 in 16/28 pts (57%). Nevertheless, no difference was observed in the rate of PBSC collection at the first attempt (p=0.7). No baseline clinical or disease characteristics were observed to have negative impact on the PBSC at first mobilization attempt, including treatment response at the end of induction therapy. Nevertheless, a significantly lower pre-mobilization level of platelet was detected in the group of D-VTd treated pts (173.000/mm 3 vs 210.000/mm 3, p=0.012) that did not meet the desired collection goal after first mobilization therapy. The median PBSC collection was 9.1x10 6 CD34+ cells/Kg in the whole cohort, with no significant difference in the two groups. A lower pre-mobilization level of neutrophils (p=0.028) and platelets (p=0.004) was observed in the D-VTd arm compared to the VTd arm, possibly reflecting prolonged daratumumab-related hematological toxicity. No significant difference was observed in the leucocyte (WBC) azimuth value in the two arms. However, the two groups reached this value on two different days. In the VTd arm the median day was 8, and in the D-VTd arm it was 11 (p=0.034). The use of G-CSF for more days did not result in an increase in CD34+ and the median azimuth value of CD34 was significantly lower in the D-VTd group than in the VTD group (p&amp;lt;0.001). The median collection volume from apheresis devices was significantly higher in the D-VTd group (372 ml) compared to VTd arm (301 ml) (p=0.05), possibly related to a higher WBC azimuth in D-VTd arm, resulting in a prolonged apheresis procedure. Pts receiving D-VTd had slightly delayed hematopoietic neutrophil (11 vs 14 days, p=0.030) and platelet (15 vs 14 days, p=0.018) engraftment, but no requiring a higher number of red cell (p=0.6) and platelet (p=0.3) transfusions and a longer hospitalization (20 vs 17 days, p=0.2) after the first ASCT, compared to pts treated with VTd. No difference in the two groups regarding rate of febrile neutropenia (65% vs 45%, p=0.2) and use of antibiotics (53% vs 57%, p=0.8) were observed. Conclusions In conclusion, frontline induction daratumumab-based therapy is likely to affect PBSC collection after first mobilization attempt, even if not clinically relevant, and potentially mitigated with higher use of plerixafor. Furthermore, the inclusion of daratumumab in pretransplant therapy regimens did not impair ASCT.

Loncastuximab Tesirine Demonstrated Substantial Single-Agent Efficacy and Manageable Safety Profile in Heavily Pretreated Chinese Patients with Relapsed or Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL)

Introduction: Patients with R/R DLBCL who failed multi-agent chemoimmunotherapies usually have a poor prognosis, leaving a significant unmet medical need. Loncastuximab tesirine (Lonca) is an antibody-drug conjugate, composed of a humanized anti-CD19 antibody conjugated to a pyrrolobenzodiazepine dimer toxin that showed clinical efficacy and manageable safety in heavily pretreated DLBCL patients in a global phase 2 study of Lonca monotherapy (NCT03075696). Here we present results from a phase 2 study (ChiCTR2300072058) of Lonca monotherapy in Chinese patients with R/R DLBCL for the first time, including analyses of responses in high-risk DLBCL subgroups. Methods: This open-label, single-arm, phase 2 study was designed to confirm the safety, efficacy and PK profiles of Lonca monotherapy in Chinese patients with R/R DLBCL who had failed ≥ 2 lines of systemic therapies. The primary endpoint was overall response rate (ORR) as assessed by IRC according to the Lugano 2014 criteria. Secondary efficacy endpoints include complete response rate (CRR), DOR, RFS, PFS, and OS. Treatment-emergent adverse events (TEAEs) were reported by CTCAE v4.0. Results: As of data cutoff (11-Jan-2023), 64 Chinese patients with DLBCL were enrolled and received at least one dose of Lonca (median: 4.0 cycles [range: 1-17]) and were evaluable for safety and efficacy analyses. The median number of prior lines of therapies was 3.0 (range: 2-12), with 67.2% of patients having ≥ 3 lines of prior therapies. Four patients (6.3%) had received prior CD19 CAR-T therapy. Forty-three patients (67.2%) were refractory to the first-line therapy (primary refractory), 56 patients (87.5%) were refractory to the most recent line of therapy and 40 patients (62.5%) were refractory to all prior lines of therapies. At data cutoff, the median follow-up was 8.5 months. The ORR by IRC was 51.6% (95% CI: 38.7% to 64.2%), and CRR was 23.4%. The median DOR (mDOR) was 6.37 months as assessed either by IRC or by investigator. For patients with a CR, the mDOR was 10.22 months (6.08 months for patients with PR). The median time to first response was 41.0 days. The median PFS and median OS were 4.96 and 9.33 months, respectively. Responses, including CRs, were observed in several high-risk subgroups (Fig. 1): ORR was 54.7% in patients with advanced stage disease (Stage III/IV) and 50.0% in patients with transformed disease. Patients who were refractory to first-line therapy, to the most recent therapy, or to all prior therapies had ORRs of 44.2%, 51.8% and 42.5%, respectively. Three patients who had received a prior SCT had an ORR of 100%. Lonca was also effective in elderly patients ≥ 65 years (ORR of 45.8%, mDOR of 6.37 months) and in patients who had received prior CD19 CAR-T therapy (ORR of 50%). Overall, 64 (100%) patients had at least one TEAE and 61 (95.3%) patients had at least one TEAE ≥ Grade 3. The most common (≥30%) all-grade TEAEs were GGT increased (71.9%), followed by anaemia (70.3%), platelet count decreased (65.6%), AST increased (64.1%), WBC count decreased (64.1%), neutrophil count decreased (60.9%), ALT increased (51.6%), hypokalaemia (37.5%), and blood ALP increased (32.8%). The most common (≥15%) TEAEs of Grade ≥3 were platelet count decreased (34.4%), neutrophil count decreased (28.1%), WBC count decreased (28.1%), GGT increased (25.0%), anaemia (18.8%), hypokalaemia (18.8%), neutropenia (17.2%), and lymphocyte count decreased (15.6%). The rate of febrile neutropenia was low (3.1%). The majority of Grade ≥ 3 TEAEs were abnormalities of clinical laboratory values as opposed to clinical symptoms and were generally reversible. Treatment-related TEAEs leading to treatment discontinuation occurred in 10 patients (15.6%), most commonly GGT increased (3 patients; 4.7%). No increase in toxicity was seen in patients aged ≥65 years compared with younger patients. Conclusions: Lonca demonstrated substantial and clinically meaningful single-agent efficacy and was well-tolerated in heavily pretreated Chinese patients with R/R DLBCL. Toxicities were generally manageable and reversible in most patients by routine clinical practice and/or with dose modifications, with neither unexpected safety concerns nor different toxicity profile in patients aged ≥65 years. Encouraging and durable responses were also observed in high-risk patient groups, including patients with advanced stage, transformed or refractory DLBCL.

Real World Outcomes of CPX-351 Compared to Traditional Chemotherapy with Cytarabine Consolidation for Treatment of Secondary Acute Myeloid Leukemia

Introduction: Outcomes in patients with secondary AML (sAML) are inferior to those with de novo AML which has led investigators to seek alternatives to traditional treatment. Liposomal daunorubicin and cytarabine, or CPX-351, for the treatment of sAML has shown superior complete remission/complete remission with incomplete count recovery (CR/CRi), event-free survival (EFS), and overall survival (OS) compared to the traditional non-liposomal formulations of daunorubicin and cytarabine (“7+3”). However, this agent was originally studied in combination with a suboptimal consolidation regimen which did not include standard of care high dose cytarabine (HiDAC). This is often cited as a limitation of the study and may have contributed to the significantly lower response rates reported when compared to historical data. Here we present a real-world comparison of the efficacy and safety of patients with sAML receiving CPX-351 versus traditional 7+3 with HiDAC consolidation. Methods: Patients were at least 18 years of age with sAML, defined as: t-AML, AML-with Myelodysplasia-Related Changes (MRC), or AML with a history of chronic myelomonocytic leukemia (CMML). Patients were included if they had received induction (and consolidation, if applicable) with CPX-351 or induction with 7+3 (daunorubicin 60 mg/m 2 for 3 days and cytarabine 100 mg/m 2 for 7 days), followed by consolidation with cytarabine (≥1000 mg/m 2 x 6 doses). Nominal data were analyzed using chi squared tests or Fisher's exact tests. Continuous data were analyzed using the Mann-Whitney U test. A Kaplan Meier estimator was used for survival outcomes. Results: Overall, 58 patients with sAML were included, with 36 (62%) receiving CPX-351 and 22 (38%) receiving 7+3 followed by cytarabine-based consolidation between April 2013 and June 2022. Patients in the CPX-351 were older (67.5 vs 62 years, p=0.04) and had a higher prevalence of poor-risk cytogenetics (p=0.22). Other baseline characteristics were similar (Table 1). The rate of CR/CRi following induction was significantly higher in patients who received 7+3-based induction vs patients who received CPX-351 (81.8% vs 44.4%, p=0.01). Twenty-five percent of patients achieved CR/CRi in the CPX-351 arm with one induction cycle, compared to 95.5% in the 7+3 group. Median progression-free survival (PFS) was 3 vs 6.1 months (p=0.67) and median OS was 18.3 vs 9.3 months (p=0.73) in the CPX-351 and 7+3 cohorts, respectively (Figure 1). Thirty-nine percent of patients in the 7+3 cohort proceeded to allogeneic stem cell transplant compared to 81% in the CPX-351 cohort, however median OS in patients who underwent transplant was similar between the two cohorts (16.8 vs 15.8 months). Median OS was longer in the CPX-351 cohort however this was not statistically significant (Figure 1). Rates of both febrile neutropenia (94.3% vs 95.5%; P&amp;gt;0.99) and confirmed infections (54.3% vs 50%) were similar amongst those treated with CPX-351 and 7+3. Bacteremia and pneumonia were the most common infections in both cohorts. Median duration of neutropenia was significantly longer in the CPX-351 cohort (43 days vs. 27 days, p=0.002) with no major difference in duration of thrombocytopenia. In the 7+3 cohort, 11 deaths were directly attributed to progression, while 5 were associated with infection. In the CPX-351 cohort, 6 deaths were directly attributed to progression, while 8 were attributed to infection. At day 60, two deaths were observed in the CPX-351 cohort and there were no deaths in the 7+3 cohort. Conclusion: These findings suggest use of traditional 7+3 induction followed by HiDAC consolidation may be an alternative to CPX-351 for patients with sAML. Although median PFS was longer in the 7+3 cohort, this did not translate into longer median OS, likely due to the low rate of patients proceeding to transplant. Similar rates of overall survival in patients undergoing allogeneic stem cell transplantation support the hypothesis that transplant should be the goal for most patients with sAML. The retrospective nature of the study may limit broader application of this data.

A Comparison of Acute Myeloid Leukemia (AML) Regimens: Hypomethylating Agents Combined with Ivosidenib or Venetoclax in Newly Diagnosed Patients with IDH1 Mutations: A Real-World Evidence Study

Background: Two frontline combination regimens are available for patients with mutant IDH1 (mIDH1) AML: ivosidenib (IVO)+hypomethylating agent (HMA), and venetoclax (VEN)+HMA. Robust comparisons between these regimens have not been performed, and small post hoc analyses have been constrained by low numbers of mIDH1 patients and clustering of IDH1 and IDH2 mutations (Pollyea 2022, Perl 2022). We evaluated a large cohort of patients with newly diagnosed (ND) mIDH1 AML to gain insights into the treatment patterns, efficacy, and safety associated with these combination regimens. Methods: We conducted a US-wide retrospective chart review of patients with ND mIDH1 AML ineligible for intensive chemotherapy (IC), treated with IVO+HMA or VEN+HMA. Treatment was initiated in community and academic settings November 2021 through November 2022, enabling a minimum follow-up of 6 months. Collected data included baseline patient and practice characteristics, treatment patterns and rationale, and efficacy and safety outcomes. Endpoints focused on events likely to occur within 6 months of follow-up, including response rates, tolerability, bridge to transplant, and acute care episodes. Results: Among 283 patients (IVO+HMA, n=182; VEN+HMA, n=101), baseline characteristics were similar between regimens. Median age was 63 years; 65.7% were male. ELN cytogenetic risk status was 59.7% and 15.2% for intermediate and poor, respectively. Prior MDS, myeloproliferative neoplasms, or secondary or secondary-like AML mutations occurred in 37.1%. A higher proportion of VEN+HMA use occurred in the academic setting (68.3% vs 55.5% for IVO+HMA; p=0.035). Median follow-up from treatment initiation was 7.1 vs 8.1 months for IVO+HMA vs VEN+HMA. Complete response (CR) plus CR with incomplete count or incomplete platelet recovery (CRi/p) rates were 63.2% vs 49.5% for IVO+HMA vs VEN+HMA ( p=0.025), with the difference based on the higher CR rate for IVO+HMA (42.9% vs 26.7%; p=0.007) (Figure). Median time to first bone marrow biopsy on treatment across cohorts was 56 days and median time to best response was 3.3 vs 4.1 months for IVO+HMA vs VEN+HMA ( p=0.002). A competing risks regression showed that 6-month event-free survival (EFS; CR within 24 weeks, and no relapse or death) favored IVO+HMA vs VEN+HMA (56.0% vs 39.6%, hazard ratio of 0.773; p=0.044). Bridge to transplant was achieved for 11.5% of patients with IVO+HMA vs 5.0% for VEN+HMA ( p=0.066). Few patients in either cohort had a dose (ie, strength) change following initial ramp-up. Treatment discontinuation was 37% for both regimens. Likewise, toxicity incidence was similar except for higher febrile neutropenia (FN) rates for VEN+HMA vs IVO+HMA within 30 days of initiation (7.9% vs 1.6%; p=0.009). Patients receiving IVO+HMA had 61% lower relative risk of unscheduled acute care use in the first 12 weeks (42.9% vs 70.3% for VEN+HMA; p&amp;lt;0.001). VEN schedule intensity was also captured, with only 22.8% receiving the full FDA-labeled 28 days of VEN during the 28-day cycles; 44.6% did not receive &amp;gt;11 days of VEN per cycle, raising concerns of clinical consequences. Median time from mIDH1 test to receipt of result was 7 days in both cohorts. Median time from diagnosis to start of treatment was 14 vs 20 days for IVO+HMA vs VEN+HMA. The biggest differential driver of regimen choice was favoring selection of VEN+HMA due to hospital protocol (30.7% vs 16.5%). Conclusions: In a large, balanced cohort of nearly 300 patients with ND mIDH1 AML ineligible for IC, patients treated with IVO+HMA had higher rates of CR and CR+CRi/p, achieved CR faster, and had longer EFS compared to those treated with VEN+HMA. Approximately half of patients receiving VEN were unable to receive &amp;gt;11-day schedules, potentially impacting the regimen's efficacy. Despite the reduced intensity of VEN relative to label, patients receiving VEN+HMA had higher early incidence of FN and greater overall need for unscheduled acute care. Wait time for mutational test results was 7 days, well within the 14- to 20-day median times to treatment. Based on the efficacy seen in this real-world assessment, consistent with the efficacy demonstrated in the AGILE clinical trial of IVO+azacitadine, clinicians and hospitals should ensure early mutational testing occurs, to enable consideration of IVO+azacitadine as the frontline treatment of choice for patients with ND mIDH1 AML.

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 &amp;lt; 0.001) and infections ≥ grade 3 (90% v. 13%, RR 6.8, p &amp;lt; 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 &amp;lt; 0.001). Post-AA MN patients had more treatment delays &amp;gt;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 &amp;lt; 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.