CPX-351 for Acute Myeloid Leukaemia: Real World Results Are Comparable to Trial Outcomes and Exceeds Them in Non-Adverse Risk Patients- a Multicentre Experience from West Midlands Hospitals on Behalf of West Midlands Research Consortium ( WMRC) UK

Patients with secondary AML or MDS derived AML have poor outcomes compared to de-novo AML. The benefits of intensive chemotherapy without anticipated transplant consolidation have been previously doubted. Outcomes in USA trial centres have not often been closely replicable in real world settings. From November 2018 CPX-351 has been available in the UK for secondary AML, therapy related AML, AML with MDS related Karyotype (AML-MRC) and licensed but not funded for AML with myelodysplastic related changes. Objectives Here we report our experience specifically on patient outcomes and toxicity across 5 Hospitals in West Midlands, UK Methods Patients receiving CPX 351 outcomes were evaluated retrospectively from 2018 to 2021. Baseline genetics, CPX 351 indications, patient's comorbidities, overall survival, remission status, number of cycles delivered, early mortality, reasons for early discontinuation, intensive care admission and time for neutrophil recovery (>0.5) was recorded. Time-to-event outcomes reported here are from a data cut on 01-06-21 Results In a total cohort of 57 patients baseline characteristics are shown on table 1 and compared with the original trial CPX-351 group. Median follow up was 376 days (range 21 to 1248 days). The mean age was 63, 17 patients were under 60, 31 males and 26 females. The most common indication for CPX-351 was AML with antecedent MDS/MPN 51% (N=29), therapy related 14% (N=8), MDS related karyotype (AML-MRC) 19% (N=11) and 16% (N=9) other patients. Mean Charleston co-morbidity score was 2.7 (range 0-6), 10.5% (N=6) had previous non myeloid malignancies, 8.7% (N=5) had prior ischaemic heart disease, only 3.5% (N=2) had ejection fractions under 50%. The most common mutations were TP53 21% (N=12), ASXL1 15.7% (N=9), TET2 15.7% (N=9), IDH2 10.5% (N=6), RUNX1 10.5% (N=6), SRSF2 7% (N=4), JAK2 3.5% (N=2), FLT3 5% (N=3), NPM1 5%(N=3) and IDH1 5% (N=3). MRC cytogenetic risk was adverse in 19 patients (33%), intermediate in 35 patients (61%) and favourable in 3 patients (5%). 30 patients (53%) had adverse European Leukaemia Network classification, 17 (30%) had intermediate and 10 (17%) had favourable. 30-day mortality was 3/57 (5%), 60-day mortality was 6 (10.5%) comparable to the 5.9% and 10.6% rates for the original trial. 9% or 5/57 patients were admitted to ITU with 2 survivors beyond 60 days. Neutropenic fever requiring antibiotics was 100% whereas only 5/57 (9%) had radiological evidence of fungal infection. Only one patient died from COVID 19. The mean time to neutrophil recovery was 35 days with a range of 12 to 84 days. 29 patients completed 1 cycle, 25 completed 2 cycles, only 3 completed 3 cycles. The reasons for stopping were death, refractory disease, drop in performance status, alternative chemotherapy chosen or moving to transplantation (39%). Composite remission rate including CRi was 61% 36/57, adverse ELN group demonstrated 50% 15/30, intermediate 76% 13/17 and favourable 80% 8/10. Mutated P53 was associated with a 50% 6/12 rate whereas in wild type P53 the remission rate was 60% 30/45. Overall median survival from diagnosis was 429 days [95% CI 274 to 788 days]. To compare with the original trial, we removed the under 60s and those with less than 1 year follow up, in this cohort of 30 patients the median survival was 289 days (9.5 months) with 95% CI of 255 to 476 days. P53 mutated patients had an estimated median survival of 257 days versus wild type p53 with 524 days hazard ratio of 2.418 (CI 1.077 to 5.248) with p value of 0.032. Median survival for ELN groups was 373 days (adverse), 413 days (intermediate) and not reached for favourable. Of the 36 patients who achieved a remission, 22 went on to receive an allogenic transplant with follow from 254 to 1248 days, median survival estimated 706 days (95% CI 429-not reached). Patients in remission who haven't received a transplant have a similar estimated survival of 788 days (305-not reached) pending longer follow up. Conclusion This is the first UK multicentre analysis to show comparable results to the landmark trial (median survival 9.5 months in equivalent cases). The improved overall remission rate 61% versus the 47% in the trial and the longer median survival 14 months versus 9.5 months in the trial is expected given the younger age and increase in favourable risk genetics. This study therefore supplies further data of CPX-351 efficacy in younger patients not included in the original studies and may now be used as a standard comparator arm. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Infectious Complications after Intensive Chemotherapy with CLAG-M or '7+3' for Adults with Acute Myeloid Leukemia and Other High-Grade Myeloid Neoplasms

Introduction Infections cause substantial morbidity and mortality in patients with acute myeloid leukemia (AML) and other high-grade myeloid neoplasms. The contemporary regimen of CLAG-M (cladribine, high-dose cytarabine, G-CSF, mitoxantrone) has favorable hematologic outcomes compared to '7+3' (standard-dose cytarabine, anthracycline) in some studies but may be more myelosuppressive. The aim of this investigation was to determine and compare the incidence and spectrum of infections after CLAG-M and 7+3. Methods For this retrospective cohort study, we identified microbiologically documented moderate to severe infections (grade ≥2 infections; Blood and Marrow Transplant Clinical Trials Network Technical Manual of Procedures (BMT CTN MOP) guideline) after the first cycle of CLAG-M for newly-diagnosed (ND) or relapsed/refractory (R/R) AML or other high-grade myeloid neoplasms (≥10% blasts in marrow or peripheral blood) and compared these findings to adults receiving 7+3 for ND disease. We recorded infections for up to 90 days from the start of chemotherapy or until the start of a second cycle or death, whichever occurred first. We compared the cumulative incidence probability of time-to-first infection between cohorts using Gray's test with start of additional therapy and death as competing risk events. Infection rates, defined as average number of infections per 1000 patient days-at-risk, were compared between cohorts using Poisson regression. Results The study included 442 individuals consisting of 196 with ND disease and 131 with R/R disease receiving CLAG-M, and 115 with ND disease receiving 7+3 (Table 1). Fifty-four (28%), 65 (50%), and 19 (17%) individuals per cohort had one or more moderate to severe microbiologically documented infection, respectively. The absolute neutrophil count was <500 cells/mm 3 at the time of each infection in 67 of 71 (94%), 82 of 86 (95%), and 27 of 27 (100%) infection events per cohort, respectively. Time to neutrophil recovery, defined as the first of three consecutive days with a neutrophil count ≥500 cells/mm 3, was shortest among individuals treated with CLAG-M for ND disease (Fig. 1). Among individuals with ND disease, overall infection rates tended to be higher in those receiving CLAG-M versus 7+3 but this trend did not reach statistical significance (Fig. 2). Individuals with R/R disease treated with CLAG-M had a significantly higher overall infection rate compared to those with ND disease, primarily driven by bacterial infections (Fig. 2). Similar patterns were observed in cumulative incidence curves of time-to-first infection (Fig. 3). First infections occurred a median of 11-13 days after start of treatment. The most frequent infections were bloodstream infections consisting of 37 (52%), 56 (65%), and 11 (41%) infection events per cohort, respectively, followed by respiratory tract infections (31 [44%], 27 [31%], and 10 [37%] infection events per cohort, respectively). Fungal infections were relatively frequent and similar between groups (Fig. 4), although mold-active prophylaxis was used more frequently in CLAG-M cohorts (44-53%) compared to the 7+3 cohort (7%). Individuals receiving mold-active prophylaxis had a lower incidence of proven and probable invasive fungal infections. Among individuals with ND disease not receiving mold-active prophylaxis, invasive fungal infections tended to be more common in the CLAG-M cohort than in the 7+3 cohort. Viral infections were uncommon. Among 29 patients (7%) who died during the study period, infection was a primary or contributing cause of death in 17 (59%). Conclusions Moderate to severe microbiologically documented infections are common after the first cycle of chemotherapy for ND or R/R AML or other high-grade myeloid neoplasms. CLAG-M may be associated with more moderate to severe microbiologically documented infections than 7+3 for ND disease. Individuals with R/R disease are at the highest risk. Invasive fungal infections were relatively frequent but may be significantly reduced by mold-active azole prophylaxis. New approaches to improve neutrophil recovery and function may reduce infection risk. Figure 1 Figure 1. Disclosures Halpern: Abbvie: Consultancy; Tolero Pharmaceuticals: Research Funding; Agios: Consultancy; Gilead: Research Funding; Agios Pharmaceuticals: Research Funding; Bayer: Research Funding; Novartis: Research Funding; Imago Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding; Nohla Therapeutics: Research Funding; Pfizer: Research Funding. Delaney: Deverra Therapeutics: Current Employment, Other: Founder, CSO. Pergam: Chimerix, Inc: Research Funding; Global Life Technologies, Inc: Research Funding; Merck & Co.: Research Funding; Sanofi Aventis: Research Funding. Boeckh: Merck: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; AlloVir: Consultancy; SymBio Pharmaceuticals: Consultancy; Helocyte: Consultancy; Evrys Bio: Consultancy; Moderna: Consultancy; GSK: Consultancy. Walter: BMS: Consultancy; Astellas: Consultancy; Agios: Consultancy; Amphivena: Consultancy, Other: ownership interests; Selvita: Research Funding; Pfizer: Consultancy, Research Funding; Jazz: Research Funding; Macrogenics: Consultancy, Research Funding; Immunogen: Research Funding; Celgene: Consultancy, Research Funding; Genentech: Consultancy; Janssen: Consultancy; Kite: Consultancy; Aptevo: Consultancy, Research Funding; Amgen: Research Funding. Hill: Gilead: Consultancy, Research Funding; Karius: Research Funding; Octapharma: Consultancy; Allovir: Consultancy, Research Funding; Amplyx: Consultancy; Takeda: Consultancy, Research Funding; Allogene therapeutics: Consultancy; CRISPR therapeutics: Consultancy; CLS Behring: Consultancy; OptumHealth: Consultancy.

186. Evaluating Clinical Outcomes for Treatment of Staphylococcal Bloodstream Infection in Patients with Febrile Neutropenia

Background Staphylococcus aureus bloodstream infections (BSIs) in patients with febrile neutropenia (FN) is associated with a mortality rate of up to 49%. For documented infections in patients with FN, guidelines recommend narrowing therapy once susceptibilities result and fever has resolved. Although anti-staphylococcal beta-lactams are the mainstay of treatment for Methicillin-Susceptible and Penicillin-Susceptible Staphylococcus aureus (MSSA and PSSA) BSIs, some clinicians opt to continue broad antibiotics against Pseudomonas during FN. Studies evaluating treatment modalities and outcomes of MSSA and PSSA BSI in patients with FN are lacking. Methods We conducted a retrospective cohort study of adult patients with MSSA or PSSA BSI who received antibiotics for the treatment of FN (absolute neutrophil count < 500 cells/L and temperature > 100.4F) at Brigham and Women’s Hospital and Dana-Farber Cancer Institute from 1/2010 to 4/2021. Patients who received < 72-h of antibiotics were excluded. The primary outcome was composite clinical failure (60-day all-cause mortality and/or 60-day BSI recurrence). Other outcomes included inpatient mortality, 60-day readmission, 60-day infection outcomes, incidence of acute kidney injury and hepatotoxicity. Data was analyzed using Chi-Square test or Fisher’s Exact test. Results Among 108 patients who met our criteria, 58% were male, median age was 57 years (IQR 44, 66), 94% had a hematologic malignancy, 4% had a solid tumor, and 2% had both. A total of 41 (38%) received combination therapy with broad spectrum and anti-staphylococcal beta-lactam, 48 (44%) received broad spectrum beta-lactam followed by anti-staphylococcal beta-lactam after neutrophil recovery, and 19 (18%) were narrowed to an anti-staphylococcal beta-lactam prior to resolution of neutropenia. Clinical failure was similar across all treatment arms (34% for combination therapy, 25% for broad spectrum beta-lactam, and 37% for anti-staphylococcal beta-lactam) (Table). Table. Outcomes Conclusion De-escalation to an anti-staphylococcal beta-lactam prior to neutrophil recovery in FN patients with MSSA or PSSA BSIs did not result in significantly higher clinical failures. Further prospective studies are needed to support antimicrobial stewardship initiatives in oncology patients. Disclosures All Authors: No reported disclosures

Hematopoietic recovery after transplantation is primarily derived from the stochastic contribution of hematopoietic stem cells

Reconstitution after hematopoietic stem cell (HSC) transplantation is assumed to occur in two distinct phases: initial recovery mediated by short-term progenitors and long-term repopulation by multipotent HSCs which do not contribute to hematopoietic reconstitution during the first 6-9 months. We have previously reported the transplantation and exclusive engraftment of the HSC-enriched CD34+CD45RA-CD90+ phenotype in a nonhuman primate model. Here, we closely followed the clonal diversity and kinetics in these animals. Enhanced sampling and high density clonal tracking within the first 3 month revealed that multipotent HSCs actively contributed to the early phases of neutrophil recovery and became the dominant source for blood cells as early as 50 days after transplant. Longitudinal changes in clonal diversity supported a stochastic engraftment of HSCs with the majority of HSCs clones vanishing early during neutrophil recovery and a smaller fraction of HSC clones expanding into bigger pools to support long-term hematopoiesis. In contrast to the bi-phasic model, we propose that hematopoietic recovery after myeloablation and transplantation is primarily derived from HSCs in a stochastic manner rather than in two phases by independent cell populations.

667 PEGYLATED RECOMBINANT HUMAN GRANULOCYTE COLONY STIMULATING FACTOR IN DEFINITIVE CHEMORADIOTHERAPY OF ESOPHAGEAL CANCER: PRELIMINARY RESULTS

To compare the efficiency and safety of pegylated recombinant human granulocyte colony stimulating factor (PEG-rhG-CSF), on the risk of neutropenia in patients with esophageal squamous cell carcinoma (ESCC) of definitive chemoradiotherapy (dCRT). Methods ESCC patients receiving dCRT in our hospital were adopted in this study. Patients in the PEG-rhG-CSF group were treated with preventive PEG-rhG-CSF 6 mg subcutaneously at 24–48 h after completion of chemotherapy of each cycle, while the control group was not. The usage of rhG-CSF was permitted when the absolute neutrophil count (ANC) ≤2 × 109/L, or white blood cell count (WBC) ≤3 × 109/L. Results A total of 34 ESCC patients were in the PEG-rhG-CSF group and 41 were in the control group. Improved chemotherapy cycle completion and radiation dose completion were identified in the PEG-rhG-CSF group (P < 0.001). Leukocyte recovery and neutrophil recovery, (P < 0.001). PEG-rhG-CSF reduced incidence of neutropenia, and time to ANC recovery in different chemotherapy cycles, with (Cycle 1–2, P < 0.001 ~ P = 0.02) or without RT (Cycle 3–4, P = 0.04 ~ P = 0.8799). Antibiotics utilization rates were significantly higher in the PEG-rhG-CSF group during concurrent chemotherapy with RT, but not during consolidative CRT (Cycle 3 and Cycle 4: P > 0.05). Conclusion PEG-rhG-CSF prescribed as prophylaxis reduces acute toxicities by concurrent CRT and contributes to completion of dCRT regime in locally advanced ESCC therapeutics. The significance was not observed in chemotherapy alone without RT in the current findings.

Neutrophil recovery with or without G-CSF in non M3 AML patient with DA 3+7 protocol

Background: Induction of acute myeloid leukaemia is associated with a high incidence of treatment related mortality mostly due to neutropenia related infections. This study primarily analyses the duration of neutrophil recovery with or without G-CSF during induction with DA 3+7 in non M3 AML patients. This study also evaluates role of G-CSF in duration febrile neutropenia, hospital stay, total blood products transfusion, total number of used injectable antibiotics and remission status. Methods: It was a Quasi Experimental - Non-Randomized Controlled Trail. There were two groups a) Case = Patients receiving G-CSF b) Control= Patients not receiving G-CSF. Sampling was purposive sampling. Results: 50 patients in two group, G-CSF group (n=25) and Control group (No G-CSF) (n=25) participated in this study. Among them 54% was female and 46% was male. Median age of the participants was 28 years. Neutrophil recovery duration in G-CSF group Vs Control group showed 22.64 Vs 24.64 days (p value 0.003). Duration of febrile neutropenia in G-CSF group Vs Control group showed 11.24 Vs 13.56 days (p value 0.038). Duration of hospital stay in G-CSF group Vs Control group showed 23.64 Vs 25.76 days (p value 0.002). Total number of blood and blood product transfusion in G-CSF group Vs Control group showed 3.80 Vs 3.88 (p value 0.597). Total number of injectable antibiotics in G-CSF group Vs Control group showed 2.72 Vs 3.12 days (p value 0.169). In G-CSF group 22 (88%) and in Control group 23 (92%) were in complete remission (p value 0.637). Conclusions: G-CSF significantly reduces the duration of neutropenia (p value 0.003), febrile neutropenia (p value 0.038) and hospital stay (p value 0.002) after induction with DA 3+7. This may cause reduction in treatment cost and sepsis related mortality. G-CSF can’t significantly reduce use of blood products (p value 0.597) and injectable antibiotics (p value 0.169) after induction with DA 3+7. G-CSF does not affect morphological remission status (p value 0.637) after induction with DA 3+7.

Austrian syndrome, ceftriaxone-induced agranulocytosis and COVID-19

We present a case of a 75-year-old woman with Austrian syndrome: pneumonia, meningitis and endocarditis all due to Streptococcus pneumoniae. Transoesophageal echocardiogram demonstrated a large mitral valve vegetation with severe mitral regurgitation. She was treated with intravenous ceftriaxone and listed for surgical repair of her mitral valve. Preoperatively, she developed an idiosyncratic drug-induced agranulocytosis secondary to ceftriaxone, which resolved on cessation of the medication. However, while awaiting neutrophil recovery, she developed an acute deterioration, becoming critically unwell. This deterioration was multifactorial, with acute decompensated heart failure alongside COVID-19. After multidisciplinary discussion, she was considered too unwell for surgery and palliated.