bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of factors to predict low risk febrile neutropenia admissions in patients with acute myeloid leukemia (AML) following intensive chemotherapy.
Authors: Pal Khushboo , Ali Zahra , Othus Megan , Russell Katie , Shaw Carole , Percival Mary-Elizabeth M. , Hendrie Paul , Walter Roland B. , Halpern Anna B. 
Published: June 2023

7031 Background: Febrile neutropenia (FN) is the most common reason for hospital readmission following chemotherapy for AML. Standard practice for FN in AML is hospitalization for rapid administration of IV antibiotics, thus FN is a major driver of healthcare resource utilization and cost. Whether this approach is justified in all situations is unknown. While FN risk models have been developed focusing on solid tumors, factors predicting uncomplicated courses of FN in AML, which may allow identification of patients suitable for outpatient management, have not been studied. We therefore examined whether baseline clinical characteristics could predict which AML patients with FN have a lower risk of progression to severe illness. Methods: We retrospectively reviewed medical records from 7/29/2014-12/24/2022 to identify adults with FN (fever >38.3C and white blood count <1000/µL). Included were patients with high-grade myeloid neoplasm (>10% blasts in blood/marrow) who received intensive chemotherapy (cytarabine dose >=100 2 /day) within 8 weeks. We collected baseline clinical and disease variables. Outcomes were: infections identified, hospital length of stay (LOS), intensive care unit (ICU) admission, and survival. A “low-risk [LR]” outcome was defined as a LOS <72hrs without ICU admission or inpatient death. Univariate and multivariable (MV) logistic regression models were used to assess covariate associations with outcomes. Results: We identified 350 FN admissions in 198 patients with a median age 62 (range: 21-87) yrs. 63% were newly diagnosed and 37% relapsed/refractory. 12% had prior transplant. Median duration of neutropenia prior to fever was 12 (1-287) days. 46% had transfusion <24 hours prior to fever. The median LOS was 5 (1-56) days. 9% of patients went to ICU and 6% died inpatient.Overall, 15% of admissions were classified as LR. 57% had an infection identified. The table shows factors in MV analysis that predicted an infection identified or high-risk (HR) admission. Conclusions: Only 15% of AML admissions for FN were LR. Factors that predict HR outcomes in standard FN models such the MASCC score—e.g. age, prior fungal infection —were not predictive of HR outcomes in AML. As a next step, we will compare our model to other published models used to predict poor outcomes after FN, which have not been developed or validated in AML. [Table: see text]
Comparison of next-generation sequencing and flow cytometry in detecting minimal residual disease in adult acute lymphoid leukemia: Evaluating clinical outcomes in a single-center study.
Authors: Nittur Vinay , Ashouri Karam , Adnani Blake , Hwang Jennifer , Chen Denaly , Schiff Kimberly , Savitala-Damerla Lakshmi , Ladha Abdullah , Woan Karrune , Tam Eric Leon , Chaudhary Preet , Yaghmour George 
Published: June 2023

7033 Background: Detection of measurable residual disease (MRD) is an important biomarker to direct treatment for adult patients with acute lymphoblastic leukemia (ALL). Currently, multiparameter flow cytometry (MFC) is standard of care and can detect residual leukemia cells in 1 out of 100,000 cells (1 × 10−5). Routine use of next-generation sequencing (NGS) assays with higher levels of sensitivity may improve disease-free survival and overall survival in adult ALL patients. The clonoSEQ MRD assay (Adaptive Biotechnologies Corporation, USA) can detect MRD at a sensitivity of 1 × 10−6 . In this study, we compare the detection of MRD by clonoSEQ assay and MFC in adult ALL patients at a single institution. Methods: We performed a retrospective study evaluating 92 adult patients with B- or T-ALL admitted to Norris Comprehensive Cancer Center between 2014 and 2022. Patients were excluded if they did not achieve complete remission (N=9) or if they presented with prior relapse (N=27). Median time to first complete remission (CR1) was 2.38 months. Among our cohort (N=56 patients), all patients underwent pre-treatment bone marrow sampling which was used for Clonoseq assay. 52 patients had contemporaneous MFC which was used for comparative analysis. MRD on MFC was defined as residual leukemia cells at a sensitivity of 1 × 10−5. MRD on Clonoseq assay was evaluated at 1 × 10−6; residual cells under this limit were considered MRD−. Results: Demographics are summarized in the table. Median time to follow-up from MRD assessment was 18.0 months. 10 patients relapsed (17.9%), 3 patients died (5.4%), and 20 patients (35.7%) underwent allogeneic transplant during first remission. Among 52 patients analyzed by both MFC and NGS at CR, 26 (50%) were concordantly MRD− by NGS and NGF, 13 (25%) were discordantly MRD− by NGF but MRD+ by NGS, and 13 (25%) concordantly MRD+ by NGS and NGF. Residual cell levels between NGS and NGF were strongly correlated (R-Squared = 0.6744, p<0.001), however, MRD status was significantly different between NGS and NGF (p<0.001 using Fisher’s Exact Test). This difference was likely driven by disparities in the limits of detection between both methods. Conclusions: Assessment of MRD using the clonoSEQ assay over a standard MFC-based approach adds crucial prognostic information among adult ALL patients who achieved CR. [Table: see text]
Results from a phase (Ph) 1 clinical study of the all-oral regimen of CC-486 and venetoclax for acute myeloid leukemia (AML).
Authors: Amaya Maria , McMahon Christine , Gutman Jonathan Aaron , Stevens Brett , Sohalski Connor , Tobin Jennifer , Smith Clayton , Jordan Craig , Pollyea Daniel Aaron 
Published: June 2023

7034 Background: Venetoclax (Ven) with azacitidine (Aza) is the standard of care for newly diagnosed AML patients who are unfit for intensive induction chemotherapy. It is well known that this treatment also has activity in the relapsed and refractory (R/R) setting. However, this regimen requires seven consecutive daily SQ or IV doses of Aza each month. The relative inconvenience of this, and its negative impact on quality of life, may lead to its early discontinuation, possibly decreasing the overall efficacy of this regimen. An all-oral regimen may decrease infusion center visits, and potentially increase the efficacy of the regimen due to improved compliance. CC-486 is the oral formulation of Aza that is currently approved for post-induction chemotherapy maintenance in AML. Methods: This is a single center open label, Ph 1 study investigating CC-486 and Ven in R/R AML patients. In the dose escalation phase, subjects received CC-486 at one of two cohorts (200 mg PO days 1-14 and 300 mg PO days 1-14). Ven was given at the 400 mg/day PO regimen, for 28 days, after an initial intra-patient dose escalation per the standard of care. Using a 3+3 study design for the two cohorts, we aimed to determine the maximum tolerated dose (MTD) of CC-486 in combination with Ven. An expansion cohort is planned for 10 patients treated at the MTD. Results: As of February 1, 2023, 8 patients have been accrued. The average age at the time of enrollment was 64, and median prior treatment regimens was 1 (range 1-3). Four patients had received Ven in prior treatments. In cohort 1, there were no DLT events. There have been no DLT events in 5/6 patients enrolled in cohort 2. The most common hematologic toxicities were Gr 3-4 neutropenia (n = 7, 88%), Gr 3-4 anemia (n = 6, 75%), and Gr 3-4 thrombocytopenia (n = 4, 50%). The most common non-hematologic toxicities were Gr 1-2 nausea (n = 4, 50%), Gr 1-2 fatigue (n = 2, 25%), and Gr 1-2 diarrhea (n = 2, 25%). Best responses were complete remission (CR) (n = 2, 25%), partial remission (PR) (n = 1, 13%), and stable disease (SD) (n = 2, 25%). Three patients proceeded to an allogeneic stem cell transplant. Conclusions: CC-486 and Ven is an all-oral regimen being investigated for the treatment of R/R AML. Our Ph 1 dose escalation thus far has demonstrated a favorable safety profile for this regimen. Full Ph 1 findings and the MTD will be presented at the meeting. Responses have been seen in both dose cohorts, and patients have been bridged to hematopoietic stem cell transplant. Clinical trial information: NCT05287568 . [Table: see text]
Clinical and molecular characteristics of patients with AML with an exceptional response to ivosidenib.
Authors: Watts Justin M. , Patel Prapti Arvind , Choe Sung , Bai Xiaofei , Marchione Dylan M. , Stein Eytan M. 
Published: June 2023

7036 Background: Ivosidenib (IVO) twas approved based on a CR/CRh rate of 31.8% in IDH1 mutant (IDH1m) R/R AML; median duration of CR/CRh (DOR) was 8.2 months (mo). The purpose of this study is to elucidate the clinical and molecular characteristics of exceptional responders to single agent IVO. Methods: We analyzed all patients (pts) with IDH1m R/R AML who received IVO 500mg QD on the phase 1 dose escalation/expansion study and had a DOR of >12 mo. Results: Of 179 pts who received IVO 500 mg QD, 57 (31.8%) achieved a CR/CRh. Of these, 20 (35.1%) had a DOR >12 mo. After excluding 7 pts who went to HSCT, 13 (22.8% of responders, 7.3% of cohort) had DOR >12 mo (exceptional response) and 8 (14% of responders, 4.5% of cohort) had DOR >24 mo. The 13 exceptional responders all achieved CR as best response, and median DOR was 42.6 mo. Median OS was not reached; estimated OS at 48 mo was 67.1%. Median EFS was 44.4 mo. Reasons for discontinuing treatment included relapse (n=4), adverse event unrelated to IVO (n=3), and patient (pt) decision (n=3). Three pts remain on treatment. All pts who relapsed had DOR between 1-2 years; none of the 8 pts with DOR >2 years relapsed. Baseline characteristics are in the table. The most common co-mutations were DNMT3A, ASXL1, SRSF2, and JAK2 (3 each, 23%). Five pts (39%) had a splicing factor mutation. No pts had FLT3 or RTK pathway mutations other than JAK2. Only 1 pt with NPM1 had an exceptional response, and 1 pt had TP53 (VAF 3.6%). Six pts (46%) had an abnormal karyotype, 6 normal (46%), and 1 missing (8%). Most pts had intermediate-risk cytogenetics (10 pts, 77%), 2 poor-risk, and 1 missing. The median IDH1 VAF was 25% (range 10-50%). The median number of co-mutations was 1 (range 0-6). Having 0-1 co-mutations was associated with a longer response. Eleven pts (85%) had an IDH1 R132C mutation; 1 each (7.7%) had R132H and R132L mutations. Mutation clearance of IDH1 was noted in 8 pts (61.5%). Conclusions: A subset of pts with IDH1m R/R AML have prolonged CR on single agent IVO without HSCT (22.8% of CR/CRh responders) and no pts in CR for >2 years (14% of CR/CRh responders) relapsed. A low mutational burden, lack of RTK pathway mutations and canonical AML drivers, and co-occurrence of mutations associated with clonal hematopoiesis appear to be associated with exceptional response. Clinical trial information: NCT02074839 . [Table: see text]
Association of intensive chemotherapy with the rate of pathogenic driver mutation clearance in acute myeloid leukemia.
Authors: Maini Ruby , Olet Susan , Hillis Emma , Saxena Raina , Haupt Carl , Philon Ernest , Davis Carter Thomas 
Published: June 2023

7040 Background: Identification of pathogenic molecular mutations (PMM) as drivers in the development of acute myeloid leukemia (AML) and in initial prognostic assessment has become clinical practice. Persistence of PMM in a morphologic leukemia free state is correlated with high risk of relapse and poor prognosis. Therapy for induction of remission and elimination of all markers of residual disease remains controversial, especially with the addition of venetoclax to hypomethylating agents (HMA). Here we compare the rates of PMM clearance between intensive chemotherapy (IC) and less intensive chemotherapy (LIC) regimens. Secondary, we assessed differences in ethnicity between white and black patients (pts). Methods: Retrospective study from a leukemia treatment center in Louisiana. De-identified pt records from 2018-2022 assessed for demographics: race, age, sex and diagnosis: AML, ELN 2017 staging, and mortality by IC vs. LIC regimen. IC included anthracycline and cytarabine containing regimens. LIC included HMA, with or without venetoclax. Chi-Squared analysis preformed, threshold for significance at p < 0.05. Results: 408 pts with non-M3 AML who underwent treatment, 180(44.1%) were female, 91(22.3%) were black, 303(74.3%) were white, 273(66.9%) received IC while 135(33.1%) received LIC. NGS found a total of 280 pre-treatment PMM. Among 217 pts who received treatment, the rate of mutation clearance with IC was 55.2%, compared with 50.8% LIC(p = 0.55). Stratifying by race, black pts had a twofold mutation clearance compared to white pts OR = 1.76, 95% CL (0.91 – 3.44). Similar proportions of pts received LIC vs IC among both white (74.1% vs 74.4%) and black (22.2% vs 22.3). There was no statistically significant difference for overall survival on chemotherapy regimen intensity (p = 0.1991), race (p = 0.2736), or gender (p = 0.6912). Conclusions: In our study, PMM clearance was similar between IC and LIC inductions. Although these findings are from a single center, the ability to clear driver mutations at a similar rate to IC may offer a significant advantage of LIC with venetoclax. Mutation clearance is often used as a surrogate marker for residual disease, it may be reasonably inferred that these regimens serve as suitable induction regimens for pts who may be considered for allogeneic stem cell transplantation. Blacks make up a greater proportion of the population in Louisiana (~33%) as compared to the national average (~13%). Often underrepresented in prospective clinical trials, blacks made up 22.7% of subjects providing increased insight to clinical responses. No difference in mortality based on race and a trend toward greater mutational clearance in blacks. Emphasizing the importance of standardizing care in treatment centers and the need for greater representation in prospective clinical trials to understand better how differences in race may impact treatment outcomes.
Capped F10, a novel DNA directed fluoropyrimidine, in TP53 mutated acute myeloid leukemia (AML).
Authors: Pardee Timothy S. , Okechukwu Charles , Pladna Kristin , Gmeiner William 
Published: June 2023

7046 Background: Acute myeloid leukemia (AML) is an aggressive malignancy characterized by resistance to treatment and poor outcomes. One of the most devastating mutations in AML involves loss of the tumor suppressor TP53. AML harboring this loss carries a dismal prognosis and there is a clear need for new approaches. Methods: To identify new therapeutics, a TP53 null and WT isogenic cell line pair was generated using CRISPR/CAS9 using a murine AML cell line. Clonal isolates were obtained and loss of detectable TP53 was confirmed by Western Blotting. A high throughput screen of currently FDA approved anticancer agents was performed. Results: When agents were ranked by equal cytotoxicity against TP53 null and WT AML cells 20% (6/30) of the top 30 agents targeted the folate/thymidylate synthase axis. This suggests that thymidylate synthase (TS) is a vulnerability in TP53 null AML cells. To confirm TS as a target in TP53 null AML an additional murine AML TP53 null/WT cell line pair was generated using CRISPR/CAS9. When these cell lines were treated with doxorubicin the TP53 null cells were significantly more resistant (p≤0.001 at 10nM). Capped F10 (CF10) is a second generation fluoropyrimidine oligonucleotide that has been shown to be a highly potent inhibitor of TS. In contrast to doxorubicin, CF10 treatment resulted in significant cell death when dosed in the low picomolar range with minimal differences between the null and WT cell lines (p = 0.31 at 50pM). To extend this result TP53 WT or null cells were injected into syngeneic recipients and upon engraftment mice were treated with CF10 at 300mg/kg twice weekly. CF10 provided a significant survival benefit in the TP53 null but not WT injected mice consistent with CF10 having activity against TP53 null AML (p = 0.035 vs 0.13). To confirm a TP53 independent mechanism, competition assays were performed with CAS9 expressing AML cells partially infected with a vector expressing an sgRNA targeting TP53 and a GFP reporter. When the mixed population was treated with the IC90 concentration of 5-fluorouracil there was a highly significant increase in GFP+ cells indicating a TP53 mediated cell death (p = < 0.001). In contrast when cells were treated with the IC90 concentration of CF10 there was a non-significant increase in GFP+ population (p = 0.074) consistent with a mainly TP53 independent mechanism. Fluoropyrimidine based therapy can be myelosuppressive especially in patients with low dihydropyrimidine dehydrogenase (DPD) activity. To assess the tolerability of CF10, healthy WAG/RAJ rats were treated with the DPD inhibitor ethynyl uracil at 2mg/kg alone or in combination with either 141 mg/kg CF10 or the molar equivalent of 50 mg/kg 5-flurouracil (5-FU) and weight determined. In contrast to 5-FU, CF10 treated animals did not have a significant change in weight compared to controls. Conclusions: Taken together these data suggest that CF10 is a promising new agent for TP53 null AML.
Effect of disease status prior to T-cell depleted allogeneic stem cell transplantation on relapse-free and overall survival in patients with adverse-risk acute myeloid leukemia (AML).
Authors: Rojek Alexandra Ewa , Mortel Mylove , Artz Andrew S. , Larson Richard A. , Liu Hongtao , Nawas Mariam , Odenike Olatoyosi , Stock Wendy , Bishop Michael Russell , Kosuri Satyajit 
Published: June 2023

7049 Background: Patients (pts) with adverse risk AML experience poor long term disease control. Some of these pts can be rescued with allogeneic stem cell transplantation (SCT). Adverse risk was defined by high risk cytogenetic and molecular markers (2017 European Leukemia Network criteria) and by disease status prior to SCT. We investigated outcomes of pts receiving in vivo T-cell depleted allogeneic SCT (TCD-SCT) at our center. Methods: We retrospectively analyzed 200 adverse-risk AML pts who received TCD-SCT from 2002-19. Pts were categorized into groups: untreated first relapse at SCT, primary induction failure with active disease at SCT, resistant to first induction but achieving morphologic complete remission (CR) by SCT, and induction sensitive CR with high-risk disease by ELN criteria. Outcomes were evaluated by 1-year (yr) and 3-yr relapse-free survival (RFS), overall survival (OS), and non-relapse mortality (NRM), and compared with log-rank tests of significance. Results: Baseline pt characteristics included a median age of 54 years (IQR, 44-61) with 62 (31%) pts older than 60, and 81 (41%) with HCT-CI score 3 or greater. All pts underwent in vivo TCD with alemtuzumab or ATG; 153 (77%) received reduced-intensity conditioning; 142 (71%) had 8/8 or 7/8 matched donors. Fourteen (7%) pts developed grade III-IV acute graft versus host disease (GVHD), and 25 (13%) developed chronic GVHD. With a median follow up of 14.3 months, cumulative incidence of relapse was 59% and NRM was 27%. Outcomes are summarized in the table. There was a statistically significant difference between categorized groups by RFS (p<0.01) and OS (p<0.01). Conclusions: We conclude that among adverse-risk AML pts, those in CR at time of TCD-SCT have superior survival outcomes to those with active disease. For those in CR at TCD-SCT, prior resistance to frontline induction was associated with inferior survival, suggesting that AML biology, treatment sensitivity, and remission status are important factors for TCD-SCT outcomes. The inferior outcomes observed for those with primary refractory disease suggest that while TCD-SCT can be effective with acceptable NRM, more work is needed to identify which pts can benefit from future transplant strategies. Better post-SCT therapy is needed to prevent relapses. [Table: see text]
Myeloablative fractionated busulfan-based conditioning regimen in patients with AML and MDS: Results of a randomized clinical trial comparing 2 fractionation schedules.
Authors: Popat Uday R. , Lontos Konstantinos , Bassett Roland L. , Alousi Amin Majid , Alatrash Gheath , Bashir Qaiser , Hosing Chitra M. , Im Jin Seon , Kebriaei Partow , Marin David , Mehta Rohtesh S. , Nieto Yago , Oran Betul , Olson Amanda Leigh , Qazilbash Muzaffar H. , Ramdial Jeremy L , Srour Samer Ali , Shpall Elizabeth J. , Champlin Richard E. , Andersson Borje S 
Published: June 2023

7051 Background: Hematopoietic stem cell transplantation (HSCT) cures leukemias, but comes at a cost of higher toxicity and non-relapse mortality (NRM). We previously showed that fractionating the busulfan (Bu) dose and starting it on day -13 instead of day -6, leads to lower toxicity and permits delivery of a myeloablative regimen, even to older patients. We designed a single institution randomized trial to validate the concept of fractionation and to test the hypothesis that further fractionation by starting chemotherapy on day -20 further reduces toxicity and lowers NRM without increasing relapse risk. Methods: Patients with AML or MDS, 18 to 70 years old, with a matched related or unrelated donor were eligible if they had adequate organ function. Patients were randomized to one of two arms: The shorter arm consisted of outpatient Bu 80mg/m2 on days -13 and -12, while the longer arm consisted of outpatient Bu 80mg/m2 on days -20 and -13. The rest of the regimen and GVHD prophylaxis were similar in both arms: On days -6 to -3, fludarabine 10mg/m2, cladribine 10mg/m2 and Bu dosed to achieve total Bu exposure of 20,000 ± 12% µMol-min for the whole course, including outpatient doses. Additionally, the last 33 patients received venetoclax from days -22 to -3 in both arms. The GVHD prophylaxis was tacrolimus and mini-methotrexate in the first 29 patients and tacrolimus and cyclophosphamide in the remainder. The only difference between the two arms was if busulfan was started on day -20 or not. Results: A total of 116 patients were randomized, 59 to the shorter day -13 arm and 57 to the longer day -20 arm. Median age was 59 in the day -13 arm and 57 in the -20 arm. 70.7% had AML. 41.4% were transplanted in first complete remission. The characteristics of the two groups were well-balanced. The median follow-up in the 67 surviving patients was 48.9 months. More patients in the day -13 group experienced grade ≥3 toxicities than in the day -20 group (93.2% vs. 73.7%, p = 0.005). The difference in toxicity led to a reduction of the 3-year NRM (19% vs. 7%, p = 0.067). There was no difference in relapse rate (p = 0.99) (Table). Conclusions: Further fractionating busulfan and moving just one dose of busulfan 1 week earlier reduces toxicities and may lower NRM, without increasing relapse rate. Clinical trial information: NCT02250937 . [Table: see text]