bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II study of hyper-CVAD with blinatumomab (blina) and inotuzumab ozogamicin (INO) for newly diagnosed Philadelphia chromosome (Ph)–negative B-cell acute lymphoblastic leukemia (ALL).
Authors: Short Nicholas James , Jabbour Elias , Jain Nitin , Haddad Fadi , Macaron Walid , Yilmaz Musa , Ferrajoli Alessandra , Kadia Tapan M. , Alvarado Valero Yesid , Maiti Abhishek , Nasr Lewis Fady , Zoghbi Marianne , Nasnas Cedric Christophe , Garris Rebecca , Zhao Min , Konopleva Marina , Ravandi Farhad , Kantarjian Hagop M. 
Published: June 2023

e19017 Background: Consolidation with blina, regardless of measurable residual disease (MRD) status, improves overall survival (OS) in adults with newly diagnosed B-cell ALL. The addition of INO may deepen responses and further improve outcomes. Methods: Patients (pts) 14-59 years of age with newly diagnosed Ph-negative pre-B-cell ALL, including pts who had received no more than 1 prior cycle of chemotherapy, were eligible. Pts received hyper-CVAD alternating with high-dose MTX/Ara-C for up to 4 cycles, followed by 4 cycles of Blina at standard doses. Pts with CD20+ disease received 8 doses of an anti-CD20 antibody. Eight doses of prophylactic IT chemotherapy were given. Maintenance was with alternating blocks of POMP (maintenance cycles 1-3, 5-7, 9-11, and 13-15) and Blina (maintenance cycles 4, 8, and 12). Beginning with pt #39, INO at a dose of 0.3 mg/m2 on day 1 and 8 was added to the 2 cycles of MTX/Ara-C and to 2 cycles of Blina consolidation (4 total cycles with INO). Results: To date, 69 pts have been treated (38 without INO and 31 with INO). Baseline characteristics are summarized in the table. Among 53 pts with active disease at study entry, 100% achieved CR. MRD negativity by flow was achieved in 56/59 evaluable pts (95%). Of the 3 pts who did not achieve MRD negativity, 2 were later found to have a NUP214: ABL1 fusion, and 1 had KMT2A rearrangement. The median follow-up of the entire cohort is 26 months. Overall, 8 pts (12%) relapsed while on study, 22 (32%) underwent stem cell transplant (SCT) in first remission (2 of whom relapsed post-SCT), 2 (3%) died in CR, and 37 (54%) remain in continuous remission without SCT. For the entire cohort, the estimated 3-year OS was 87% and the 3-year continuous remission duration was 83%. With a median follow-up in the INO cohort of 15 months, 3 pts (10%) have relapsed, all with CNS-only relapses, and none has died. The 15-month OS in the cohorts with and without INO were 100% and 87%, respectively (P=0.06). One pt discontinued Blina due to recurrent grade 2 neurotoxicity. No pts have discontinued INO due to toxicity and no cases of SOS/VOD have been observed. Conclusions: In pts with newly diagnosed Ph-negative B-cell ALL receiving hyper-CVAD with sequential Blina, OS may be improved with the addition of INO. Clinical trial information: NCT02877303 . [Table: see text]
Identification of a novel NPM1 mutation in acute myeloid leukemia.
Authors: Yao Yiyi , Lin Xiangjie , Wang Chen , Gu Ying , Zhu Hong-Hu , Jin Jie , Zhu Yinghui , Wang Huafeng 
Published: June 2023

e19019 Background: Nucleophosmin (NPM1) is predominant nucleolar localization. NPM1-mutant acute myeloid leukemia (AML) account for 25-35% of adult AML patients, has been defined as a distinct AML entity in the 2022 WHO classification. The majority of NPM1 mutations reported affect exon 12 (classical type A mutation), account for 75-80% of adult NPM1-mutated AML cases, which generate an extra nuclear export signal (NES) in the C-terminal leading to aberrant cytoplasmic localization. Similar aberrant cytoplasmic translocation has also been reported in NPM1 mutants that identified in exons 9 and 11. Identification of novel non-type A mutants is paramount for diagnosis, risk stratification, and prognosis for targeted population. Methods: Somatic mutation analysis is performed on 566 AML patients using next-generation sequencing (NGS). Immunofluorescence and immunohistochemistry were used to identify the cytological localization of mutant NPM1. HEK-293T cells transiently transfected with plasmids for ectopic expression of the GFP-mutated NPM1 fusion proteins were treated with the specific Crm1/XPO1 inhibitor leptomycin B and to evaluate the NES dependence of their subcellular localization. Results: We identified one AML patient with NPM1 mutant located on exon 5. This patient was a 59-year-old female with de novo AML, with an 18-nucletide in-frame insertion at position 405 (c.405_406insGCCCTGGAACTGGGGAAC, named MutSong) in the middle of exon 5 [variant allele fraction (VAF), 11.9%]. It generated a new NPM1 mutant protein (p.135insALELGN), and containing a leucine-rich NES. Notably, different with all NPM1 mutant in other exons reported so far, our exon 5 mutant retained the functional c-terminal but insert one leucine-rich NES, similar finding was recently reported in NPM1 mutants that identified in exon 5 but on different position. This NPM1 mutant in exon 5 resulted in cytoplasmic localization both by confocal and immunohistochemistry in AML patient sample. HEK-293T overexpressing the new GFP-NPM1 exon 5 fusion protein indicated the aberrant localization in the cytoplasm and partially in nucleoli. Moreover, NES-dependent cytoplasmic localization was inhibited by exportin-1 inhibitor leptomycin B, indicated that the novel NES generated by exon 5 mutant is responsible for cytoplasmic localization. This patient carried WT1, IKZF1, JAK2, and NUP98 mutations, and was intravenously treated with daunorubicin plus cytarabine for induction followed by 3 cycles of intermediate-dose cytarabine as consolidation. Then the patient received allogeneic hematopoietic stem cell transplantation (allo-HSCT). Unfortunately, the patient died of severe pulmonary infection and viral encephalitis 14 months after the initial remission, 7 months after allo-HSCT. Conclusions: Our finding of the novel NPM1 mutation in exon 5 supported that beside exon 12, exon 5 mutant is another NPM1 “born to be exported” mutant critical for leukemogenesis.
A retrospective analysis of the outcomes among hospitalized patients with myeloid leukemia undergoing leukapheresis: Insight from the National Inpatient Sample.
Authors: Arya Yajur , Syal Arshi , Casipit Bruce Adrian , Dourado Claudia 
Published: June 2023

e19021 Background: Hyperleukocytosis often complicates the clinical picture in hematological malignancies. Historically, leukapheresis has been used to reduce the quantity of circulating white cells to reduce leukostasis, which can predispose to hypercoagulability and thromboembolism. Literature shows that leukapheresis does not offer any long-term survival benefits to patients, with some evidence of even worse outcomes at 6 months. Methods: We utilized the 2018-2020 National Inpatient Sample (NIS) Database in conducting a retrospective cohort study. We identified hospitalized patients who have myeloid leukemia undergoing leukapheresis using appropriate ICD-10 CM codes. We stratified patients based on whether they underwent leukapheresis or not. A survey multivariable logistic and linear regression analysis was used to calculate adjusted odds ratios (ORs) for the primary and secondary outcomes. A p value of < 0.05 was considered statistically significant. The aim of this study is to investigate the outcomes among hospitalized patients with myeloid leukemia undergoing leukapheresis looking primarily at the in-hospital mortality, hospital length of stay (LOS) as well as total hospital charges. Results: We identified a total of 27,000 hospitalized patients with acute and chronic myeloid leukemia, of which 0.5% (135/27,000) underwent leukapheresis. The overall in-hospital mortality among those with myeloid leukemia was 9.86% (2662/27,000). Among those who underwent leukapheresis, the overall in-hospital mortality rate was significantly higher at 22.22% (30/135) (p = 0.05). Utilizing a stepwise survey multivariable logistic regression model that adjusted for patient and hospital level confounders, the use of leukapheresis among hospitalized myeloid leukemia patients did not significantly decrease the risk for in-hospital mortality (adjusted OR 2.54 95% confidence interval [CI], 0.84-7.73; p = 0.10), hospital LOS (adjusted OR 2.76; 95% confidence interval [CI], -2.11-7.62; p = 0.27) or total hospital charges (p = 0.19). Conclusions: Our analysis showed that among hospitalized patients with myeloid leukemia, leukapheresis did not significantly decrease the risk for in-hospital mortality, hospital LOS as well as total hospital charges. Caution should be exercised in interpreting the higher rate of in-hospital mortality among those who underwent leukapheresis as the higher mortality rate can be due to small sample size, or the fact that patients who require leukapheresis have uncontrolled and more advanced disease. Hyperleukocytosis in these patients may indicate a worse prognosis. A prospective study with a larger sample size to test for possible confounders is warranted in order to further delineate these associations.
Gilteritinib plus azacitidine and venetoclax for FLT3-ITD mutated relapsed/refractory acute myeloid leukemia.
Authors: Chen Nianci , Zhou Yile , Tong Hongyan , Wei Juying , Lou YinJun , Zhou De , Fan Cuihua , Huang Li , Mao Liping , Li Chenying , Wang Huafeng , Jin Jie 
Published: June 2023

e19024 Background: Gilteritinib is a second-generation FLT3 tyrosine kinase inhibitor that has been shown significantly increase the survival of relapsed/refractory (r/r) FLT3-mutated acute myeloid leukemia (AML) patients. We investigated the clinical benefit of gilteritinib plus azacitidine and venetoclax in the treatment of r/r FLT3-ITD mutated AML in the real word. Methods: Gilteritinib was given by oral administration at a dose of 80 or 120mg/d for each cycle. Azacitidine was intravenously administrated at a dose of 75 mg/m2/day d1-7. Venetoclax was given by oral administration at a dose of 100mg/d then ramp-up at 400mg/d, some patients were administrated at a dose of 400mg/d due to prior exposure. The composite complete response (CRc) rate (complete response [CR] and CR with incomplete blood count recovery [CRi]) were assessed, and then the overall survival (OS), event-free survival (EFS), relapse-free survival (RFS) was evaluated. Results: We retrospectively analyzed the outcomes of gilteritinib plus azacitidine and venetoclax in 14 r/r FLT3-ITD mutated AML patients. The CRc rate of the triple therapy was 57.1% (CR, n = 5, 35.7%; CRi, n = 3, 21.4%), in which, all patients achieved minimal residual disease (MRD) negative measured by multi-color flow cytometry. At a median follow-up of 136.5 days, the median OS was 216.0 days, the median EFS was 97.0 days, and the median RFS were 184 days. The common grade 3/4 hematologic adverse events included neutropenia (n = 14, 100.0%), anemia (n = 12, 85.7%), and thrombocytopenia (n = 11, 78.6%). The common grade 3/4 non-hematologic adverse events were pulmonary infection (n = 5, 35.7%), other adverse events were relatively less and milder. Conclusions: In conclusion, the current data demonstrated promising response of the triple therapy in r/r FLT3-ITD mutated AML patients, and the regimen represented a potential option as a bridge to transplant. Prospective studies are warranted to further define the risk or benefit for more patients.
Biomarker subpanel customization for different use cases in acute myeloid leukemia research.
Authors: Li Wenjun , Liang Shaoheng , Roberts Hannah , Dao Long , Wu Yalei , Zhang David , Pinto Alessandro 
Published: June 2023

e19026 Background: Treatment guidance and decision making according to modified RECIST guidelines often depends on characterization of these biomarkers in patients with cancer. Although panels with larger breadths of coverage are useful for initial detection of these biomarkers for evaluation of disease burden and prognosis, their cost-effectiveness decreases as treatment and disease progress; smaller subpanels may yield equally valuable information into disease progress and guide treatment in a more cost-effective manner, potentially leading to more datapoints in decision making in comparison to larger panels. Methods: QBDA is an NGS enrichment research technology that allows the enrichment of rare variants, reducing the sequencing cost while maximizing the sensitivity. Here we introduce a new capability of our platform that allows tailoring sequencing panel breath to the disease stage needs. We demonstrate the ability to generate a 384-plex NGS subpanel from a 2400-plex acute myeloid-leukemia (AML) measurable residual disease (MRD) targeting research panel. Both panels were tested on both wild-type and 0.1% variant allele frequency (VAF) AML MRD contrived samples. Results: Without any optimization of the subpanel itself, the subpanel exhibited similar or better performance to the main panel. The main panel had a ~80% uniformity of coverage whereas the subpanel had a uniformity of coverage exceeding 75%. The subpanel covers fewer genes of interest and requires fewer overall reads. Both panels had a bulk LoD of below 0.1% VAF. Conclusions: This data represents proof-of-concept for the design of small custom panels from large-scale multiplex panels for different use cases, potentially increasing cost-effectiveness.
Sequential salvage chemotherapy and lintuzumab-Ac225 results in deep responses and prolonged survival in adverse risk relapsed/refractory AML and in AML patients that received prior venetoclax therapy.
Authors: Abedin Sameem M. , Guru Murthy Guru Subramanian , Desai Avinash , Chen Mary , Atallah Ehab L. 
Published: June 2023

e19030 Background: Lintuzumab-Ac225 is a humanized CD33 antibody conjugated to an alpha emitting isotope, Ac225, delivering high energy radiation to CD33 expressing AML blasts. Preclinical studies indicate Lintuzumab-Ac225 also depletes the anti-apoptotic protein MCL-1, which is a known resistance factor in BCL2-inhibitor (venetoclax (Ven)) exposed patients (pts). We performed a Phase I study where Lintuzumab-Ac225 was administered after salvage chemotherapy, and this study demonstrated safety and encouraging response rates in R/R AML. Herein, we report results of high-risk patients who enrolled to this study. Methods: R/R AML pts deemed fit, and with CD33 expression on >25% of blasts were enrolled onto a Phase I study, Lintuzumab-Ac225 in Combination with Cladribine + Cytarabine + Filgrastim + Mitoxantrone (CLAG-M). Induction consisted of G-CSF, 300mcg/d on D1-6, cladribine 5mg/m2 on D2-6, cytarabine 2g/m2 on D2-6, and mitoxantrone 10mg/m2 on D2-4. Lintuzumab-Ac225 was administered once on D8 ±1 day. The trial enrolled to 4 cohorts, with Lintuzumab-Ac225 at doses ranging from 0.25 uCi/kg to 1.0 uCi/kg. We defined high-risk pts as those who met ELN 2019 criteria for adverse risk disease, or pts who received a Ven combination prior to trial enrollment. Response is descriptively reported, and KM estimator was used to report overall survival (OS). Results: 19 pts on trial met high-risk criteria. Of these, 16 pts had ELN adverse risk disease, a TP53 mutation was detected in 75% (n=12) of pts. Median age was 65 yrs, pts received a median 2 lines of prior therapy, including prior allo-HCT in 58% (n=11), and prior Ven combination in 68% (n=13) of pts. In high-risk pts, 42% (n=8) of pts achieved CRc (CR+CRi), 16% (n=3) achieved MLFS, for an overall response rate (ORR) of 58%. Among evaluable pts achieving CRc, 71% achieved flow MRD negativity. Median OS was 7.4 months. Table reports results in select subgroups. Prior to treatment initiation, 7 pts were deemed eligible for first HCT. 4 (57%) were successfully able to bridge to HCT. Median survival among transplanted pts was 28 months. Post-HCT, one pt died due to GVHD, one due to relapse. Conclusions: CLAG-M in combination with Lintuzumab-Ac225 yielded significantly better clinical outcomes in high-risk populations, particularly in pts previously treated with Ven combinations (median OS 13.8 mo.) and in pts with TP53 mutations (median OS 7.3 mo.), for which recent studies have reported a survival of 4 months or less. The results support further advance in late-stage clinical development of Lintuzumab-Ac225 in combination with CLAG-M in R/R AML, especially in high-risk pts. Clinical trial information: NCT03441048 . [Table: see text]
Survival outcomes of acute erythroid leukemia in the United States: A 20-year population-based study.
Authors: Gera Kriti , Martir Daniela , Xue Wei , Wingard John R. 
Published: June 2023

e19031 Background: Acute Erythroid Leukemia (AEL), also known as pure erythroid leukemia, is a rare subtype of Acute Myeloid Leukemia (AML) characterized by proliferation of malignant erythroid precursors. It can occur at any age and portends aggressive course with dismal outcomes. Treatment consists of high-intensity chemotherapy and allogeneic hematopoietic stem cell transplant. Outcome data at a population level is scarce. Methods: We performed a retrospective analysis of the Surveillance Epidemiology and End Results (SEER) database, a U.S. population-based registry maintained by National Cancer Institute. All cases with histologically confirmed diagnosis of Acute erythroid leukemia during the period of 2000-2019 were included in the study. Survival analysis was performed using Kaplan-Meier method. The survival between groups was compared using log-rank test. Results: A total of 968 patients were included in the study. The median age was 68 years (range 0-95). 62% of patients were males. 11% patients were Hispanic and 89% were non-Hispanic (72% white and 7% black). 62.5% (n=605) patients were treated with chemotherapy. Median Overall Survival (OS) for patients with age <18 years (n=50) was 69 months with 1-year OS of 77%. In contrast, median OS for adults with age >18 years (n=918) was only 5 months with 1-year survival of 26.7%. Patients who received chemotherapy had significantly improved OS compared to patients who did not among both adults (Median OS 8 vs 1 months, p<0.0001) and children (Median OS 152 vs 2 months, p=0.004). There were no significant differences in OS based on sex, race, ethnicity and median household income. Median OS for adults diagnosed in 2000-04, 2005-09, 2010-14, 2015-19 was 4, 6, 6 and 3 months respectively with no significant difference in OS between these groups. Conclusions: AEL occurs in all age groups but is most common in elderly. Outcomes are poor with current chemotherapeutic agents, with no improvement in last two decades. This study stresses the urgent need for new investigational agents and treatment strategies. [Table: see text]
Busulfan versus treosulfan conditioning for acute myeloid leukemia and myelodysplastic syndrome: A systematic review and meta-analysis.
Authors: Rehman Mohammad Ebad Ur , Khan suheb Mahammed , Umar Haddaya , Farheen Naaz Fnu , Shah Zunairah , Khan Zarak , Cheema Huzaifa Ahmad , Basit Jawad , Fazal Faizan , Maqbool Shahzaib , Farhan Muhammed , Dhama Kuldeep , Akbar Usman Ali , Iftikhar Raheel , Iftikhar Ahmad , Anwer Faiz 
Published: June 2023

e19032 Background: Busulfan containing myeloablative conditioning regimens are widely used before allogeneic hematological stem cell transplantation (HSCT) in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Treosulfan-based conditioning regimens are a potential alternative with potent myelotoxic immunosuppressive characteristics and favorable extramedullary toxicity profile compared to busulfan. In order to determine the optimal conditioning regimen, we conducted a systematic review and meta-analysis to compare the efficacy and safety outcomes of busulfan and treosulfan based conditioning regimens in patients with AML/MDS. Methods: A retrospective systematic literature search was undertaken on PubMed, Cochrane, Embase and Clinicaltrials.gov, using MeSH terms and relevant keywords for AML, MDS, busulfan and treosulfan, to retrieve studies published prior to February 5, 2023. Efficacy outcomes were overall survival (OS), disease-free survival (DFS), and relapse. Safety outcomes included non-relapse mortality (NRM), acute (a) and chronic (c) graft-versus-host disease (GvHD). The random-effects model with the Mantel-Haenszel method was used to pool risk ratios (RR) for dichotomous variables in Revman version 5.4. Results: The initial search retrieved 1094 articles. After removal of duplicates, reviews and non-relevant articles, data was extracted from seven different studies. Busulfan and treosulfan were employed in 4706 and 1979 patients, respectively. The median age ranged from 55 to 61 years, and the median follow-up ranged from 14 to 58 months. The treosulfan and busulfan doses administered ranged from 10-42 g/m2 and 0.8-12.8 mg/kg, respectively. Treosulfan was superior to busulfan in terms of OS (RR 1.39, 95% CI 1.15-1.68, p-value 0.0007, I2 58%), DFS (RR 1.39, 95% CI 1.10-1.75, p-value 0.006, I2 60%) and NRM (RR 0.95, 95% CI 0.90-1.00, p-value 0.05, I2 67%). The two regimens were comparable in terms of relapse (RR 0.96, 95% CI 0.89-1.04, p-value 0.33, I2 76%), aGvHD (RR 1.00, 95% CI 0.65-1.54, p-value 1.00, I2 94%) and cGvHD (RR 1.00, 95% CI 0.95-1.05, p-value 0.92, I2 0%). Conclusions: Treosulfan was superior in terms of OS, EFS and NRM, whereas both regimens were comparable in terms of relapse, aGvHD and cGvHD. Treosulfan may be more favorable compared to busulfan as conditioning in AML/MDS. Large scale prospective studies are needed to confirm the most suitable option.