tbuckley/cabot-search huggingface dataset:
Mutation patterns and prognostic implications in acute myeloid leukemia with chromosomal 7 deletions.
Authors: Eitan Kugler, Enes Dasdemir, Bofei Wang, Alex Bataller, Courtney Denton Dinardo, Naval Guastad Daver, Musa Yilmaz, Nicholas James Short, Tapan M. Kadia, Koji Sasaki, Alexandre Bazinet, Sherry Pierce, Patrick Kevin Reville, Farhad Ravandi-Kashani, Hussein Abbas
Journal: Journal of Clinical Oncology (2024)

6547 Background: Chromosomal 7 deletions (del7/7q) are the most common adverse cytogenetic event in acute myeloid leukemia and are associated with high rate of relapse. We analyzed gene mutation profiles in del7/7q AML patients who relapsed after initial remission to identify molecular patterns associated with clinical outcomes. Methods: Out of 351 newly diagnosed AML patients with del7/7q, 115 (32%) achieved complete remission after first-line treatment between 2012-2023. Of the 115 patients, 77 (67%) patients relapsed during the study follow-up. Kaplan-Meier and Cox regression were used to analyze survival outcomes. Next-generation sequencing was performed on a targeted panel of 81 genes for 59 patients who relapsed on bone marrow samples at diagnosis and relapse for paired analysis. Results: The median age of the 115 patients at diagnosis was 74 (41-93). Thirty-four patients (30%) received intensive treatment. With 30.8-month median follow-up, the median overall survival (OS) was 10.4 months, with improved survival in patients without TP53 mutation (13.04 vs. 8.6 months, p=0.005) or complex karyotype (12.4 vs. 8.6 months, p=0.03). The median duration of response for the 77 patients who relapsed was 5 months (2-7). Allo-HSCT significantly improved median OS (not reached vs. 8.5 months, P=6e-06), and was identified as the key variable impacting survival in multivariate analysis. TP53 was the most commonly mutated gene at diagnosis (67%) and relapse (71%). Mutations in CBLC and KDM6A were cleared after induction therapy, while BCOR and BCORL1 were commonly acquired at relapse (Table). At diagnosis, a lower co-mutation burden was observed in TP53 mutant patients as compared with wild type (average 1.84 vs. 3.65 respectively, p=0.0001). Patients with mutated TP53 and coexisting mutations in GATA2, NF1, BCORL1, or RUNX1 at diagnosis had shorter relapse free survival (RFS, 2 vs. 5 months, p=0.01) and OS (7.2 vs. 10.4 months, p=0.01) compared to patients with solely mutated TP53 (HR 2.2; 95% CI 1.2-4; P = 0.004). Allo-HSCT significantly improved the OS in patients with mutated TP53 (13 vs. 8 months, p=0.01). Conclusions: Mutated TP53 clones persist from diagnosis to relapse in patients with del7/7q AML. In patients with mutated TP53, co-occurring mutations in GATA2, NF1, BCORL1or RUNX1 at diagnosis were linked to a shorter RFS and indicate a particularly high-risk subgroup that require proceeding to allo-HSCT in CR1 without delay. [Table: see text]
Post-transplant cyclophosphamide-based graft-<i>versus-</i>host disease prophylaxis following mismatched unrelated donor peripheral blood stem cell (PBSC) transplantation.
Authors: Monzr M. Al Malki, Stephanie Bo-Subait, Brent Logan, Janelle Olson, Erin Leckrone, Juan Wu, Heather E. Stefanski, Jeffery J. Auletta, Stephen R. Spellman, Craig Malmberg, Brian C. Shaffer, Dipenkumar Modi, Farhad Khimani, Mahasweta Gooptu, Mehdi Hamadani, Larisa Broglie, Bronwen E. Shaw, Steven Michael Devine, Antonio Martin Jimenez Jimenez
Journal: Journal of Clinical Oncology (2024)

6503 Background: Our prior prospective multi-center clinical trial (15-MMUD; NCT02793544) estimated 79% overall survival (OS) at one year in adult patients with hematological malignancies undergoing reduced intensity conditioning (RIC), receiving bone marrow (BM) grafts from HLA-mismatched unrelated donors (MMUD), and post-transplant cyclophosphamide (PTCy)-based graft- versus-host disease (GVHD) prophylaxis (Shaw et al, J Clin Oncol 2021). We sought to determine whether OS in adults receiving mobilized PBSC from MMUD would be comparable. Methods: We conducted a prospective, multi-center Phase II study (ACCESS; NCT04904588) to assess the impact of PTCy-based GVHD prophylaxis on OS following MMUD transplantation in adults and children with advanced hematological malignancies. The study included three strata: two for adults based on conditioning regimen intensity [myeloablative (MAC) or RIC] using PBSC, and one pediatric cohort using MAC and BM. Eligible donors were matched at 4-7/8 HLA-loci (HLA -A, -B, -C, and -DRB1) and &lt; 35 years. The primary endpoint was OS at one year following transplantation. We report the results of a planned interim analysis of the first 70 adult patients enrolled on the RIC PBSC stratum. Results: Thirteen sites enrolled 70 patients with the following demographics: median age of 65 years (range 24-77); 50% male; diagnoses: AML (53%), MDS (26%), ALL (7%), other heme malignancies (14%); and patient race/ethnicity: non-Hispanic white (48%). Donor characteristics included: median age 25y (range 18-35); male (44%); and HLA match level: 7/8: 67%; 6/8: 27%; 5/8: 6%. Conditioning regimens included fludarabine (flu) and melphalan (63%), flu/busulfan (20%), other (17%). OS at one year post HCT was 79% (95% confidence interval (CI): 68-87%). Secondary endpoints are provided in the table. Conclusions: Encouraging OS was observed at one year following MMUD PBSC in patients receiving RIC and PTCy. Notably, half of enrolled patients were people of color. OS was similar to our prior study using BM grafts. Rates of GVHD and other complications appear comparable to those in HLA-matched donor recipients, suggesting MMUD HCT could expand access to a potentially life-saving therapy. Accrual to both adult strata of ACCESS is complete, with over 200 patients in follow-up. Accrual to the pediatric stratum continues. Clinical trial information: NCT04904588 . [Table: see text]
Impact of protein energy malnutrition on hospitalized patients with acute myeloid and lymphoid leukemia: A United States population-based cohort study.
Authors: Arshi Syal, Yajur Arya, Bruce Adrian Casipit, Elvis Obomanu, Gordon Heller, Claudia M. Dourado, John Charles Leighton
Journal: Journal of Clinical Oncology (2024)

6548 Background: Acute leukemia poses a significant burden to the society and the healthcare system. Advances in chemotherapeutics and hematopoietic stem cell transplantation (HSCT) have increased survival in these patients. Protein energy malnutrition (PEM) frequently complicates the clinical picture in patients with cancer, however data on the impact of PEM in patients with acute myeloid and lymphoid leukemia is limited. Methods: We utilized the 2020 National Inpatient Sample (NIS) Database in conducting this retrospective cohort study. We identified patients with acute leukemia (myeloid and lymphoid) and PEM using appropriate ICD-10 diagnostic codes. We stratified patients with acute leukemia based on the presence or absence of PEM. 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 &lt;0.05 was considered statistically significant. The aim of this study was to investigate the impact of PEM on in-hospital mortality, hospital length of stay (LOS), and total hospitalization charge among patients with acute leukemia. Results: We identified a total of 30995 hospitalized patients with acute leukemia, of which 13.06% (4050/30995) had comorbid PEM. The overall in-hospital mortality among patients with acute leukemia was 8.95% (2775/30995). Among those with co-morbid PEM, the mortality rate was significantly higher at 12.47% (505/4050, p&lt;0.001). Utilizing a stepwise survey multivariable logistic regression model that adjusted for patient and hospital level confounders, PEM was found to be an independent predictor of increased in-hospital mortality (adjusted OR 1.50; 95% (confidence interval [CI], 1.18 -1.91); p=0.001), longer LOS (coefficient 10.50; CI 8.59 -12.41; p&lt;0.001), and higher total hospitalization charge ($208,308; CI $147,516- $269,100; p&lt;0.001). Conclusions: Our analysis demonstrated that PEM was widely prevalent in hospitalized patients with acute leukemia and significantly worsened outcomes including increased in-hospital mortality, LOS, and cost of healthcare utilization. A proactive approach for prevention and early management of cancer associated malnutrition is required. Further prospective multicentric studies are needed to better describe these associations.
Outcomes of patients with bone marrow fibrosis in de novo and secondary acute myeloid leukemia.
Authors: Samuel Urrutia, Hagop M. Kantarjian, Farhad Ravandi-Kashani, Elias Jabbour, Rashmi Kanagal-Shamanna, Sanam Loghavi, Keyur P. Patel, Guillermo Montalban-Bravo, Nicholas James Short, Naval Guastad Daver, Gautam Borthakur, Courtney Denton Dinardo, Tapan M. Kadia, Lucia Masarova, Prithviraj Bose, Naveen Pemmaraju, Guillermo Garcia-Manero, Koji Sasaki
Journal: Journal of Clinical Oncology (2024)

6538 Background: The outcomes of patients with de novo acute myeloid leukemia (AML) with bone marrow fibrosis (MF) have not been systematically studied. Our objective was to define the prognosis of patients with AML and multiple degrees of bone marrow fibrosis, efficacy of therapy, and survival outcomes. Methods: We retrospectively evaluated 2302 patients diagnosed with AML at a single center from 2007 to 2023 and annotated clinicopathologic characteristics and outcomes. Results: We identified 492 (21%) with AML and MF. We found 344 (69.9%) had MF 0-1 and 148 (30.1%) had MF 2-3. Median age was 67 (IQR: 57-73). Fifty-five (11.1%) had a history of myeloproliferative neoplasm (MPN). Patients with MF 2-3 were associated with complex cytogenetics (39.2%), JAK2 mutations (25.7%), and lower incidence of IDH2(16.9%) or CEBPA(15.5%) mutations (Table). For patients with MF 0-1, median overall survival (mOS) was 14.2 months compared to 7.5 months for those with MF 2-3 (p&lt;0.005). Survival in patients with MPN history was 9.4 months compared to 12.4 months in patients with de novo AML. In a multivariate analysis, MF 2-3 (HR 2.00 95%CI 1.59-2.51), non-diploid cytogenetics (HR 1.29, 95%CI 1.33-1.69), and number of co-morbidities (HR 1.26 95%CI 1.10-1.43) were prognostic for shorter mOS. Sixty-four percent were treated with low-intensity chemotherapy (LIC), 36.1% with intensive chemotherapy (IC). Complete remission (CR)/CR with incomplete count recovery (CRi) rates were 63.5% for IC vs 37.9% for LIC (p=0.007). Four-week mortality after induction was 5.8% with IC, 8.4% with LIC (p = 0.809). In patients aged 60 and older, with MF 2-3, intensive therapy did not result in improved survival (6.5 months vs 7.0 months, p = 0.19). Conclusions: Patients with AML and MF 2-3 have worse outcomes irrespective of MPN history. For patients aged 60 and above, intensive chemotherapy does not result in improved survival. [Table: see text]
A phase II study of venetoclax (VEN) in combination with 10-day decitabine (DEC) in older/unfit pts with newly diagnosed (ND) or pts with relapsed/refractory (R/R) acute myeloid leukemia (AML), or high-risk myelodysplastic syndrome (HR-MDS).
Authors: Mahesh Swaminathan, Courtney Denton Dinardo, Abhishek Maiti, Naveen Pemmaraju, Maro Ohanian, Naval Guastad Daver, Guillermo Garcia-Manero, Ghayas C. Issa, Gautam Borthakur, Farhad Ravandi-Kashani, Guillermo Montalban-Bravo, Tapan M. Kadia, Yesid Alvarado Valero, Elias Jabbour, Nicholas James Short, William G. Wierda, Nitin Jain, Steven Mitchell Kornblau, Hagop M. Kantarjian, Marina Konopleva
Journal: Journal of Clinical Oncology (2024)

6549 Background: We report long-term results of phase 2 study of 10-day DEC and VEN (DEC10-VEN) in AML/HR-MDS. Methods: This single-institution study (NCT03404193) included intensive chemotherapy-ineligible pts &gt;60y with ND de novo AML or secondary AML (sAML), or R/R AML, or HR-MDS. Induction therapy: DAC 20 mg/m 2 IV x 10d + VEN days 1-28. VEN was stopped on day 21 if bone marrow blasts ≤5%. Consolidation included DEC IV x 5 days + VEN days 1-21, every 4-8 weeks as previously described (DiNardo et al. Lancet Haem. 2020). Primary endpoint was ORR. Secondary endpoints are duration of response, OS, RFS, and safety. Here, we report an update with 232 pts and results of HR-MDS/CMML cohort. Results: 232 pts were enrolled thus far (ND AML-86; sAML-49; R/R AML-76; HR-MDS/CMML-21). Median follow up is 39 mo (36-46 mo). Median age was 73y in ND AML and 64y in R/R AML (Table). Three-fourths of pts inAML cohort were adverse risk by ELN 2022 risk. CR/CRi rates in ND AML, sAML, and R/R AML were 92%, 53%, and 40% and ORR was 88%, 69%, 58%, respectively. Median OS was 12.3 mo in frontline (FL, ND (16.7 mo) and sAML (10.4 mo)) and 7.6 mo in R/R. Similarly, median RFS was 9.1 (ND-10 mo and sAML-6.4 mo) and 7.5 mo, respectively. Median time to ANC ≥500 x 10 9 /L in cycle 1 was 41 days and Plt ≥50 x 10 9 /L was 31 days in FL pts. 30-day mortality was 2% in FL and 5% in R/R cohort. 18% in FL and 22% in R/R cohort proceeded to SCT. In HR-MDS cohort, the median age was 71y; 18/21 pts had prior treatment. ASXL1 was the most frequent mutation. ORR was 52% (CR+CRi-33%). Median OS-12.1, RFS-7.3 mo. Median time to ANC ≥500 x 10 9 /L was 55 and plt ≥50 x 10 9 /L was 51 days. Most common grade 3/4 AEs were infection with neutropenia (38%), febrile neutropenia (32%), thrombocytopenia (17%), and neutropenia (15%), consistent with HMA + VEN experience. Conclusions: DEC10-VEN demonstrated expected safety and efficacy in a particularly high-risk cohort of ND and R/R pts, with no evidence that 10-days of DEC provides improved responses over standard 5-days DEC. Clinical trial information: NCT03404193 . [Table: see text]
Achievement of therapeutic levels using dose-reduced peg-asparaginase in adult patients with acute lymphoblastic leukemia.
Authors: Leah Ann Goldberg, Anjani Kapadia, Andrew Palmer, Syed Abdul Mannan Shah, Hamed Rahmani Youshanlouei, Adam DuVall, Wendy Stock, Emily Dworkin, Anand Ashwin Patel
Journal: Journal of Clinical Oncology (2024)

6530 Background: Peg-asparaginase (PEG) doses range from 2000-2500 IU/m 2 in pediatric-inspired regimens for acute lymphoblastic leukemia (ALL). Pediatric PEG dosing in adolescents and young adults (AYAs) has resulted in improved outcomes, but PEG-associated toxicities increase with age and often limit its use. Therapeutic dosing is determined by asparagine (ASP) depletion for 14 days after dose; L-asparaginase levels can act as a surrogate marker of ASP depletion. We previously showed dose reduced PEG (defined as &lt;2000 IU/m 2 ) results in high rates of therapeutic L-asparaginase 7 days post PEG (Derman et al, Leuk Lymphoma 2020). Here we describe prolonged duration of ASP depletion and comparable toxicities after dose reduced PEG in adults with ALL. Methods: Patients ≥18 years with ALL or lymphoblastic lymphoma (LBL) who received PEG from 1/1/2008 to 9/28/2023 were identified for retrospective chart review. Those with ≥1 PEG trough level (defined as 10-20 days after dose) were included. The primary endpoint was therapeutic PEG levels (≥0.1IU/mL L-asparaginase) at 7 and 14 days post administration, with secondary endpoint being induction grade 3+ toxicities (CTCAE v.5.0). Results: 49 patients met inclusion criteria, of which 48 received PEG during induction. Median age was 34.7 (range 18-66), 67% were male and 53% had B-cell ALL. 17 (35%) received an induction dose ≤ 500 IU/m 2 , 22 (46%) received 501 to ≤1000 IU/m 2 and 9 (19%) received &gt;1000 IU/m 2 . Induction median dose was 1000 IU/m 2 . Among those with PEG trough levels, 79% were therapeutic after induction; of note, 4 patients were transitioned from PEG to Erwinia asparaginase due to silent inactivation. During induction, 23 (48%) patients had ≥1 grade 3+toxicity, including 5 (10%) with hepatotoxicity, 1 (2%) with pancreatitis, and 2 (4%) with a thrombotic event. There was no statistical relationship between dose level and toxicities (p=.8). Conclusions: This study demonstrates durability of therapeutic L-asparaginase levels and ASP depletion that persists 14 days despite dose reduction. There were decreased rates of hepatotoxicity and comparable rates of pancreatitis and thrombotic events compared to rates reported in CALBG 10403 (C10403) (Stock et al, Blood 2019), which utilized standard pediatric dosing. In addition, our cohort’s median age was significantly older than those treated on C10403. This suggests PEG dose reduction may offer similar therapeutic ASP depletion with comparable or reduced toxicities. Dose reduction should be studied prospectively in AYAs with ALL. [Table: see text]
Molecular characterization and biomarker identification in pediatric B-cell acute lymphoblastic leukemia.
Authors: Yu Du, Xiankai Zhang, Ming Sun, Li Yang, Fei Long, Shanshan Qi, Linlin Luo, Chenxuan Wang, Xiaoyan Lv, Xiaoying Wu, Liuqing Zhu, Qiuxiang Ou, Hao Xiong
Journal: Journal of Clinical Oncology (2024)

6524 Background: B-cell acute lymphoblastic leukemia (B-ALL) is the most prevalent hematologic malignancy in children and a leading cause of mortality. Despite high cure rates, the management of B-ALL remains challenging due to its high heterogeneity and propensity for relapse. This study aimed to delineate molecular features of pediatric B-ALL and explore the clinical utility of circulating tumor DNA (ctDNA) as a biomarker in B-ALL. Methods: The study analyzed 146 primary pediatric B-ALL patients who were diagnosed from August 2020 to April 2023 and received systemic chemotherapy in Wuhan Children's Hospital. Baseline bone marrow (BM) and plasma samples were collected for next-generation sequencing (NGS) to profile the mutational landscape. BM samples collected on day 19 of the treatment were utilized for minimal residual disease (MRD) testing to assess treatment efficacy. Transcriptomic profiling of baseline BM samples was performed via bulk RNA sequencing. Fisher's exact test and the Wilcoxon rank sum test were utilized to compare categorical and continuous variables between groups, respectively. A two‐tailed P-value&lt;0.05 was considered statistically significant unless indicated otherwise. Results: Transcriptomic analysis revealed that 86.3% of patients (126 out of 146) could be categorized into 13 distinct molecular subtypes, with hyperdiploidy emerging as the predominant subtype. Baseline BM NGS identified gene fusions in 61% of patients, including 37 novel fusions previously unreported in B-ALL. Specifically, the KMT2A-TRIM29 novel fusion was detected and validated in a male child diagnosed with the KMT2A-rearranged subtype. Despite initially responding well to therapy, the patient experienced disease progression after a year, indicating a poor prognosis. We also found that elevated mutant counts and maximum-variant-allele-frequency (maxVAF) in baseline BM were associated with significantly poorer response to chemotherapy ( P=0.0012 and 0.028, respectively). Additionally, MRD-negative patients exhibited upregulated expression of immune-related pathways ( P&lt;0.01) and increased CD8+ T cell infiltration ( P=0.047), indicating a more active immune microenvironment in better responding tumors. Baseline plasma ctDNA, which exhibited high mutational concordance with paired baseline BM samples, also demonstrated significant associations with chemotherapy efficacy, highlighting its potential as a non-invasive tool for disease monitoring and treatment outcome prediction. Conclusions: This study elucidated novel gene fusions and potential biomarkers for treatment response in pediatric B-ALL. Importantly, both baseline plasma ctDNA and BM samples offer promising prognostic insights into chemotherapy responses, paving the way for non-invasive monitoring strategies in the management of pediatric B-ALL.
Frailty risk assessment and impact on acute myeloid leukemia outcomes (FRAIL-AML): A population-based study from Ontario, Canada.
Authors: Gopila Gupta, Sho Podolsky, Ning Liu, Matthew Cheung, Aniket Bankar
Journal: Journal of Clinical Oncology (2024)

6506 Background: In acute myeloid leukemia (AML), treatment decisions, specifically intensive versus non-intensive approaches, depend on the clinician’s assessment of patient fitness. Frailty as a measure of fitness is a broader concept than commodities and is associated with worse outcomes in many cancers. Frailty assessment is incorporated to provide the precision to oncology treatment selections in addition to disease-related factors. The impact of frailty on outcomes in AML is not well studied. Methods: This retrospective cohort study from population-based health administrative databases in Ontario, Canada (ICES) included all patients (pts) ≥18 years diagnosed with AML between 2006 and 2021, treated within 90 days after diagnosis. Frailty was measured using McIsaacs’s frailty index (MFI)- a validated tool. Progressively increasing tertiles of MFI were categorized as fit (FT), pre-frail (PFR), or frail (FR). Treatment intensity was classified as intensive (IT) or non-intensive (NIT) based on standard practices. The primary outcome was overall survival (OS). Association of frailty with OS was measured using Cox regression separately for IT and NIT AML. Results: Out of 5450 pts, with a median age of 65 (IQR 54-74), 55.8% were males and 44.2% were females. 65% (n=3543) received IT, out of which 29.4% and 35.5% pts were FR and PFR respectively. Remaining 35% (n=1907) received NIT, with 41.1% and 32.3% pts being FR and PFR. Median overall survival in months (OS, 95% CI) for the entire group, IT, and NIT were 12.5 (12.0-13.2), 16.7 (15.7-18.2), and 7.6 (7.0-8.2), respectively. OS (table) was notably lower in FR pts compared to fit pts (p&lt;0.0001) in both IT and NIT. Univariate and multivariate analyses identified frailty, advanced age, and previous non-AML malignancy as risk factors associated with worse OS in both IT and NIT groups (table). Conclusions: Higher frailty is independently associated with worse OS in AML pts after adjusting for advanced age. A substantial proportion of AML pts in both IT and NIT groups exhibit a mismatch in treatment intensity assignments based on their frailty status, with about 30 % FR pts receiving IT and over 25 % FT pts receiving NIT. This study sheds light on the need for frailty evaluations using standardized tools to optimize treatment decisions in AML pts. [Table: see text]