bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase 2 study of the combination of decitabine (DAC), venetoclax (VEN), and ponatinib in patients (Pts) with chronic myeloid leukemia (CML) in accelerated phase (AP)/myeloid blast phase (MBP) or Philadelphia-chromosome positive (Ph+) acute myeloid leukemia (AML).
Authors: Senapati Jayastu , Ravandi Farhad , Dinardo Courtney Denton , Issa Ghayas C. , Sasaki Koji , Konopleva Marina , Macaron Walid , Nasr Lewis Fady , Zoghbi Marianne , Nasnas Cedric Christophe , Pemmaraju Naveen , Chien Kelly Sharon , Ohanian Maro , Jabbour Elias , Maiti Abhishek , Kantarjian Hagop M. , Short Nicholas James 
Published: June 2023

e19044 Background: CML-AP/MBP and Ph+ AML are therapeutic challenges. Based on published pre-clinical data of synergism (Leonard et.al., Sci Transl Med 2016), we hypothesized that combining ponatinib with DAC and VEN might lead to high rates of response and facilitate allogeneic stem cell transplantation (SCT). Methods: The study (NCT04188405) enrolled pts ≥ 18 years of age with CML-AP, CML-MBP or Ph+ AML with ECOG PS ≤ 3 and adequate liver/renal function. Pts with significant uncontrolled cardiovascular comorbidities were excluded. Therapy was with DAC (20 mg/m2/day) x 5 days, VEN (400 mg equivalent dose/day) x 21 days, and ponatinib (45mg/day) x 21 days in cycle 1 and then continuously in cycles 2-24. Each cycle was for 28 days. Ponatinib was reduced to 30mg/day for pts in CR/CRi and to 15 mg/day for pts in CMR. Intrathecal prophylaxis with 4 doses of cytarabine was recommended. The primary objective was to determine the overall response rate (ORR) with the regimen. Results: From Jul 2020 to Jan 2023, 15 pts were treated, 4 with CML-AP, 10 with CML-MBP and 1 with Ph+ AML (Table). 11 pts (73%) had prior TKI exposure, including 4 pts with prior ponatinib. 5 of 13 tested pts (38%) had an ABL1 kinase domain mutation (T315I, Q252H, L384M in 1 pt each and E255K in 2 pts). The median number of cycles received was 3 (range, 1-7). 11 pts (73%) responded; 6 pts (40%) with CR/CRi and 5 (33%) with MLFS. Best response was achieved after cycle 1 in 9 of 11 (82%) responders. All 4 pts with CML-AP responded, and 9 of 11 pts (82%) with prior TKI exposure responded. Four pts underwent subsequent SCT. At a median follow-up of 9.8 months, the median overall survival (OS) was 11.0 months, and the estimated 10-month OS was 63%. The median relapse-free survival was 5.7 months. Among the 11 responders, 5 relapsed (one after SCT), and 6 are in ongoing response (3 after SCT). One pt had a related grade 3 mucositis. No grade 4-5 related non-hematological adverse events were observed. Of the 10 pts who received > 1 cycle of therapy, 5 pts had delay (>1 week) in initiation of subsequent cycles due to cytopenias. The 60-day mortality rate was 0%. Two pts died on study, one from leukemia and one from infection while in MLFS. Conclusions: A triplet combination of DAC, VEN and ponatinib was well-tolerated and resulted in an ORR of 73% in this poor-risk population of pts with advanced Ph+ leukemias. Clinical trial information: NCT04188405 . [Table: see text]
Massively multiplex blocker displacement amplification (BDA) for the detection of measurable residual disease in acute myeloid leukemia.
Authors: Li Wenjun , Liang Shaoheng , Roberts Hannah , Dao Long , Pinto Alessandro , Zhang David , Wu Yalei 
Published: June 2023

e19045 Background: Next-generation sequencing (NGS) technologies, used to accomplish high throughput characterization of DNA, have an inherent error rate of between 0.1-1%. However, many important DNA sequences possess variant allele frequencies (VAFs) below this rate, potentially precluding their detection and identification by NGS. The previously published blocker displacement amplification (BDA) research technology has enabled selective amplification of sequences with variants, facilitating detection by NGS of these sequences with low VAFs at low read depths. Methods: Here we present the massively multiplex BDA library preparation method for the NGS-based detection of low VAF sequences. By optimizing our previously published Simulated Annealing Design using Dimer Likelihood Estimation (SADDLE) algorithm, we designed a 4 tube assay, comprising up to ~2400 amplicons in each tube, and ~8300 total amplicons. Tube 1 was designed with the highest likelihood of on-target amplification and the lowest likelihood of dimerization or non-specific amplification. While Tube 1 targeted ~1000 regions covering the most-frequently observed mutations in current public databases of patients with acute myeloid leukemia (AML) across more than 200 genes, Tubes 2-4 were designed for enrichment of the full coding sequence of 63 genes. To highlight the performances of SADDLE, coverage uniformity, primer dimerization, and non-specific amplification of tube 1 were compared to those of a naively designed tube. The panel was further tested with contrived and reference samples to demonstrate its analytical performance. Results: The SADDLE algorithm design decreased the first pass amplicon dropout rate more than 10-fold, from 30% to ~2%, and further improved the overall on-target rate compared to the naively designed panel. Through SADDLE, we were able to achieve an 80% median coverage of 63 genes. The resulting panel has a bulk limit of detection (LoD) of below 0.1% VAF. Conclusions: Massively multiplex BDA enabled the NGS characterization of DNA targets with VAFs suitable for detection of AML measurable residual disease (MRD). This technology represents a 100-fold increase in current plexity for the detection of low VAF alleles over our previously published multiplex BDA technology, demonstrating the ability to perform high throughput sequencing of rare mutations.
Acute lymphocytic leukemia incidence and survivability trends in the United States over the last two decades: SEER data set from 2000-2019.
Authors: Ghosh Ishan , Mukherjee Sudipto 
Published: June 2023

e19050 Background: The primary objective of this study is to evaluate how race, age at which patients were diagnosed, sex, and phenotype affect incidence and survivability for acute lymphocytic leukemia (ALL) patients in the United States. Keeping these factors in consideration this study was developed to see how existing cancer registry data can assist us in early detection of ALL in patients. Our hypothesis was that statistically significant correlations exist between race, age at which patients were diagnosed, sex, and phenotype of the ALL patients. Methods: The rate of incidence and survivability data were evaluated using SEER*Stat statistical software from National Cancer Institute. For incidence calculation we used the SEER 22 registry that covered approximately 47.99% of the U.S. population, while survival statistics were calculated using the SEER 17 registry that covered 26.5% of the U.S. population, both containing records from 2000 through 2019. In calculating the incidence statistics only the first primary tumor and reported diagnosis of the disease was accounted for. Results: There were statistically significant correlations between sex, race/ethnicity, age at which patients were diagnosed, phenotype of the ALL patient, and their rate of incidence. Analysis of All incidence data showed that the disease was more prevalent among Caucasian population. Among ALL patients, 59% patients were between 0 to 19 years of age when diagnosed, and 56% were male. ALL are mostly associated in patients with B-cell phenotype (73%). Evaluation of survivability data showed a slightly higher 5-year survival rate than 10-year survival rate. Conclusions: Survivability rates of African Americans patients were the lowest compared to Caucasian, Asian, Pacific Islanders, Alaskan Native, Native Americans and others. Survivability rates progressively decreased for older patients. Additionally, this study looked into the common treatment approaches that were administered in ALL patients which primarily included chemotherapy supplemented with some form of radiation therapy, as and when needed. The study showed chemotherapy was quite effective in improving patients’ survival probabilities, while the prognosis from the disease was not quite good for those who did not receive any treatment. This updated study on ALL incidence, survival rate, and common treatment options will further assist the health care professionals in effectively screening potential patients, their early detection, and in implementing a successful treatment regimen. This could potentially improve survival rates among those diagnosed at an older age who have a far greater mortality rate from ALL compared to younger patients.
Age-standardized incidence, mortality rates, mortality-to-incidence ratios, and disability-adjusted life years for acute lymphoblastic leukemia in the European Union 15 + countries, Australia, and United States of America.
Authors: Jain Akhil , Jani Chinmay , Patel Sagar , Raval Maharshi , Singh Harpreet 
Published: June 2023

e19052 Background: Though acute lymphoblastic leukemia (ALL) has been described historically more frequently in children, its burden has been increasing in adults. Therefore we aimed to describe ALL's age-standardized rates in incidence (ASIR), mortality (ASMR), and disability-adjusted life years (DALYs) between 1990-2019 between countries with comparable healthcare structure. Methods: Using the International Classification of Diseases versions 10 and 9, we extracted data from the Global Burden of Disease Study database for European Union (EU 15+) countries, Australia and USA. Individual countries' ASIR, ASMR, and DALYs stratified by sex were extracted for 1990-2019, and mortality-to-incidence indices (MII) were calculated. The indices were reported per 100,000 people. Results: ASIRs increased globally (males +60.35%, females +57.02%) as well as in all countries, with the highest in Portugal for males (+315.4%) and females (+195.06%). ASIR increase was less than global aggregate figures in Australia and Norway. USA had decreasing ASIR for males (-19%) and minimal change in females (+1%). ASMR decreased globally (males -15.75%, females -21.45%), all countries had decreasing ASMR across males and females with the highest decrease for males in Denmark (-56.28%) and females in Portugal (-56.16%). More importantly, MII had decreased globally, reaching 50% change both in males and females. USA observed lesser decrease in MII for males (-11%) and females (-24%) whereas all other EU countries and Australia had larger changes ( > 50%). Though Italy had the highest ASIR (males 11.54, females 8.33) as well as ASMR (males 0.71, females 0.46) in 2019, its MII had large changes (males -70%, females -54%). DALYs decreased in males (-20.23%) and females (-26.86%) globally. Decrease in Australia was more pronounced in Australia (males -50%, females -47%) than USA (males -36%, females -30%) and many other EU countries. Greece had smallest decrease in DALYs (males -16.04%) and Austria (females -16.92%). Conclusions: Though the incidence is increasing, mortality of ALL is decreasing globally for males and females. MII and DALYs have also decreased for males and females despite increased ASIR. This reflects the success on multiple fronts including precise diagnosis and prognostication, and the utility of dose-intensive chemotherapy, which can achieve sustainable complete remission. Implementing monoclonal antibodies in first-line treatment over the next few years will improve disease control.
Clinical outcomes of core binding factor acute myeloid leukemia in the modern era.
Authors: Hang Yiwei , Bouligny Ian Michael , Murray Graeme , Patel Tilak , Doyel Michael , Boron Josh , Tran Valerie , Gor Juhi , Ho Thuy , Zacholski Kyle , Venn Chad Michael , Alnimer Yanal Mufeed , Wages Nolan , Grant Steven , Maher Keri Renee ,   LCRT
Published: June 2023

e19054 Background: Acute myeloid leukemia (AML) with alterations in core binding factor (CBF) has a favorable prognosis. The impact of complex cytogenetics or ELN 2022 adverse genetic risk markers — such as ASXL1, RUNX1, EZH2, SRSF2, (and the rest of the secondary-type mutations [STMs]) and TP53 — in CBF-AML is unclear. Additionally, treatment outcomes in CBF-AML using front-line novel approaches, such as a hypomethylating agent (HMA; decitabine or azacitidine) with venetoclax, are unknown. This study analyzed outcomes of CBF-AML with respect to higher-risk molecular and cytogenetic cohorts and treatment approaches. Methods: We identified 58 consecutive patients with CBF-AML treated at VCU Massey Cancer Center from January 1, 2013 to January 1, 2022. We used Fisher’s exact test for between-group comparisons. We analyzed survival by the Kaplan-Meier method and compared groups with the log-rank test. The date of death was used to calculate overall survival; patients were censored at the date of the last contact. Measurable residual disease (MRD) was assessed using PCR-based methods or multiparameter flow cytometry with a minimum sensitivity of 10-3. Results: We analyzed 58 patients with inv(16) or t(8;21) AML treated in the front-line setting. Seven of these patients had concomitant genetic or molecular abnormalities typically considered high risk, including complex cytogenetics or TP53mut. Forty-nine (84.5%) patients received intensive chemotherapy (IC) with FLAG, CPX-351, or conventional 7+3 with or without gemtuzumab ozogamicin; nine patients (15.5%) received lower-intensity therapies with HMAs with or without venetoclax. No differences in overall survival were seen between the patients with CBF-AML with or without complex cytogenetics or TP53mut (not reached for either cohort, median follow-up time of 6.1 y. and 5.0 y., respectively, p = 0.969). There was no difference in the rates of MRD negativity in CBF-AML with or without complex cytogenetics or TP53mut ( p = 0.544). The presence of secondary-type mutations also did not appear to significantly impact survival in CBF-AML ( p = 0.654). There was no difference in the rates of MRD negativity in CBF-AML with STMs and those without STMs ( p = 0.500). Patients that were ineligible for IC and were treated with venetoclax + HMA or HMA monotherapy had significantly reduced composite complete remission rates (CRR; CR + CRi; 25% vs 91.3%, p = 0.007) and median overall survival (3.7 m. versus not reached, p = 0.038). Conclusions: Our data confirm the superior outcomes in induction candidates of CBF-AML treated with IC. The presence of complex cytogenetics, TP53mut, or secondary-type mutations did not appear to influence the rates of MRD negativity or overall survival in CBF-AML.
Trends in hematopoietic stem cell transplantation for leukemia, lymphoma and multiple myeloma in the United States: 2016 to 2020.
Authors: Amadife Stacy , Ojo Ademola Samuel , Ali Ahmed 
Published: June 2023

e19059 Background: Hematopoietic stem cell transplantation (HSCT) is a core component of the standard of care for many patients with leukemia, lymphoma and multiple myeloma. We aim to evaluate the trend in HSCT for patients with leukemia, lymphoma, and myeloma in the United States. Methods: This is a retrospective cross-sectional study of transplant activity performed at HSC transplant centers in the United States from January 2016 to December 2020 based on the reports submitted to the Center for International Bone Marrow Transplant Research (CIBMTR). CIBMTR transplant data were evaluated for trends in number of transplant, donor type, cell source and age of patients with leukemia, lymphoma and myeloma who received stem cell transplantation. Results: A total of 87,723 patients with leukemia, lymphoma and myeloma received stem cell transplantation during the study period. The transplant recipients were 0-17 years (4.1%), 18-64 years (66.7%) and ≥ 65 years (29.2%). Indication for the transplantations were multiple myeloma (44.7%), Hodgkin lymphoma (5.5%), non-Hodgkin lymphoma (19.4%), acute lymphoblastic leukemia (8%), acute myeloid leukemia (19.4%), chronic myeloid leukemia (1.4%) and other leukemias (1.5%). Donor types were autologous (64.8%), allogeneic related (16.3%) and unrelated (18.9%). Peripheral blood was the most common cell source (91.6%), followed by bone marrow (6.2%) and cord blood (2.2%). Eighty six percent of all cord blood transplantation were performed for acute leukemias. The total number of transplantation trended up across all disease categories from 2016 to 2019 but slightly declined in 2020. Allogeneic HCT for non-Hodgkin lymphoma and multiple myeloma declined by 11% and 50% respectively between 2016 and 2020. Conclusions: The COVID pandemic has minimal impact on HSCT in the US. HSCT is more commonly performed for myeloma than for patients with lymphoma or leukemia. Most transplants are autologous with peripheral blood as the cell source. There is a progressive decline in the use of allogeneic HSCT for myeloma and non-Hodgkin lymphoma possibly due to emerging novel therapies. [Table: see text]
Comparison of outcomes of Clostridium difficile infection in autologous stem cell transplant recipients compared to allogenic stem cell transplant recipients.
Authors: Bains Kanwal , Dhaliwal Armaan , Sohal Aalam , Chaudhry Hunza , Singh Ishandeep , Dukovic Dino , Arora Kirti , Kalra Shivam , Somasundar Ponnandai Sadasivan 
Published: June 2023

e19064 Background: Hematopoietic stem cell transplant (HSCT) recipients are at a higher risk of clostridium difficile infection (CDI). The incidence of CDI in allogenic SCT recipients has been shown to be about 2-fold compared to autologous SCT recipients in certain studies. These differences can be attributed to myeloablative chemotherapy and increased duration of immunosuppression in allogenic SCT patients. In this study we evaluate the impact of CDI on in-hospital outcomes in these two groups of patients. Methods: We included all patients with a prior diagnosis or a procedure code for HSCT and CDI using ICD-10 codes from National Inpatient Sample 2016-2019. Patients were stratified into two groups based on the presence or absence of autologous stem cell transfusion. Information was collected regarding patient demographics, Charlson comorbidities, resource utilization (LOS and total hospitalization charges), and outcomes. The outcomes included sepsis, shock, acute kidney injury, ICU admission, and in-hospital mortality. The differences in outcomes between the two groups were studied. Results: The incidence of CDI in autologous stem cell transplant recipients was lower compared to the allogenic HSCT group (5.1% vs. 6.1%, p-0.003). 7,605 patients were included in the study. Of them, 2,460 (32.25%) patients had autologous stem cell transplantation, while the remaining had allogenic stem cell transfusion. A higher proportion of patients in the autologous stem cell transplant group were males (60.7% vs. 54.32%), and patients aged 45-64 years (55.7% vs. 46.4%). Patients who received autologous stem cell transplants had a lower incidence of death (1.6% vs. 7.8%, p < 0.001), sepsis (17.28% vs. 28.18%, p- < 0.001), shock (4.7% vs. 12%, p < 0.001), AKI (15% vs. 31.6%, p < 0.001) and ICU admissions (5.7% vs. 10.7%, p- < 0.001). There was no significant difference in the length of stay between the two groups (21.30 days vs 22.97 days). Patients in the autologous stem cell transplant group had lower hospitalization charges ($318,072.3 vs $402,281.5, p < 0.001) than the allogenic group. Conclusions: Like prior studies, our study is compatible with the lower incidence of CDI in autologous SCT recipients. Our study also suggested a lower in-hospital mortality and better outcomes compared to patients with allogeneic stem cell transplants. Resource utilization was also noted to be lower in autologous stem cell transplant patients. Further research should be conducted to explain the differences and to allow physicians to provide timely treatments to prevent worse outcomes.
Treatment failure with first line imatinib for patients with chronic myeloid leukaemia in Kenya vs high-income countries.
Authors: Mcligeyo Angela Awino , Abinya Nicolas , Mwanzi Sitna Ali , Oyiro Peter Omondi , Odhiambo Andrew Oluoch , Ezzi Mohammed Shabbir , Ong'ondi Matilda , Mutebi Miriam Claire , Nyangasi Mary Flaviane , Mwenda Valerian 
Published: June 2023

e19068 Background: Chronic Myeloid Leukemia (CML) occurs in all age groups but predominantly in adults. The disease pathogenesis is typified by the presence of BCR-ABL fusion protein coded for by BCR-ABL gene, a product of reciprocal translocation between the long arms of chromosomes 9 and 22 denoted: t(9;22)(q34;q11). This results in leukaemogenic aberrant tyrosine kinase activity. The clinical course is characterized by three phases namely – chronic stable phase, accelerated phase and acute (blastic phase). Imatinib mesylate, an inhibitor of BCR-ABL was approved for treatment of CML and revolutionized its treatment and outcome. There is however a failure rate on imatinib of about 15 % that is partially addressed by second- and third-line tyrosine kinase inhibitors. Methods: We retrospectively collected data on patients treated at the Glivec International Patient Assistance Program (GIPAP), later Max Access Solutions (MAS) clinics at the Nairobi Hospital. Patient demographics, date of diagnosis, disease phase, and date of commencement of imatinib were documented. Treatment failure/switch, and reason were also documented. Results: A total of 1347 patients were included. Mean age was 44.12 years, males were 748 (55.5%), females 599 ((44.5%). All except two (1345) were initiated on imatinib, 206 (15.3%) were switched to second-line therapy due to various reasons including 31(2.3%) due to adverse events, 148 (11%) treatment failure, 15 (1.1%) due to unspecified reasons and 1 due to drug stock-outs. Second line medications were given to 204 patients: 100 (49%) dasatinib, 50 (24.5%) bosutinib, 38 (18.6%) nilotinib, 16 (7.8%) ponatinib. Deaths or losses to follow-up were 181 (13.4%). Conclusions: Overall about 15% failed on imatinib first-line therapy, similar to the experience from high-income countries. The most preferred second-line TKI was dasatinib, based on availability and toxicity profile.