bluuebunny/crossref_metadata_2025 huggingface dataset:
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.
Stopping study in chronic myeloid leukemia: Defining a new paradigm for Ontario CML1.
Authors: Ravipati Siri , Bakheet Waffa , Hamm Caroline M.
Published: June 2023

e19069

Background: The National Comprehensive Cancer Network (NCCN) guidelines state that in order to safely stop tyrosine kinase inhibitor (TKI) therapy in chronic myeloid leukemia (CML) patients, we need access to reliable polymerase chain reaction (PCR) tests on a monthly basis (4 weeks). However, Ontario, Canada can only provide a 6-week turnaround reliably. Therefore, we aimed to test a new paradigm for safely stopping TKI treatment by monitoring molecular response every 6 weeks for 6 months instead of the recommended 4-week intervals. Methods: A prospective pilot cohort study was conducted to assess the outcome of cessation of TKI treatment in chronic-phase CML patients. Eligibility criteria includes obtaining MMR4 (4-log reduction) for 2 years and had to have been on TKI therapy for 5 years. Patients' PCR for BCR-ABL, a driver of CML, was tested every 6 weeks for 30 weeks to ensure ongoing major molecular response (MMR). The primary endpoint was successful maintenance of MMR3 (3-log reduction) or greater at 36 weeks. Secondary endpoints include incidence of withdrawal syndrome, psychological effects, and quality of life (QoL) as per the EORTC Global Quality of Life scoring system were assessed during each visit every 6 weeks for 30 weeks. The secondary endpoint was assessing whether MMR was regained once lost. Results: 18 consenting patients were enrolled, 2 were censored from data analysis as additional time is required to assess whether they regained deep molecular response after stopping, 1 patient was deemed too early to analyze. 12 of the 17 enrolled participants were able to successfully stop TKI therapy and remain in remission at 30 weeks, yielding a 71% success rate. 5 patients had relapsed and 3 successfully regained MR 3.0 with resumption of TKI therapy. Conclusions: The findings demonstrated in a small pilot study that testing at 6-week intervals is safe and effective. Most Ontario CML patients treated in large community centers and have not stopped TKI therapy based on the NCNN guidelines that recommend a 4-week testing turnaround. We plan to expand this study to other sites in Ontario and if successful, this new paradigm may enable more CML patients to stop TKI therapy in a safe manner leading to significant financial and clinical impact. Data will be updated at the time of the conference. By determining that Q6 weekly is a safe paradigm, there is potential for increased comfort in patients unable to maintain Q4 weekly testing for various reasons such as compliance or patients in rural settings. Clinical trial information: OCT1250 , CML1 .
The genetics of transformation from myelodysplastic syndrome to secondary acute myeloid leukemia.
Authors: Zhang Zhenyu , Zhang Hong , Lin Yani , Zhao Miaoqing , Ru Kun
Published: June 2023

e19073

Background: Gene mutations play key role in the transformation from myelodysplastic syndrome (MDS) to secondary acute myeloid leukemia (s-AML). The aim of this study was to explore the clonal progression pattern from MDS to s-AML. Methods: A total of 663 patients diagnosed with MDS (n = 291), s-AML (n = 86), and primary AML (p-AML) (n = 286, M3 excluded) were enrolled in this study from May 2018 to December 2021, and the median age was 57 year-old (range 1~88). The diagnosis was established according to the WHO criteria. The MDS patients were divided into low-risk MDS ( n = 158) and high-risk MDS (n = 133) according to 2012 IPSS-R. Next generation sequencing was performed to detect the mutations of entire coding regions of 112 genes related with hematologic tumors in all patients. Results: It was found that mutations from 31 genes occurred in both MDS and AML, including DNA methylation ( DNMT3A, TET2, IDH1, IDH2, WT1), chromatin modification ( SETBP1, ASXL1, EZH2, PHF6), RNA splicing ( U2AF1, SF3B1, SRSF2, ZRSR2), transcription regulation ( TP53, CEBPA, RUNX1, ETV6, GATA2, BCOR, BCORL1), signal transduction pathways ( NRAS, KRAS, PTPN11, NOTCH1, FLT3, JAK2, KIT), and others ( NPM1, FAT, STAG2, DDX41). By enrichment analysis, those mutations were classified into two categories: type A mutations ( FLT3, IDH1, NPM1, NRAS, PTPN11, WT1, CEBPA) and type B mutations ( IDH2, KRAS, U2AF1, ZRSR2, SRSF2, STAG2, DNMT3A, EZH2, RUNX1, ETV6, TP53). The type A genes were significantly enriched in p-AML than in MDS, while some type B mutations, particularly RNA splicing, were significantly enriched in MDS than in p-AML. The VAFs of type A mutations were significantly lower than those of type B mutations. The longitudinal analysis of 10 patients with s-AML revealed two main models of clonal evolution, linear evolution and clone sweeping. Although the two models differed in the disease development, new sub-clones appeared in 9/10 patients. Interestingly, many of the new mutations were type A mutations (n = 7, 7/10), and 7 out of 10 patients carried type B mutations when they were at MDS state. The VAF data also showed that the preexisting mutations were generally higher than the newly emerging genetic alterations. Finally, an individual case was used to delineate the clone evolution. The patient was initially diagnosed with 5q syndrome and U2AF1 mutation (type B) was identified. After treatment, the patient experienced remission, and developed a new ETV6 mutation while the clonal size of U2AF1 decreased. When the patient relapsed, the clone size of ETV6 decreased while U2AF1 mutated clone size were amplified, a typical “clone sweeping” pattern. When the patient eventually transformed to s-AML, three type A mutations ( NRAS, KRAS and PTPN11) appeared simultaneously. Conclusions: This study revealed that the type A mutations are mainly responsible for the progression of MDS to AML, and the type B mutations are related to the clonal origin of MDS.
Incidence of cardiac events in patients with MDS or AML receiving azacitidine or decitabine within a large community health system.
Authors: Naffakh Noor , Williams Michael , Patel Priyam , Pedersen Rachel , Peterson Michael , DeFranco Anthony , Medlin Stephen , Sana Sherjeel , Gul Zartash
Published: June 2023

e19074

Background: Hypomethylating agents (HMA) such as decitabine and azacitidine are frontline therapies for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Limited data exist on subsequent cardiovascular (CV) events. Johnson et al. reported 170 patients receiving HMA + venetoclax with a CV event rate of 20%. Aims: To investigate the incidence of CV events in patients receiving HMA. Methods: We analyzed adult AML and MDS patients with > 1 dose of azacitidine or decitabine from 1/2018-12/2020. New CV events were defined as new atrial fibrillation, acute coronary syndrome, cardiomyopathy, congestive heart failure, myocarditis, or pericarditis. Competing risks regression identified baseline predictors associated with time to first CV event while accounting for the competing event of death. Results: 94 patients with no CV history were evaluated which consisted of a mean age 69 +/- 12 years and 50% male. 56% had MDS and 44% AML. Patients with BMI ≥ 30 accounted for 38.3% of the sample. 44 (47%) patients had baseline echocardiogram assessments prior to initiation of HMA with EF of 61+/- 8%; 57 (61%) had a documented prescription of beta-blocker, ACE-I, or ARB at time of HMA initiation. In the 94 patients, 16 new cardiac events occurred. Median survival after therapy initiation was 14.8 months. In a competing risks univariate analysis, lower prior EF (after adjusting for no EF performed) and absence of pre-chemotherapy beta-blocker, ACE-I, or ARB were significantly associated with having a new cardiac event post chemotherapy start (hazard ratio per 5-unit decrease = 1.62 (1.33-1.99), p<0.01 and HR=2.89 (1.08-7.77), p=0.03, respectively). Baseline BMI did not affect risk of a new CV event on HMA therapy (HR per 5 units=1.08 (0.78-1.50), p=0.63). Total HMA dose did not show significance as a predictor for CV events (HR=0.99 (0.987-1.009), p=0.72). Conclusions: We observed a CV event incidence of 19% at 3 years after the start of HMAs. Among patients receiving HMA chemotherapy, those with a lower baseline EF and those not on beta-blocker, ACE-I or ARB therapy prior to initiation of HMA had a higher incidence of cardiotoxicity. Neither pre-HMA BMI nor total HMA dose received appeared to predict risk for CV events. Further research is warranted evaluating the association between HMAs and cardiotoxicity. [Table: see text]
Real-world (RW) treatment (tx) patterns of patients (pts) with higher-risk myelodysplastic syndrome (MDS) in a US RWE database (COTA).
Authors: Komrokji Rami S. , Hernandez Donoso Leyla , Hodzic Sejla , Owusu Henry F , Nolan Kevin , Nourry Claire , Diez-Campelo Maria
Published: June 2023

e19077

Background: Pts with higher-risk MDS have poor outcomes. To understand current tx patterns/identify unmet needs, the COTA database, using pt-level curated electronic health record (EHR) data from centers across the US, was analyzed. Methods: This was a retrospective, descriptive analysis of deidentified secondary data from the COTA MDS RWE database. Data were abstracted from EHRs using these criteria: inclusion of adults with IPSS-R intermediate (I)/high (H)/very high-risk (vHR) MDS on/after 1/1/2012, exclusion of pts with no diagnosis date/clinician notes or pts with concurrent malignancies. Follow-up was until the last recorded event (last visit/other cancer/death; data cutoff 06/2022). Results: Data from 640 pts were included in this analysis. See Table for baseline demographic data. Most pts with IR- (225/281, 80%) and HR-MDS (162/239, 68%) were treated at community centers; pts with vHR-MDS were equally treated at academic (59/120, 49%) and community centers (61/120, 51%). Genetic/molecular data were limited; among pts with data available, the most common genetic mutation was TP53 (75/215, 35%). Of 640 pts, 108 (17%) did not receive tx and 110 (17%) received allogeneic stem cell transplant (alloSCT). Of those given systemic tx, hypomethylating agents (HMAs) were the most common first-line tx (444/532, 83%). Venetoclax was given to 35/640 pts (5%; as first line: 10/532, 2%; as second line: 20/170, 12%; as third line: 4/66, 6%). Median time to start tx from diagnosis was 2.2, 1.1, and 0.9 mo for IR-, HR-, and vHR-MDS, respectively. Of 512 pts assessed for first-line tx with duration data, tx duration was 7.4, 5.4, and 4.2 mo for IR-, HR-, and vHR-MDS, respectively. In 340 pts—including pts who underwent alloSCT—with response data, pts with IR-, HR-, and vHR-MDS had RW response rates (any response) of 73%, 72%, and 58%, respectively. Median OS (mOS) from start of tx was 29.0, 20.3, and 11.9 mo for IR-, HR-, and vHR-MDS, respectively. mOS (from tx start) according to tx: alloSCT 31.4 mo, chemotherapy 19.1 mo, HMAs 23.1 mo, investigational 22.1 mo, venetoclax 10.1 mo, and others 23.8 mo. About 20% of pts transformed into acute myeloid leukemia, chronic myeloid leukemia, chronic myelomonocytic leukemia, or chronic lymphocytic leukemia. Conclusions: This RW study showed that available tx for pts with higher-risk MDS in the US is limited and remains a high unmet need. [Table: see text]
Predictors of survival outcomes in patients with MECOM EVI1 rearrangement aberrations in AML or MDS.
Authors: Kusne Yael , McGary Alyssa , Kelemen Katalin , Litzow Mark Robert , Al-Kali Aref , Foran James M. , Badar Talha , Patnaik Mrinal S , Mangaonkar Abhishek A , Sproat Lisa Ostrosky , Palmer Jeanne M. , Greipp Patricia T. , Arana Yi Cecilia Ysabel
Published: June 2023

e19078

Background: MECOM (EVI1) rearrangements in MDS/AML are rare and carry an unfavorable prognosis. Although allogeneic stem cell transplantation (allo-HSCT) may prolong survival, factors impacting outcomes are not known. We conducted a retrospective analysis of patients with MECOM (EVI1) to associate clinicopathologic variables with prognosis. Methods: This study was approved by the Mayo Clinic IRB. Patients >18 years of age with MDS or AML and MECOM EVI1 at Mayo Clinic between 01/2012 and 12/2022 were included. Response was defined by ELN criteria. Intensive chemotherapy was defined as 7+3 or high dose cytarabine. Non-intensive chemotherapy included hypomethylating agents with or without venetoclax. Median overall survival (OS) and median leukemia free survival (LFS) were estimated using the Kaplan-Meier method. Outcome differences between sub-groups and univariate analyses were assessed with Cox regression. Results: Sixty patients met criteria for inclusion. Sixty-three percent (n = 38) were male and the median age at diagnosis was 67.8 yrs (range, 56 – 75). Eighty percent had AML (n = 48) and 18% had MDS (n = 11). Sixty-seven percent of patients had secondary AML/MDS (n = 40). Inv(3)/t(3;3) was present in 65% (n = 39) and t(3;21) was present in 12% (n = 7). Thirty-eight percent (n = 23) of patients had cooccurring monosomy 7 or 7q deletion and 5% had complex karyotype (n = 3). SF3B1 was the most common cooccurring mutation in 31% (n = 10), followed by KRAS in 19% (n = 6). Thirty-eight percent of patients (n = 23) received intensive chemotherapy. Complete response (CR) rates were 36% with intensive treatment (n = 8) and 4% with non-intensive treatment (n = 1; p = 0.007). Thirty percent (n = 18) underwent SCT (78% in CR1 and 22% in CR2) and of those, myeloablative conditioning (MAC) was used in 38% while 61% received reduced intensity conditioning (RIC). The mOS in the entire cohort was 11 months (95% CI 6.2, 17). Patients who received a SCT had longer mOS compared to patients who did not (19 vs 6.2 months, HR = 0.31, 95% CI 0.16,0.64; p = 0.001). AML-MRC was a poor prognostic factor in the HCST group for OS (HR = 4.23, 95% CI 1.02, 17.5, p = 0.047). Intensive vs. non-intensive chemotherapy, response prior to transplant (CR vs. no CR), or having 2 or more mutations on NGS did not significantly impact OS or LFS. Conclusions: In line with previous reports, allo-HSCT was associated with improved survival outcomes. Our results showed a high frequency of secondary AML/MDS, but only AML-MRC was associated with decreased survival outcomes. Regardless of therapy type, outcomes were poor. Novel therapies are urgently needed for these patients.
Juvenile myelomonocytic leukemia: A national analysis of demographic features.
Authors: Whooley Maximillian , Hsia Beau , Keirns Darby , Luker Andrew , Silberstein Peter T. , Wu Xinxin
Published: June 2023

e19086

Background: Juvenile Myelomonocytic Leukemia (JMML) is a rare hematological cancer originating in the bone marrow. It is a type of myelodysplastic syndrome (MDS) characterized by abnormal production of myeloid progenitor cells and monocytes. This malignancy is predominant in males, has a median age of diagnosis of 2 years, and carries a poor prognosis. It only accounts for 1% of all pediatric leukemias but constitutes 20-40% of pediatric MDS cases, making it the most common MDS subtype in children. Hematopoietic stem cell transplant (HSCT) is the only known cure for JMML, but its efficacy is just 50%. Without treatment, patients survive for a median of 10-12 months. Given the rarity of JMML, an analysis of demographic trends could offer valuable epidemiological insight. The National Cancer Database (NCDB) database was used to examine major demographic features of JMML. Methods: A retrospective analysis of all patients diagnosed with JMML between 2004 – 2020 in the NCDB (N = 242) was performed. Demographic factors including sex, race, Hispanic ethnicity, household income status, insurance status, urban/rural status, and Charlson-Deyo score were examined by descriptive statistics. Treatment statistics were also analyzed. Linear regression was used to determine incidence trends. Results: A total of 242 patients were identified with a histologically-confirmed diagnosis of JMML. Most patients were male (67.4%). The average age of diagnosis was 2 years (SD = 3.69, range = 0-33). The average incidence was 14.2 patients diagnosed per year (SD = 3.7, range = 9 – 21, R2 = 0.131). 93.8% had a Charlson-Deyo comorbidity score of 0. The majority of patients were White (74.4%), followed by Black (11.6%). 16.1% of patients were of Hispanic ethnicity. The distribution of median household income was 27.4% in the top quartile, 26.9% in the second, 26.9% in the third, and 18.7% in the fourth. Most patients were either privately insured (49.6%) or insured by Medicaid (42.6%). 75.5% of patients lived in a county with 250,000 people or more. Most patients received treatment (84.6%), while some only received active surveillance (8.7%) or no treatment (6.7%). Conclusions: This is the first NCDB analysis describing the demographic trends of JMML. Patients were twice as likely to be male than female. They were most likely to be White, with an average age of 2 years. This data reflects the expected age group and sex/race predominance described in the literature. The proportion of Hispanic JMML patients was comparable to Hispanics in the general US population. JMML appeared to be nearly evenly distributed among the top three household income quartiles. The lowest income quartile and rural inhabitants were least affected by this disease, which may indicate underdiagnosis in these populations. Further studies are needed to better define the relevance of these individual factors in the diagnosis, treatment, and survival of patients with JMML.
Influence of modified Lugano criteria by pre-infusion tumor kinetics on early survival prediction for patients with lymphoma under chimeric antigen receptor T-cell therapy.
Authors: Kunz Wolfgang G. , Blumenberg Viktoria , Rejeski Kai , Buecklein Veit , Schmidt Christian , Dekorsy Franziska , Bartenstein Peter , Ricke Jens , von Bergwelt Michael , Subklewe Marion , Winkelmann Michael
Published: June 2023

e19500

Background: Chimeric antigen receptor T-cell therapy (CART) is effective for patients with refractory or relapsed (r/r) lymphoma with prolongation of survival. We aimed to improve the prediction of Lugano criteria for overall survival (OS) at 30-day follow-up (FU1) by including the pre-infusion tumor growth rate (TGRpre-BL) and its early change to 30-day FU1 imaging (TGRpost-BL). Methods: Consecutive patients with pre-baseline (pre-BL), baseline (BL) and FU imaging around day 30 with CT or PET/CT before CART were included. TGR was defined as change of Lugano criteria-based tumor burden between pre-BL, BL and FU examinations in relation to days between imaging exams. Overall response and PFS were determined based on Lugano criteria. Proportional Cox regression analysis studied association of TGR with OS. For survival analysis, OS was analyzed using Kaplan-Meier survival curves. Results: 59 out of 81 patients met the inclusion criteria. At 30-day FU 8 patients (16%) had a CR, 25 patients (42%) a PR, 15 patients (25%) a SD, and 11 patients (19%) a PD according to Lugano criteria. The Median TGRpre-BL was -0.6 mm2/d, 24.4 mm2/d, -5.1 mm2/d, and 18.6 mm2/d and the median TGRpost-BL was -16.7 mm2/d, -102.0 mm2/d, -19.8 mm2/d and 8.5 mm2/d in CR, PR, SD, and PD patients, respectively. PD patients could be subclassified into a cohort with an increase in TGR (7 of 11 patients [64%], PD TGRpre-to-post-BL INCR) and a cohort with a decrease in TGR (4 of 11 patients [36%], PD TGRpre-to-post-BL DECR) from pre- to post-BL. PD TGRpre-to-post-BL DECR patients exhibited similar OS to patients classified as SD, while PD TGRpre-to-post-BL INCR patients had significantly shorter OS (65 days vs 471 days, p < 0.001). Conclusions: In the context of CART, the additional use of TGRpre-BL and its change to TGRpost-BL determined at 30-day FU1 showed better OS prognostication for patients with overall progressive disease according to Lugano criteria. Therefore, this modification of the Lugano classification should be explored as a potential novel imaging biomarker of early response. [Table: see text]
Chronic lymphocytic leukemia/small lymphocytic lymphoma nationwide analysis: Comparing sociodemographic and survival outcomes among Hispanics and non-Hispanics in the United States.
Authors: Toro-Vélez Esteban , Rosas Daniel , Velez-Mejia Carolina , Liu Qianqian , Michalek Joel , Diaz Duque Adolfo Enrique
Published: June 2023

e19505

Background: In essence, chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are the same , CLL being the most common leukemia in Western countries. (Blood PMID 29540348, CA Cancer J Clin PMID 35020204) Survival outcomes in CLL/SLL among Hispanics (HI) and Non-Hispanics (NH) have been controversial. (Cancer Causes Control PMID 34677741, Cold Spring Harb Mol Case Stud PMID 33593728) This analysis attempts to clarify if sociodemographic characteristics influence survival of HI diagnosed with CLL/SLL in the United States (US). Methods: Retrospective data analysis on CLL/SLL patients in the US reported to the Surveillance, Epidemiology, and End Results (SEER) 18 database from 2000-2018. Demographics, disease characteristics, and survival patterns were analyzed across ethnic groups, HI vs NH. Kaplan-Meier and Cox regression analyses were used to compare overall survival (OS). Multivariate analysis and propensity score matching was performed, adjusting for age, stage, and B-symptoms. Results: 98884 CLL/SLL patients were included, 5012 HI. Males predominated in both HI and NH. HI compared to NH, were diagnosed at a younger median age, 68 years vs 70 years, respectively [p<0.001]. Majority of patients belonged to the age bracket of 60-80 years; favoring a younger age distribution in HI. Most patients were white, and NH had greater heterogeneity [p<0.001]. Unknown stage at diagnosis followed by advance stage (III/IV) prevailed for both ethnicities [p=0.075]. B-symptoms were mostly unknown in both groups. The tendency was towards not receiving radiation as part of the treatment. Survival probability at 2, 5 and 10 years for HI (0.829, 0.677, and 0.474) was similar compared to NH (0.831, 0.664 and 0.437), respectively. The median survival time was 9.3 years for HI vs 8.5 years for NH, with a statistically significant difference in OS favoring HI [p=0.0045] On multivariate analysis, patients older than 80 years and between 60-80, had worse OS than those less than 60, with hazard ratio (HR) 7.5 [95% CI: 7 – 8.1] and 2.5 [95% CI: 2.4-2.7], respectively. Also, stage III and IV, had inferior OS than those at early stages, with HR 1.4 [95% CI: 1.1 – 1.6] and HR 1.2 [95% CI: 1 – 1.4], respectively. Conclusions: In this analysis, HI with CLL/SLL have a superior OS, which was noted to be statistically significant. Also, multivariate analysis showed correlation of better OS when CLL/SLL was identified at a younger age and early stages. Although demographic differences may be driving the survival effect in HI as they were noted to be younger; identification and better understanding of intrinsic disease characteristics, treatment patterns, and biological variables; may aid in the understanding on how these factors contribute and impact the survival advantage in this ethnic group.
Association of congestive heart failure with hospital outcomes among patients with chronic lymphocytic leukemia in the United States: Analysis of nationwide inpatient sample.
Authors: Olusoji Rahman Adesoji , Idowu Abiodun , Adabale Olanrewaju , Mohamed Salih Rajaa , Omore Ibrahim , Ahluwalia Meena
Published: June 2023

e19506

Background: Chronic Lymphocytic Leukemia (CLL) is adults' most prevalent chronic leukemia. There is an increased report of cardiovascular comorbidities in these patients due to the multi-systemic impact of both the insidious disease and the associated side effects of its treatment. This study aimed to provide real-world contemporary data on the in-hospital outcomes among patients admitted for CLL with comorbid Congestive Heart Failure (CHF) in the United States. Methods: The study is a retrospective study that used the National Inpatient Sample database. We identified patients hospitalized for CLL from 2018-2020 and stratified them into two cohorts – with CHF and without CHF. Inclusion criteria include age ≥ 18 years and hospitalization primarily for active CLL. We excluded patients with aortic stenosis and those whose CLL were in remission. Inferential statistics - chi-squared test and Student t-test (as applicable) - was done on extracted data. The odds ratio was calculated using univariate and multivariate analyses. All analyses were done at a 95% confidence interval with a 2-tailed p-value <0.05 set as the cut-off for statistical significance. Results: A total of 210,012 hospitalizations of CLL were identified, of which 27.5% (57,650) had comorbid CHF. On univariate logistics regression analysis, the average length of hospitalization was statistically (p<0.001) prolonged by one day, and the cost of hospitalization increased by 9,640 + 1482 US dollars among those with CHF and active CLL. The odds of all-cause in-hospital mortality increased by 1.6 folds in these patients (P<0.001). However, after adjusting for individual patients and hospital-level cofounders, active CLL did not have a significant clinical impact on the duration and total cost of heart failure hospitalization. Active CLL, however, significantly increased the risk of all-cause in-hospital mortality by 1.3 folds (4.7% vs 7.2%; adjusted odds ratio 1.31, 95% CI 1.17-1.46; p<0.01) in patients with heart failure. Conclusions: Patients hospitalized for active CLL with a comorbid diagnosis of CHF have increased odds of in-hospital mortality compared to those without comorbid heart failure. This finding suggests the need for integrative multi-disciplinary care for CLL patients with comorbid CHF, such as cardio-oncology.
Efficacy of immune checkpoint inhibitors for the treatment of advanced melanoma (AM) in patients with concomitant chronic lymphocytic leukemia (CLL).
Authors: Cass Samuel , Tobin Joshua , Seo Yongwoo David , Gener-Ricos Georgina , Keung Emily Zhi-Yun , Burton Elizabeth M. , Walsh Danielle M. , Davies Michael A. , McQuade Jennifer Leigh , Lazar Alexander J. , Hampel Paul Joseph , Wargo Jennifer Ann , Ferrajoli Alessandra
Published: June 2023

e19511

Background: CLL is the most prevalent adult leukemia and is associated with an increased risk of melanoma. CLL alters systemic immunity and can induce T-cell exhaustion, which may limit the efficacy of ICI in patients with CLL. Immune checkpoint inhibitors (ICI) have revolutionized management of AM, but data on ICI effectiveness have largely been restricted to clinical trials, thereby excluding patients with co-existing malignancies. We, therefore, sought to examine the efficacy of ICI for melanoma in patients with concomitant CLL and AM. Methods: In this international and multicentre retrospective study, review of clinical databases identified patients with concomitant CLL and AM treated with ICI from two US tertiary cancer centers (n = 39) and an Australian multi-institutional experience (AUS, n = 19). Objective response rates (ORR), defined as complete or partial response by RECIST v1.1, and survival outcomes (overall survival, OS, and progression-free survival, PFS) among patients with CLL and AM were assessed. Clinical factors associated with improved ORR and survival were explored. Results: Between 1997 and 2020, 58 patients with CLL were treated with ICI for concomitant AM. Among all patients with CLL and AM, ORR to ICI was 41% and median duration of response was 18 months. A majority were untreated for CLL (64%) at the time of ICI. Patients with prior history of treatment for CLL had significantly reduced ORRs (21% vs 51%, p = 0.04), PFS (3.6 vs. 14.6 months, p = 0.005), and OS (7.4 vs. 52.2 months, p = 0.002), compared to patients on observation for their CLL. Prior treatment with T-lymphocyte depleting chemoimmunotherapy (fludarabine, bendamustine, and alemtuzumab) was particularly associated with poor outcomes (median OS of 7.0 months, median PFS of 3.4 months). On univariate analysis, prior treatment for CLL, high risk CLL 17p deletion, and higher CLL Rai stage were associated with shorter PFS from ICI, though CLL treatment was the only factor independently associated with shorter PFS in the multivariate model (HR 6.5, [CI 2.1-20.3], p = 0.001]. Overall, 3 patients developed CLL progression while on ICI, though in two of these patients, the AM had an objective, durable clinical response to ICI. Overall, immune-related adverse events (irAE) occurred following 38% of ICI and rates of irAE were similar by CLL treatment status. Conclusions: Our case series of patients with concomitant CLL and melanoma demonstrate frequent, durable clinical responses to ICI However, those with prior chemoimmunotherapy treatment for CLL had significantly worse outcomes. We found that CLL disease course is largely unchanged by treatment with ICI.