bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of FLT3 and NPM1 mutations in patients with acute myeloid leukemia with metabolomic patterns determined by mass spectrometry.
Authors: Toprak Selami Kocak , Gerekci Yesilyurt Selin , Koyun Derya , Ozcan Muhit , Özen Can
Published: June 2023

e19003

Background: Patients diagnosed with Acute Myeloid Leukemia (AML) are categorized into risk groups based on cytogenetic and molecular abnormality tests, which determine the specific treatment regimes. Since mutation tests take time and some emergency patients require immediate treatment, a method to provide fast clinical data that will be the basis for initial treatment regime is needed. Aim of the study is to discover patterns associated with FLT3 and NPM1 mutations in AML patients, which will provide a fast clinical information to clinicians. The hypothesis is based on the previous studies which indicate a link between NPM1 and FLT3 mutations with metabolism. The mutations were chosen based on their high frequency in AML patients and their critical role in risk group determination. Methods: All AML patients (n = 42) and healthy individual samples (n = 16) were obtained from Ankara University Hematology Department. Patient groups were divided into five groups based on the mutation status. Pattern determination of the mutations was achieved by LC-MS/MS measurements of amino acid and acyl carnitine panels that are highly associated with metabolism. After preprocessing of the raw data, univariate (ANOVA) and multivariate analyses (PCA and PLS-DA) were performed to define class discrimination between sample groups. The remarkable analytes that have significant power in the discrimination were determined by VIP analysis. The developed model was validated with K-Fold cross validation method and permutation test. The most significant pathways in class discrimination were identified with pathway analysis. Visualization was accomplished via Metaboanalyst 5.0 software. Results: Principal Component Analysis (PCA) showed that 79% of the total variance of the sample groups was explained by the model. In order to increase class discrimination, Partial Least Squares-Discriminant Analysis (PLS-DA) was performed. R2Y and Q2 were found as 0.845 and 0.619, respectively. PLS-DA model was validated with K-fold analysis and permutation test. In all the validation experiments, a low cross-validation error was observed. In VIP analysis, the most significant analytes that cause the class discrimination were found as C0 carnitine, glutamic acid, aspartic acid, respectively. In the pathway enrichment analysis performed with these analytes, aminoacyl t-RNA biosynthesis, arginine biosynthesis, valine-leucine-isoleucine biosynthesis were found as statistically significant pathways responsible for the class discrimination. Conclusions: A preliminary model based on the targeted metabolomics approach was developed for the prediction of mutation status of NPM1 and FLT3 proteins in AML patients. Proposed model has a high fit value, validity, and strong predictive power. The reliability and validity of the model can be further increased by future multicenter studies.
Molecular and cytogenetics abnormalities in acute myeloid leukemia at Puerto Rico.
Authors: Marrero-León William Doel , Cintron-Colon Hector R. , Cruz-Rodriguez Steven , Caceres William , Rodriguez-Arocho Cristian I. , Cruz Alexis
Published: June 2023

e19005

Background: Acute myeloid leukemia (AML) is a highly heterogeneous disease. Specific cytogenetic and molecular features permit stratification of this disease. Prognosis within these categories varies widely. Determining optimal management has been complicated by the multiple molecular disease subsets with different responses to standard therapeutics. The comprehensive genetic analysis of AML in the past 10 years has revealed recurrent, somatically mutated genes, leading to the development of new targeted therapies including inhibitors of FLT3 and IDH. Decisions about the choice of therapy in patients with AML currently depend on the identification of a selected set of genetic markers at diagnosis. At Puerto Rico, AML data of cytogenetic and molecular markers is lacking. According to the Puerto Rico Cancer Registry from 2015 to 2019 a total of 551 cases of AML were reported. The San Juan City Hospital-hematology oncology department is one of the major referral centers on the island for initial evaluation and management of AML. The objective of our retrospective study was to identify the most common cytogenetic and molecular abnormalities present in our population. Patient conditions were stratified as favorable, intermediate, or high risk, in terms of prognosis using the ELN revised 2022 stratification. Methods: This study examined the frequency of molecular markers in newly diagnosed (ND) patients with AML. We evaluated patients that were at least 18 years of age or older with cytogenetic and molecular analysis in a period of 4 years (2019-2022). All data regarding demographic, bone marrow biopsy, cytogenetics, and molecular markers were obtained from electronic medical record at our institution with institutional review board approval. Results: A total of 140 patients with ND AML were identified during the study period. 58% female and 42% male with a median age of 57 years old at time of diagnosis. In terms of molecular markers, the most common were RUNX1 (22%), follow by IDH2 (14%), FLT3-ITD (14%) and TP53 (11%). Complex cytogenetics was identified in 40% patients, and 34% had Myelodysplasia related cytogenetic. Using the ELN 2022 criteria to classify AML patients in terms of risk with cytogenetics and molecular markers, our study revealed 21% favorable risk, 31% intermediate, and 48% adverse. Conclusions: Our study suggests that our population has higher prevalence of AML with myelodysplasia-related gene mutations and molecular related to adverse risks, such as RUNX1. Further studies with appropriate sub-group analysis need to be followed to determine if there is any genetical predisposition on the puertorrican population for myelodysplasia related genes or for RUNX1.
Inotuzumab ozogamicin (INO) for the treatment of measurable residual disease (MRD) in patients with B-cell acute lymphoblastic leukemia (B-ALL): Results from a phase II study.
Authors: Nasr Lewis Fady , Short Nicholas James , Senapati Jayastu , Alvarado Valero Yesid , Jain Nitin , Konopleva Marina , Macaron Walid , Ravandi Farhad , Dinardo Courtney Denton , Sasaki Koji , Ferrajoli Alessandra , Nasnas Cedric Christophe , Zoghbi Marianne , Jacob Jovitta , Mayor Ejiroghene , Milton Anna , Loiselle Christopher , Garris Rebecca , Kantarjian Hagop M. , Jabbour Elias
Published: June 2023

e19008

Background: INO is effective in relapsed/refractory B-ALL and may have utility in eradicating MRD in patients (pts) in MRD-positive (MRD+ve) remission. Methods: This is a phase II trial of pts with B-ALL in complete remission (CR) with persistent MRD+ve or with MRD+ve relapse. Eligible pts were required to be MRD+ve at ≥0.01%. MRD negativity (MRD-ve) was defined as undetectable MRD by flow cytometry (sensitivity 10-4) for Philadelphia (Ph)-negative (Ph-) B-ALL and undetectable MRD by both flow and PCR for BCR:ABL1 for Ph-positive (Ph+) B-ALL. INO was given at a dose of 0.6 mg/m2 on D1 and 0.3 mg/m2 on D8 of cycle 1 and 0.3 mg/m2 on D1 and 8 of subsequent cycles (up to 6 total cycles, given every 21-28 days) along with ursodiol prophylaxis. Pts with Ph+ ALL received concomitant TKI. Results: 27 pts with MRD+ve B-ALL were treated between 11/2018 and 6/2022 (Table). 17 pts (63%) had Ph+ B-ALL (15 received ponatinib and 2 dasatinib), and 10 pts had Ph- B-ALL. 20 pts (74%) were in CR1, and 7 pts (26%) were in CR2 or beyond. 14 pts (52%) had received prior blinatumomab and 5 pts (18%) had prior stem cell transplantation (SCT). 18 pts (67%) became MRD-ve (responders), 16 after the 1st cycle and 2 after the 2nd cycle of INO. In the Ph+ group, 10/17 pts (59%) responded; another 3 pts achieved major molecular response. 8/10 (80%) pts with Ph- B-ALL responded. The median number of cycles of INO were 3 (range, 1-6). Rates of MRD response were higher in pts without prior blinatumomab (11/13 pts [80%]), compared with those with prior blinatumomab exposure (7/14 [50%]) ( P=0.06). After a median follow-up of 21 months, 13/18 responding pts (72%) are in ongoing MRD-ve CR. Among the 18 responders, 6 pts underwent allogeneic stem cell transplant (ASCT) after a median of 3 cycles of INO (range, 1-4); all were in MRD-ve CR at the time of ASCT. 4/18 responders (22%) relapsed, 1 of whom relapsed after ASCT. Median RFS and OS for the whole group were not reached; estimated 2-year RFS and OS were 61% and 62%, respectively. 2-year OS for responders and non-responders were 76% and 50% (P=0.34), respectively. 2-year RFS for pts with or without prior blinatumomab was 23% and 91%, respectively; P=0.04. No grade 4 non-hematological toxicities were observed. 1 pt (who had a history of prior ASCT) had grade 3 sinusoidal obstruction syndrome. Conclusions: Low-dose, fractionated INO is effective at eradicating MRD in pts with B-ALL and can result in durable MRD-ve remissions. Clinical trial information: NCT03441061 . [Table: see text]
10-year real-world data on acute myeloid leukemia: The paradigm of a public health center in Brazil.
Authors: Campos Camilla Correia de A P , Teixeira Lais , Salvino Marco Aurelio
Published: June 2023

e19022

Background: Acute myeloid leukemia (AML) is a heterogeneous disease with different predominant molecular pathways. The last few years have witnessed great advances in targeted therapy. There are several trials in developed countries evaluating clinical outcomes. Nevertheless, data from low and middle-income (LMIC) countries frequently describe inferior results. Methods: This was a retrospective single-center cohort conducted in a university hospital in Northeast Brazil. We have analyzed the outcomes of all 62 patients diagnosed with AML between 2007 and 2017. Patients were classified using the European LeukemiaNet 2017 model into favorable (n=8), intermediate (n=18), and adverse risk (n= 7). 29 were not otherwise classified because of the absence of cytogenetic and/or molecular tests. We used logistic regression for data analysis assessing death as the outcome. Survival measures were estimated using the Kaplan-Meier method. The impact of bone marrow transplant (BMT) on patients eligible for intensive treatment on overall survival (OS) was assessed using a Cox proportional hazards model. Results: The median OS (mOS) of the entire cohort was 7 months (CI: 3.14-10.85). Stratifying by the risk, the mOS was shorter in patients with unknown and adverse risk (3 and 5 months, respectively) than in favorable and intermediate risk (22 and 11 months, respectively, P = 0.05). 16 (38%) patients were submitted to allogeneic BMT. We found a survival advantage (hazard ratio, HR: 0.32, 95% CI: 0.15-0.71) – p=0.005) in transplant patients, with superior median overall survival (mOS) (49 months) when compared with the chemotherapy group (6 months) ( P = 0.003). A total of 48 (77%) patients died during the follow-up and most deaths (n=39, 81%) occurred during the first year of diagnosis. Univariate analysis of clinical and laboratory characteristics found no association with death. A multivariate model including AML origin, risk stratification, and alloBMT as predictor variables demonstrated the protective power of alloBMT (table). Conclusions: Inferior outcomes found in LMIC are the result of a multifactorial scenario that reflects the absence of proper diagnostic tools, hospital infrastructure, and the lack of more effective and less toxic therapies. We suggest that patients with inadequate risk assessment should undergo consolidation with alloBMT as this remains the primary curative intervention in the real-world setting of LMIC. [Table: see text]
Why adult patients with acute leukemias are dying in the developing world: The other side of the coin.
Authors: Voskanyan Astghik , Ivanyan Arusyak , Harutyunyan Lusine , Movsisyan Alisa , Ghahramanyan Nerses , Sahakyan Lusine , Danielyan Samvel , Tamamyan Gevorg
Published: June 2023

e19035

Background: Majority of the patients with acute leukemias can reach complete remission (CR) in case of appropriate therapy and many of those in CR are expected to remain in remission for several years, which could be considered a cure. Because of progress in recent decades, less and less patients in the developed world are dying. In the developing world the situation is different and with the current work we would like to report the state of leukemias in Armenia and significant disparities, which affect the treatment outcomes of those patients. Methods: We analyzed the medical records of all expired adult patients diagnosed with acute leukemia at the Hematology Center of Armenia from 01/01/2016 until 12/31/2020. Hematology Center is the only institution in Armenia treating leukemias, meaning the data is a countrywide report. Death dates were taken from the United Information System of Electronic Healthcare in the Republic of Armenia. Results: Over the five-year period, 431 patients were diagnosed with AL, of which 310 (71.9%) died. 244 medical records were available for further analysis. The median age of patients at the time of diagnosis was 59 (18-85), 45.9% (112) were female. 23.8% (58) of patients died before starting chemotherapy, of which 44.8% (26) refused the treatment, the others died from different complications due to disease progression. 33.6% (82) patients reached CR of which 29.3% (24) died in first remission: 3 pts from acute heart failure, 1 from COVID-19, 3 from septic shock, 1 from pulmonary aspergillosis, 2 from acute respiratory failure, in 14 patients the causes of death were unknown. 58(70.7%) of those patients, who developed relapse, only 12% (7) of them reached 2nd remission. In 82.8% (48) of patients the death was because of disease progression. One patient died from acute kidney failure, 1 from acute respiratory failure, 1 from COVID-19,1 from septic shock. 50 patients died during induction therapy, form which 58% (29) was due to disease progression, the other reasons were: septic shock, acute heart failure, brain hemorrhage, acute respiratory failure, mesenteric venous thrombosis, multiple organ failure. 30 patients were resistant to the first line therapy and refused further therapy. In 24 patients it was not possible to clarify if they have developed remission and what were the death causes. Conclusions: In our analyzed cohort 23% of all patients refused the treatment, almost half of which did not even start the treatment. It should also be mentioned that because of stigma about cancer, some of those patients did not know their diagnosis and the decisions were made by the relatives. Other reasons for such high abandonment rates are mostly financial and social.
Olutasidenib in post-venetoclax patients with mIDH1 AML.
Authors: Cortes Jorge E. , Schiller Gary J. , Numerof Robert , Floryk Daniel , Jonas Brian Andrew
Published: June 2023

e19041

Background: Olutasidenib is a potent, selective, oral inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1). Olutasidenib is FDA approved for the treatment of relapsed/refractory (R/R) acute myeloid leukemia (AML) based on the registrational cohort (n = 153) of the Phase 2 trial, which demonstrated a rate of complete remission (CR) or CR with partial hematologic recovery (CRh) of 35%, with a duration of response of 25.9 months. Venetoclax (VEN) in combination with a hypomethylating agent (HMA) is standard treatment for AML patients unfit for chemotherapy and has adequate efficacy in IDH1-mutated AML. The sequence of therapy following failure of a VEN-based regimen in IDH1-mutated AML has not been established. We evaluated the efficacy and safety of olutasidenib in a subset of 17 patients from the Phase 2 trial (NCT02719574) previously treated with VEN combination regimens. Methods: Adults with mIDH1 R/R AML received olutasidenib 150 mg twice daily alone (n = 15) or in combination with azacitadine (AZA) (n = 2). The primary endpoint was achievement of a CR/CRh. Secondary endpoints included time to and duration of CR+CRh and rate of transfusion independence (TI). Data cut-off for the analysis was 18 June 2021. Results: Of 17 patients with prior VEN treatment, 5 are ongoing and 12 discontinued due to progressive disease (6), adverse events (4), or withdrawal by subject (2). Median age was 73 (range 65-83). Median time since diagnosis was 19.5 months (1.2-41). Cytogenetic risk class was intermediate in 9, poor in 6, favorable in 1 and unknown in 1. Most patients had relapsed; 6 were refractory to prior treatment. The median number of prior regimens was 2 (range 1-6); 13 had prior HMA, 2 had prior olutasidenib. VEN was generally used for induction. Some patients received VEN in multiple regimens. VEN was used with azacytidine (AZA) in 8 patients, after AZA (1), and with decitabine (5), cytarabine +/- idarubicin (5), and dinaciclib (2). The best response to olutasidenib was CR/CRh in 5/17 (29.4%), of which 4 (23.5%) were CR. In the 8 patients who previously received the combination of VEN-AZA, 3 (37.5%) patients achieved a CR/CRh. Time to CR/CRh was median 2.1 months (actual: 1, 1.9, 2.1, 2.8 and 2.8). Duration of CR/CRh was median 18.5+ months (4.8, 9.0+, 18.5+, 22.6+, and 28.5+ months as of cut-off date). Other responses included CR with incomplete blood count recovery (CRi) in 2 patients, stable disease (SD) in 2, progressive disease (PD) in 3, not done (ND) in 2, not evaluable (NE) in 1 and not listed in 2. At baseline 14/17 were red blood cell (RBC) dependent, and 4 of the 14 (28%) had a 56-day period of RBC transfusion independence (TI). Ten were platelet dependent at baseline and 5 of the 10 (50%) had a 56-day period of platelet TI while receiving olutasidenib. Conclusions: Olutasidenib induced durable remissions in patients with mIDH1 R/R AML, including those failing prior treatment with a venetoclax-based regimen. Clinical trial information: NCT02719574 .
Venetoclax pharmacokinetics in subjects with end-stage renal disease undergoing hemodialysis.
Authors: Noorani Behnam , Menon Rajeev , Cen Xin , Marsh Kennan , Huang Weize , Gupta Shelly , Dobkowska Edyta , Marbury Thomas , Salem Ahmed H.
Published: June 2023

e19042

Background: Venetoclax is a first-in-class Bcl-2 inhibitor approved for the treatment of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia(AML) and is currently being investigated as a treatment for t(11;14)-positive relapsed/refractory multiple myeloma (MM). Renal insufficiency is a common comorbidity in patients with hematologic malignancies, and no clinical study has been conducted to assess how end stage renal disease might affect venetoclax pharmacokinetics. This study aimed to assess the pharmacokinetics of venetoclax after oral administration of a single 100 mg dose of venetoclax in subjects with normal renal function and end-stage renal disease, including those undergoing hemodialysis. Methods: Venetoclax was administered as a single 100 mg dose to 7 healthy female subjects with normal renal function (eGFR > 90 ml/min) and 6 female subjects with end-stage renal disease (ESRD) (eGFR < 15 ml/min) both prior to hemodialysis (Period 1) and between hemodialysis days (Period 2). Intensive PK and protein binding samples were collected from all subjects. Arterial and venous samples were collected from ESRD subjects during hemodialysis to assess the effect of hemodialysis on the pharmacokinetics of venetoclax. Pharmacokinetic parameters were estimated using non-compartmental methods. Results: There was no difference in plasma venetoclax concentrations between arterial and venous samples, suggesting that hemodialysis did not affect the PK of venetoclax. The fraction unbound (fu) of venetoclax increased approximately 2-fold for subjects with ESRD compared to subjects with normal renal function.The unbound Cmax and AUC0-48 of ESRD subjects, between dialysis days were comparable to unbound Cmax and AUC0-48 observed in the normal renal function subjects. The harmonic mean t1/2 between groups (normal renal function vs. ESRD) ranged from 11 and 12.2 hours, demonstrating that end-stage renal disease did not affect the half-life of venetoclax. Conclusions: End-stage renal disease does not alter unbound venetoclax plasma concentrations and no dose adjustment is neededfor patients with renal insufficiency based on pharmacokinetics. Clinical trial information: NCT04810598 .
Characteristics and survival of secondary acute myeloid leukemia arising from myelodysplastic syndrome (MDS-sAML).
Authors: Adrianzen Herrera Diego Andres , Sparks Andrew , Batra Akshee , Zakai Neil A.
Published: June 2023

e19075

Background: sAML is a heterogenous category including therapy-related AML, AML arising from MDS or myeloproliferative neoplasm, and other biologically distinct groups. Combining these as one entity likely masks important clinical and therapeutic differences. We defined the clinical profile and survival for MDS-sAML. Methods: The population consisted of patients (pts) with MDS identified in SEER-Medicare (2007-17) by ICD-O-3 histology codes and continuous Medicare parts A+B coverage. Transformation to leukemia was confirmed by at least 2 AML codes during follow up. Established algorithms identified MDS type and risk group, Charlson comorbidity index (CCI), and transfusion dependence for red blood cells (RBC) and platelets. Logistic regression identified risk factors for transformation to MDS-sAML. Kaplan-Meier estimation and multivariable Cox regression were used to analyze overall survival (OS). Results: Of 15,227 MDS pts, 1,871 transformed to AML. MDSsAML incidence varied by MDS risk group and histology. Time to transformation was shorter with higher risk groups. Younger age (odds ratio [OR] = 1.6, 95% confidence interval [95 CI]: 1.4-1.9), lower CCI (OR = 1.6, 95 CI: 1.4-1.9), higher risk (OR = 2.3, 95 CI: 2.0-2.5), transfusion dependence for RBC (OR = 1.2, 95% CI: 1.1-1.3) or platelets (OR = 2.5, 95 CI: 2.1-3.0), were associated with transformation (all respective p < 0.05). Median OS (mOS) after transformation was 3.3 months. The 1- and 2-year OS rates for MDS-sAML were 25% and 12%. MDS-sAML survival varied by antecedent MDS histology and risk group, being longer for pts with antecedent low risk MDS (p < 0.001). Sex, race, and CCI did not affect survival after transformation. Older age (hazard ratio [HR] = 1.5, 95 CI: 1.2-2.0), higher MDS risk (HR = 1.5, 95 CI: 1.2-1.9), RBC transfusion dependence (HR = 1.4, 95 CI: 1.3-1.6), and platelet transfusion dependence (HR = 1.5, 95 CI: 1.3-1.7), were associated shorter MDS-sAML survival (all respective p < 0.05). Conclusions: Risk of MDS-sAML is substantial, with 5% AML transformation even in lower risk MDS histology. Real-world survival of MDS-sAML pts is dismal and lower than reported in clinical trials. Worse MDS risk group before transformation is associated with lower OS after developing AML. These data support a unique pathophysiology of MDS-sAML. [Table: see text]
Racial and ethnic representation in large B-cell lymphoma trials and real-world databases.
Authors: Munoz Javier , Mutebi Alex , Wang Tongsheng , Zhang Guihua , Yu Junhua , He Jing , Chibber Anindit , Kamalakar Rajesh , Jun Monika P. , Adejumo Kelechi , Yang Shibing , Kalsekar Anupama
Published: June 2023

e19530

Background: In large B-cell lymphoma (LBCL) trials, racial and ethnic representation is difficult to determine due to underreporting in some regions, or because some patients may not provide data. It is difficult to understand the full extent of any underrepresentation of specific races or ethnicities in these trials relative to the prevalence of LBCL in clinical practice. The objective of this study was to characterize racial and ethnic representation in LBCL real-world databases and recently published LBCL studies. Methods: Analyses of the distribution of different racial and ethnic categories were conducted across 6 real-world clinical practice databases from the United States (US): SEER-Medicare, COTA, Medicare, Optum Market Clarity, Optum CDM, and ConcertAI RWD. In addition, a targeted review of recently published studies in patients with LBCL was conducted to identify reported race and ethnicity distributions. Distributions were described using counts and percentages for each race (Asian, Black, White, and other/unknown/not reported) and ethnicity (Hispanic, non-Hispanic, and other/unknown/not reported) category. Results: Patients with LBCL from the databases included: COTA (N=5848), SEER-Medicare (N=102,548), Medicare (N=136,466), Optum Market Clarity (N=19,649), Optum CDM (N=22,175), and ConcertAI (N=1828). Race and ethnicity distributions are reported in the table. Across databases, Asian (2–6%) and Black (5–8%) races were substantially lower than White race (69–88%). Across various lines of therapy, distributions were similar: 3–5% Asian, 3–5% Black, and 78–82% White. Hispanic ethnicity (5–22%) was substantially lower than non-Hispanic ethnicity (70–91%). In the targeted review, 14 publications of LBCL therapies were identified; of these, 10 did not report racial/ethnic composition. In 4 publications (Salles et al, 2020; Sehn et al, 2020; Bannerji et al, 2022; and a real-world study by Shenoy et al, 2011), Asian, Black, White, and other/unknown/not reported represented 2–13%, 0–7%, 71–89%, and 1–11%, respectively. Conclusions: Information on racial and ethnic distributions in LBCL studies is underreported, particularly in global trials. If this information was reported and reflective of LBCL in clinical practice in the US, the numbers of Asian and Black patients would be low at ≤8%, and most patients would be expected to be White and non-Hispanic. [Table: see text]
Cryptococcosis in non-HIV/non-transplant hematological patients: A 12-year retrospective clinical analysis in a Peruvian referral cancer center.
Authors: Meza Kelly , Holguin Alexis , Velarde Juan , Intimayta-Escalante Claudio , Sulca-Huamani Oliver , Poquioma Ebert , Vidal Jose Ernesto , Cuellar Luis E
Published: June 2023

e19536

Background: Globally, cryptococcal infection has become a public health challenge. However, relatively little is known about cryptococcal infection in non-HIV/non-transplant oncohematological patients. Methods: We developed a retrospective cohort study that includes hematological patients who had cryptococcosis infection seen in the Instituto Nacional de Enfermedades Neoplasicas between 2007 and 2018. We exclude HIV and transplant recipients patients. Results: During the 12-year study period, among 14908 individuals with hematological malignancies (HM), a total of 21 cases of cryptococcosis were identified, representing an incidence rate of 1.41 per 1000 HM diagnosed in our center. Non-Hodgkin lymphoma (NHL) (47.6%), acute leukemias (23.8%), multiple myeloma (19.1%), and Hodgkin lymphoma (9.5%). Three cases of adult T-cell leukemia/lymphoma were identified. The sub-group analysis showed that NHL (7.35 per 1000 NHL) and Multiple myeloma (4.59 per 1000 MM) had the highest incidence rates. Regarding the clinical presentation, the time between the diagnosis of cryptococcosis and HM was 42 (18–161) days. Cryptococcal fungemia and antigenemia was the most frequent diagnosis (85.7%), followed by pulmonary (52.4%) and central nervous system (38.1%) involvement. At the time of the diagnosis of cryptococcosis, 61.5% were receiving chemotherapy, 53.9% were in the induction phase, and 7.7% were on maintenance therapy. The use of immunosuppressants and chemotherapy within a month of the diagnosis of cryptococcosis was the most common risk factor (90.5%). Regarding the subanalysis performed between the different types of malignancies (NHL versus other HM), age at admission (p = 0.02), site of cryptococcosis presentation (p = 0.01), and lymphocyte count at admission (p = 0.01) were statistically different between these groups. In the NHL subgroup, there was less involvement of the lungs and higher fungemia (p = 0.01). The overall survival (OS) of our cohort at 15 and 120 days was 70% (95%CI: 0.43-0.86) and 51% (95%CI: 0.26-0.72), respectively. OS for patients with NHL was 57% at 15 days (95% CI: 0.17-0.83) and 42% at 120 days (95%CI:0.09-0.73). OS for other HM was 90% at 15 days (95%CI:0.47-0.98) and 60% at 120 days (95%CI: 0.25-0.82). Conclusions: Our cohort characterized the distinct clinical presentation, risk factors, and outcomes of cryptococcal infection in hematologic malignancies subgroups. NHL was the HM with the worst prognosis and the highest incidence rate. [Table: see text]
Effect on hospital outcomes of hematopoietic stem cell transplant recipients with Clostridium difficile infection.
Authors: Dhaliwal Armaan , Sohal Aalam , Chaudhry Hunza , Bains Kanwal , Singh Ishandeep , Kalra Shivam , Dukovic Dino , Patel Jay , Somasundar Ponnandai Sadasivan
Published: June 2023

e20003

Background: Hematopoietic stem cell transplant (HSCT) recipients are at increased risk of Clostidium difficile infection (CDI) due to use of cytotoxic chemotherapy, broad-spectrum antibiotics, and sustained neutropenia. Because of the immunocompromised nature of these patients, the prevalence rates of CDI in HSCT recipients are high. In this study we evaluate the impact of CDI on in-hospital outcomes. Methods: We included all patients with a prior diagnosis or a procedure code for HSCT using ICD-10 codes from National Inpatient Sample. We excluded patients admitted for less than 14 days to exclude admissions for elective chemotherapy or catheter placement. Patients were stratified into two groups based on the presence of CDI. Information was collected regarding patient demographics, Charlson comorbidities, underlying hematologic disease, resource utilization (LOS and total hospitalization charges), and outcomes. The outcomes included sepsis, shock, acute kidney injury, ICU admission, and in-hospital mortality. The association between CDI and outcomes was studied using multivariate analysis. Results: 62,415 patients were included in the study. Of them, 5,275 (8.5%) patients developed CDI. The majority of the patients with CDI were White (70.4%), men (57.1%), and aged between 45-64 years (52.5%). Patients with CDI had a higher incidence of sepsis (21.1% vs. 16.5%), shock (8.1% vs. 5.8%), AKI (23.8% vs. 19.4%), ICU admission (9.6% vs. 7.6%) and in-hospital mortality (5.8% vs. 4%). After adjusting for confounding factors, CDI was associated with a 32% higher odds of in-hospital mortality (aOR-1.32, 95% CI-1.01-1.74, p-0.046). CDI was also associated with 26% higher odds of developing shock (aOR-1.26, 95% CI-1.01-1.72, p-0.013) and 27% higher odds of developing AKI (aOR-1.27, 95% CI-1.09-1.49,p-0.002). No statistically significant difference was noted in the risk of ICU admission between the two groups. Patients with CDI had a longer length of stay (29.5 days vs. 24.8 days, p < 0.001) and higher hospitalization charges ($400,017 vs. $508,090, p < 0.001). Conclusions: Our study suggested a relationship between CDI and worse outcomes in HSCT recipients. Physicians should be aware of this association and promptly recognize and initiate treatment in these patients to improve outcomes. [Table: see text]
Bortezomib-induced cardiotoxicity: Real-world data from a single-center.
Authors: Chennapragada Suma Sri , Ananthaneni Anil , Sharma Shivani , Devarashetty Sindhu Priya , Shi Runhua , Ramadas Poornima
Published: June 2023

e20008

Background: Bortezomib (Velcade) has emerged as the leading component of first-line therapies in both standard and high-risk multiple myeloma since the SWOGS0777 results were published in 2016. Although the incidence of cardiac side effects is reported to be lower with bortezomib compared to carfilzomib, standardized protocols for cardiac toxicity monitoring are unavailable. Currently, reported rates of cardiomyopathy with Velcade use range between 1-5%. We aim to examine bortezomib related cardiac adverse events and their association with demographics and traditional risk factors, especially in the setting of an ethnically diverse population that our hospital serves. Methods: Our institutional retrospective study extended between 01/2015 - 12/2020 and included patients aged > 18 years who received Velcade for myeloma and excluded prisoners, pregnant women. Our primary objective was to investigate the incidence of Velcade-induced cardiomyopathy, arrythmias and coronary artery disease (CAD) as dependent variables. Independent variables included demographics, prior personal/family history of heart disease, comorbid conditions such as hypertension/diabetes/obesity/hyperlipidemia/smoking/atrial fibrillation/chronic kidney disease, myeloma subtype and RISS staging. Descriptive statistics were used to report frequencies and percentages. Fisher’s exact tests were used to report associations between dependent and independent variables. Results: This study included a total of 64 patients. Majority were males (58%), African Americans (79%), and had a mean age of 62 years. Free light chain and IgG kappa were the most common types of myeloma (73%). Mean dose of velcade and dexamethasone received was 52.4 mg/m2 and 834 mg respectively, over a mean duration of 26.14 weeks. Personal and family history of cardiovascular disease was reported in 39% and 23% patients respectively. A new diagnosis of cardiomyopathy was made in 14% of the patients. No new arrythmias or CAD were seen after Velcade use. In the unadjusted model, incidence of new cardiomyopathy was statistically significant in patients with personal (p = 0.043) and family history (p = 0.022) of cardiovascular disease. No other statistically significant associations were found with other independent variables, including dose or duration of velcade/steroid use. Multi-variate analysis is not reported due to low sample size. Conclusions: Our institution treats a diverse population with a higher multi-morbidity burden as opposed to physically and medically fit population recruited into clinical trials. This gives us an opportunity to bring forward some real world data. Given the higher incidence of cardiac toxicity in our study as opposed to current available data, we propose that high-risk patients with personal or family history of cardiovascular disease could benefit from closer monitoring during the course of their treatment with Velcade.
Outcomes of patients with multiple myeloma refractory to different administration schedules of bortezomib.
Authors: Goel Utkarsh , Charalampous Charalampos , Kapoor Prashant , Binder Moritz , Buadi Francis , Dingli David , Dispenzieri Angela , Fonder Amie L. , Gertz Morie A. , Gonsalves Wilson I. , Hayman Suzanne R. , Hobbs Miriam A. , Hwa Yi Lisa , Kourelis Taxiarchis , Lacy Martha , Leung Nelson , Lin Yi , Warsame Rahma M. , Rajkumar S. Vincent , Kumar Shaji
Published: June 2023

e20011

Background: Drug refractoriness is an important factor determining choice of next therapy and prognosis in multiple myeloma (MM). It is debatable whether refractoriness to a drug varies among patients (pts) with MM progressing on different administration schedules of the drug. Outcomes of MM pts refractory to different doses of lenalidomide have been previously described, but similar data about proteasome inhibitors (PIs) are limited. In this study, we assessed the impact of refractoriness to different schedules of bortezomib (V) on outcomes with subsequent therapies in MM pts. Methods: We retrospectively reviewed MM pts at our center diagnosed between January 2004 and December 2018, who progressed on/ after receiving first line therapy with V containing regimens. At first relapse, we divided pts into 3 groups- MM progressing on or within 60 days of receiving (1) 1-1.3 mg/m2 V once weekly or more frequently (Standard Dose Refractory), (2) 1-1.3 mg/m2 V once every 2 weeks or less frequently (Low Dose Refractory), and (3) MM progressing at least 60 days after stopping V (Not Refractory). In addition to V, we classified pts as being refractory to cyclophosphamide and immunomodulatory drugs (IMiDs) at first relapse. We classified salvage regimens into daratumumab (Dara), PI, IMiD, PI+IMiD, and VDTPACE like regimens. We then assessed progression free survival (PFS) and overall survival (OS) for next line therapy, and for next V containing therapy using Kaplan Meier and Cox models. Results: A total of 302 pts were included. Median age at diagnosis was 62 years and 60% pts were male. Overall, 23%, 31%, and 27% were International Staging System (ISS) stage I, II, and III respectively; 40% had high risk FISH as per mSMART. Of the 302 pts, 134 (44%) pts received another V containing regimen after the first line therapy at any time during the disease course. Using a multivariable Cox model to adjust for ISS, high risk FISH, refractoriness to other drugs, duration of first line therapy, and treatment received at relapse, the Not Refractory Group had a better PFS for both 2nd line therapy and the next V containing line of therapy, while no significant differences were seen between the Standard Dose Refractory and Low Dose Refractory groups. OS differences followed the same trend but were not statistically significant (Table). Conclusions: On multivariable analysis, the PFS did not differ among standard dose vs low dose refractory pts, and both were significantly inferior to pts not refractory to V. These data suggest that refractoriness to V might not be a dose dependent phenomenon. [Table: see text]
Longitudinal changes in echocardiographic variables and endothelial function to predict cardiovascular toxicities in patients with multiple myeloma receiving carfilzomib.
Authors: Johnston Hannah , Prabhu Nicole , Cunningham Claire , Cooperrider Jennifer H. , Andreatos Evangelia , Gorski Martha , Major Sarah , Wolfe Brittany , Kruse Eric , Derman Benjamin Avi , Lang Roberto , Jakubowiak Andrzej , Major Ajay , DeCara Jeanne
Published: June 2023

e20012

Background: Carfilzomib (CFZ) is a second-generation proteasome inhibitor with activity in multiple myeloma (MM) that is associated with cardiotoxicity and dyspnea. The pathophysiology and risk factors for developing these toxicities are not well described. We are conducting a prospective observational study (NCT04827563) of longitudinal changes in cardiovascular and endothelial function among MM patients receiving CFZ. We hypothesize that baseline and longitudinal variations in cardiovascular and endothelial function correlate with development of cardiotoxicity and dyspnea in MM patients receiving CFZ. Methods: Patients with MM receiving first-time CFZ therapy are prospectively enrolled and undergo the following study procedures prior to CFZ initiation and then every 2 weeks for the first 6 weeks of CFZ therapy (C1D1, C1D15, C2D1, C2D15): 24-hour ambulatory blood pressure monitoring, echocardiography, pulse wave velocity, and EndoPAT endothelial function assessment. Patient-reported outcomes are also collected. Cardiovascular adverse events (CVAEs) and dyspnea are assessed at all timepoints, as well as at 3 and 6 months after enrollment, by CTCAE v5.0 and are adjudicated by a cardio-oncologist. Patients with endothelial dysfunction will be defined as reactive hyperemia index (RHI) <1.67 via EndoPAT. Baseline variables were analyzed with unpaired t-tests and longitudinal variables were analyzed by one-way repeated measures ANOVA. Results: Ten patients have completed 6 months of follow-up. Demographic data is summarized in the table. Four patients (40%) developed dyspnea, 2 with grade 1 and 2 with grade 3 at maximum, with most patients developing dyspnea by C1D15. Two patients had ongoing grade 1 dyspnea at follow-up. Four patients (40%) developed grade 3 or higher CVAEs, most of which were grade 3 hypertension and/or grade 3 HFpEF. Baseline left ventricular mass was significantly higher in patients who developed dyspnea compared to those who did not (p=0.040). EndoPAT values were significantly different between C1D1 and C1D15 in those with CVAEs (2.28 vs 1.74, p=0.0223). NTproBNP values were also significantly different between C1D1 and C1D15 in those with dyspnea (74.5 vs 129.3, p=0.006). Conclusions: MM patients that developed dyspnea during treatment with CFZ had a higher baseline LV mass and were more likely to develop increases in NTproBNP despite preserved ejection fraction, consistent with HFpEF. This group also had a greater change in EndoPAT values suggesting that short-term alterations in endothelial function may have a role in the development of dyspnea in those who may have the anatomic substrate for HFpEF. Clinical trial information: NCT04827563 . [Table: see text]
Management and outcomes of advanced stage cardiac AL amyloidosis in the daratumumab era.
Authors: Feuvrier-Rivera Ariana , Kumar Anupama Deepa , Urey Marcus Anthony , Costello Caitlin
Published: June 2023

e20058

Background: AL amyloidosis is plasma cell disorder involving irreversible deposition of amyloid fibrils, leading to end-organ damage. Treatment strategies include systemic therapy, autologous stem cell transplant (ASCT), and organ transplant. The ANDROMEDA trial established daratumumab (Dara) in combination with cyclophosphamide, bortezomib (Bor), and dexamethasone (CyBorD) as a new standard of care in newly diagnosed AL amyloidosis. Notably, only 2% of the trial population had stage IIIB cardiac disease by Mayo 2004 criteria. We present real world data of orthotopic heart transplantation (OHT) recipients with AL amyloidosis at our institution to understand the safety and outcomes of Dara use in the setting of advanced cardiac involvement. Methods: We performed a retrospective review of 9 patients at our institution who had received OHT since 2019 for AL amyloidosis. Demographics, disease details, treatment selection, response, and outcomes data were collected and described. Results: The cohort included 22% Black and 22% Hispanic patients, and the median age at diagnosis was 56. All patients had Revised Mayo stage 3 or 4 disease with advanced cardiac involvement requiring OHT. Patients had a median of 3 (2-4) suspected organs involved; none had symptomatic myeloma. Four patients received induction CyBorD; 2 achieved complete response (CR), 1 very good partial response (VGPR), and 1 partial response (PR) prior to OHT. Three of 4 received bridging therapy (Dara-Bor triplet or Bor alone) prior to ASCT, 2 due to inadequate response and 1 to maintain CR, and all achieved CR post-ASCT. Median time from OHT to ASCT was 13.5 months (range: 8-17), with bridging therapy starting at a median of 6 months post-OHT if received, with concomitant reduction in OHT immunosuppression. Five patients received DaraCyBorD induction: 2 achieved CR, 2 achieved VGPR, and 1 achieved PR prior to OHT. No patient who received DaraCyBorD received ASCT. Those not in CR received further therapy post-OHT. At the time of this analysis, 89% of patients remain in CR with 2 receiving ongoing therapy. All patients are alive with a median follow-up of 22 months (range: 11-35) since OHT without evidence for organ rejection. Conclusions: We demonstrate that the use of subcutaneous Dara is tolerable and effective in advanced stage cardiac AL amyloidosis, an underrepresented group in the literature. Patients who received DaraCyBorD followed by OHT without ASCT achieved similar outcomes to those who received CyBorD, OHT, and ASCT. The routine use of Dara may therefore negate the need for ASCT in this setting, given its favorable toxicity profile and reduced cost. [Table: see text]
Risk of MGUS, a multiple myeloma precursor, in relation to food and beverage intake in the National Health and Nutrition Examination Survey (NHANES).
Authors: Joseph Janine , Tang Li , Hillengass Jens , Landgren Ola , Usmani Saad Zafar , Lesokhin Alexander M. , Moysich Kirsten B. , Shah Urvi A
Published: June 2023

e20062

Background: Monoclonal gammopathy of undetermined significance (MGUS) is a plasma cell disorder (PCD) with a prevalence of 3% in adults over age 50. The annual risk of progression to multiple myeloma (MM) is 1%. Although one cohort study in Caucasians reported that diets low in certain plant-based foods were associated with MGUS (Thordardottir et al. 2018), research on diet and MGUS in a more diverse population is scarce. Given that diet can vary greatly across ethnic/racial groups, we conducted a population-based study with multiple races and ethnicities. Methods: Using the National Health and Nutrition Examination Survey (NHANES), we conducted a case-control study in 373 individuals with MGUS and 1,406 controls frequency matched on age, body mass index, NHANES cycle, sex, and race. Diet was characterized by one 24-hour dietary recall, with gram intake of individual foods and beverages aggregated into groups. MGUS status was determined by blood screening. Unconditional multivariable logistic regressions were used to model associations between MGUS and intake, with odds ratios and 95% confidence intervals reported for the highest quantile of intake. Results: Daily intake of several food and beverage groups were significantly associated with MGUS, low-risk MGUS (LRMGUS) or intermediate/high-risk MGUS (IHRMGUS). Whole-grain bread, oats, and rice; fruits and vegetables; tomatoes; and cruciferous vegetables were associated with significantly lower risk (28-78%). Sugar- and artificially sweetened beverages were associated with significantly higher risk (34-113%). Interestingly, there were more significant findings for LRMGUS than IHRMGUS, suggesting potential contributing etiologic differences for LRMGUS and IHRMGUS. Conclusions: Our study shows that low intake of whole grains, fruits and vegetables and high intake of sweetened beverages are associated with MGUS. The identification of dietary risk factors for MGUS in a diverse population is of direct public health relevance. These findings also provide rationale for exploration of mechanistic links between diet and PCDs, such as the ongoing studies NCT04920084, NCT05640843, and NCT05312255. [Table: see text]
FGR methylation in blood as a potential marker for the pre-clinical detection of early lung cancer: A case-control study.
Authors: Yang Rongxi , Zhang Wenjing , Zhu Qiang , Song Yakang , Song Huapeng , Zhou Xiajie
Published: June 2023

e20500

Background: Lung cancer (LC) is the leading cause of cancer-related death. Although low-dose computed tomography (LDCT) is a routine clinical test for early detection of LC, it can introduce excessive false positives. DNA specific methylation identification in peripheral blood can be used for noninvasive diagnosis and monitoring. Therefore, We applied a candidate approach and assess the association between blood-based FGR methylation and the risk of lung cancer in a case–control cohort. Methods: A total of 426 patients with LC and 428 age-and sex-matched healthy controls were recruited from two hospitals to collect peripheral blood and clinical information. The methylation levels of four CPG sites in FGR gene were determined by quantitative mass spectrometry. Linear regression models were used to estimate the association between DNA methylation site levels and lung cancer. And stratified analysis of age and sex. Results: It was found that the hypermethylation of FGR_CPG1 and FGR_CPG2 was associated with early LC (OR = 1.60 (95%CI: 1.35, 1.89, p = 5.35E-08) and 1.08 (95%CI: 1.01, 1.16, p = 3.58E-02), respectively). These associations persist in patients with very early LC (stage I). Stratified analysis showed that the association between hypermethylation of FGR_CPG2 and LC was only found in men and subjects younger than 55 years of age. Conclusions: This work reveals a novel association between aberrant FGR gene methylation in blood and early LC. These results suggest that FGR gene methylation may be used to predict early lung cancer and provide guidance for the prevention and control of lung cancer.