Adult Hematologic Malignancy Research Articles

Immediate inpatient toxicities associated with CAR T-cell therapy: Real world data from a national inpatient sample.

e18605 Background: Chimeric antigen receptor T-cell therapies (CAR-T) have shown overall survival benefits in multiple hematological malignancies. Since Tisageneleleucel's first approval in 2017 for ALL in pediatric and young adults, FDA has approved 5 CAR-T cell product for adult hematological malignancies all in refractory/relapsed setting. Cellular therapies are associated with severe immune related adverse events (IRAE) like Cytokine release syndrome (CRS), Immune effector-cell associated neurotoxicity (ICANS), and Hemophagocytic Lymphohistiocytosis (HLH). Limited real world data available for CAR T-cell associated immediate toxicity. CMS approved recent updates in ICD coding leading to better identification of IRAE in discharge data. We used NIS 2020 database with updated ICD codes to quantify immediate inpatient toxicity related to CAR T-Cell therapy. Methods: We identified patients with CAR T-cell from discharge data by utilizing ICD-10 procedure codes of CAR T-cell therapy for 5 approved products. Codes for acute lymphoblastic leukemia (ALL), DLBCL (diffuse large B-cell lymphoma), multiple myeloma (MM,) Follicular lymphoma (FH), Mantle Cell Lymphoma (MCL) were used to identify the indication. Patients without these indications were categorized as "Others". Appropriate weights were applied to the analyses to obtain national estimates. We analyzed in-hospital outcomes i.e Length of stay(days), and mortality. CAR T-cell related specific toxicity i.e CRS, ICANS, and HLH were identified and reported along with other complications. Cost to charge ratio adjusted hospitalization cost were estimated. Results: 2240 patients were identified on review of the NIS 2020 with 61.1% males, 74.11% NHW, mean age 57.54 years (95%CI 55.31-59.78), while 42.19% of the patients were age ≥65 years. 47.1% patients had private insurance while 39.06 % had Medicare. CAR-T cell was used for DLBCL in 60.94%, FH 2.23%, MCL 7.37%, MM 8.93% and ALL 9.38% patients respectively. The use of CAR-T was approximately equally distributed among four geographical regions of the United States. The mean length of stay was 19.4 days (17.05-21.75) and in patient mortality was observed in 3.79% of the patient population. The IRAE noted were CRS (17.19%), ICANS (12.5%) and HLH (2.46%). Other significant complications among patients were sepsis (9.15%), acute kidney injury (15.85%), Seizures (1.79%) and intubation (4.46%). Overall cost associated with the CAR-T therapy was found to be 270,446.9 (235670.5 - 305223.3). Conclusions: CAR-T therapy has appeared as a breakthrough in cancer management. Demographic variation is still an important issue and majority of the patients treated are white and have private insurance. DLBCL remains the most common target for CAR-T. Neurological syndromes remain significant adverse effects of the therapy and should be closely monitored.

Implementing a germline testing program using fingernail specimens for patients with hematologic malignancies and initial clinical findings.

10632 Background: About 5-20% of hematologic malignancies (HM) occur in the setting of a genetic cancer predisposition syndrome. Additionally, overt constitutional syndromes involving multiple systems may also predispose to HM. The spectrum of cancer predisposition in patients with HM has been limited partially due to the difficulty of germline sample ascertainment from patients with liquid tumors as skin biopsies and fibroblast cultures are often required for testing. Methods: Hematologic malignancy patients enrolled in Memorial Sloan Kettering Cancer Center’s institutional 12-245 study who were having somatic testing performed on their tumor were given the option to consent to germline testing using fingernail specimens. The validated germline assay using nails as a sample type was approved as a clinical test by the New York State Department of Health. Samples were analyzed using a custom panel consisting of 82 cancer predisposition genes. Single nucleotides, insertions deletions, and copy number variants were detected using our analytic pipeline and analyzed according to ACMG criteria for pathogenicity. Only pathogenic and likely pathogenic germline variants (gPV) were returned. Results: Among 86 HM patients (acute myeloid leukemia, n = 19; myelodysplastic syndrome, n = 16; acute B lymphoblastic leukemia, n = 9; acute T-cell leukemia, n = 4; mixed phenotypic acute leukemia, n = 1; chronic lymphocytic leukemia, n = 7; hairy cell leukemia, n = 1; chronic myeloid leukemia, n = 4; chronic myelomonocytic leukemia, n = 1, non-Hodgkin lymphoma, n = 12; Hodgkin lymphoma, n = 8; and multiple myeloma, n = 4), gPV were detected in 16 % (14/86). Heterozygous gPV identified in high/moderate penetrant genes included 2 BRCA1, 2 ATM, 1 PALB2, and 3 CHEK2. Monoallelic carriers for homozygous disease included 2 MUTYH and 1 MSH3. Biallelic gPV were identified in 3 patients (1 FANCA, 1 ATM, 1 MSH6); the patients with Fanconi anemia (age 25) manifesting with MDS and constitutional mismatch repair deficiency (age 13) presenting with T-cell lymphoblastic lymphoma had not been previously diagnosed with these conditions and did not have obvious clinical features outside of their cancer diagnosis. In all 3 patients, identification of an autosomal recessive syndrome impacted therapeutic planning. Conclusions: Our study demonstrates the feasibility of utilizing nails, a non-contaminated germline sample source, for HM predisposition with a significant proportion of pediatric and adult HM patients identified to harbor gPV in a cancer predisposition gene. Autosomal recessive diseases should be considered not only in pediatrics but also adult patients and requires confirmation of allele segregation in parents. Our data also demonstrate the importance of gPV in HM for therapeutic planning.

Pharmacological inhibition of BCL-2 with the FDA-approved drug venetoclax impairs longitudinal bone growth

Treatment-related skeletal complications are common in childhood cancer patients and survivors. Venetoclax is a BCL-2 inhibitor that has shown efficacy in hematological malignancies in adults and is being investigated in pediatric cancer clinical trials as a promising therapeutic modality. Venetoclax triggers cell death in cancer cells, but whether it exerts similar effects in normal bone cells, is unknown. Chondrogenic ATDC5 cells, E20 fetal rat metatarsal bones, and human growth plate biopsies were treated with different concentrations of venetoclax. Female NMRI nu/nu mice were treated with venetoclax or vehicle for 15 days. Mice were X-rayed at baseline and at the end of the experiment to assess longitudinal bone growth and body weight was monitored throughout the study. Histomorphometric and immunohistochemical analyses were performed to evaluate treatment effects on the growth plate cartilage. Venetoclax decreased the viability of chondrocytes and impaired the growth of ex vivo cultured metatarsals while reducing the height of the resting/proliferative zone and the hypertrophic cell size. When tested in vivo, venetoclax suppressed bone growth and reduced growth plate height. Our experimental data suggest that venetoclax directly targets growth plate chondrocytes suppressing bone growth and we, therefore, encourage careful monitoring of longitudinal bone growth if treating growing children with venetoclax.

CAPN1 is a novel biomaker of patients with AML based on comprehensive analysis

ABSTRACT Acute myeloid leukemia (AML) is a common hematologic malignancy in adults. Recent studies investigating the potential pathogenesis of AML have significantly advanced our understanding of this disease. While cytogenetics and molecular abnormalities are crucial for confirming chemotherapy response and long-term outcomes, there are additional potential therapeutic targets and prognostic factors. The CAPN1 gene, which encodes a large subunit of the ubiquitous enzyme calpain, has not been extensively studied in hematological diseases. In this study, we used data from the TCGA public database to perform a bioinformatic analysis and found that CAPN1 is differentially expressed in multiple cancers and is associated with an unfavorable prognosis in AML. We employed R software and websites such as David and STRING to conduct differential analysis, GO and KEGG analysis, and explore the correlation between CAPN1 and physiological processes and key pathways. Our findings suggest that CAPN1 is significantly associated with the structure of the extracellular matrix and receptor-ligand interactions, indicating its potential role in disease progression. Additionally, we used CYBERSORT and ssGSEA to analyze the immune environment of CAPN1 and found that it is associated with most immune components, particularly CD56 cells and neutrophils. In conclusion, CAPN1 is a key prognostic gene in AML that is significantly correlated with disease progression, clinical features, and immune invasion.

Management of Multiple Myeloma: A Review for General Practitioners in Oncology

Multiple myeloma (MM) is a malignant clonal plasma cell disorder in the bone marrow and is the second-most common hematologic malignancy in adults. Although patients with MM have a moderate life expectancy, it remains a heterogeneous disease that often requires multiple lines of chemotherapy for durable control and long-term survival. This review outlines current management strategies for both transplant-eligible and transplant-ineligible patients as well as for relapsed and refractory disease. Advances in drug therapies have widened management options and improved survival. In this paper, we also discuss implications for special populations and survivorship care.

Benefits and Barriers of Technology for Home Function and Mobility Assessment: Perspectives of Older Patients With Blood Cancers, Caregivers, and Clinicians.

Advances in digital health technology can overcome barriers to measurement of function and mobility for older adults with blood cancers, but little is known about how older adults perceive such technology for use in their homes. To characterize potential benefits and barriers associated with using technology for home functional assessment, we conducted three semistructured focus groups (FGs) in January 2022. Eligible patients came from the Older Adult Hematologic Malignancies Program at Dana-Farber Cancer Institute (DFCI), which includes adults 73 years and older enrolled during their initial consult with their oncologist. Eligible caregivers were 18 years and older and identified by enrolled patients as their primary caregiver. Eligible clinicians were practicing DFCI hematologic oncologists, nurse practitioners, or physician assistants with ≥2 years of clinical experience. A qualitative researcher led thematic analysis of FG transcripts to identify key themes. Twenty-three participants attended the three FGs: eight patients, seven caregivers, and eight oncology clinicians. All participants valued function and mobility assessments and felt that technology could overcome barriers to their measurement. We identified three themes related to potential benefits: making it easier for oncology teams to consider function and mobility; providing standardized, objective data; and facilitating longitudinal data. We also identified four themes related to barriers to home functional assessment: concerns related to privacy and confidentiality, burden of measuring additional patient data, challenges in operating new technology, and concerns related to data improving care. These data suggest that specific concerns raised by older patients, caregivers, and oncology clinicians must be addressed to improve acceptability and uptake of technology used to measure function and mobility in the home.

In vivo and molecular docking studies of the pathological mechanism underlying adriamycin cardiotoxicity

Adriamycin (ADR), one of the most effective broad-spectrum antitumor chemotherapeutic agents in clinical practice, is used to treat solid tumors as well as hematological malignancies in adults and children. However, long-term ADR use causes several adverse reactions, including time- and dose-dependent cardiotoxicity, which limit its clinical application. In addition, the mechanism by which ADR induces cardiotoxicity remains unclear. Therefore, we used zebrafish as animal models to evaluate ADR toxicity during embryonic heart development owing to the similarity of this process in zebrafish to that in humans. Exposure of zebrafish embryos to 1.25, 2.5, and 5 mg/L ADR induced abnormal embryonic development, with the occurrence of cardiac malformations, pericardial edema, decreased movement speed and activity, and increased distance between the venous sinus and the arterial bulb (SV-BA). ADR exposure induced dysregulated cardiogenesis during the precardiac mesoderm formation period. We also observed irregular expression of cardiac-related genes, an upregulation of apoptotic gene expression, and a dose-dependent increase in oxidative stress levels. Furthermore, oxidative stress-induced apoptosis exerted deleterious effects on cardiac development in zebrafish embryos, and treatment with astaxanthin (ATX) alleviated these heart defects. ADR- and Wnt pathway-related genes exhibited good energy and spatial matching, and ADR upregulated the Wnt signaling pathway in zebrafish. Moreover, IWR-1 effectively alleviated ADR-induced heart defects. In conclusion, we demonstrated that the toxic effects of ADR on cardiac development in zebrafish embryos could provide a theoretical basis for explaining the pathogenesis of ADR-induced cardiotoxicity, which occurs through the upregulation of oxidative stress and Wnt signaling pathway, as well as its prevention and treatment in humans. These findings will help develop effective treatment strategies to combat ADR-induced cardiotoxicity and broaden the application of ADR for clinical practice.

Predicting outcomes of hematological malignancy patients admitted to critical care

BackgroundCritical care (CC) admission has traditionally been viewed as likely to result in a poor outcome for hematological malignancy (HM) patients. Such a view can have implications for decisions surrounding CC admission. Recent studies have challenged this poor prognostication, however, there still remains limited data to support CC admission and escalation decisions and to elucidate risk factors which independently predict short- and longer-term survival outcomes.MethodsWe retrospectively analyzed a large cohort of adult HM patients (n=437) admitted to CC over a sixteen-year period, with the specific aim of identifying risk factors present at CC unit admission that could help to predict outcome. We assessed all-cause mortality at CC discharge (CC mortality, primary outcome) and at further time points (hospital discharge and 12-months post-discharge from CC). Single variable and multivariate analyses were performed to identify independent predictors of outcome.ResultsCC unit and hospital mortality rates were 33.4% (146 patients) and 46.2% (202 patients) respectively. At six-month and one-year follow-up, mortality increased to 59.5% and 67.9% respectively. At single variable adjusted regression analysis, eight factors were associated with CC mortality: APACHE II score, the number of organs supported, requirement for continuous renal replacement therapy (CRRT), cardiovascular support, or respiratory support (invasive and non-invasive), the ratio between arterial partial pressure of oxygen (PaO2) and the inspired oxygen concentration (FiO2) (P/F ratio) on CC admission, and the lowest P/F ratio during CC admission. However, only three factors showed independent predictive capacity for CC outcome at multivariate logistic regression analysis; APACHE II score on admission, requirement for ventilation and lowest P/F ratio.ConclusionOne third of HM patients admitted to CC died on the unit and, following admission to CC, approximately one-third of HM patients survived over 1 year. Our data show that, while a diagnosis of HM should not preclude admission of patients who might otherwise benefit from CC support, the prognosis of those with a high APACHE II score upon admission, or those requiring IMV remains poor, despite considerable advances in IMV techniques.

Monoclonal Light Chains in Multiple Myeloma: The Sinister Immunoglobulin

Multiple myelomas are the commonest hematological malignancy in adults, next to the heterogeneous group non-Hodgkin lymphomas, and account for about 10% of such tumors. About 21% of the multiple myelomas are associated with higher levels of free monoclonal light chains.

COVID-19 Vaccination Outcomes in Children, Adolescents, and Young Adults with Acute Lymphoblastic Leukemia

Background:While several studies have shown that less than half of adults on active therapy for chronic hematological malignancies develop an immune response to COVID-19 vaccination, little is known about the efficacy of COVID-19 vaccines in the midst of active therapy for acute lymphoblastic leukemia (ALL). Furthermore, COVID-19 vaccine outcomes in pediatric leukemia remain uncharacterized. Given the differences in the intensity of chemotherapy regimens between pediatric ALL and adult chronic hematological malignancies as well as age related immune differences, there is a need to specifically define vaccination outcomes in pediatric ALL. This study aims to define the safety and efficacy of COVID-19 vaccination in children and adolescents and young adults with ALL, the most common pediatric leukemia. Methods: We conducted a prospective single center Institutional Review Board approved study. Eligible patients were ages 5-25 years with a diagnosis of ALL or receiving ALL-like therapy who had received COVID-19 vaccination. Pediatric oncology patients at our center undergo universal surveillance for COVID-19 via nasopharyngeal PCR regardless of symptom status, prior to any sedation or hospitalization. Labs were drawn at 3,6-, and 12-months post-vaccination for anti-COVID-19 spike (S) and nucleocapsid (N) IgG ELISA and anti S neutralizing antibody assays, in vitro COVID-19 peptide stimulation T-cell response studies, and T-cell receptor (TCR) sequencing for COVID specific TCR. These tests were validated in healthy COVID-19 infection convalescent and healthy post-vaccination cohorts. Results: Between April 2021 and April 2022, the study enrolled 21 patients (median age 12.5 years). Diagnoses included high risk B-ALL (n=13), mixed-phenotype acute leukemia (MPAL) (n=2), and standard risk B-ALL (n=6). Three had relapsed ALL. All were in complete remission and receiving chemotherapy at the time of vaccination (17 receiving maintenance therapy and 4 in an intensive chemotherapy phase). Twenty received the BNT162b2 mRNA vaccine (10mcg dose n=11 and 30mcg dose, n=9); one received the Ad26.COV2.S vaccine. One patient received one dose (excluded from efficacy analysis), 17 received 2 doses, and 2 received three doses (i.e. a booster dose) of BNT162b2. Vaccinations were well tolerated with no patient experiencing anaphylaxis or an allergic reaction, including 10 patients with PEG-asparaginase allergy (BNT162b2 contains PEG). Three patients presented to the emergency department with fever; one of those was hospitalized for hypotension. Thirteen of 20 patients (65%) were positive for spike (S) anti-COVID-10 IgG following two doses of BNT162b2 (n=12) or one dose of Ad26.COV2.S (n=1). Eleven of these 13 were negative for N IgG, an antibody profile (S IgG+, N IgG-) consistent with an immune response to vaccination rather than a prior undiagnosed COVID-19 infection. All three patients with ≥ 6 months post-vaccination data continue to be positive for S IgG. Notably, 6 of 12 lymphopenic patients (absolute lymphocyte count <500 at the time of vaccination) and 3 of 4 patients in an intense phase of therapy during vaccination showed an immune response. Six of 8 patients with PEG-allergy had an immune response. All patients with positive S IgG showed presence of neutralizing anti-S antibodies. There was no difference in immune response based on vaccine dose. Five of 20 patients (3 of 13 patients who were S IgG+ following vaccination) developed COVID-19 infection following vaccination; one of these occurred after the third dose. Hospitalization was needed in one of five cases of COVID-19. All infections occurred during the omicron wave and included 3 sequencing confirmed omicron infections (variant testing not done for 2). Conclusions: In our study, two doses of COVID-19 vaccination induced a neutralizing antibody response in over half of the children and AYA actively receiving ALL chemotherapy including those who were receiving intensive chemotherapy or had PEG allergy. Adverse events were uncommon. Omicron infections occurred in our study, a finding consistent with the occurrence of breakthrough omicron variant infections in immunocompetent vaccinated individuals. T-cell response studies for our cohort are ongoing. Additional long-term follow-up and larger studies are needed to investigate durability of immune response and optimal vaccine frequency especially in the setting of omicron variants. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Perspectives of Older Patients with Blood Cancers, Caregivers, and Oncology Clinicians on Benefits and Barriers of Technology for Home Functional Assessment

Introduction: Advances in technology used to measure function and mobility may overcome barriers to their assessment in older adults with blood cancers. However, quantitative data regarding uptake and patient adherence in using such technology is mixed (Manz et al., J. Clin. Oncol, 2022), and qualitative data regarding acceptability from stakeholders is lacking. We conducted focus groups of older patients with blood cancers, their caregivers, and hematologic oncology clinicians to determine the potential benefits and barriers associated with the use of technology to measure function in the home. Methods: We conducted three semi-structured focus groups led by a trained moderator in January 2022: two 90-minute focus groups of older patients with either myelodysplastic syndrome (MDS) or multiple myeloma and caregivers, and one 60-minute focus group of blood cancer clinicians. Eligible patients came from the Older Adult Hematologic Malignancies Program at Dana-Farber Cancer Institute (DFCI, Boston, MA), which includes adults ≥ 70 years enrolled on their initial consult visit with their oncologist. Eligible caregivers were ≥ 18 years and identified by enrolled patients as their primary caregiver. Eligible clinicians were practicing DFCI hematologic oncologists, nurse practitioners, or physician assistants with at least two years of experience. Participants were asked about their general perspectives with technology and function/mobility assessments. The study team presented examples, supplemented with brief videos, of two of the main classes of technology currently being explored for measuring function and mobility in patients’ homes: (1) intermittent wearable sensors (represented by a smartphone gait application) and (2) passive monitoring devices (represented by a contactless device that continuously measures activity). All focus groups were conducted using a secure video-conferencing platform (Zoom), recorded, and professionally transcribed. A qualitative researcher (A.C.R.) led thematic analysis, discussing each step with the interdisciplinary study team. Analysis focused on identifying key patterns, concepts, contexts, and themes within and across groups to characterize perspectives on the potential benefits and barriers associated with the use of technology to measure home functioning. This process was supported by NVivo 12 Software (QSR International, Melbourne, Australia). Results: Twenty-three participants attended the three focus groups: four patients with MDS, four patients with multiple myeloma, and seven caregivers attended the first two, and seven physicians and one nurse practitioner spanning specialization in leukemia/MDS (3), multiple myeloma (2), lymphoma (2), and stem cell transplant (1) attended the third. Patients, their caregivers, and oncology clinicians valued functional and mobility assessment but felt that the current approach to these assessment was insufficient. Across focus groups, we identified four themes related to potential benefits of technology that would facilitate its acceptability in measuring functioning in patients’ homes (Table 1): (1) making assessments easier; (2) providing more standardized, objective assessments; (3) allowing for more longitudinal assessments; and (4) having prior familiarity with technology in everyday life. We found four themes related to barriers of technology that may limit its acceptability in measuring functioning in patients’ homes: (1) concerns related to privacy and confidentiality; (2) burden of measurement and having to review additional patient data; (3) challenges in operating new technology; and (4) concerns related to specific data collected and how these data would improve care. The main concern specific to the wearable sensor was patients reporting they might modify their walking knowing it was being measured. The main concern specific to the passive monitor was patient privacy in having home activities continuously monitored. Conclusion: Although patients, caregivers, and oncology clinicians reported several potential benefits of technology used to measure function and mobility in patients’ homes, they also voiced concerns about several barriers that could limit acceptability and uptake. Clinician-patient communication, best practices in data security, and further investigation will enhance implementation of these technologies in research and practice. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Improving the discharge medication reconciliation process for an inpatient hematologic malignancies service by utilizing a pharmacist-facilitated workflow

BackgroundThere is an opportunity for pharmacists to play a greater role during discharge medication reconciliation (MR), particularly in the oncology setting. ObjectivesThis initiative aims to decrease the number of medication discrepancies that occur during discharge MR and improve physician satisfaction with the discharge MR process for patients discharged from an inpatient adult hematologic malignancies (HM) service. Practice descriptionPatients on the HM service at Sibley Memorial Hospital, a community hospital located in Washington, DC, are co-managed by hospitalists and HM oncologists. The care team for the service also includes nursing staff and a clinical pharmacist. Practice innovationThe HM service piloted a pharmacist-facilitated workflow that involved the clinical pharmacist reconciling inpatient and outpatient medications prior to discharge, reviewing the discharge MR with the HM oncologist, and pending the discharge MR in the electronic medical record for the discharging hospitalist to review and sign. Evaluation methodsPrior to pilot implementation, discharge MRs of patients discharged from the HM service from November 2021 to December 2021 were analyzed by a pharmacist to identify medication discrepancies through retrospective chart review. This process was repeated to analyze pharmacist-facilitated discharge MRs for discrepancies for patients discharged between December 2021 to April 2022. Physician satisfaction with the process was assessed via survey pre and post-pilot. ResultsA total of 30 and 37 discharge MRs were analyzed pre- and post-pilot, respectively. There were 19 medications discrepancies identified in the pre-pilot group and 6 discrepancies noted in the post-pilot group (P=0.038). Median physician satisfaction with the process was found to be 3.3 pre-pilot, and 5 post-pilot (on a scale of 1-5, with 5 being very satisfied). ConclusionA pharmacist-facilitated workflow for discharge MR increased the accuracy of the discharge MR for patients on the HM service and improved physician satisfaction with the discharge MR process.

AD80 INHIBITS FLT3-MEDIATED SIGNALING AND HAS ANTINEOPLASTIC EFFECTS ON ACUTE MYELOID LEUKEMIA CELLS

Acute myeloid leukemia (AML) is one of the most common types of hematological malignancy in adults. Activating mutations in different tyrosine kinases have been identified as important factors in the development and progression of hematological neoplasms. For AML, FLT3-ITD has been described as a key mutation, activating signaling pathways such as PI3K, RAS, and STAT5. AD80 is a multikinase inhibitor able to inhibit the activity of kinases RET, RAF, S6K, and ERK. It is a new compound and, therefore, few studies have been carried out to date verifying its effects on tumor cells. In the present study, the cellular and molecular effects of AD80 in AML cell lines were analyzed. For the study, 6 human (FLT3-ITD: MV4-11 and MOLM13, BCR: ABL1: K562 and KU812, JAK2V617F: SET2 and HEL) and 5 murine (Ba/F3 with activating mutations: BCR::ABL1, BCR:ABL1T315I, JAK2V617F, MPLW515L, CSF3RT618I) cell lines representing different hematological neoplasms were utilized. Cell viability was assessed using MTT assay. Apoptosis, autophagy, and mitochondrial membrane potential were determined by flow cytometry. Colony formation assays were performed to analyze clonogenic ability. Protein expression/activation was assessed by western blot. In all cellular models, AD80 reduced cell viability in a time- and dose-dependent manner (all p < 0.05). MOLM13 and MV4-11 cells were the most sensitive, with IC50 ranging from 0.4 to 1.1 nM. In FLT3-ITD cell lines, AD80 induced apoptosis and autophagy, disrupted mitochondrial membrane potential, as well as decreased clonogenic ability in a dose-dependent manner (all p < 0.05). AD80 markedly decreased the activation of AKT, STAT5, S6RP, and induced PARP1 cleavage and γH2AX. AD80 was more potent in reducing the viability of FLT3-ITD AML cell lines. Indeed, it has been shown that AD80 strongly inhibits wild-type and mutated FLT3 in an in vitro assay (>90% of inhibition; Dar et al. Nature, 486:80–84, 2012). Similarly, AD80 also inhibits, in less extension, wild-type and mutated ABL1 and JAK2, which corroborate our cell viability findings. Previous studies from our group showed that AD80 has effects on AML cell lines without the tyrosine kinase-related mutations, with IC50 values ranging from 1.6 to 27.2 μM. In contrast, AD80 concentrations at 0.64 nM were able to induce apoptosis and disrupt mitochondrial membrane potential at 72 h, and induced autophagy at 24 h of treatment in FLT3-ITD AML cell lines. In the molecular scenario, this compound decreases the expression/activating of proteins related to cell growth and proliferation and increases molecular markers of autophagy and apoptosis. AD80 exhibits antineoplastic effects against FLT3-ITD mutated cell lines at nanomolar concentrations, highlighting a noticeably on-targeted effect, and opening up research possibilities that could potentially evolve to further investigations. FAPESP, CNPq, and CAPES.

P413 Screening and diagnosis of Candidemia in adult hematological malignancies of northern India

Poster session 3, September 23, 2022, 12:30 PM - 1:30 PMCandidemia is caused by Candida species which has become a common cause of fungal infection in the bloodstream infection throughout the world. In hematological malignancies, patients have a high rate of morbidity and mortality due to Candidemia.AimTo identify Candidemia in immunocompromised patients with the help of various conventional methods as well as automated methods for early detection and treatment.Material and MethodsThis study was conducted from 2018 to 2021. In this study, we enrolled immunocompromised patients with hematological malignancies. For early diagnosis of Candidemia we did conventional method as well as PCR. Compare the conventional, automated, and PCR methods for diagnosis of Candidemia and was performed antifungal susceptibility testing for treatment in hematological patients.ResultsTotal 187 patients were enrolled on the basis of febrile neutropenia. A total of 125/187 males (66.8%) and 62/187 females (33.2%) participated in the present study followed by age range from 10 to 77 years (mean = 33.16, standard deviation = 16.29). A total of 5 patients (2.6%) were positive from blood culture, and 9 patients (4.8%) were positive from PCR. In 4 patients of AML C. tropicalis was (3; 1.60%) and C. auris (1; 0.5%) followed by 1 patient with pancytopenia C. tropicalis (1; 0.5%). The sensitivity was done according to the Clinical Laboratory Standards Institute (CLSI) guideline M27-A3 reference document for C. tropicalis (4), and C. auris (1). A total of 4 isolates of C. tropicalis were sensitive to drug VRC (MIC range 0.125 μg/ml), AMP (MIC range 1 μg/ml), FLU (MIC range 1 μg/ml), CAS (MIC range 0.25 μg/ml) and 1 resistant pattern toward FLU (MIC range 4 μg/ml). Candida auris was resistant toward AMP (MIC range 2 μg/ml), FLU (MIC range 64 μg/ml), and sensitive toward CAS (MIC range 0.5 μg/mL). A total of 4 isolates of C. tropicalis was sensitive for drug VRC (80%), AMP (80%), FLU (60%), CAS (80%), and resistant pattern for FLU (20%). Candida auris was resistant toward AMP (20%), FLU (20%), and sensitive toward CAS (20%). In all, 9/187 patients’ blood was positive for fungal infection, primer NL-1 and NL-4 were able to amplify the D1/D2 region of 28S r-DNA of large ribosomal subunit which target rDNA yielding Product of PCR give 600 bp related to all fungus. Primer P4501 and P4502 identify the P-450 lanosterol 14α-demethylase gene which is target Candida species genes single band of around 350 bp. Mannan antigen of Candida was performed by ELISA method for diagnosis of candidemia in hematological patients.ConclusionThis present observational study recognizes the main association of Candidemia with hematological malignancies. We try to develop PCR and automated methods in routine mycology laboratory to diagnose Candidemia in an early stage in hematological malignancies along with other immunocompromised patients for better treatment to cure the disease.

Immuno-PET Imaging and Radioimmunotherapy of Lymphomas.

Monoclonal antibodies (Ab) have revolutionized the management of lymphomas, the most common hematologic malignancy in adults. Indeed, incorporation of rituximab into the regimen for indolent non-Hodgkin's lymphomas (NHLs) has dramatically improved treatment response and disease outcome. Yet, newer Ab therapeutics against promising antigen targets need to be developed to treat refractory or relapsed patients. Treatment efficacy can be further enhanced by conjugating toxic molecules to the Abs. Radioimmunotherapy (RIT) harnesses Abs as vehicles for targeted delivery of therapeutic radionuclide payloads for direct killing of targeted tumor cells. Positron emission tomography (PET) with radiolabeled Abs (called immuno-PET) can facilitate the development of new Ab therapeutics and RIT by providing pharmacokinetic and pharmacodynamic information and by quantifying tumor antigen level relevant for treatment decision. Immuno-PET has recently gravitated toward labeling Abs with 89Zr, a radiometal with a 3.3 day half-life that is trapped following Ab internalization and thus provides high-resolution PET images with excellent contrast. Immuno-PET methods against major lymphoma antigens including CD20 and other promising targets are currently under development. With continued improvements, immuno-PET has the potential to be used in lymphoma management as an imaging biomarker for patient selection and assessment of treatment response.

Abstract 6374: BMP6 overcomes multiple myeloma-induced bone disease by inducing the expression of small leucine-rich proteoglycans

Abstract Multiple myeloma (MM), the second most common hematologic malignancy in adults, is characterized by clonal proliferation of malignant plasma cells and tumor-induced complications, including MM-induced bone disease (MBD). Up to 90% of MM patients develop MBD during the course of their disease, which is a major cause of morbidity and mortality. MM therapy focuses primarily on agents that seek to eradicate the tumor cells and others which inhibit bone resorption. In contrast, no drugs are currently available to promote bone formation in MM patients and reverse MBD. Towards addressing this unmet therapeutic need, we applied a modified version of our “humanized” bone marrow (BM)-like scaffold (huBMsc)-based xenograft model, where MM cells and bone marrow mesenchymal stromal cells (BMMSCs) are co-implanted. In this system, we investigated the impact of MM cells on BMMSCs to identify markers that can be targeted with the intent to reverse MBD. After confirming that MM cells indeed inhibit bone formation in vivo, we performed transcriptional analysis of ex vivo expanded “unexposed” control BMMSCs vs. “MM-exposed” BMMSCs and found 332 differentially expressed genes. Next, we compared these data with transcriptional profiles of BMMSCs after in vitro differentiation towards osteoblasts, as well as publicly available data of transcriptional profiles of BMMSCs obtained from MM, ALL, and AML patients. Combined, this analysis identified 8, MM-specific, differentially expressed genes, including the small leucine-rich proteoglycans (SLRPs), ASPN, OGN and OMD, that are 1) suppressed in the presence of MM (xenograft model and patient-derived BMMSCs); 2) induced during in vitro osteogenic differentiation; and 3) not dysregulated in BMMSCs in other hematological malignancies. As reported previously, we observed that bone morphogenetic protein (BMP)6 can upregulate the expression of these SLRPs in BMMSCs, while inducing osteogenic differentiation. Moreover, incubation of MM cells with BMP6 in either mono- or co-cultures with stromal cell lines, resulted in reduced MM cell viability. In addition, pretreatment of BMMSCs with BMP6 completely abolished their support of MM proliferation. Interestingly, BMP6, in contrast to BMP2 and BMP4, did not induce, but inhibited receptor activator of nuclear kappa-B ligand (RANKL)-dependent osteoclast generation. Collectively, our analyses identify BMP6 as a master regulator that promotes osteogenic differentiation, inhibits RANKL-dependent osteoclastogenesis and can directly induce MM cell death. Therefore, by reshaping the BM microenvironment to become less tumor-supportive, BMP6 represents an attractive candidate for MM treatment. Citation Format: Jiaxian Wang, Thomas Baardemans, Ricardo de Matos Simoes, Olga Dashevsky, Huipin Yuan, Joost D. de Bruijn, Anton C. Martens, Constantine S. Mitsiades, Richard W. Groen. BMP6 overcomes multiple myeloma-induced bone disease by inducing the expression of small leucine-rich proteoglycans [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6374.

Implication of microRNAs in Carcinogenesis with Emphasis on Hematological Malignancies and Clinical Translation.

MicroRNAs (miRNAs) are evolutionarily conserved small non-coding RNAs, that are involved in the multistep process of carcinogenesis, contributing to all established hallmarks of cancer. In this review, implications of miRNAs in hematological malignancies and their clinical utilization fields are discussed. As components of the complex regulatory network of gene expression, influenced by the tissue microenvironment and epigenetic modifiers, miRNAs are “micromanagers” of all physiological processes including the regulation of hematopoiesis and metabolic pathways. Dysregulated miRNA expression levels contribute to both the initiation and progression of acute leukemias, the metabolic reprogramming of malignantly transformed hematopoietic precursors, and to the development of chemoresistance. Since they are highly stable and can be easily quantified in body fluids and tissue specimens, miRNAs are promising biomarkers for the early detection of hematological malignancies. Besides novel opportunities for differential diagnosis, miRNAs can contribute to advanced chemoresistance prediction and prognostic stratification of acute leukemias. Synthetic oligonucleotides and delivery vehicles aim the therapeutic modulation of miRNA expression levels. However, major challenges such as efficient delivery to specific locations, differences of miRNA expression patterns between pediatric and adult hematological malignancies, and potential side effects of miRNA-based therapies should be considered.

A Novel Risk Predictive Scoring Model for Predicting Subsequent Infection After Carbapenem-Resistant Gram-Negative Bacteria Colonization in Hematological Malignancy Patients.

BackgroundThis study investigated the high-risk factors associated with the increased vulnerability for subsequent clinical CR-GNB infection in carbapenem-resistant Gram-negative bacteria (CR-GNB)-colonized hematological malignancy (HM) patients and built a statistical model to predict subsequent infection.MethodAll adult HM patients with positive rectoanal swabs culture for CR-GNB between January 2018 and June 2020 were prospectively followed to assess for any subsequent CR-GNB infections and to investigate the risk factors and clinical features of subsequent infection.ResultsA total of 392 HM patients were enrolled. Of them, 46.7% developed a subsequent clinical CR-GNB infection, with 42 (10.7%) cases of confirmed infection and 141 (36%) cases of clinically diagnosed infection. Klebsiella pneumoniae was the dominant species. The overall mortality rate of patients colonized and infected with CR-GNB was 8.6% and 43.7%. A multivariate analysis showed that remission induction chemotherapy and the duration of agranulocytosis, mucositis, and hypoalbuminemia were significant predictors of subsequent infection after CR-GNB colonization. According to our novel risk-predictive scoring model, the high-risk group were >3 times more likely to develop a subsequent infection in comparison with the low-risk group.ConclusionOur risk-predictive scoring model can early and accurately predict a subsequent CR-GNB infection in HM patients with CR-GNB colonization. The early administration of CR-GNB-targeted empirical therapy in the high-risk group is strongly recommended to decrease their mortality.

Effects of exercise interventions for physical fitness, fatigue, and quality of life in adult hematologic malignancy patients without receiving hematopoietic stem cell transplantation: a systematic review and meta-analysis

Effects of exercise interventions for physical fitness, fatigue, and quality of life in adult hematologic malignancy patients without receiving hematopoietic stem cell transplantation: a systematic review and meta-analysis

The Use of qSOFA, SOFA, and Ramathibodi Early Warning Score (REWS) to Predict Severe Complications in Hematologic Malignancy Patients.

BackgroundSepsis causes high mortality in vulnerable groups such as hematologic malignancy (HM) patients. There are various early warning scores of sepsis, eg, qSOFA, SOFA, and Ramathibodi Early Warning Score (REWS). This study aimed to compare REWS, qSOFA, and SOFA in predicting severe complications in hematologic malignancy patients visiting ED.MethodsThe study was conducted as a retrospective cohort study at the ED of Ramathibodi Hospital, Bangkok, Thailand. Adult HM patients suspected of sepsis and have visited ED between March 2016 and December 2019.ResultsAmong 124 patients in our cohort, 51 (41%) had serious complication in ED and 20 (16%) died within 28 days after admission. The AUROCs of SOFA and qSOFA indicate significantly higher predicting in serious complication in ED than REWS (SOFA, 0.81 [95% CI, 0.73–0.89], qSOFA, 0.73 [95% CI, 0.65–0.81], REWS, 0.62 [95% CI, 0.52–0.72] p=0.004) while the predicting in 28-day mortality is not statistically significantly different (SOFA, 0.73 [95% CI, 0.60–0.85], qSOFA, 0.69 [95% CI, 0.58–0.80], REWS, 0.60 [95% CI, 0.44–0.75] p=0.25).ConclusionThe SOFA score is highest in predicting severe complications among hematologic malignancy patients.