Types Of Hematological Malignancies Research Articles

Characteristics of CRC01, an investigational CD19 CAR-T product with PD-1 and TIGIT genes silenced by shRNAs.

e14514 Background: Currently, CAR-T therapy has been successful in the treatment of certain types of hematological malignancy. However, not all patients benefit from this novel therapy due to various resistance mechanisms, such as suppression of immune cell function by inhibitory immune checkpoint signaling. To overcome this, we have developed a novel two-in-one lentiviral vector system that can efficiently induce shRNA-based silencing of PD-1 and TIGIT genes in CAR-T cells while maintaining robust CAR expression. This PD-1 and TIGIT-silenced CD19 CAR-T, CRC01, showed an enhanced anti-tumor activity in vitro and in vivo, compared to conventional CD19 CAR-T. For the development of CRC01 as an investigational new drug, IND-enabling non-clinical studies have been conducted and CRC01 is currently being evaluated in a clinical trial for r/r LBCL patients (NCT04836507). Methods: T cells were enriched from leukapheresis products of r/r LBCL patients and transduced with the two-in-one lentiviral vector. Transduced T cells were expanded within a semi-closed culture system and formulated for cryopreservation. For phase I clinical trial of CRC01, ten batches of CRC01 were manufactured and characterized in quality. Results: In the manufacturing of ten batches of CRC01, manufacturing time was in the range of 8-14 days and total cells expanded 32-53 folds. In the final product of CRC01, T cell percentage (Live CD3+) and viability were not less than 98% and 85%, respectively. The range of transduction efficiency was 11.3%-28.6% and the range of vector copy number was 1.0-3.5 copies/CAR-T. Generally, CRC01(CAR-positive T cells) showed higher CD4/CD8 ratio than leukapheresis product and CAR-negative T cells, and central memory and effector memory T cell subsets were the main populations of CRC01. All batches of CRC01 released IFN-γ in response to CD19-expressing target cells, but the level of IFN-γ production was quite different from batch to batch. When PD-1 and TIGIT expression levels of CRC01 were analyzed after CD3/CD28 stimulation, CAR-positive T cells were found to express PD-1 and TIGIT much lower than CAR-negative T cells, demonstrating an efficient silencing of PD-1 and TIGIT genes in CRC01. Conclusions: Ten batches of CRC01 were manufactured in GMP facility for CRC01 phase I clinical trial. All batches met acceptance criteria for release, showing that CRC01 manufacturing process is a robust one and that silencing of PD-1 and TIGIT genes via shRNAs, a unique feature of CRC01, was successfully implemented in the investigational products.

CAR-T Cells Shoot for New Targets: Novel Approaches to Boost Adoptive Cell Therapy for B Cell-Derived Malignancies.

Chimeric antigen receptor (CAR)-T cell therapy is undeniably a promising tool in combating various types of hematological malignancies. However, it is not yet optimal and a significant number of patients experience a lack of response or relapse after the treatment. Therapy improvement requires careful analysis of the occurring problems and a deeper understanding of the reasons that stand behind them. In this review, we summarize the recent knowledge about CAR-T products’ clinical performance and discuss diversified approaches taken to improve the major shortcomings of this therapy. Especially, we prioritize the challenges faced by CD19 CAR-T cell-based treatment of B cell-derived malignancies and revise the latest insights about mechanisms mediating therapy resistance. Since the loss of CD19 is one of the major obstacles to the success of CAR-T cell therapy, we present antigens that could be alternatively used for the treatment of various types of B cell-derived cancers.

Immunogenicity of COVID-19 vaccines in patients with diverse health conditions: A comprehensive systematic review.

It remains unclear how effective COVID‐19 vaccinations will be in patients with weakened immunity due to diseases, transplantation, and dialysis. We conducted a systematic review comparing the efficacy of COVID‐19 vaccination in patients with solid tumor, hematologic malignancy, autoimmune disease, inflammatory bowel disease, and patients who received transplantation or dialysis. A literature search was conducted twice using the Medline/PubMed database. As a result, 21 papers were included in the review, and seropositivity rate was summarized by specific type of disease, transplantation, and dialysis. When different papers studied the same type of patient group, a study with a higher number of participants was selected. Most of the solid tumor patients showed a seropositivity rate of more than 80% after the second inoculation, but a low seropositivity was found in certain tumors such as breast cancer. Research in patients with certain types of hematological malignancy and autoimmune diseases has also reported low seropositivity, and this may have been affected by the immunosuppressive treatment these patients receive. Research in patients receiving dialysis or transplantation has reported lower seropositivity rates than the general population, while all patients with inflammatory bowel disease have converted to be seropositive. Meta‐analysis validating these results will be needed, and studies will also be needed on methods to protect patients with reduced immunity from COVID‐19.

Prognostic role of TNF alpha, LT alpha, MDR1 and codon 72 Tp53 gene polymorphisms on multiple myeloma Egyptian patients

Multiple Myeloma (MM) is a type of hematologic malignancies that characterized by uncontrolled plasma cell proliferation. So, the diagnosis depends on the increased numbers of abnormal, immature, or atypical plasma cells in the bone marrow, and many patients present with laboratory abnormalities, such as anemia, hypercalcemia, renal disease, and high protein levels in blood and urine. We aim to analyze the association of some genetic polymorphisms and its effect on the overall survival (OS) among MM patients. Subjects and methodsWe analyzed TNFα 308 G/A, TNFα 238 G/A, LTA252A/G, MDR 3435 C/T, MDR 1236 C/T, TP53 Arg72Pro in 110 multiple myeloma case and 112 healthy controls. The genotyping was performed using PCR-RFFLP. ResultsIn TNF308 AA genotype and A allele were significantly lower with protective effect against MM development (OR=0.318, 0.742) respectively. LTA 252, GG genotypes had lower frequency in MM cases compared to control group with protective effect against MM development (OR=0.361). In TNF238, MDR1 3435 C/T, TP53 codon 72 polymorphism we didn’t find any statistically significant relation between MM and control groups. In Uni and multivariant analysis show ISS, IgG, TP53 Arg72ProGC+CC as risk predictors of shorter OS.But TNFα-308 GA+AA and LTA 252 AG+GG were considered as predictors of longer OS in MM cases. ConclusionOur result confirms the association of TNF-308, LTA and TP53 codon72 with prognostic outcome in MM. As a result, we suggest involving these genes as a biomarker test to predicts the risk and prognostic outcome of MM. Also, we recommend further investigations of these polymorphisms in MM especially LTA and TP53codon 72 polymorphism which have very low reported studies. MicroAbstractMany genes can affect the prognosis of MM. We analyzed some of them in 110 MM and 112 controls using PCR-RFLP. TNFα-308 AA and LTA-252 GG had lower frequency while MDR1–1236 TT had higher frequency in MM. TNFα-308 AA and LTA-252 GG were significantly associated with higher OS but TP53 codon72 polymorphism CC with lower OS. These findings confirm the association of these genes with prognostic outcome in MM.

NADH dehydrogenase subunit 1/4/5 promotes survival of acute myeloid leukemia by mediating specific oxidative phosphorylation.

Acute myeloid leukemia (AML) is a type of hematological malignancy caused by uncontrolled clonal proliferation of hematopoietic stem cells. The special energy metabolism mode of AML relying on oxidative phosphorylation is different from the traditional ‘Warburg effect’. However, its mechanism is not clear. In the present study, it was demonstrated that the mRNA expression levels of NADH dehydrogenase subunit 1, 4 and 5 (ND1, ND4 and ND5) were upregulated in AML samples from The Cancer Genome Atlas database using the limma package in the R programming language. Reverse transcription-quantitative PCR and ELISA were used to verify the upregulation of ND1, ND4 and ND5 in clinical samples. Pan-cancer analysis revealed that the expression of ND1 was upregulated only in AML, ND2 was upregulated only in AML and thymoma, and ND4 was upregulated only in AML and kidney chromophobe. In the present study, it was demonstrated that silencing of ND1/4/5 could inhibit the proliferation of AML cells in transplanted tumor of nude mice. Additionally, it was found that oxidative phosphorylation and energy metabolism of AML cells were decreased after silencing of ND1/4/5. In conclusion, the present study suggested that ND1/4/5 may be involved in the regulation of oxidative phosphorylation metabolism in AML as a potential cancer-promoting factor.

Cancer related anaemia (CRA)

Cancer-related anemia (CRA) is a complicated and multifaceted problem that can occur as a result of tumor, as an adverse reaction of chemotherapeutic agent, or as a result of neurotoxic effects. The symptoms of CRA vary depending on an individual's response to blood loss or reduction in the number of red blood cell production. Patients with severe anemia have different characteristics depending on the type of haematological malignancy they have. Clinical and biochemical evaluations, as well as bone marrow examinations, may be useful diagnostic tools in many cases. Iron therapy can be usedalone or in combination with ESA to improve the response of Hb and to decrease the need of RBC transfusion. lood transfusion carries a number of risks, some of which can be mitigated or even eliminated.. Even though erythropoietin-stimulating agents (ESAs) have been shown to be effective in preventing anemia and reducing the need for blood transfusions, it would be helpful for identifying high-risk patient groups that would benefit the most from these expensive treatments. Blood transfusions should be used on a specific instance basic principle in patients with advanced cancer, depending on the extent of distressing symptoms and life expectancy.

Are Induced Pluripotent Stem Cells a Step towards Modeling Pediatric Leukemias?

Despite enormous improvements in pre-clinical and clinical research, acute leukemia still represents an open challenge for pediatric hematologists; both for a significant relapse rate and for long term therapy-related sequelae. In this context, the use of an innovative technology, such as induced pluripotent stem cells (iPSCs), allows to finely reproduce the primary features of the malignancy and can be exploited as a model to study the onset and development of leukemia in vitro. The aim of this review is to explore the recent literature describing iPSCs as a key tool to study different types of hematological malignancies, comprising acute myeloid leukemia, non-down syndrome acute megakaryoblastic leukemia, B cell acute lymphoblastic leukemia, and juvenile myelomonocytic leukemia. This model demonstrates a positive impact on pediatric hematological diseases, especially in those affecting infants whose onsets is found in fetal hematopoiesis. This evidence highlights the importance of achieving an in vitro representation of the human embryonic hematopoietic development and timing-specific modifications, either genetic or epigenetic. Moreover, further insights into clonal evolution studies shed light in the way of a new precision medicine era, where patient-oriented decisions and therapies could further improve the outcome of pediatric cases. Nonetheless, we will also discuss here the difficulties and limitations of this model.

Abstract PO-083: Descriptive pilot study results of belief in research, religious coping, and willingness to participate in clinical trials among African Americans with hematologic malignancies

Abstract African Americans (AAs) are disproportionately affected by certain types of hematologic malignancies. AAs have a 45% higher probability of dying from acute lymphoblastic leukemia and a 12% higher risk of death from acute myeloid leukemia than Hispanics (6%) and non-Hispanic Whites. AAs also present with chronic lymphocytic leukemia at a younger age, have a more advanced stage disease, and lower survival rates in diffuse large B-cell lymphoma and Hodgkin lymphoma compared to non-Hispanic Whites. Despite the efforts of investigators, AAs with hematologic malignancies remain grossly underrepresented in cancer clinical trials. Underrepresentation of this subset of AAs leads to the non-generalizability of clinical trial findings, disparities in cancer treatment outcomes, and survival compared to other minority populations. Even so, few studies have evaluated the underrepresentation of this subgroup of patients in the context of their beliefs and willingness to participate in clinical trials. Yet, the willingness to participate in cancer clinical trials among AAs with solid tumors is well documented. There is also little evidence relating to the moderating effect of religious coping on the association of belief in research and willingness to participate in clinical trials among this subset of patients. Knowing, as well as believing, are essential elements to participating in any clinical trial. Thus, the aims of the descriptive pilot study were to determine if a relationship exists between belief in research and willingness to participate in clinical trials and determine if religious coping moderates the relationship between belief in research and willingness to participate in clinical trials. To address the aims, data on religious coping were captured at one time-point from 31 AAs with leukemia, lymphoma, and multiple myeloma using the validated Brief RCOPE scale and questions that addressed beliefs associated with research and willingness to participate in cancer clinical trials. The results show that there was no statistical difference between belief in research and willingness to participate in clinical trials, and religious coping did not moderate the effect of belief in research on willingness to participate in clinical trials. Statistically significant differences were found between education and belief in research. Participants with less than a high school education had lower belief in research scores than those with some college education, who showed higher belief in research scores. These findings provide preliminary results that suggest future studies are warranted in the study of AAs' beliefs in research. Such studies may contribute to the development of educational interventions to improve the recruitment of AAs with hematologic malignancies into the therapeutic clinical trials for these diseases, with a particular emphasis on educational interventions for those AAs with less than high school education. Citation Format: Marjorie Petty. Descriptive pilot study results of belief in research, religious coping, and willingness to participate in clinical trials among African Americans with hematologic malignancies [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-083.

Evaluation of oral mucositis in pediatric cancer patients in Hiwa Hospital in Sulaymaniyah city, Kurdistan Region, Iraq

Background and objective: Oral mucositis is caused by the destruction of the oral mucosal epithelium and suppression of its growth secondary to antineoplastic treatment in the form of chemotherapeutic drugs, substances, or radiotherapy. This study aimed to evaluate oral mucositis in pediatric cancer patients because it is one of the common side effects of cancer therapy that influences the outcome. Methods: This is a cross-sectional study that enrolled 100 pediatric patients with both hematological and non-hematological cancer. The age of the patients ranged from 1-18 years, involving both genders. Cases admitted to Hiwa hospital were clinically evaluated for oral mucositis, and ethical permission was taken from parents. Risk factors were assessed, including age, sex, cancer type, type of chemotherapy, radiotherapy, number of cycles, complete blood count, interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha, and tumor necrosis factor-beta. Results: Baseline serum cytokines levels showed significant correlation between Interleukin-6 and intensity of the oral mucositis (P = 0.003, rho = 0.314) and no correlation between severity of oral mucositis with tumor necrosis factor-alpha, tumor necrosis factor-beta nor interleukin-1 beta (P = 0.140 and rho = 0.258, P = 0.463 and rho = -0.079, and P = 0.706 and rho = -0.041, respectively). There was significant relationship between Hemoglobin level, neutropenia and type of non-hematological cancer with the intensity of oral mucositis respectively (P ≤0.001 and rho = -0.352, P = 0.027 and rho = -0.221, and P = 0.035 and rho = 0.095, respectively). Correlation between age, gender, white blood cell count, platelet count, type of hematological malignancy and past history with the intensity of the oral mucositis did not show significant result. Conclusion: Intensity of oral mucositis increased with anemia, neutropenia, high interleukin-6 level, and the type of non-hematological cancer. It is recommended to treat anemic, neutropenic patients as soon as possible before exacerbating the mucositis. Methotrexate is the most aggressive drug alone and in combined chemotherapy agents, which may cause mucositis and needs prophylaxis like topical nystatin suspension or other methods. Keywords: Oral mucositis; Pediatric cancer; Non-hematological; Hematological; Sulaymaniyah.

COVID-19 Vaccine Response in Patients with Hematologic Malignancy: A Systematic Review and Meta-Analysis

Introduction:Emerging data suggests that seroresponse (SR) in patients with hematologic malignancy following COVID-19 vaccination is likely lower than in patients without blood cancer. The objective of this study was to perform a systematic review and meta-analysis on SR in patients with hematologic malignancy who received COVID-19 vaccination (submitted to PROSPERO for registration).Methods:We searched PubMed and EMBASE from December 1, 2020, to July 22, 2021, to identify studies of SR following COVID-19 vaccine in adult patients with hematologic malignancy (including studies in which patients with hematologic malignancy represented a subset of a broader population). Patients with positive serologic response at baseline (prior to vaccination) or known COVID-19 infection were excluded. The primary outcomes were pooled SR estimates following COVID-19 vaccination in patients with hematologic malignancy, and pooled SR estimates of subgroups based on hematologic malignancy type. Secondary outcomes were pooled relative risk ratio (RR; compared to non-cancer controls) based on dichotomous-effect SR in all patients, and subgroups based on hematologic malignancy type, treatment status, and use of anti-CD20 therapy. Pooled estimates and RR with its associated 95% confidence intervals (CIs) were calculated using MetaXL (EpiGear), and Reference Manager (Cochrane) using random effects model.ResultsA total of 17 studies comprising 2834 patients with hematologic malignancy from Europe, United Kingdom and North America were included (Figure 1). The pooled estimate for SR was 58% (95% CI 48-67%, I 2 95%), with a RR of 0.53 (95% 0.42-0.66, I 2 94%) when compared to controls (10 studies with comparison group, 1092 hematologic malignancy patients, 830 controls; Figure 2). The pooled estimate for SR varied by type of hematologic malignancy: lymphomas SR 52% (95% CI 36-68%, 7 studies, 832 patients, I 2 94%); chronic lymphocytic leukemia (CLL) SR 42% (95% CI 25-60%, 6 studies, 921 patients, I 2 93%); plasma cell dyscrasias SR 66% (95% CI 47-83%, 8 studies, 611 patients, I 2 95%); myeloproliferative neoplasms (MPNs, including chronic myelogenous leukemia) SR 83% (95% CI 68-95%, 6 studies, 227 patients, I 2 58%); acute leukemia SR 86% (95% CI 77-94%, 2 studies, 67 patients, 46 acute myelogenous leukemia [AML] and 15 acute lymphocytic leukemia], I 2 0%). The RR for SR also varied by type of hematologic malignancy: lymphomas (excluding CLL) RR 0.48 (95% CI 0.34-0.68, 4 studies, 337 patients, I 2 89%); CLL RR 0.37 (95% CI 0.25-0.53, 3 studies, 194 patients, I 2 54%); plasma cell dyscrasias RR 0.73 (95% CI 0.62-0.86, 5 studies, 323 patients, I 2 70%); RR MPN 0.78 (95% CI 0.62-0.99, 3 studies, 199 patients, I 2 90%). The pooled estimate for SR in those receiving treatment was 42% (95% CI 26-58%, 9 studies, 683 patients, I 2 94%). The pooled estimates for SR for those receiving anti-CD20, bruton tyrosine kinase inhibitor (BTKi), or venetoclax were 13% (95% CI 1-32%, 6 studies, 367 patients, I 2 88%), 42% (95% CI 17-71%, 3 studies, 319 patients, I 2 75%), and 20% (95% CI 0-54%, 3 studies, 39 patients, I 2 66%), respectively. The RR for those receiving treatment for their hematologic malignancy compared to those who were not receiving treatment was 0.51 (95% CI 0.37-0.71, 8 studies, 579 patients, I 2 89%; Figure 3). . The RR of patients receiving anti-CD20 therapy compared to non-cancer controls was 0.13 (95% CI 0.02-0.93, 102 patients, I 2 73%). For patients treated with anti-CD20 therapy, the RR of those receiving vaccination within 9-12 months compared to beyond 9-12 months was 0.12 (95% CI 0.06-0.25, 2 studies, 74 patients, I 2 0%; Figure 4).Conclusion:Our systematic review and meta-analysis suggests that patients with hematologic malignancy have a lower SR rate following vaccination compared to controls. Furthermore, SR is variable across different types of hematologic malignancy, with very good response rates seen in patients with myeloid diseases (MPN and AML) and poor response rates seen in lymphoma and CLL. Active treatment, particularly anti-CD20 therapy within 12 months of vaccination, is associated with a particularly low SR following vaccination. Additional studies are needed to understand non-humoral responses to vaccination, and to guide decisions regarding how to optimize vaccine response in patients with blood cancer. We plan to update the systematic review and meta-analysis as more data become available. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Risks for Hospitalization and Death Among Patients with Blood Disorders from the ASH RC COVID-19 Registry for Hematology

Risks for Hospitalization and Death Among Patients with Blood Disorders from the ASH RC COVID-19 Registry for Hematology

Clinical Predictors of Outcome in Adult Patients with Acute Leukemias and Myelodysplastic Syndrome and COVID-19 Infection: Report from the American Society of Hematology Research Collaborative (ASH RC) Data Hub

Clinical Predictors of Outcome in Adult Patients with Acute Leukemias and Myelodysplastic Syndrome and COVID-19 Infection: Report from the American Society of Hematology Research Collaborative (ASH RC) Data Hub

Outcomes of COVID-19 in Hematopoietic Stem-Cell Transplant Recipients: A Single Institution Observational Study

Intro: Hematopoietic stem-cell transplant (HSCT) recipients are considered to be at high risk for poor outcomes following COVID-19 infection given their co-morbidities and immunosuppression. Sharma et al published the CIBMTR observational report data that showed that recipients of allogeneic HSCT who contract COVID-19 have poor overall survival with a 30-day mortality of 32%. That being said, there have been relatively few studies that look into the effect of COVID-19 on HSCT recipients in the setting of in vivo T cell depletion protocols. With the increased use of post-transplant cyclophosphamide (PTCy) based GVHD prophylaxis regimens for our match related and match unrelated HSCT recipients since 2018 at our institution, we are interested to see if our COVID-19 outcomes differ from those published in the CIBMTR report.Methods: This is a single institution retrospective analysis evaluating outcomes of HSCT recipients who were diagnosed with COVID-19 between March 2020 and April 2021. Patients 18 years or older who underwent HSCT and subsequently contracted COVID-19 were included in the data collection. Demographic data including age, type of hematologic malignancy, conditioning regimen, GVHD prophylaxis, date of COVID-19 infection, with pre- and post-COVID-19 infection labs were obtained. Our primary endpoint in this retrospective analysis was non-relapse mortality within 30 days of COVID-19 diagnosis.Results: There were 21 patients at our institution who had undergone HSCT and subsequently contracted COVID-19. The most common primary disease types were acute lymphoblastic leukemia (33.3%), acute myeloid leukemia (23.8%), and myelodysplastic syndrome (19.0%). The median age of our patient population was 53 years (range, 24-66). 6 of the patients received match related allografts. 7 received cells from match unrelated donors. 7 received cells from haploidentical donors. 1 patient had received an autologous stem cell transplant. Of the remaining 20 allo-HSCT recipients, 14 of them (70.0%) received myeloablative conditioning regimens, whereas 6 (30.0%) received reduced intensity or non-myeloablative regimens. Our GVHD prophylaxis regimens were PTCy/Tacro/MMF (12 pts, 60.0%) and Tacro/MTX (8 pts, 40.0%).Patient demographics and outcomes are found on Tables 1 and 2. Our patients were diagnosed with COVID-19 a median 469 days post-transplant, with 8 patients (38.1%) diagnosed with COVID-19 within 1 year of transplant. 11 of the patients (52.4%) received steroids following their diagnosis with COVID-19. Of the 20 allo-HSCT recipients with confirmed COVID-19 infection, 1 passed away 20 days after the diagnosis was made. This gives us a 5.0% case fatality rate attributable to COVID-19 in our population in our allo-HSCT population. 16 of the 20 patients were symptomatic at the time of diagnosis (80.0%). 7 of the 20 patients (35.0%) were hospitalized for a median of 7 days (range, 5-17 days), with 2 requiring ICU level of care. The one patient who passed away tested positive for COVID-19 177 days post-transplant and was hospitalized approximately 7 days after diagnosis, where he was intubated on hospital day 4 and ultimately passed away on hospital day 13. The patient had received Tacro/MTX for GVHD prophylaxis.Discussion: Although this is a small sample size, our data suggests that our allo-HSCT recipients who contracted COVID-19 have had generally good short-term outcomes. Our study is limited by the small number of patients who got infected with COVID-19, particularly those within 1-year post-transplant. Furthermore, we acknowledge it is difficult to claim that the PTCy based GVHD prophylaxis regimens for our HSCT recipients were solely responsible for their improved outcomes since 40% of allo-HSCT recipients did not get PTCy for GVHD prophylaxis. However, we believe it would be valuable to evaluate in a prospective analysis. We are currently evaluating if a COVID-19 diagnosis has any effect on long term transplant related complications and outcomes in this population. [Display omitted] DisclosuresChaudhary: Angeles Therapeutics: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Founder, Patents & Royalties: Cell therapy ; Celldex: Current equity holder in publicly-traded company; Moderna: Current equity holder in publicly-traded company; Pancella: Consultancy; Oncotartis: Consultancy; Athelas: Consultancy, Current holder of stock options in a privately-held company; TCR2: Current equity holder in publicly-traded company; Allogene: Current equity holder in publicly-traded company. Yaghmour: Novartis: Consultancy, Speakers Bureau; BMS: Speakers Bureau; Alexion: Speakers Bureau; Astellas: Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Jazz: Speakers Bureau; Agios: Consultancy, Speakers Bureau.

Dibenzofuran Derivatives Inspired from Cercosporamide as Dual Inhibitors of Pim and CLK1 Kinases.

Pim kinases (proviral integration site for Moloney murine leukemia virus kinases) are overexpressed in various types of hematological malignancies and solid carcinomas, and promote cell proliferation and survival. Thus, Pim kinases are validated as targets for antitumor therapy. In this context, our combined efforts in natural product-inspired library generation and screening furnished very promising dibenzo[b,d]furan derivatives derived from cercosporamide. Among them, lead compound 44 was highlighted as a potent Pim-1/2 kinases inhibitor with an additional nanomolar IC50 value against CLK1 (cdc2-like kinases 1) and displayed a low micromolar anticancer potency towards the MV4-11 (AML) cell line, expressing high endogenous levels of Pim-1/2 kinases. The design, synthesis, structure–activity relationship, and docking studies are reported herein and supported by enzyme, cellular assays, and Galleria mellonella larvae testing for acute toxicity.

Healthcare utilization and cost of cancer-related care prior to allogeneic hematopoietic cell transplantation for hematologic malignancies in the US: a retrospective real-world analysis

BackgroundHematopoietic cell transplantation (HCT) is a potentially curative therapy as well as a costly procedure. Published studies have examined the cost of HCT in the US and the complications that follow but little is known about the cancer-related healthcare costs and resource utilization prior to the procedure and none of the studies have examined the variability in cost based on the type of hematologic malignancy involved. The aim of this study was to estimate mean cancer-related costs and resources incurred before the HCT is performed from the time the hematologic malignancy first develops.MethodsThe IBM® MarketScan® Research Databases were used to identify adult patients ≥18 years of age with commercial or Medicare supplemental insurance who had undergone allogeneic HCT for hematologic malignancies from January 1, 2008 to December 31, 2017. Healthcare utilization and costs were assessed during the 6 months prior to diagnosis (pre-diagnostic period) and the follow-up period from diagnosis just prior to the HCT (pre-HCT period). Multivariable regression models were constructed to estimate total all-cause costs and cancer-related costs as well as healthcare utilization by type in each time period.ResultsA total of 2663 commercially insured patients and 266 with Medicare supplemental insurance were included in the study population. The mean-adjusted incremental cancer-related costs for commercially insured patients was $399,011 in the overall observation period including the pre-diagnostic and pre-HCT periods combined, 9% of which was incurred in the pre-diagnostic period. The corresponding mean-adjusted incremental cancer-related costs for Medicare supplemental patients was $195,575 for the same time period but the patterns of healthcare utilization were similar to the commercially insured population. Inpatient care accounted for approximately one-half the cost in both patient populations. By type of hematologic malignancy, costs were lowest for myeloproliferative disorders ($211,561) and highest for acute lymphocytic leukemia ($462,072) in the commercially insured population.ConclusionThis study demonstrates that overall patients with hematologic malignancies requiring HCT have considerable cancer-related healthcare resource utilization and costs leading up to HCT compared to the period of time prior to developing cancer.

Chimeric Antigen Receptor T-Cell Therapy: An Overview of the Changing Face of Cancer Immunotherapy

: Chimeric antigen receptor (CAR) T-cell therapy has emerged as the revolutionary cancer treatment method in recent years due to the heartwarming clinical outcomes in several types of hematologic malignancies. Since 2017, the US Food and Drug Administration has approved four CAR T-cell products, including tisagenlecleucel [for B-cell acute lymphoblastic leukemia and diffuse large B-cell lymphoma (DLBCL)], axicabtagene ciloleucel (for DLBCL), brexucabtagene autoleucel (for mantle cell lymphoma), and lisocabtagene maraleucel (for DLBCL). The efficacy optimization and toxicity management methods of CAR T-cell therapy are among the most investigated fields of cancer immunotherapy. Furthermore, the favorable outcomes achieved by the aforementioned CAR T-cell products in hematologic malignancies have encouraged researchers to bring successful outcomes to solid tumor patients. This study aimed to highlight the outstanding characteristics and the manufacturing process of CAR T-cells and discuss the key lane leading to their clinically approved products.

ROLE OF BACTERIAL COLONIZATION IN TRACHEAL SECRETIONS AMONG INTENSIVE CARE UNIT PATIENTS

Purpose: Parvovirus B19 (B19) is associated with a wide range of diseases in humans, whose severity depends on the immunological and haematological status of the host. Objective: To determine the incidence of B19 DNA and specific IgM and IgG frequency among patients suffering from different haematological malignancies and to determine the viral load using real-time PCR. Materials and Methods: A total of 70 patients were included in the study, in addition to a control group consisting of 20 apparently healthy volunteers. B19 DNA quantitative analysis was performed using real-time PCR while screening for IgM and IgG anti-B19 antibodies was performed using ELISA. Results: B19 DNA was detected in 26 patients (36.14%) and 3 controls (15%) using real-time PCR. Anti-parvovirus B19 IgM antibodies were detected in 9 patients (12.6%) and 2 controls (10%). Anti-parvovirus B19 IgG antibodies were detected in 32 patients (45.71%) and 5 controls (25%). The difference between the patient and control groups was found to be statistically non-significant in all of the three tests (P < 0.05). The difference in B19 incidence among patients receiving multiple transfusions and non-transfused patients was also found to be statistically non-significant (P < 0.05). Conclusion: We found a high incidence of B19 infection among patients diagnosed with different types of haematological malignancies. We recommend that all cases of haematological disorders should be examined for specific antibodies and tested for the presence of B19 DNA in serum by PCR technique.

Association of MEG3 Hypermethylation and MiR-21 Upregulation with the Incidence in Iraqi Acute Myeloid Leukaemia Patients

Background: Acute myeloid leukaemia (AML) can be defined as a hematologic malignancy that distinguished by genetic defects and epigenetics alterations. LncRNA MEG3 was shown to play the role of tumour suppressor, and play a pivotal role in leukemogenesis, MEG3 hypermethylation has been reported to be related to different types of haematological malignancies. MIR-21 is regarded as a significant miRNA, it considered to play a vital role in AML progressions. Results: The levels of methylation in the MEG3 promoter region in AML patients were significantly increased than in healthy controls, as the MEG3 expression levels were significantly lowered (P ≤ 0.05) in AML patients in contrast with healthy controls. On the other hand, results showed elevated expression levels of miR-21 in AML patients compared with healthy controls. Conclusion: The present study indicates that the hypermethylation of MEG-3 promoter region could explain MEG-3 expression level loss. Our findings also revealed that the overexpression of miR-21 supports its function as an oncogene.

Abstract 1429: Characterization of trametinib combined with venetoclax in acute myeloid leukemia (AML) treatment

Abstract Acute myeloid leukemia (AML) is a type of hematologic malignancy with rapid progression and high genetic heterogeneity. Activating RAS pathway mutations are found in approximately 10 - 25% of AML patients and have been implicated to targeted drug resistance and disease relapse suggesting a potential benefit of MAPK pathway inhibitors in AML therapy. In patients with RAS-mutated myeloid malignancies, an inhibitor targeting MEK1/2, trametinib, demonstrated benefit in a phase 1/2 clinical study. Effective combinations of trametinib with other drugs has remained elusive. To identify potential combinatorial strategies, we generated AML cell lines resistant to MEKi. Whole exome sequencing revealed MEK1 variants in these cells. Drug sensitivity assays performed on parental AML cells and cells harboring wild type and the MEK1 variants validated their ability to confer trametinib resistance. BCL2 inhibitors, including venetoclax, were able to re-sensitize the resistant cells to trametinib, suggesting potential efficacy of combining trametinib with venetoclax. Indeed, this drug combination revealed synergistic efficacy in AML cell lines with diverse genetic backgrounds and in the resistant cells.To further investigate combination of trametinib and venetoclax in AML, we examined ~200 primary AML patient specimens using an ex vivo drug sensitivity assay, whole exome, and RNA sequencing data. We confirmed the enhanced efficacy of this combination relative to single agents. Patient samples resistant to trametinib showed increased sensitivity to venetoclax. Since, hyper-activation of MAPK signaling has been correlated with venetoclax resistance, we analyzed venetoclax resistant specimens and observed increased sensitivity to MEK and ERK inhibitors. We also observed correlation of MEK1 but not MEK2 RNA levels with trametinib sensitivity and negative correlation of MEK1 RNA levels with that of BCL2. AML samples with FLT3-ITD, NPM1, WT1, FLT3, CEBPA, DNMT3A, IDH1, IDH2, SRSF2, and TP53 mutations exhibited increased sensitivity to the combination. Samples with NRAS, KRAS, and PTPN11; although, highly sensitive to trametinib, did not benefit from this combination. Consistent with previous studies, we observed that venetoclax sensitivity was correlated with higher blast percentage. We also observed correlation of higher percentage of bone marrow blast and sensitivity to the combination. Moreover, while monocytic leukemias (AML-M4/M5) showed reduced sensitivity to venetoclax, they were sensitive to trametinib and showed increased expression of MEK1. Furthermore, we demonstrated that while venetoclax treatment increased protein levels of MCL1 in MOLM13 AML cells, combining trametinib with venetoclax reduced MCL1 levels. In summary, we demonstrate efficacy of trametinib and venetoclax combination in AML and propose mechanisms underlying the synergistic relationship of this drug combination. Citation Format: Alisa Damnernsawad, Christopher A. Eide, Sofia Beer, Haijiao Zhang, Daniel Bottomly, Stephen E. Kurtz, Jeffrey W. Tyner. Characterization of trametinib combined with venetoclax in acute myeloid leukemia (AML) treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1429.

Abstract 2540: Belief in research, religious coping, and willingness to participate in clinical trials among African Americans with hematologic malignancies: a pilot study

Abstract Purpose: The purpose of the proposed prospective cohort, pilot study is to recruit 30 AAs with hematologic malignancies to determine if a relationship exists between belief in research and willingness to participate in cancer clinical trials. The secondary objective is to determine whether religious coping moderates the effect of belief in research on the relationship between willingness to participate. Description: African Americans (AAs) are disproportionately affected by certain types of hematologic malignancies, yet despite the efforts of investigators, they remain grossly underrepresented in cancer clinical trials. Few studies have evaluated the underrepresentation in clinical trials in this subgroup, while studies evaluating the same problem in AAs with solid tumors is well documented. A known barrier to clinical trial enrollment is knowledge of clinical trials; however, knowledge does not necessarily mean one will participate. One has also to believe and be willing to participate in clinical trials. Even so, it is unknown if a relationship exists between belief in research and willingness to participate in clinical trials in AAs with hematologic malignancies. Similarly, it is unknown if religious coping influences the possible association between belief in research and willingness to participate in AAs with hematologic malignancies. Due to sparse literature showing the connection of the concepts within this subset of AAs, research investigating the relationship between belief in research and willingness to participate is warranted. Summary: Data will be captured at one time using the validated Brief Religious Coping Scale and researcher generated questions that address belief in research and willingness to participate in cancer clinical trials. Conclusion: Findings will help in the design of future studies and the feasibility of recruiting AAs with hematologic malignancies. Citation Format: Marjorie Petty. Belief in research, religious coping, and willingness to participate in clinical trials among African Americans with hematologic malignancies: a pilot study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2540.