High Risk Of Transformation Research Articles

High Risk of Transformation and Secondary Malignancies in Follicular Lymphoma Patients Treated With First-Line Bendamustine Rituximab and Rituximab Maintenance

High Risk of Transformation and Secondary Malignancies in Follicular Lymphoma Patients Treated With First-Line Bendamustine Rituximab and Rituximab Maintenance

CDC7 inhibition impairs neuroendocrine transformation in lung and prostate tumors through MYC degradation

Neuroendocrine (NE) transformation is a mechanism of resistance to targeted therapy in lung and prostate adenocarcinomas leading to poor prognosis. Up to date, even if patients at high risk of transformation can be identified by the occurrence of Tumor Protein P53 (TP53) and Retinoblastoma Transcriptional Corepressor 1 (RB1) mutations in their tumors, no therapeutic strategies are available to prevent or delay histological transformation. Upregulation of the cell cycle kinase Cell Division Cycle 7 (CDC7) occurred in tumors during the initial steps of NE transformation, already after TP53/RB1 co-inactivation, leading to induced sensitivity to the CDC7 inhibitor simurosertib. CDC7 inhibition suppressed NE transdifferentiation and extended response to targeted therapy in in vivo models of NE transformation by inducing the proteasome-mediated degradation of the MYC Proto-Oncogen (MYC), implicated in stemness and histological transformation. Ectopic overexpression of a degradation-resistant MYC isoform reestablished the NE transformation phenotype observed on targeted therapy, even in the presence of simurosertib. CDC7 inhibition also markedly extended response to standard cytotoxics (cisplatin, irinotecan) in lung and prostate small cell carcinoma models. These results nominate CDC7 inhibition as a therapeutic strategy to constrain lineage plasticity, as well as to effectively treat NE tumors de novo or after transformation. As simurosertib clinical efficacy trials are ongoing, this concept could be readily translated for patients at risk of transformation.

Mesenchymal Stem Cells in Myelodysplastic Syndromes and Leukaemia.

Mesenchymal stem cells (MSCs) are one of the main residents in the bone marrow (BM) and have an essential role in the regulation of haematopoietic stem cell (HSC) differentiation and proliferation. Myelodysplastic syndromes (MDSs) are a group of myeloid disorders impacting haematopoietic stem and progenitor cells (HSCPs) that are characterised by BM failure, ineffective haematopoiesis, cytopenia, and a high risk of transformation through the expansion of MDS clones together with additional genetic defects. It has been indicated that MSCs play anti-tumorigenic roles such as in cell cycle arrest and pro-tumorigenic roles including the induction of metastasis in MDS and leukaemia. Growing evidence has shown that MSCs have impaired functions in MDS, such as decreased proliferation capacity, differentiation ability, haematopoiesis support, and immunomodulation function and increased inflammatory alterations within the BM through some intracellular pathways such as Notch and Wnt and extracellular modulators abnormally secreted by MSCs, including increased expression of inflammatory factors and decreased expression of haematopoietic factors, contributing to the development and progression of MDSs. Therefore, MSCs can be targeted for the treatment of MDSs and leukaemia. However, it remains unclear what drives MSCs to behave abnormally. In this review, dysregulations in MSCs and their contributions to myeloid haematological malignancies will be discussed.

Generation and External Validation of a Histologic Transformation Risk Model for Patients with Follicular Lymphoma

Follicular lymphoma (FL) is the most frequent indolent lymphoma. Some patients (10%-15%) experience histologic transformation (HT) to a more aggressive lymphoma, usually diffuse large B-cell lymphoma (DLBCL). This study aimed to validate and improve a genetic risk model to predict HT at diagnosis.We collected mutational data from diagnosis biopsies of 64 FL patients. We combined them with the data from a previously published cohort (total n = 104; 62 from nontransformed and 42 from patients who did transform to DLBCL). This combined cohort was used to develop a nomogram to estimate the risk of HT. Prognostic mutated genes and clinical variables were assessed using Cox regression analysis to generate a risk model. The model was internally validated by bootstrapping and externally validated in an independent cohort. Its performance was evaluated using a concordance index and a calibration curve.The clinicogenetic nomogram included the mutational status of 3 genes (HIST1HE1, KMT2D, and TNFSR14) and high-risk Follicular Lymphoma International Prognostic Index and predicted HT with a concordance index of 0.746. Patients were classified as being at low or high risk of transformation. The probability HT function at 24 months was 0.90 in the low-risk group vs 0.51 in the high-risk group and, at 60 months, 0.71 vs 0.15, respectively. In the external validation cohort, the probability HT function in the low-risk group was 0.86 vs 0.54 in the high-risk group at 24 months, and 0.71 vs 0.32 at 60 months. The concordance index in the external cohort was 0.552. In conclusion, we propose a clinicogenetic risk model to predict FL HT to DLBLC, combining genetic alterations in HIST1H1E, KMT2D, and TNFRSF14 genes and clinical features (Follicular Lymphoma International Prognostic Index) at diagnosis. This model could improve the management of FL patients and allow treatment strategies that would prevent or delay transformation.

International Prognostic Score for Nodular Lymphocyte-Predominant Hodgkin Lymphoma.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare cancer, and large international cooperative efforts are needed to evaluate the significance of clinical risk factors and immunoarchitectural patterns (IAPs) for all stages of pediatric and adult patients with NLPHL. Thirty-eight institutions participated in the Global nLPHL One Working Group retrospective study of NLPHL cases from 1992 to 2021. We measured progression-free survival (PFS), overall survival (OS), transformation rate, and lymphoma-specific death rate. We performed uni- and multivariable (MVA) Cox regression stratified by management to select factors for the lymphocyte-predominant international prognostic score (LP-IPS) validated by five-fold cross-validation. We identified 2,243 patients with a median age of 37 years (IQR, 23-51). The median follow-up was 6.3 years (IQR, 3.4-10.8). Most had stage I to II (72.9%) and few B symptoms (9.9%) or splenic involvement (5.4%). IAP was scored for 916 (40.8%). Frontline management included chemotherapy alone (32.4%), combined modality therapy (30.5%), radiotherapy alone (24.0%), observation after excision (4.6%), rituximab alone (4.0%), active surveillance (3.4%), and rituximab and radiotherapy (1.1%). The PFS, OS, transformation, and lymphoma-specific death rates at 10 years were 70.8%, 91.6%, 4.8%, and 3.3%, respectively. On MVA, IAPs were not associated with PFS or OS, but IAP E had higher risk of transformation (hazard ratio [HR], 1.81; P < .05). We developed the LP-IPS with 1 point each for age ≥45 years, stage III-IV, hemoglobin <10.5 g/dL, and splenic involvement. Increasing LP-IPS was significantly associated with worse PFS (HR, 1.52) and OS (HR, 2.31) and increased risk of lymphoma-specific death (HR, 2.63) and transformation (HR, 1.41). In this comprehensive study of all ages of patients with NLPHL, we develop the LP-IPS to identify high-risk patients and inform upcoming prospective clinical trials evaluating de-escalation of therapy for patients with low LP-IPS scores (<2).

Abstract 2004: CDC7 inhibition prevents neuroendocrine transformation in the lung and prostate through MYC degradation

Abstract Neuroendocrine (NE) transformation occurs as a mechanism of resistance to targeted therapy in up to 14% and 30% of EGFR-mutant lung and AR-dependent prostate adenocarcinomas, respectively, leading to poor prognosis. Even if we know the tumor population at high risk of transformation (TP53/RB1-mutated), no therapies to prevent NE relapse are currently available. To identify therapeutic vulnerabilities for tumors undergoing NE transformation, we performed an in vitro CRISPR screen in a NE-transformed lung tumor model. This screen identified CDC7, involved in DNA replication and DNA damage response, as a potential therapeutic target in this setting. Proteogenomic analyses revealed CDC7 upregulation in lung and prostate clinical samples undergoing NE transformation, detected already in pre-transformation adenocarcinomas. These results indicated that CDC7 expression is induced already at early steps of transformation. Consistently, TP53/RB1-mutated lung and prostate adenocarcinomas exhibited higher CDC7 expression than their double wild-type counterparts. Combined ChIP-seq and promoter reporter assays indicated that CDC7 expression was directly regulated by TP53 and RB1 inactivation. Importantly, TP53/RB1-inactivation induced sensitivity to the CDC7 inhibitor simurosertib, unraveling a therapeutic vulnerability in tumors at high risk of NE transformation. Thus, we tested the combination of simurosertib with targeted therapy in vivo in different lung and prostate patient-derived models of NE transformation, namely TP53/RB1-knock out adenocarcinomas known to undergo NE transformation on targeted therapy. In these, simurosertib was able to suppress NE transformation and dramatically delay tumor relapse. Trajectory analysis on single-cell transcriptomic data for such models revealed a NE transformation transcriptional program occurring already in the untreated tumors before transformation. Remarkably, simurosertib treatment reverted this transcriptomic state and induced a reversion to the original adenocarcinoma transcriptomic profile. CDC7 inhibition led to increased proteasomal activity and degradation of MYC, a stemness transcription factor involved in NE transformation. Ectopic overexpression of MYCT58A, a proteasome degradation-resistant MYC isoform, rescued the NE phenotype in these transformation models, suggesting that CDC7 inhibition-induced MYC degradation is the mechanism by which NE transformation is prevented. In sum, CDC7 inhibition may suppress, or at least dramatically delay NE transformation in patients with lung and prostate adenocarcinomas at high risk of transformation, by inducing MYC proteasomal degradation. The clinical availability of CDC7 inhibitors, currently in phase II clinical trials after demonstrating tolerability and preliminary efficacy, will allow rapid translation of these results into the clinics. Citation Format: Alvaro Quintanal-Villalonga, Fathema Uddin, Kenta Kawasaki, Esther Redin, Vidushi Durani, Amin Sabet, Wouter Karthaus, Yingqian A. Zhan, Samir Zaidi, Moniquetta Shaffer, Harsha Sridhar, Juan Qiu, Parvathy Manoj, Elisa De Stanchina, Michael C. Haffner, Charles L. Sawyers, Charles M. Rudin. CDC7 inhibition prevents neuroendocrine transformation in the lung and prostate through MYC degradation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2004.

Transformation risk and associated survival outcome of marginal zone lymphoma: A nationwide study.

Histological transformation into an aggressive B-cell lymphoma indicates a poor survival outcome for patients with indolent marginal zone lymphoma (MZL), which has been less studied. Large-scale data with long-term follow-up to investigate MZL transformation is limited. Here, by reporting a US-Nationwide cohort of 30,619 MZL patients diagnosed between 2000 and 2019, we found that transformation occurred in 2.08% (N = 624) of MZL cases, with the transformation incidence of 3.1 per 1,000 person-years. Advanced Ann Arbor stage, nodal MZL (NMZL) and splenic MZL (SMZL) were associated with an elevated risk of transformation. Certain subtype-specific characteristics, such as non-gastric extra-nodal MZL (vs. gastric, HR, 1.51, 95%CI 1.13-2.04; p = 0.006), and receiving splenectomy for SMZL (HR, 2.04, 95%CI 1.28-3.26; p = 0.003), also indicated a higher risk of transformation. Besides, transformation independently increased the overall mortality risk (HR, 1.38, 95%CI 1.24-1.53, p < 0.001), especially the higher lymphoma-caused mortality risk (HR, 3.21, 95%CI 2.81-3.67, p < 0.001). Transformation was also associated with a higher percentage of lymphoma-caused deaths. The post-transformation prognostic analyses demonstrated that female gender and age ≥ 65 years independently affected patients' mortalities. These findings, based on the largest cohort to date, contribute to a better understanding of transformed MZL, and provide valuable reference points for guidelines and patient counseling.

Pyloric gland adenoma - a rare tumor of the upper gastrointestinal tract with a high risk of malignancy

Pyloric gland adenomas (PGA) are rare neoplasms of the gastrointestinal tract. According to the literature, these lesions may be underdiagnosed, and their true frequency of occurrence is underestimated. Clinical and morphological analysis of eight PGA cases of the upper gastrointestinal tract. The study included 8 cases of detection of PGA. In 7 out of 8 cases, the tumor was diagnosed by examining endoscopic biopsies, in 1 case, PGA was an accidental finding in the surgical material after proximal gastric resection. 6 out of 8 patients were female, the median age was 65 years (minimum 36 years and maximum 78 years). In 6 cases, PDA was localized in the stomach, in 1 - in the esophagus and in 1 - in the duodenum The size of the tumors ranged from 0.6 cm to 7.5 cm. 4 out of 6 stomach tumors appeared on the background of confirmed autoimmune gastritis, 1 - on the background of lymphocytic gastritis. 4 tumors were found in the body of the stomach, 1 - in the cardia, 1 - in the bottom of the stomach. In 2 out of 8 cases, there were signs of malignancy of the tumor with the transition to a highly differentiated adenocarcinoma. According to the results of the IHC study, the absence of a p53 mutation was noted in these cases. PGA should be considered as neoplasms with a high risk of transformation into invasive adenocarcinoma. Increasing the recognition of PGA among pathologists and further understanding of the molecular mechanisms involved in their neoplastic transformation will improve the diagnosis and treatment of this pathology.

Prognosis of Progressive Follicular Lymphoma within 24 Months of First-Line Therapy Is Not Influenced By the Initial Regimen Intensity

CONCLUSIONS Progression of follicular lymphoma (FL) within 24 months of initiating first-line therapy (POD24) is a strong driver of poor outcomes and is associated with a high risk of transformation. Previous reports suggest that POD24 has less prognostic significance in patients treated with rituximab alone as front-line therapy. We aimed to evaluate the impact of POD24 on outcome as well as the influence of the intensity of front-line therapy on the prognosis of POD24 in our local cohort of FL patients. We included patients with FL grade 1, 2 or 3A and stages II to IV who received front line therapy between 01/01/2014 and 31/12/2020 at our centre, and excluded patients treated with radiotherapy alone. Our primary objective was to describe and compare the clinical outcomes following different front-line regimens used in FL at our center. Rituximab (R) alone and R-Cyclophosphamide, Vincristine and Prednisone (R-CVP) were defined as attenuated-intensity regimens and R-CHOP (R-CVP with adriamycin) and bendamustine-rituximab (BR) as high-intensity regimens. The following endpoints were analyzed: event-free survival (EFS), defined as time from therapy initiation (D1C1) to progression, relapse, transformation to an aggressive lymphoma, or death of any cause, progression-free survival (PFS), defined as time from D1C1 to progression or death and overall survival (OS), defined as time from D1C1 to death of any cause. POD24 was defined as progression or relapse within 24 months of D1C1. We identified 85 patients with FL. At diagnosis, median age was 61 years (range: 38-85), 86 % had an ECOG performance score of 0-1, 81% had grade 1-2 FL, 91% had stage III-IV and 27% had high LDH. FLIPI score was available for 82 patients and 54% had a FLIPI of 3-5. Seventy-eight patients (92%) received a combination of rituximab and chemotherapy (R-chemo) and 7 (8%) received rituximab alone (R). Front line BR is approved at our center since November 2019. R-chemo regimens included R-CVP (40 patients, 47%), R-CHOP (29 patients, 34%) and BR (9 patients, 11%). Fifty-four patients received rituximab maintenance. Rituximab maintenance was not offered following BR. Twenty-eight (33%) patients had POD24 and 57 patients (67%) did not (non-POD24 group). Median follow-up was 5 years. Median and 5-year results for the 85 patients are: EFS 4.2 years and 45%, PFS 4.2 years and 45% and OS not reached and 86%. Patients with POD24 and non-POD24 had a 5-year OS of 66% (38-84) and 94% (81-98) (p=0.007) respectively. The proportion of POD24 among patients treated with R-chemo or R alone was 32% (25/78) and 43% (3/7). The rates of POD24 after R-CVP, R-CHOP and BR were 25% (10/40), 38% (11/29) and 44% (4/9), respectively. Among patients treated with R-chemo, 5-year OS was 67% for POD24 and 93% for non-POD24 (p=0.01). Among patients treated with an attenuated-intensity regimen, 5-year OS was 85% for POD24 and 93% for non-POD24 (p=0.567). Among patients with POD24, 5-year OS with an attenuated-intensity regimen was 85%, whereas it was 33% in the group of patients treated with R-CHOP or BR (p=0.18). Transformation incidence to an aggressive lymphoma was 15% at 5 years for the whole cohort, 32% in the POD24 group and 6% in the non-POD24 group (p=0.0004). BR was the regimen associated with the highest rate of transformation reaching a rate of 83% compared to none with R, 8% with R-CVP and 14% with R-CHOP (p=0.0005). Median time to transformation in aggressive lymphoma from D1C1 was 329 days (range 140-2688). On multivariable analysis, no patient- or disease-related factor before the first line treatment was associated with the occurrence of POD24. Our real-world study highlights the inferior outcome of patients with POD24 retrieved in pooled analysis from larger cohorts, irrespective of the intensity of the induction regimen. The small number of patients is a limitation of our study. The identification of clinical features associated with POD24 before 1L initiation is needed to improve outcomes of FL. Acknowledgments The study has been supported by the C3i Lymphoma Registry

Transformation to diffuse large B-cell lymphoma and its impact on survival in patients with marginal zone lymphoma: A population-based study.

Some patients with marginal zone lymphoma (MZL) experience histological transformation to diffuse large B-cell lymphoma (DLBCL). Because of the paucity of long-term data on transformation, we conducted a population-based study to estimate the risk of transformation and its impact on survival in MZL. Using the Surveillance, Epidemiology and End Results database, we identified 23 221 patients with histology-proven MZL between 2000 and 2018. Competing risk method, Kaplan-Meier and Cox proportional hazards regression were performed to analyze time-to-event outcomes. Based on 420 events of transformation, the 10-year cumulative incidence rate of transformation is 2.23% (95% CI: 2.00%-2.46%) in MZL, 1.5% (95% CI: 1.3%-1.8%), 2.7% (95% CI: 2.3%-3.2%) and 5.8% (95% CI: 4.6%-7.1%) in extranodal, nodal and splenic MZL (EMZL, NMZL and SMZL), respectively. Patients with SMZL (subdistribution hazard ratio [SHR], 2.96; 95% CI: 2.21-3.96) or NMZL (SHR, 1.49; 95% CI: 1.17-1.90) have a higher risk of transformation than those with EMZL. For each MZL subtype, patients with transformation had a significantly shorter overall survival. Patients with transformation >18 months since MZL diagnosis had longer OS than those who presented within 18 months (5-year rate, 87.4% [95% CI: 83.7%-91.2%] vs 47.9% [95% CI: 38.8%-59.0%]; P < .001). Compared to patients with matched de novo DLBCL, those whose DLBCL was transformed from MZL had a shorter OS (5-year rate, 56.6% [95% CI: 51.9%-61.8%] vs 46.1% [95% CI: 40.9%-51.9%]; P < .001). We concluded that patients with SMZL had the highest risk of transformation. Regardless of MZL subtype, transformation resulted in significantly increased mortality.

Outcomes of individuals with clonal hematopoiesis evaluated at a cancer center.

7072 Background: Clonal hematopoiesis (CH) refers to the presence of somatic mutations in individuals without overt hematological disorders. CH, including CH of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance (CCUS), is associated with hematologic malignancies and other systemic comorbidities. There are currently no established guidelines regarding the optimal monitoring and management of patients with CH, and the impact of CH in patients with concomitant underlying malignancies remains unknown. Methods: Patients seen at a tertiary cancer center with at least 1 somatic mutation detected by next generation sequencing on bone marrow aspirate or peripheral blood between January 2015 and March 2021 were included. Patients with donor-derived CH or any morphologic evidence of a myeloid neoplasm were excluded. Results: We evaluated 78 patients – 76% had a history of malignancy and 73% had other comorbidities. The mutations most frequently observed were DNMT3A (40%), TET2 (31%), TP53 (26%), and ASXL1 (18%). The median overall survival for all patients was not reached (2-year survival rate of 79%). Most deaths were related to primary malignancies (35%), comorbidities (20%), or myeloid neoplasms (20%). Due to concomitant use of antineoplastic therapy and other causes of cytopenia in 19 patients, we further categorized patients into 4 groups: CHIP on treatment (CHIP-T), other CHIP (CHIP-O), CCUS on treatment or with a non-myeloid hematologic malignancy (CCUS-T), and other CCUS (CCUS-O). Transformation to a myeloid neoplasm occurred in 12 patients (15%). The 3-year cumulative incidence of transformation was higher in CCUS-O (24%) and CCUS-T (21%) compared to the CHIP group (6%, p = 0.48). On univariate analysis, increasing age, variant allele frequency (VAF) ≥ 0.2, hemoglobin &lt; 10 g/dL, and any chromosomal abnormalities were associated with higher risk for transformation. By multivariate analysis, transformation was only significantly associated with VAF ≥ 0.2 (hazard ratio (HR) 18.25; 95% confidence interval (CI): 3.59, 92.73; p = 0.0005) and hemoglobin &lt; 10 g/dL (HR 15.62; 95% CI: 3.29, 74.05; p = 0.0005). Conclusions: CH in predominantly cancer patients is associated with cardiovascular disease and transformation to myeloid neoplasms, especially in those with higher mutational burdens and anemia. However, patients die more frequently from their primary malignancy or comorbidities than from a myeloid neoplasm. Close monitoring of hematologic progression and extra-hematologic manifestations of CH is crucial. Further investigation into the identification of individuals at high risk of myeloid transformation and potential early therapeutic interventions for this population is warranted.

Ectopic liver tissue adherent to the gallbladder serosa: two cases report from Syria.

Case 1 involved a 52-year-old man who was admitted to the hospital due to an abdominal grip in the right hypochondrium and epigastrium for 1 month. The patient underwent laparoscopic cholecystectomy. During the gross examination, a well-circumscribed brownish nodule with a smooth outer surface, located at the fundus region was found. Case 2 involved a 40-year-old man with 2 months history of epigastric pain radiating to the right shoulder. Calculus chronic cholecystitis was diagnosed by ultrasound. The patient undergoes elective laparoscopic cholecystectomy. A gross inspection showed a small nodule attached to the serosa of the gallbladder. Microscopically, both cases revealed ectopic liver tissue. Ectopic liver tissue is an uncommon entity that occurs during the embryological development of the liver and can be found below and above the diaphragm, especially the gallbladder. Histologically, it usually has the normal architecture of the liver. Although ectopic liver tissue is an exceptional finding, pathologists should be aware of it because it has a high risk of transformation into malignancy. Hepatic choristoma is a rare failure of embryological liver development. It should be removed when recognized and examined histologically to rule out malignancy.

Therapeutic Targets in Myelodysplastic Neoplasms: Beyond Hypomethylating Agents.

To discuss novel targeted therapies under investigation for treatment of myelodysplastic neoplasms (MDS). Over the last few years, results of phase 3 trials assessing novel therapies for high-risk MDS have been largely disappointing. Pevonedistat (NEDD-8 inhibitor) and APR-246 (TP53 reactivator) both did not meet trial endpoints. However, early phase trials of BCL-2, TIM3, and CD47 inhibitors have shown exciting data and are currently under phase 3 investigation. Moreover, combination of hypomethylating agents (HMA) with novel therapies targeting the mutational (IDH, FLT3, spliceosome complex) or immune (PD-1/PDL-1, TIM-3, IRAK-4) pathways are being investigated in early phase clinical trials and have shown adequate safety and promising efficacy. Myelodysplastic neoplasms (MDS) are a group of hematopoietic neoplasms defined by cytopenias and morphological dysplasia. They are characterized by clonal proliferation of aberrant hematopoietic stem cells caused by recurrent genetic abnormalities. This leads to ineffective erythropoiesis, peripheral blood cytopenias, abnormal cell maturation, and a high risk of transformation into acute myeloid leukemia (AML). Allogeneic hematopoietic stem cell transplantation is the only curative therapy; however, it is not a suitable option for majority patients due to their age, comorbidities, and the high rate of treatment-related complications. HMAs remain the only FDA-approved treatment option for high-risk MDS. Due to intolerance, primary, and secondary resistance to HMA, there is a large unmet need to develop new safe and effective therapies for patients with MDS. In this review, we focus on the current management strategies and novel therapies in development for treatment of high-risk MDS.

Bone marrow mesenchymal stem cells regulate the dysfunction of NK cells via the T cell immunoglobulin and ITIM domain in patients with myelodysplastic syndromes

BackgroundMyelodysplastic syndrome (MDS) is a clonal disease of hematopoietic cells, characterized by hematopoietic cell hematopoiesis and a high risk of transformation into acute myeloid leukemia (AML). Although the underlying mechanism is unclear, MDS is often associated with immune system disorders, especially cellular immune abnormalities. We analyzed the number of lymphocyte subsets by flow cytometry assay and explored the alteration of lymphocyte subsets in MDS.MethodsHealthy controls, inpatients with primary MDS and patients with AML diagnosed from January 2017 to July 2021 were included. Flow cytometry assays were used to study lymphocyte subsets obtained from the bone marrow of the participants as well as changes in natural killer (NK) cell function. One-way analysis of variance and Student’s t-test were used to analyze the data.ResultsWe found a reduction in the number and function of NK cells in patients with MDS. By further measuring the activating and inhibitory receptors on the surface of NK cells, we found that the T cell immunoglobulin and ITIM domain (TIGIT) was the highest expressed marker on NK cells. Additionally, the expression of CD155, which is the ligand of TIGIT, was significantly higher than expressions of CD112 and CD113 on bone marrow mesenchymal stem cells (BMSCs).ConclusionsThe co-culture results of BMSCs and NK cells demonstrated that BMSCs regulate NK cells through the TIGIT/CD155 interaction, indicating that NK cells play a vital role in MDS progression. BMSCs regulate the function of NK cells via TIGIT/CD155.EvM_ycHj6U8mjawjepZzLzVideo

EP16.03-030 AKT Inhibition as a Therapeutic Strategy to Constrain Histological Transdifferentiation in EGFR-mutant Lung Adenocarcinoma.

In lung adenocarcinomas (LUADs), lineage plasticity drives neuroendocrine (NE) and squamous cell (LUSC) transdifferentiation in the context of acquired resistance to targeted inhibition of driver mutations, with up to 14% and 9% incidences in EGFR-mutant tumors relapsed on EGFR inhibitors, respectively. Notably, survival of patients with NE- or LUSC-transdifferentiated tumors is remarkably lower than those of LUAD or de novo LUSC patients. The paucity of transforming clinical specimens amenable for molecular analyses has hindered the identification of histological transformation drivers, and to date no specific therapies aimed to prevent or delay transdifferentiation-led therapy relapse are available for patients at high risk of transformation.

Abstract 658: AKT pathway as a therapeutic target to constrain lineage plasticity leading to histological transdifferentiation

Abstract Lineage plasticity contributes to therapeutic resistance in cancer. In lung adenocarcinomas (LUADs), this phenomenon drives neuroendocrine (NE) and squamous cell (LUSC) histologic transdifferentiation in the context of acquired resistance to targeted inhibition of driver mutations, with up to 14% and 9% incidences in EGFR-mutant tumors relapsed on EGFR inhibitors, respectively. Notably, survival of patients with NE- or LUSC-transdifferentiated tumors is lower than that of either LUAD or de novo LUSC patients. To date, little is known about the molecular effectors enhancing lineage plasticity and driving histological transdifferentiation due to the paucity of well annotated pre- and post-transdifferentiation clinical samples amenable for molecular analyses. Currently no specific therapies for LUSC or NE transdifferentiation prevention are available for patients at high risk of transformation. We performed multi-omic profiling of transdifferentiating clinical samples, as well as control never-transformed LUAD and de novo LUSC and small cell carcinomas, including comprehensive and integrative genomic (whole exome sequencing), epigenomic (bisulfite sequencing), transcriptomic (RNAseq) and protein (antibody arrays) characterization. Findings were validated in preclinical models including cell lines as well as LUSC- and NE-transdifferentiation patient-derived xenograft models. Our data suggest that histological transdifferentiation is driven by epigenetic -rather than mutational- events, and indicate that transdifferentiated tumors retain molecular features of their previous LUAD state. Integrative analysis revealed biological pathways dysregulated specifically for distinct histological outcomes, including downregulation of RTK signaling and Notch-related genes in NE-transformed tumors, and upregulation of genes involved in Hedgehog and Notch signaling and MYC targets in LUSC-transdifferentiated tumors. Most interestingly, these analyses revealed commonly dysregulated pathways for transdifferentiated tumors, including marked downregulation of a variety of immune-related pathways and upregulation of genes involved in AKT signaling and in the PRC2 epigenetic remodeling complex. Concurrent activation of AKT and MYC overexpression induced a squamous phenotype in EGFR-mutant LUAD preclinical models, further accentuated by EGFR inhibition. Pharmacological targeting of AKT in combination with osimertinib delayed both squamous and NE transformation in EGFR-mutant patient-derived xenograft transdifferentiation models. These results identify common and histology-specific drivers and dysregulated pathways in NE and LUSC transdifferentiation, and nominate AKT as a therapeutic target to constrain lineage plasticity and prevent the acquisition of resistance to EGFR-targeted therapies through histological transdifferentiation. Citation Format: Alvaro Quintanal-Villalonga, Hirokazu Taniguchi, Yingqian A. Zhan, Fathema Uddin, Viola Allaj, Parvathy Manoj, Nisargbhai S. Shah, Umesh K. Bhanot, Jacklynn Egger, Juan Qiu, Elisa de Stanchina, Natasha Rekhtman, Brian Houck-Loomis, Richard P. Koche, Helena A. Yu, Triparna Sen, Charles M. Rudin. AKT pathway as a therapeutic target to constrain lineage plasticity leading to histological transdifferentiation [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 658.

AKT inhibition as a therapeutic strategy to constrain histological transdifferentiation in EGFR-mutant lung adenocarcinoma.

e21166 Background: In lung adenocarcinomas (LUADs), lineage plasticity drives neuroendocrine (NE) and squamous cell (LUSC) transdifferentiation in the context of acquired resistance to targeted inhibition of driver mutations, with up to 14% and 9% incidences in EGFR-mutant tumors relapsed on EGFR inhibitors, respectively. Notably, survival of patients with NE- or LUSC-transdifferentiated tumors is remarkably lower than those of LUAD or de novo LUSC patients. The paucity of transforming clinical specimens amenable for molecular analyses has hindered the identification of histological transformation drivers, and to date no specific therapies aimed to prevent or delay transdifferentiation-led therapy relapse are available for patients at high risk of transformation. Methods: We performed multi-omic profiling of LUAD-to-LUSC and LUAD-to-NE transdifferentiating clinical samples, including comprehensive and integrative genomic (whole exome sequencing), epigenomic (bisulfite sequencing), transcriptomic (RNAseq) and protein (antibody arrays) characterization. Clinical findings were validated in preclinical models including cell lines as well as LUSC- and NE-transdifferentiation patient-derived xenograft models. Results: Our data supports that histological transdifferentiation from LUAD to LUSC or NE tumors is driven by epigenetic remodeling rather than by mutational events, and indicate that transdifferentiated tumors retain epigenomic features of their previous LUAD state. Integrative epigenomic, transcriptomic and protein analysis revealed divergent biological pathways dysregulated for each histological outcome, such as downregulation of RTK signaling and Notch-related genes in NE-transformed tumors, and upregulation of genes involved in Hedgehog and Notch signaling and MYC targets in LUSC-transdifferentiated tumors. Most interestingly, these analyses identified commonly dysregulated pathways in both NE- and LUSC-transdifferentiating tumors, including remarkable downregulation of a variety of immune-related pathways and upregulation of genes involved in AKT signaling and in the PRC2 epigenetic remodeling complex. Concurrent activation of AKT and MYC overexpression induced a squamous phenotype in EGFR-mutant LUAD preclinical models, further accentuated by EGFR inhibition. Pharmacological targeting of AKT in combination with osimertinib delayed both squamous and NE transformation in different EGFR-mutant patient-derived xenograft transdifferentiation models. Conclusions: These results identify common and divergent dysregulated pathways in NE and LUSC transdifferentiation, and nominate AKT as a therapeutic target to prevent the acquisition of resistance to EGFR-targeted therapies through histological transdifferentiation.

MYD88 Mutations: Transforming the Landscape of IgM Monoclonal Gammopathies.

The MYD88 gene has a physiological role in the innate immune system. Somatic mutations in MYD88, including the most common L265P, have been associated with the development of certain types of lymphoma. MYD88L265P is present in more than 90% of patients with Waldenström’s macroglobulinemia (WM) and IgM monoclonal gammopathy of undetermined significance (IgM-MGUS). The absence of MYD88 mutations in WM patients has been associated with a higher risk of transformation into aggressive lymphoma, resistance to certain therapies (BTK inhibitors), and shorter overall survival. The MyD88 signaling pathway has also been used as a target for specific therapies. In this review, we summarize the clinical applications of MYD88 testing in the diagnosis, prognosis, follow-up, and treatment of patients. Although MYD88L265P is not specific to WM, few tumors present a single causative mutation in a recurrent position. The role of the oncogene in the pathogenesis of WM is still unclear, especially considering that the mutation can be found in normal B cells of patients, as recently reported. This may have important implications for early lymphoma detection in healthy elderly individuals and for the treatment response assessment based on a MYD88L265P analysis.

К вопросу о диагностике, лечении и прогнозе миелодиспластического синдрома

Given the difficulties of diagnosis, the absence of a typical clinical picture of myelodysplastic syndrome accompanied by cytopenia, a high risk of transformation into acute myeloid leukemia, discussion of the formation, terminology, pathogenesis, classification, features of the clinical course and principles of management of this group of tumor diseases is very relevant

The Eatl-001 Trial: Results of a Phase 2 Study of Brentuximab Vedotin and CHP Followed By Consolidation with High-Dose Therapy - Autologous Stem-Cell Transplantation (HDT-ASCT) in the Frontline Treatment of Patients with Enteropathy-Associated T-Cell Lymphoma

BackgroundEnteropathy-associated T-cell lymphoma (EATL), previously designated type 1 EATL, is a neoplasm of intraepithelial T cells that occurs in individuals with celiac disease (CD). It is a rare lymphoma, accounting for approximately 3% of all peripheral T-cell lymphomas (PTCLs). EATL may be preceded by refractory CD (RCD), defined as persistent or recurrent symptoms and signs of malabsorption with villous atrophy despite a strict gluten-free diet for more than 12 months. Currently, RCD is categorized into 2 types, based on immunophenotypic and molecular criteria. In RCD-II, intraepithelial lymphocytes (IELs) have an aberrant phenotype and a clonal TCR gene rearrangement. RCD-II is considered a low-grade lymphoma of intraepithelial T cells, with a high risk of transformation into EATL. CD or RCD may be diagnosed prior to or concomitant with EATL.EATL has a poor prognosis due to perforation or obstruction of the bowel, sepsis, malnutrition and treatment resistance, with 2-year OS of 20% (de Baaij, CCR 2015). An EATL prognostic index (EPI) has been developed, that can distinguish 3 risk groups (de Baaij, CCR 2015).Optimal treatment of EATL is an unmet need, and novel therapeutic approaches are required. Most EATLs are CD30+ and could be targeted by brentuximab vedotin (BV). Based on the encouraging activity and manageable safety profile of BV and CHP (cyclophosphamide, doxorubicin and prednisone) combination in CD30+ PTCLs, the EATL-001 phase 2 trial was initiated to assess the efficacy and safety of BV-CHP followed by HDT-ASCT for the frontline treatment of patients (pts) with EATL (ClinicalTrials.gov No. NCT03217643). Here we report the first results of the EATL-001 trial.MethodsEATL-001 is an Investigator Initiated-Sponsored Research phase 2 study, on behalf of the CELAC (French NCI-labeled network of Centers of Expertise for Lymphomas Associated with Celiac disease). Key inclusion criteria were as follows: Newly diagnosed CD30+ (≥10% of neoplastic cells by central review) EATL (WHO 2016 criteria), 18-65 years, PS 0-3. Response was assessed according to the Lugano classification. Pts were scheduled to receive 4 cycles of BV+CHP as induction. Responding pts received 2 cycles of Etoposide (200 mg/m2) + Methotrexate (3 g/m2) followed by HDT-ASCT (BEAM conditioning regimen). The primary endpoint was 2-year PFS per investigator. Underlying CD/RCD diagnosis was based on uninvolved duodenal histology (including CMF and TCR gene rearrangement analysis of IEL), serology and HLA typing.ResultsA total of 14 pts were included between February 2018 and February 2021. The median age was 54 years (range, 34-65) and 64% were male. 11 pts (79%) had initial surgery for bowel obstruction (n=6) or jejunal perforation (n=5). All pts had CD, diagnosed prior to (n=4) or concomitant with (n=10) EATL. 9 pts (64%) had RCD-II. CD30 expression ranged from 10% to 100%, nine cases having 100% positivity. EPI was high-risk in 4 pts (29%), intermediate-risk in 6 pts (43%), and low-risk in 4 pts (29%).Preliminary results by investigator assessment show an overall response rate following completion of the induction of 79% (11/14) with 64% (9/14) achieving a complete response. 3 pts had primary progressive disease (all had high-risk EPI), of which 2 died of the lymphoma. The 11 responding pts, still in response before intensification, underwent HDT-ASCT. 2 pts died of septic shock during HDT-ASCT. With a median follow-up of 2.1 years, there was no relapse and the 2-year PFS and OS for all pts were 63% and 68%, respectively.The incidence of AEs was consistent with the known safety profiles of BV-CHP regimen.ConclusionsEATL-001 is the first prospective phase 2 study dedicated to EATL. BV-CHP was well tolerated and induced high response rates, allowing the majority of patients to be transplanted. This novel therapeutic approach shows promising efficacy compared to historical controls. DisclosuresSibon: Takeda: Consultancy; Roche: Consultancy; Janssen: Consultancy; Abbvie: Consultancy; iQone: Consultancy. Cartron: Roche, Celgene-BMS: Consultancy; Danofi, Gilead, Novartis, Jansen, Roche, Celgene-BMS, Abbvie, Takeda: Honoraria. Morschhauser: Incyte: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria; AstraZenenca: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy; Janssen: Honoraria; Roche: Consultancy, Speakers Bureau; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genmab: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy. Hermine: Takeda: Consultancy. OffLabel Disclosure:Brentuximab vedotin is not approved in Europe for EATL.