Lymphoproliferative Malignancies Research Articles

Abstract Db1-01: Anthracyclines …to give or not to give? “For” argument

Abstract Anthracyclines have been one of the mainstays of early breast cancer treatment for decades. In a recent patient-level meta-analysis including data from over 18,000 patients, anthracycline-containing regimens were associated with improvements in disease-free survival and overall survival, regardless of estrogen receptor or nodal status. Importantly, trials specifically designed and powered to assess the safety of anthracyclines omission failed to demonstrate the non-inferiority of taxane-based anthracycline-free regimens and confirmed the benefit of these agents, particularly in patients with node-positive and hormone receptor-negative breast cancer. Several therapies incorporated into the management of early breast cancer were studied in populations largely treated with anthracycline-based chemotherapy backbones in both HER2-negative (i.e., perioperative pembrolizumab, post neoadjuvant olaparib and capecitabine) and HER2-positive disease (i.e., dual HER2 blockade, adjuvant T-DM1). It is uncertain whether the benefits demonstrated by these strategies would be maintained if anthracyclines were omitted. While anthracyclines are associated with some long-term toxicities, particularly with an increased risk of lymphoproliferative malignancies and dose-dependent cardiotoxicity, these adverse events are not associated with an increased risk of death (including deaths from cardiovascular causes) when compared to anthracycline-free regimens. The identification of risk factors for cardiotoxicity, combined with improvements in monitoring strategies, allows improvements in patient selection, early detection of myocardial damage and, possibly, implementation of cardioprotective interventions, leading to improved cardiovascular outcomes. Until high-quality evidence demonstrates the safety of omitting anthracyclines in high-risk populations, these agents should continue to be used in carefully selected patients after individual risk versus benefit assessment to be shared with the patient. Citation Format: Martine Piccart, Guilherme Nader-Marta. Anthracyclines …to give or not to give? “For” argument [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr Db1-01.

Role of Positron Emission Tomography/Computed Tomography (PET/CT) in Assessment and Follow-up of Gastrointestinal Tract Malignancies

Positron Emission Tomography/Computed Tomography (PET/CT) is a highly advanced imaging method that has several uses in oncology, such as determining the stage of cancer, evaluating the effectiveness of treatment, reevaluating the stage of cancer, and monitoring for the return of cancer over time. PET advancement has brought out a new capacity in medical diagnosis: being able to non-invasively examine the physiological condition of interior tissues. The integration of PET with simultaneous CT combines two procedures that enable the diagnosis of metabolic or receptor-specific abnormalities together with precise anatomical localization. In comparison to PET alone, the PET/CT combination is more effective in accurately identifying the location of abnormalities and distinguishing between normal and abnormal uptake of FDG along with additional tracers. PET/CT has become an essential component of management guidelines in many diseases such as lung, breast, and lymphoproliferative malignancies. The ability to image metabolic processes like glucose metabolism adds to the information provided by structural imaging, especially in the context of treatment monitoring, where metabolic changes can often precede structural changes.

Nonbacterial thrombotic endocarditis of mitral valve associated with a lymphoproliferative malignancy: case report and literature review

BackgroundNon-bacterial thrombotic endocarditis (NBTE) is a rare condition marked by sterile vegetations on cardiac valves, often linked to rheumatologic diseases, autoimmune disorders, and advanced solid malignancies. An early diagnosis and treatment of the associated clinical condition are mandatory, although they do not usually eliminate valvular vegetations, making anticoagulation essential to prevent embolic events. Despite variability, the prognosis of NBTE is usually unfavorable due to recurrent embolic events and the severity of the primary condition, typically advanced cancer.Case presentationWe present a case of a 57 years-old male who presented to the emergency department with a 5-day history of painful bilateral digital edema and color change episodes (from pallor to cyanosis). Physical examination revealed erythrocyanosis in the distal extremities, prompting consideration of secondary Raynaud syndrome.Despite medical therapy, progressive digital ischemia led to multiple finger amputations. During etiological investigation, anticoagulation tests and autoimmune analysis yielded negative results. A transesophageal echocardiogram was performed, revealing an irregular hyperechogenic mass on the anterior leaflet of the mitral valve without valve dysfunction, and a thoracic computed tomography scan with contrast showed an enlarged right paratracheal lymph node. Histopathological analysis from a transthoracic needle biopsy of the paratracheal lymph node revealed diffuse large B-cell lymphoma. The patient underwent aggressive R-CHOP chemotherapy, achieving a favorable complete response.ConclusionThis is a particular case involving the occurrence of NBTE and Raynaud phenomenon as the initial paraneoplastic manifestations in a previously healthy young man. Reports of NBTE associated with lymphoproliferative conditions are quite rare, with fewer than ten cases described in the literature. To our knowledge, this is the first case of NBTE specifically associated with diffuse large B-cell lymphoma.

Clinical Characteristics and Treatment Outcome of Waldenstrom Macroglobulinemia: Experience from a Tertiary Cancer Centre

Background: Waldenstroms macroglobulinemia (WM) or Lymphoplasmacytic lymphoma is a rare B cell lymphoproliferative malignancy characterized by serum monoclonal immunoglobulin M (IgM) protein and lymphoplasmacytic infiltration in the bone marrow. Patients usually present in their seventh decade with symptoms related to the infiltration of the marrow or the effects of monoclonal IgM in the blood. Objective: Was to study the clinical characteristics and treatment outcome of patients diagnosed with WM. Materials and Methods: This is a retrospective analysis of 26 cases of WM treated at a tertiary cancer centre. Results: WM constituted 0.68% of our nonHodgkin’s lymphoma. The median age at presentation was 67 years with a male to female ratio of 2:1. Four patients had lymphadenopathy, six had splenomegaly and four patients had evidence of hyper viscosity. All patients had IgM paraproteinemia, the M band was IgM-kappa in 19 patients and IgM-lambda in seven patients. All patients had a histopathological confirmation. According to IPSS-WM, 12 patients each were in the intermediate and high risk group and 2 in the low risk group. Among the 26 patients, 20 patients received upfront treatment and four patients were kept under observation. The indications for treatment were cytopenia in ten patients, constitutional symptoms in five, hyper viscosity in four and symptomatic lymphadenopathy in one patient. Sixteen patients received rituximab-based chemotherapy. Four patients with features with hyper viscosity underwent plasmapheresis. The three year progression free survival and overall survival were 69.4% and 78 % respectivel. Conclusions: WM is a low grade B cell lymphoproliferative disorder having an indolent course and do not require treatment for prolonged period. Diagnosis is challenging due to lack of distinct diagnostic features. Rituximab containing regimens are the standard of care. Newer targeted treatment options may improve the outcome of this incurable disease.

High monocytic MDSC signature predicts multi-drug resistance and cancer relapse in non-Hodgkin lymphoma patients treated with R-CHOP.

Non-Hodgkin Lymphoma (NHL) is a heterogeneous lymphoproliferative malignancy with B cell origin. Combinatorial treatment of rituximab, cyclophsphamide, hydroxydaunorubicin, oncovin, prednisone (R-CHOP) is the standard treatment regimen for NHL, yielding a complete remission (CR) rate of 40-50%. Unfortunately, considerable patients undergo relapse after CR or initial treatment, resulting in poor clinical implications. Patient's response to chemotherapy varies widely from static disease to cancer recurrence and later is primarily associated with the development of multi-drug resistance (MDR). The immunosuppressive cells within the tumor microenvironment (TME) have become a crucial target for improving the therapy efficacy. However, a better understanding of their involvement is needed for distinctive response of NHL patients after receiving chemotherapy to design more effective front-line treatment algorithms based on reliable predictive biomarkers. Peripheral blood from 61 CD20+ NHL patients before and after chemotherapy was utilized for immunophenotyping by flow-cytometry at different phases of treatment. In-vivo and in-vitro doxorubicin (Dox) resistance models were developed with murine Dalton's lymphoma and Jurkat/Raji cell-lines respectively and impact of responsible immune cells on generation of drug resistance was studied by RT-PCR, flow-cytometry and colorimetric assays. Gene silencing, ChIP and western blot were performed to explore the involved signaling pathways. We observed a strong positive correlation between elevated level of CD33+CD11b+CD14+CD15- monocytic MDSCs (M-MDSC) and MDR in NHL relapse cohorts. We executed the role of M-MDSCs in fostering drug resistance phenomenon in doxorubicin-resistant cancer cells in both in-vitro, in-vivo models. Moreover, in-vitro supplementation of MDSCs in murine and human lymphoma culture augments early expression of MDR phenotypes than culture without MDSCs, correlated well with in-vitro drug efflux and tumor progression. We found that MDSC secreted cytokines IL-6, IL-10, IL-1β are the dominant factors elevating MDR expression in cancer cells, neutralization of MDSC secreted IL-6, IL-10, IL-1β reversed the MDR trait. Moreover, we identified MDSC secreted IL-6/IL-10/IL-1β induced STAT1/STAT3/NF-κβ signaling axis as a targeted cascade to promote early drug resistance in cancer cells. Our data suggests that screening patients for high titre of M-MDSCs might be considered as a new potential biomarker and treatment modality in overcoming chemo-resistance in NHL patients.

Mogamulizumab Combined with Extracorporeal Photopheresis as a Novel Therapy in Erythrodermic Cutaneous T-cell Lymphoma.

Primary cutaneous T-cell lymphomas (CTCLs) are rare lymphoproliferative malignancies characterized by significant morbidity and mortality in advanced disease stages. As curative approaches apart from allogeneic stem cell transplantation are lacking, establishing new treatment options, especially combination therapies, is crucial. This retrospective study included 11 patients with SS or MF receiving therapy with mogamulizumab in combination with ECP from four European expert centers. The response rates in the skin and blood as well as treatment use and adverse events (AE) were described. 8/11 patients (73%) showed an overall response (OR) in the skin. The mean mSWAT decreased from 98.2 ± 40.8 to 34.6 ± 23.8. The overall response rate (ORR) in the blood was 64% with two complete responses. During combination therapy, the mean number of Sézary cells decreased from 3365.3 × 106/L before treatment to 1268.6 × 106/L. The mean minimum known period without progress was 7.2 months in the skin and 7.6 months in the blood. The most common AEs were mogamulizumab-associated rash (MAR) (45.5%), anemia (27.3%), lymphocytopenia (27.8%), and infusion related reaction (16.7%). No AE led to treatment discontinuation. Our study presents the combination of mogamulizumab and ECP as an effective therapy in the blood and skin in CTCL with good tolerability, similar to mogamulizumab monotherapy.

An investigation on the nutritional status and support of in-patients with common variable immunodeficiency

The study aimed to reveal for the first time the clinical characteristics, nutritional and metabolic status and support of hospitalized patients with common variant immunodeficiency disease (CVID), and provide reference to improve the long-term nutritional management for such patients. This is a retrospective cross-sectional study. Through searching the electronic medical record system of Peking Union Medical College Hospital, the study included 33 consecutive in-patients with CVID diagnosed in Jan 2016 to Jun 2021, with the male to female ratio of 16∶17. All their medical data, nutritional assessment and intervention retrospectively summarized and analyzed. Data with normal distribution were described using (x¯±s), and analyzed with independent sample t-test. Data with non-normal distribution were compared with non-parametric test. The results showed that the median onset-age of the included patients was 22 (10.0,36.5) years old, and the median duration was 9.0 (2.0,16.0) years. All patients had recurrent infections involving various systems (33/33), with development of autoimmune diseases (8/33) and lymphoproliferative disease or malignancy (9/33) in some cases among them. The nutritional risk screening 2002 (NRS 2002) scores revealed that 85.19% of adults had an NRS 2002≥3 points, and 33.33% of children had a BMI-for-age z score<-2. Weight loss occurred in 66.67% of patients (22/33), while 87.88% (29/33), 69.70% (23/33) and 81.82% (27/33) of patients respectively had anemia, hypoalbuminemia and decreased prealbumin. Among 22 patients with micronutrients status evaluated, 77.27% (17/22), 22.73% (5/22) and 31.82% (7/22) of patients respectively had lowered serum iron, folate deficiency and vitamin B12 insufficiency. Six patients underwent 25-OH-VD3 measurement, and were all testified to have vitamin D deficiency. Among all patients with nutritional risk, 56.00% of them underwent nutritional support: oral nutritional supplements (14 cases), enteral feeding (4 cases) and parenteral nutrition (5 cases). In conclusion, the condition of malnutrition was prevalent in patients with CVID, but was under-recognized and undertreated to some degree.

Breast Cancer and Autoimmune Hemolytic Anemia: A Rare Paraneoplastic Syndrome

Autoimmune hemolytic anemia (AIHA) is a pathological process involving the destruction of red blood cells by the humoral immune system. Although there is a well-established relationship between the presence of AIHA and lymphoproliferative malignancies, AIHA rarely presents in association with solid malignancies. Few cases of solid cancer associated with AIHA have been reported. AIHA rarely presents as a paraneoplastic syndrome indicative of solid cancer. We report a case of breast cancer revealed by AIHA.

Clinical Significance of a Slightly Abnormal FLC Levels/Ratio

The employment of Free Light Chain (FLC) test in the community is continuously expanding and incorporated into the assessments of unexplained tiredness or nonspecific complaints, even in the absence of clear suspicion of plasma cell dyscrasia (PCD). Consequently, there has been a growing occurrence of “incidental detection” of slightly abnormal FLC tests, in the absence of additional laboratory abnormalities, and data regarding the significance of this finding are limited. The current study aims to explore the clinical significance of an “incidental” finding of slightly increased FLC test in a cohort of seemingly “healthy” subjects, defining patients at risk of developing PCD or lymphoproliferative malignancy (LPM). This research employs a non-interventional retrospective cohort study design, utilizing data extracted from the electronic medical records of individuals insured in Maccabi Healthcare Services (MHS) tested for FLC in peripheral blood between 2007 and 2023. The index date is defined as the date of first FLC test, encompassing FLC-K, FLC-L, and FLC-R (FLC-K/FLC-L ratio) measurements. Inclusion criteria were age ≥ 18 years and registration in MHS ≥12 months(m) prior to and ≥6m after FLC testing. Patients diagnosed with MM/SMM/MGUS/NHL/AL ±6 months from the index date and those presenting with elevated total protein (TP) levels were excluded. Patient characteristics, including demographics, pre-existing co-morbidities, and laboratory tests, all performed at MHC laboratory on the index date, were recorded (table1). The index FLC results were categorized as normal if FLC-K/L/R were within normal limits, or abnormal if at least one of the FLC-K/L/R components was outside the normal range. FLC-R was divided into four categories: normal (0.26-1.65), slightly abnormal (SliAb) (0.1-0.26 / 1.65-4), abnormal (Ab) (0.05-0.1 / 4-8), and significantly abnormal (SigAb) (Ratio&amp;lt; 0.05 or &amp;gt;8). The follow-up period was up to 5 years from index test, and documentation of new events of PCD/LPM were captured (figure1). Factors predicting a higher risk to develop MGUS/MM/NHL in patients with normal TP and abnormal FLC were analyzed. 11,241 patients with no prior history of PCD/LPM underwent FLC tests. 8,942 patients, fulfilling the study criteria, were analyzed. 6,687had an “abnormal” FLC and 2,255 had a normal FLC result. The proportion of males and the median age in the abnormal FLC cohort were higher (50% vs 37%, p &amp;lt; 0.001; and 67 vs. 59 years, p &amp;lt; 0.001). Almost no patients had anemia, nor aRF, though, the proportions of both were higher in the abnormal cohort (7.4% vs 1.8% and 6.67% vs 0.9%, p&amp;lt;0.001, p&amp;lt;0.001, respectively). 1,153 patients presented with concomitant increase in Ig levels (IgG-464 (10.1%); IgA-205 (4.2%); IgM-484 (10.67%), and monoclonal protein was reported in 143 (2.14%). The index FLC-R was normal in 6,620 (74.1%), SliAb in 2,181 (24.4%), Ab in 68 (0.76%), and SigAb in 66 (0.74%). Within a median follow-up of 52 months, 1065 were diagnosed with PCD (965-MGUS; 96-MM, 4-plasmacytoma) and 92 were diagnosed with LPM. Median time to PCD/LPM was 22 months (range: 6-60); 21.5 (6-60) for the detection of MGUS, 23.5 (6-60) for MM, and 57 (6-60) for the detection of NHL. A multivariate Cox regression analysis confirmed FLC-R to be a significant predictor for PCD/LPM development (SliAb HR =1.47 (CI: 1.25-1.71, p&amp;lt; 0.001), Ab HR = 6.8 (CI: 4.65-9.44, p&amp;lt; 0.001), and SigAb HR= 7.61 (CI: 5.15-11.25, p&amp;lt; 0.001). In addition, age &amp;gt; 75 HR 1.83 (CI: 1.37-2.43, p &amp;lt; 0.001), elevate levels of both IgG (HR: 1.34, CI: 1.07-1.68, p=0.01, IgM (HR: 1.73, CI: 1.41-2.1, p&amp;lt;0.001), IgA (HR: 1.62, CI: 1.2-2.2, p=0.001), and osteoporosis ( HR of 1.36 (CI: 1.16-1.6, p &amp;lt; 0.001) were found to independently predict a higher risk for PCD/LPM. Concurrently, increased IgM level (HR: 3.2, CI: 1.8-5.7, p= 0&amp;lt;0.001) or a decreased IgM level (HR: 2.5, CI: 1.3-4.8, p=0.006) were associated with increased risk for LPM. Our retrospective cohort study emphasizes the independent clinical significance of elevated FLC levels and abnormal FLC-R in “healthy” individuals, being a “rough” predictor for PCD/LPM development, even in patients with no increase in their TP levels. This can be used as a simple risk assessment model that would incorporate all independent factors found to be associated with increased risk for PCD/LPM; thereby enabling physicians, especially in the community, to monitor their patients and promote an early detection, when required.

Clinical Outcome of Covid-19 in Haematologic Malignancy Patients with a Fourth Dose of Anti-Sars-Cov-2 Vaccine: A Final Epicovideha Report

Background: There is a general scepticism on anti-SARS-CoV-2 fourth dose efficacy due to lack of data. In pts with haematological malignancies (HM), this results that only few individuals received a fourth dose. We evaluted the clinical outcome of breakthrough SARS-CoV2 infections in HM who previously received a fourth dose of anti-SARS-CoV-2 vaccine, in particular HM from a multi-national European registry. Methods: Patients (pts) from the EPICOVIDEHA registry were eligible as long as they could fulfil these criteria: a) active HM within the last five years (ys) before COVID-19 diagnosis, b) pts ≥18 ys old, c) laboratory-based diagnosis of SARS-CoV-2 infection, and d) reception a fourth anti-SARS-CoV-2 dose before COVID-19 diagnosis. Results. As of August 2023, 6867 HM pts with SARS-CoV-2 infection have been registered in the EPICOVIDEHA registry. Out of these, 51 (0.7%) were diagnosed with COVID-19 after having received a fourth vaccine dose. Most of those (30/51, 58.8%) were male; median age was 71 ys of age (IQR 65-73), with only three pts below the age of 50 ys of age. Twelve pts (12/51, 23.5%) did not present any baseline underlying conditions besides the HM. Lymphoproliferative malignancies were prevalent (47/51, 92%). Most pts had a controlled HM at the time of COVID-19 diagnosis (30, 58.8%). Pts had their fourth vaccine dose at a median of 32 days (IQR 13-54) before COVID-19 diagnosis, almost exclusively mRNA based (50/51, 98%). COVID-19 remained asymptomatic or mild in almost all pts (49/51, 96%), with only one patient with critical infection (2%) requiring intensive care. Hospital admission rate was 47.1% with a median hospital stay of 9 days (IQR 5-14). Only 26 pts (51%) received a specific treatment for SARS-CoV-2, with almost all of them (18/26, 69.2%) receiving monoclonal antibodies. Pts were followed up for a median of 65 days (IQR 26-86) and only two died (3.9%) due to COVID-19. Conclusions. With the caution derived from the limited number of pts and the intrinsic nature of this study, our data show favourable clinical presentation and outcome of breakthrough SARS-CoV2 infections in HM who previously received a fourth dose of anti-SARS-CoV-2 vaccine. The data suggests that a second vaccine booster may be of particular importance to protect this vulnerable HM patient population from severe or potentially life-threatening COVID-19.

Single Cell RNA Sequencing Enables Identification of Mantle Cell Lymphoma Subclones with Drug-Resistant Profiles Already at Diagnosis and May be Used for Therapy Prognostication and Personalization

Mantle cell lymphoma (MCL) is a chronically relapsing B cell lymphoproliferative malignancy characterized by translocation t(11;14)(q13;q32), cyclin D1 overexpression and significant chromosomal instability. One of the main hypotheses of MCL relapses is a clonal evolution driven by therapy selection of subpopulations carrying adverse genetic and epigenetic aberrations. Our previous whole exome sequencing analysis of 25 MCL tumors showed that the majority of the detected single-nucleotide variants and copy number variants (CNV) were already detectable at diagnosis. To further analyze the subclonal structure of MCL at diagnosis and clonal evolution at relapse, we implemented single cell RNA sequencing analysis of five patients with MCL at diagnosis and at the first clinical relapse after failure of standard immunochemotherapy. All analyzed patients achieved at least partial remission. Fresh-frozen tumor cells were sorted to obtain Hoechst − CD45 + population which was processed using single cell 3′ protocol (10X Genomics). The libraries were paired-end sequenced on Novaseq 6000 (Illumina). The reads were aligned to GRCh38 human genome. The MCL cells were distinguished from the normal B cells based on of CCND1 expression and unsupervised clustering. CNVs were predicted using inferCNV package. These CNVs shared a high degree of similarity with the CNVs predicted using available exome sequencing data. The t-SNE representation of the data clearly showed unique positions for the malignant lymphocytes obtained from each of the five analyzed patients ( Figure 1a). In contrast, non-malignant cells (T cells, B cells and monocytes) have grouped together irrespective of the patient or compartment of origin ( Figure 1b). These data suggest two conclusions. First, each patient's malignant cells have unique genetic background. Second, the impact of the microenvironment does not override the impact of the genetic makeup of the non-malignant cells. The data thus suggest comparability of the malignant cells obtained from different compartments. Hierarchical clustering of the per-cell CNV profiles revealed subclonal heterogeneity of the MCL population in all analyzed compartments both at diagnosis and at relapse. In all analyzed patients the clustering identified several large subclones with significant differences (DG L) and at least one minor subclone (DG S) with significant similarities compared to the major clone detectable at relapse (R L). These data suggest that the majority of the diagnostic MCL cells (i.e., DG L clones) were indeed eliminated by therapy, which on clinical level corresponded to achieving remission. On the other hand, the data also suggest that MCL cells with CNV profiles highly similar to the major relapse clone (i.e., R L) were detectable already at diagnosis (i.e., DG S, Figure 1c). To gain a better insight into the biology of the DG S clones with potential drug-resistant phenotype, we analyzed transcriptome differences between DG S and DG L clones. For each patient we identified different sets of significantly upregulated genes in DG S compared to DG L. These included genes coding for important cell surface molecules ( MARCKS, CD52, CD79A, LTB), regulators of cell motility and cytoskeleton dynamics ( STMN1, SWAP70, CFL1, TUBB, TUBA1B, TMSB4X), transcription factor PRDM2, energy metabolism proteins ( MT-ND4, MT-CO1, ATP5MG), protein degradation proteins ( UBA52, PSMC4, UFD1, UBE2L3) and others. Among these genes, significant upregulation of TMSB4X, SWAP70, HLA-A, TUBB4B, RPS26, UBA52, PSMB2, SNRPG, ARPC1B, ATP5MG was detected in three out of five patients. Many of these genes code for oncogenes involved in cell motility and aggressiveness. To further characterize subclonal clusters in MCL population we used marker gene detection and subsequent gene set enrichment analysis, which identified cell adhesion molecules as major category upregulated in four out of five patients in clusters associated with relapse. Our data shows the applicability of the single cell genomic approaches not only to analyze subclonal heterogeneity for the study of disease biology, but also to identify drug-resistant subclones at diagnosis, predict response to various types of therapies thereby enabling therapy personalization. Acknowledgement: Supported by Grant Agency of the Czech Republic GA23-05474S and National Institute for Cancer Research (EXCELES) LX22NPO5102.

Intent to Treat Allogeneic Stem Cell Transplantation Outcomes in Relapsed/Refractory T-Cell Lymphomas

Introduction T-cell lymphomas (TCL) are a heterogeneous group of lymphoproliferative malignancies with an overall poor prognosis. Despite aggressive first-line therapy, most patients experience disease relapse or progression. Allogeneic stem cell transplant (AlloSCT) is a standard of care for relapsed/refractory (R/R) TCL. However, many patients do not receive this potentially curative therapy. There is a paucity of data regarding the frequency of and barriers to undergoing AlloSCT in R/R TCL. To address this knowledge gap, we conducted a retrospective analysis of R/R TCL patients intending to undergo AlloSCT and hypothesized the primary barrier to AlloSCT to be lack of effective disease control. Methods We identified patients with a primary diagnosis of R/R TCL seen at the University of Washington/Fred Hutchinson Cancer Center (UW/FHCC) between 1/2008 and 6/2023 and linked these patients with the UW/FHCC bone marrow transplant (BMT) database to identify those who were intended for transplant. Intention to transplant (ITT) was defined as undergoing human leukocyte antigen (HLA) typing for purposes of AlloSCT. Patients with T-cell lymphoblastic leukemia/lymphoma were excluded. The primary endpoint was the rate of patients who underwent AlloSCT. Secondary endpoints included progression-free (PFS) and overall survival (OS) in patients who underwent AlloSCT and specific barriers to AlloSCT. Results Overall, 163 patients met ITT criteria. Males comprised 66% of patients. Median age was 65 (range 34-81) years and the median number of treatment regimens prior to HLA typing was 3 (range 1-10). The majority of patients (60%) were non-Hispanic whites (NHW), with Asians/Pacific Islanders (API), Hispanics/Latinos (HL), African Americans (AA) and Alaskan Natives/American Indians (ANAI) contributing 17%, 12%, 7% and 4%, respectively. Sixty-four patients (39%) had peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), 23 (14%) had angioimmunoblastic TCL (AITL), 17 (10%) had anaplastic large cell lymphoma (ALCL; 6 with ALK+), 16 (10%) had NK/TCL, 11 (7%) had hepatosplenic TCL, 12 (7%) had T-cell prolymphocytic leukemia, 5 (3%) had adult T-cell leukemia/lymphoma and 12 (7%) had primary cutaneous TCL. Twenty-two (13%) patients had secondary CNS involvement and 27 (17%) had previous autologous stem cell transplant. Of all patients who received HLA typing, 154 (94%) had a transplant consult, 54 (33%) initiated pre-AlloSCT workup and 51 (31%) underwent AlloSCT. Barriers to AlloSCT included progressive disease, patient preference, inability to identify a donor, indolent disease, poor functional status/multiple comorbidities and lack of a caregiver in 55%, 9%, 8%, 5%, 3% and 1%, respectively (Figure 1A). Six (5%) patients are currently receiving salvage therapy with plans for subsequent AlloSCT. AlloSCT occurred in NHW, API, HL, AA and ANAI patients at rates of 35%, 11%, 26%, 36% and 50%, respectively. All patients who were unable to undergo transplant due to lack of a donor were from groups other than NHW. AlloSCT rates were 30%, 39% and 17% in PTCL-NOS, AITL and ALCL, respectively. At a median follow-up time of 24.2 months, 101 (63%) patients are deceased with 83 (82%) due to disease. Twenty (39%), 17 (33%), 11 (22%) and 3 (6%) patients received an AlloSCT with a matched unrelated, matched related, mismatched unrelated and haploidentical donor, respectively. Fifteen (29%) patients underwent a myeloablative while 36 (71%) underwent a reduced intensity conditioning regimen. None of the 51 patients who underwent AlloSCT had pre-transplant measurable disease. Of transplanted patients, median PFS was 55.7 months and OS was 62.4 months (Figure 1B). Sixteen (31%) patients had eventual disease relapse. Eighty percent of relapses occurred within 3 months after AlloSCT. Seven (13%) and 6 (12%) of the transplanted patients were deceased within 12 months after AlloSCT due to disease relapse and complications of AlloSCT, respectively. Conclusions Although AlloSCT may be highly effective for R/R TCL achieving a CR, only a small minority of patients are able to undergo AlloSCT and the outcomes for the ITT population is dismal. Common barriers to undergoing AlloSCT include progressive disease and inability to identify suitable donors, particularly in minority populations. More effective pre-transplant salvage therapies and alternative AlloSCT donors are greatly needed.

Abstract 17431: A Rare Cause of Constrictive Pericarditis in a Case of Adult T-cell Lymphoma

Introduction: Adult T-cell lymphoma (ATCL) is a rare T cell lymphoproliferative malignancy that typically presents with lymphadenopathy, hepatosplenomegaly, lytic lesions, hypercalcemia or skin lesions. Cardiac involvement is rare. Case presentation: A 66-year-old male with a history of chronic kidney disease and hypertension presented with dyspnea. Transthoracic echocardiography revealed a moderate pericardial effusion and a left ventricular ejection fraction of 45%. Further workup with MRI and transesophageal echocardiography found extensive circumferential pericardial thickening with enhancement and extensive mediastinal and hilar lymphadenopathy along with a mass along the course of the superior vena cava with extension of disease into the right atrium along the right atrial wall (Figure 1). Endobronchial biopsy of the mediastinal lymph nodes was positive for T-cell lymphoma. Chemotherapy was initiated; however, the patient decided to focus on comfort measures only. Discussion: Cardiac involvement in ATCL is rare and usually detected in postmortem autopsies. Incidence is unknown, and experience is limited to case reports. The largest case series to date found 16 patients who had antemortem diagnosis of symptomatic cardiac involvement of ATCL. The characteristic features included infiltration of the myocardium, pericardial effusion, valvular lesions, and masses in the atrium, similar to what was seen in our patient. To our knowledge, there have been no reported cases of ATCL causing constriction. Prognosis is poor, with median survival of 5 months after development of symptoms (n = 15, range 0-120 months). Conclusion: The incidence of cardiac ATCL is unknown, but it is an extremely rare occurrence. It can present with a wide variety of cardiac involvement, including constriction. The prognosis of cardiac ATCL remains poor.

Complete miRNA-15/16 loss in mice promotes hematopoietic progenitor expansion and a myeloid-biased hyperproliferative state

Dysregulated apoptosis and proliferation are fundamental properties of cancer, and microRNAs (miRNA) are critical regulators of these processes. Loss of miR-15a/16-1 at chromosome 13q14 is the most common genomic aberration in chronic lymphocytic leukemia (CLL). Correspondingly, the deletion of either murine miR-15a/16-1 or miR-15b/16-2 locus in mice is linked to B cell lymphoproliferative malignancies. However, unexpectedly, when both miR-15/16 clusters are eliminated, most double knockout (DKO) mice develop acute myeloid leukemia (AML). Moreover, in patients with CLL, significantly reduced expression of miR-15a, miR-15b, and miR-16 associates with progression of myelodysplastic syndrome to AML, as well as blast crisis in chronic myeloid leukemia. Thus, the miR-15/16 clusters have a biological relevance for myeloid neoplasms. Here, we demonstrate that the myeloproliferative phenotype in DKO mice correlates with an increase of hematopoietic stem and progenitor cells (HSPC) early in life. Using single-cell transcriptomic analyses, we presented the molecular underpinning of increased myeloid output in the HSPC of DKO mice with gene signatures suggestive of dysregulated hematopoiesis, metabolic activities, and cell cycle stages. Functionally, we found that multipotent progenitors (MPP) of DKO mice have increased self-renewing capacities and give rise to significantly more progeny in the granulocytic compartment. Moreover, a unique transcriptomic signature of DKO MPP correlates with poor outcome in patients with AML. Together, these data point to a unique regulatory role for miR-15/16 during the early stages of hematopoiesis and to a potentially useful biomarker for the pathogenesis of myeloid neoplasms.

Clinical Warburg effect in lymphoma patients admitted to intensive care unit

BackgroundThe Warburg effect, characterized by elevated lactate levels without tissue hypoxia or shock, has been described in patients with aggressive lymphoproliferative malignancies. However, the clinical characteristics and long-term outcomes in this population remain poorly understood.MethodsWe retrospectively analyzed 135 patients with aggressive lymphoproliferative malignancies admitted to the ICU between January 2017 and December 2022. Patients were classified into three groups: Clinical Warburg Effect (CWE), No Warburg with High Lactate level (NW-HL), and No Warburg with Normal Lactate level (NW-NL). Clinical characteristics and outcomes were compared between the groups and factors associated with 1-year mortality and CWE were identified using multivariable analyses.ResultsOf the 135 patients, 46 (34%) had a CWE. This group had a higher proportion of Burkitt and T cell lymphomas, greater tumor burden, and more frequent bone and cerebral involvement than the other groups. At 1 year, 72 patients (53%) died, with significantly higher mortality in the CWE and NW-HL groups (70% each) than in the NW-NL group (38%). Factors independently associated with 1-year mortality were age [HR = 1.02 CI 95% (1.00–1.04)], total SOFA score at admission [HR = 1.19 CI 95% (1.12–1.25)], and CWE [HR = 3.87 CI 95% (2.13–7.02)]. The main factors associated with the CWE were tumor lysis syndrome [OR = 2.84 CI 95% (1.14–7.42)], bone involvement of the underlying malignancy [OR = 3.58 CI 95% (1.02–12.91)], the total SOFA score at admission [OR = 0.81 CI 95% (0.69–0.91)] and hypoglycemia at admission [OR = 14.90 CI 95% (5.42–47.18)].ConclusionCWE is associated with a higher tumor burden and increased 1-year mortality compared to patients without this condition. Our findings underscore the importance of recognizing patients with CWE as a high-risk cohort, as their outcomes closely resemble those of individuals with lymphoma and shock, despite not requiring advanced organ support. Clinicians should recognize the urgency of managing these patients and consider early intervention to improve their prognosis.

The Effectiveness of Bivalent mRNA Omicron Containing Booster Vaccines Among Patients With Hematological Neoplasms.

Last year was characterized by the appearance of novel SARS-CoV-2 virus variants, mainly the omicron sub-lineages BA.2.12.1, BA.4, and BA.5, which have confirmed resistance to the acquired immune response developed following first-generation mRNA vaccines. Given the ability to use mRNA technology to respond quickly to variant strains, novel bivalent vaccines against novel omicron variants were generated. In the current work, we evaluated the efficacy and safety of novel bivalent mRNA Omicron-containing booster vaccines among patients with hematological neoplasms, including both lymphoproliferative and myeloid malignancies. Cohort patients were obtained from electronic medical records of Maccabi Healthcare Services (MHS), the second-largest healthcare organization in Israel. We analyzed the outcome of all patients with hematological neoplasms, between September 21, 2022, and December 31, 2022, who were identified as having SARS-CoV-2 infection based on polymerase chain reaction (PCR) tests. The Kaplan-Meier method was used to compare the proportion of patients hospitalized for SARS-CoV-2 infection within 30 days among recipients and non-recipients of omicron vaccine. During the study period, 472 patients were infected with Omicron. We compared the outcome of 70 patients who received the bivalent mRNA booster to 402 who did not. Fewer bivalent recipients needed COVID-19-related hospitalization [2 of 70 (2.9%)] in comparison to the non-vaccinated cohort [42 of 402 (10.4%)] (p-value=0.0304). This represents an 89% relative risk reduction in COVID-19-related hospitalization in patients with hematological neoplasms. The median duration of hospitalization was 7 days for the non-vaccinated group and 4 for the vaccinated group. A statistically significant increase in ischemic stroke rates due to bivalent mRNA Omicron-containing booster vaccine was not observed. The bivalent Omicron-containing vaccine mRNA booster has a protective effect in preventing and shortening hospitalization in patients with hematological neoplasms with an acceptable safety profile.

Assessment of Metabolic Syndrome and Kidney and Heart Function in Childhood Cancer Survivors

Background: The survivors of childhood cancer suffer from a number of long-term side effects. These include atherosclerosis and cardiovascular diseases (CVDs) that develop earlier in adulthood than in the rest of the population. The aim of this study was to identify prognostic factors of developing atherosclerosis before the development of symptomatic CVD. Methods: A total of 141 children that were 7–18 years old were examined; there were 116 survivors of childhood malignancies (hematopoietic and lymphoproliferative malignancies—52; neuroblastoma—22; Wilms tumor—24; other solid tumors—18) and 25 healthy controls. Anthropometric measurements, blood pressure measurements, ultrasonography of the abdomen, echocardiography, and laboratory tests were performed. Results: There were no significant differences in gender distribution, time from the end of the treatment, weight, BMI, prevalence of central obesity, blood pressure and resistive index of the renal arteries, lipid profile, or glucose and fibrinogen levels. Patients with solid tumors had a significantly lower height and worse renal function. Patients with hematological malignancies significantly presented the lowest shortening fraction of the left ventricle. The salusin β levels were significantly higher in the control group than among the patients. Conclusions: The type and severity of side effects are closely related to the type of neoplasm and the treatment that has been undergone. Careful observation and regular follow-up are necessary.

The protective role of the microenvironment in hairy cell leukemia treatment: Facts and perspectives.

Hairy cell leukemia (HCL) is an incurable, rare lymphoproliferative hematological malignancy of mature B cAlthough first line therapy with purine analogues leads to positive results, almost half of HCL patients relapse after 5-10 years, and standard treatment may not be an option due to intolerance or refractoriness. Proliferation and survival of HCL cells is regulated by surrounding accessory cells and soluble signals present in the tumor microenvironment, which actively contributes to disease progression. In vitro studies show that different therapeutic approaches tested in HCL impact the tumor microenvironment, and that this milieu offers a protection affecting treatment efficacy. Herein we explore the effects of the tumor microenvironment to different approved and experimental therapeutic options for HCL. Dissecting the complex interactions between leukemia cells and their milieu will be essential to develop new targeted therapies for HCL patients.

Therapeutic implication of chimeric antigen receptor T-cell therapy for head and neck squamous cell carcinoma.

Therapeutic implication of chimeric antigen receptor T-cell therapy for head and neck squamous cell carcinoma.

Plateletcrit as a prognostic marker in Hodgkin lymphoma: A pilot study

Background/Aim: Hodgkin lymphoma (HL) is a lymphoproliferative malignancy associated with inflammation. Plateletcrit (PCT) is a mean platelet volume (MPV) and platelet count-derived marker that is useful for evaluating malignancies and inflammatory diseases. International Prognostic Score (IPS-7) and more recently, IPS-3, are two indices indicating the prognosis of patients; however, widespread and easy to interpret prognostic markers are still needed for HL evaluation. Very few studies evaluating the prognostic significance of platelet indices in HL have been published, so we aimed to show the relationship between PCT and other adverse prognostic factors in HL and evaluate whether PCT can be used as a prognostic marker in HL. Methods: After excluding patients with insufficient data, 75 patients diagnosed with HL and 150 healthy controls were retrospectively analyzed in this case-control study. Evaluation of relationship of PCT and adverse HL prognostic factors, such as age, gender, hemoglobin, leukocytes, lymphocytes (absolute value and percentage), albumin, Ann Arbor stage and B symptoms, IPS-3 and-7 prognostic scores and post-treatment relapse, and progression-free survival of the patients were studied. Results: Mean MPV values were significantly lower, mean platelet values were significantly higher inpatient group (all P&lt;0.001). Patients with high sedimentation had significantly higher mean PCT than those without (P=0.031) and a moderately positive correlation between PCT and sedimentation were found (r=0.33, P&lt;0.01). Mean PCT values after treatment significantly decreased compared to baseline levels (P&lt;0.001). Conclusion: PCT may be useful as a prognostic marker in HL. Further studies were needed to evaluate the relationship between PCT and other prognostic factors, such as IPS-3 and -7.