Thompson, Carrie A.

Abstract Activated B cell (ABC) type diffuse large B cell lymphoma (DLBCL), double hit lymphoma (DHL) and double expressor lymphoma (DEL) have poor outcomes to frontline R‐CHOP but impact of these molecular features on outcomes of relapsed/refractory (R/R) disease is not well‐characterized. We evaluated the association of diagnostic cell of origin (COO), double hit and double expressor status with overall survival after first relapse in DLBCL patients who were enrolled into the Molecular Epidemiology Resource (MER) cohort. COO was available from immunohistochemistry (IHC) using Hans criteria or gene expression profiling (GEP) (Nanostring) on the diagnostic FFPE biopsy. Of 373 pts with R/R DLBCL, 278 had COO by IHC: 152 were GCB, 107 were non‐GCB. One hundred and fourty had COO by GEP: 44 were ABC, 65 were GCB and 13 were unclassifiable. Nineteen out of 163 (12%) were DHL; 30 out of 135 (22%) had DEL. COO, either by IHC (2 years OS GCB: 45% [CI 95 : 38–54] vs. non‐GCB: 44% [CI 95 :36–55], p > 0.05) or GEP (2 years OS ABC: 42% [CI 95 : 29–59] vs. GCB: 40% [CI 95 : 30–54], p > 0.05), was not associated with difference in OS. DHL (2 years OS 16 [CI 95 :6–45] vs. 45% [CI 95 : 34–59], p < 0.01) and DEL (2 years OS 33% [CI 95 : 20–56], vs. 50% [CI 95 : 41–60], p < 0.05) had lower OS than non‐DHL and non‐DEL/non‐DHL counterparts, respectively. COO by IHC or GEP was not associated with OS in R/R DLBCL while DHL and DEL were adverse prognostic markers in DLBCL at first relapse.

Abstract Background Speckle tracking echocardiography (STE) has shown to be a good tool to foresee early myocardial dysfunction in lymphoma patients who receive anthracycline based chemotherapy. Conventional STE such as global longitudinal strain (GLS) is a good predictor of cardiotoxicity in these patients, however, a more in-depth characterization of conventional and comprehensive STE parameters to predict a hard end-point as chemotherapeutic related heart failure (HF) has not been evaluated. Purpose The aim of this prospective study was to evaluate predictability of cancer therapeutic-related clinical HF by conventional and comprehensive STE. Methods We enrolled 269 Hodgkin & non-Hodgkin lymphoma patients who underwent chemotherapy at Mayo Clinic from 2013 through 2021. All patients had an echocardiogram performed at baseline (T0), during chemotherapy (T1) and after (T2). HF was diagnosed by a cardiologist and defined as the first occurrence after the initiation of chemotherapy. Conventional (GLS) and comprehensive strain analyses that included: global circumferential strain (GCS), global radial strain (GRS), global longitudinal early diastolic strain rate (GLSRe), global longitudinal systolic strain rate (GLSRs), global circumferential early diastolic strain rate (GCSRe), global circumferential systolic strain rate (GCSRs), global radial early diastolic strain rate (GRSRe), and global radial systolic strain rate (GRSRs), were performed offline. Logistic regression analyses were used to evaluate the association of 2D and 3D STE measurements with the development of clinical HF. Results Overall, 215 (79.9%) patients had non-Hodgkin lymphoma while 54 (20.1%) had Hodgkin lymphoma. Mean age was 58.4±16.1 years and 64.7% of the patients were males. The most prevalent comorbidities were hypertension (101/37.5%), dyslipidemia (87/32.3%) and diabetes (28/10.4%). HF occurred in 21 (7.8%) patients, including 9 (3.3%) during chemotherapy and 12 (4.5%) after chemotherapy. The best predictors of HF were: i) GLSRe and GCSRs performed at baseline (T0) to predict HF at T1 with an AUC of 0.85 each and p values of 0.0006 and 0.0005 respectively (Table 1); ii) GCSRs and GCS at baseline (T0) to predict HF at T1 or T2 with AUCs of 0.82 (p, &lt;0.0001) and 0.81 (p, 0.0004), respectively. Basic strain (GLS) was able to predict HF when measured at T0 but not when measured at T1. All the AUCs for GLS were below 0.75 (Figure 1). Conclusions To our knowledge this is the first study to evaluate the use of conventional and comprehensive STE to predict a hard end-point as heart failure in patients with lymphoma who received anthracyclines. Comprehensive STE measurements as GLSRs, GLSRe, GCS, GCSRs and GCSRe are better than GLS to predict HF in patients with lymphoma who received anthracycline based chemotherapy. These findings can be crucial for the management of these patients by guiding when to start cardioprotection and/or avoid interruptions of cancer treatment. Funding Acknowledgement Type of funding sources: Private hospital(s). Main funding source(s): Department of cardiovascular diseases, Mayo Clinic, Rochester, MN

Abstract Background Assessing cardiac performance of patients receiving chemotherapy is a cornerstone for adequate cardiovascular care. Mitral annular plane systolic excursion (MAPSE) has been considered as a surrogate for Ejection Fraction (EF). However, little is known about its role in predicting Cardiotoxicity or Heart Failure in Lymphoma patients, as its relationship with Global Longitudinal Strain (GLS) and EF. Purpose Our aims were: i) to evaluate if MAPSE and GLS can predict the development of CT and/or HF in lymphoma patients treated with anthracyclines and ii) to evaluate its correlation with GLS and EF. Methods For this prospective observational study, 325 Hodgkin (HL) & non-Hodgkin (NHL) lymphoma patients (n=325) treated with anthracyclines were recruited from 2013 to 2021 and followed for 1 year. MAPSE by M-mode and GLS by Speckle-Tracking (ST) were measured at baseline (T0), during treatment (T1), and up to 1 year after chemotherapy completion (T2). CT was defined as a decrease in EF by &gt;10% to a value &lt;50% and HF by a cardiologist as the first occurrence after the initiation of anthracyclines. Logistic regression analyses with Receiving operator characteristics (ROC) and Area under the curve (AUC) were performed. Pearson's correlation coefficient was also calculated. A p-value &lt;0.05 was considered statistically significant. Results Two hundred sixty-four patients (81.2%) had NHL and 61 (18.8%) HL. Of these, fifteen (4.6%) and 21 individuals (6.4%) developed CT at T1 and T2, respectively. Nine subjects (2.8%) developed HF at T1 and 14 (4.3%) at T2. MAPSE at T0 had the highest AUC to predict both HF at T1 (AUC=0.865, cut-off 14.9, sensitivity 100%, specificity 63%, p=0.008) and at T2 (AUC=0.757, cut-off 10.9, sensitivity 67%, specificity 93%, p=0.045). This same variable at T1 predicted HF at T2 with an AUC of 0.752 (cut-off 11.4, sensitivity 67%, specificity 94%, p=0.004). For CT prediction at T2, MAPSE at T1 had an AUC of 0.738 (cut-off 12.5, sensitivity 56%, specificity 85%, p&lt;0.0001). GLS at T0 predicted CT at T1 (AUC=0.657, cut-off −19, sensitivity 67%, specificity 63%, p=0.012) and when obtained at T1, it predicted CT at T2 (AUC=0.776, cut-off −17, sensitivity 74%, specificity 75%, p-value &lt;0.0001) (Table 1). Pearson's correlation between MAPSE and GLS at T0 (coefficient −0.25, p=0.023) at T1 (coefficient −0.38, p&lt;0.0001) at T2 (coefficient −0.037, p&lt;0.0001) and MAPSE with EF at T0 (coefficient 0.33, p=0.0002) at T1 (coefficient 0.28, p&lt;0.0001) and T2 (coefficient 0.29, p&lt;0.001). Conclusions To our best knowledge, this is the first time that MAPSE and GLS were compared to predict CT and HF in lymphoma patients receiving anthracycline-based chemotherapy; we have demonstrated that MAPSE measured at T0 was a very good predictor of HF at T1. Either MAPSE or GLS assessment at T0 and T1 were able to predict CT or HF. Future studies could explore the combination of these two variables to predict either CT or HF. Funding Acknowledgement Type of funding sources: Private hospital(s). Main funding source(s): Department of Cardiovascular Medicine. Mayo Clinic, Rochester-MN

PURPOSE:High-dose methotrexate (HDMTX; > 500 mg/m2) is an important component of lymphoma therapy. Serum MTX monitoring at 48 hours is the standard approach to identify those at increased risk of developing MTX toxicity. Our aim was to characterize the incidence of complications and their association with MTX levels.METHODS:A retrospective review of our institutional electronic medical record was conducted to identify patients with lymphoma who received HDMTX between January 1, 2002, and December 31, 2018. We characterized the incidence of acute kidney injury (AKI), intensive care unit (ICU) admission, length of hospital stay (LOS), and 30-day mortality across 48-hour MTX levels. To establish an association between 48-hour MTX levels and the complications listed, we performed chi-square analysis for dichotomous variables and Kruskal-Wallis for nonparametric data. Receiver operator characteristic curve analysis was performed to identify the MTX level where AKI grade ≥ 2 was more likely. Multivariate logistic regression analysis was performed to identify risk factors for this MTX level.RESULTS:We identified 642 patients with 2,804 cycles of HDMTX. The incidence of AKI was 19.1% with AKI grade ≥ 2 making up 21% of cases. Rates of AKI, ICU admission, and 30-day mortality are associated with elevated 48-hour MTX levels. There was a significant increase in median LOS with elevated MTX levels ( P < .001). Receiver operator characteristic curve analysis for AKI grade ≥ 2 demonstrated a 48-hour MTX level threshold of 1.28 μmol/L. Multivariate logistic regression analysis revealed age, male sex, elevated body surface area, higher MTX dose, monotherapy, and first cycle as independent factors.CONCLUSION:Elevated MTX levels are associated with a significant increased rate of AKI, ICU admission, prolonged LOS, and 30-day mortality. Elevated 48-hour MTX levels, particularly > 1.28 μmol/L, should alert clinicians for complications and to initiate measures to reduce MTX levels.

Abstract An enhanced understanding of the molecular heterogeneity of diffuse large B-cell lymphoma (DLBCL) has opened the door to clinical trials evaluating novel agents with subtype-specific activity. It is an emerging question whether core needle biopsies (CNB) can adequately meet the increasing tissue requirements of these clinical trials. This can potentially lead to selective enrollment of patients who can undergo excisional biopsy (EB). It is also important to know whether patients who can undergo extensive diagnostic work up differ in their disease characteristics and outcomes from those who cannot. In this observational study, we describe the characteristics, outcomes, and adequacy of diagnostic tissue in patients with newly diagnosed DLBCL and primary mediastinal large B-cell lymphoma who underwent EB vs CNB. Of the 1061 patients, 532 (49.8%) underwent EB and 529 (50.1%) underwent CNB. A significantly higher proportion of patients with CNB had advanced stage disease, an international prognostic index of ≥3, and inadequate tissue for molecular analyses. Patients with CNB had significantly worse 5-year event-free survival (67.6% vs 56.9%; hazard ratio [HR], 0.76; confidence interval [CI]95, 0.6-0.9, P &lt; .001) and 5-year overall survival (76.4% vs 69.2%; HR, 0.8; CI95, 0.6-0.9, P &lt; .001). Thus, patients who underwent CNB have poor-risk features and inferior outcomes on frontline chemoimmunotherapy, are more likely to have inadequate tissue for molecular analyses, and might not meet the tissue requirements of biomarker-driven clinical trials. Thus, the increasing tissue requirements of biomarker-driven clinical trials may result in the exclusion of patients with high-risk DLBCL who need novel agents.

AbstractThe number of non‐Hodgkin lymphoma (NHL) survivors is increasing. With the advancement of NHL therapies, it is crucial to focus on the challenges these survivors may face. Three main categories are to be considered in NHL survivorship, including quality of life and uncertainty about the future, possible physical health complications (including cardiovascular disease, infertility, and subsequent neoplasms), and the impact of novel NHL treatments and their potential complications. The latter includes CAR T‐cell therapy, monoclonal antibodies, checkpoint inhibitors, and hematopoietic stem cell transplantation. In this report, we aim to shed the light on these aspects and to discuss survivorship care plan for NHL.

Abstract Low-grade B-cell lymphomas other than follicular and small lymphocytic lymphoma (LGBCL) account for 10% of all B-cell non-Hodgkin lymphomas. Despite improvements in survival outcomes for these patients, little is known about cause of death (COD) in the rituximab era. For a better understanding, we studied 822 newly diagnosed patients with marginal zone, lymphoplasmacytic, and unclassifiable low-grade B-cell lymphoma prospectively enrolled in the University of Iowa/Mayo Clinic Specialized Program of Research Excellence Molecular Epidemiology Resource from 2002 to 2015. COD was assigned based on medical record review using a standard protocol. At a median follow-up of 107 months, 219 (27%) patients had died. The incidence of lymphoma-related deaths when pooling across subtypes was lower than non–lymphoma-related deaths (10-year incidence, 8.0%; 95% confidence interval [CI]: 6.2-10.4 vs 13.6%; 95% CI: 11.2-16.6). The incidence of lymphoma-related deaths varied by subtype, ranging from 3.7% at 10 years in extranodal marginal zone lymphoma to 19.3% in lymphoplasmacytic lymphoma/Waldenström macroglobulinemia. Patients with early progression or retreatment events, defined using event-free survival at 24 months from diagnosis, had significantly higher likelihood of lymphoma-related death compared with patients without early events (10-year estimate: 19.1% vs 5.1%, respectively; P &lt; .001), whereas the rates for non–lymphoma-related death were comparable in patients with or without early events (10-year estimates: 11.0% vs 15.3%, respectively). In conclusion, the most common COD in LGBCLs in the first decade after diagnosis was for causes other than lymphoma. Progression or retreatment within the first 2 years of diagnosis was a strong predictor for risk of lymphoma-related death.

Abstract Intravascular lymphoma (IVL) is a rare extranodal non‐Hodgkin lymphoma. We performed a retrospective analysis of 55 IVL patients who were treated at our institution 2003–2018. Median age at diagnosis was 68 years, and 64% were males. The most frequent presenting symptoms were skin rash 43% and weight loss 30%. MRI brain on IVL patients with CNS involvement (CNS‐IVL) showed multifocal involvement in 76% (13/17). 89% (17/19) of non‐CNS‐IVL patients with abnormal FDG‐PET had biopsy of an avid lesion resulting in definitive diagnosis. The top diagnostic biopsy site was the bone marrow (45%). 56% had multiorgan involvement. Based on CNS involvement, 36.5% (20/55) had CNS‐IVL and 63.5% (35/55) had non‐CNS‐IVL. CNS‐IVL group consists of clinically isolated CNS involvement (CNS‐only IVL) (22%;12/55) and mixed clinical CNS and peripheral site involvement (M‐IVL) (14.5%; 8/55). Non‐CNS‐IVL group consists of clinically isolated skin involvement (skin‐only IVL) (9%; 5/55) and peripheral IVL with or without skin involvement (P‐IVL); (54.5%; 30/55). Skin involvement was predominantly in the lower extremities. Pathologically, 89% (48/54) were B‐cell IVL. Rituximab + high‐dose methotrexate‐based regimen were used in 75% (12/16) of CNS‐IVL patients and RCHOP in 60% (17/28) of non‐CNS‐IVL patients. Estimated 5‐year progression free survival (PFS) and overall survival (OS) for the entire cohort were 38.6% and 52%, respectively. Skin‐only IVL was associated with excellent survival. Platelet count <150x10 9 /L, age > 60Y, and treatment without Rituximab were poor prognostic factors. Further research is necessary to identify novel therapies.