Paludo, Jonas

PURPOSE Patients with Waldenström macroglobulinemia (WM) have disparate outcomes. Newer therapies have emerged since the development of International Prognostic Scoring System, and MYD88 L265P mutation is now frequently assessed at diagnosis, warranting reexamination of the prognostic parameters. PATIENTS AND METHODS We reviewed records of 889 treatment-naïve patients with active WM, consecutively seen between January 01, 1996, and December 31, 2017, to identify clinical predictors of overall survival (OS) in univariate analyses. Patients with complete data for the parameters significant on the univariate analyses (n = 341) were included in a multivariable analysis to derive a prognostic model, subsequently validated in a multi-institutional cohort. RESULTS In the derivation cohort (n = 341), age (hazard ratio [HR], 1.9 [95% CI, 1.2 to 2.1]; P = .0009), serum lactate dehydrogenase (LDH) above upper limit of normal (HR, 2.3 [95% CI, 1.3 to 4.5]; P = .007), and serum albumin <3.5 g/dL (HR, 1.5 [95% CI, 0.99 to 2.3]; P = .056) were independently prognostic. By assigning a score of 1 point each to albumin <3.5 g/dL (HR, 1.5) and age 66-75 years (HR 1.4) and 2 points for age >75 years (HR, 2.6) or elevated LDH (HR, 2.3), four groups with distinct outcomes were observed on the basis of the composite scores. Five-year OS was 93% for the low-risk (score 0), 82% for low-intermediate risk (score 1), 69% for intermediate-risk (score 2), and 55% for the high-risk (score ≥3; P < .0001) groups. In the validation cohort (N = 335), the model maintained its prognostic value, with a 5-year OS of 93%, 90%, 75%, and 57% for the four groups, respectively ( P < .0001). CONCLUSION Modified Staging System for WM (MSS-WM), utilizing age, albumin, and LDH is a simple, clinically useful, and externally validated prognostic model that reliably risk-stratifies patients with symptomatic WM into four groups with distinct prognosis.

AbstractIntroductionThe infusion of autograft Natural Killer Cells (NKC)/CD14+HLA‐DRDIM ratio is a predictor of survival in lymphoma patients undergoing autologous peripheral blood hematopoietic stem cell transplantation (APBHSCT). This study evaluated if the Day 100 NKC/CD14+HLA‐DRDIM ratio still functions as a prognostic immune‐biomarker.MethodsThis was a retrospective, single‐institution, cohort analysis including 107 patients in this study that had clinical assessment at Day 100 post‐APBHSCT from our prior phase III trial. We evaluated the prognostic ability of the Day 100 NKC/CD14+HLA‐DRDIM ratio to predict overall survival (OS) and progression‐free survival (PFS) using Cox regression model for outcome analysis and survival by Kaplan–Meier method.ResultsThe median follow‐up from day 100 was 94.7 months (range 4.83–158.1 months) for the entire cohort. Patients with a Day 100 NKC/CD14+HLA‐DRDIM ratio ≥1.67 experienced better OS and PFS versus those with a Day 100 NKC/CD14+HLA‐DRDIM ratio <1.67: median OS was not reached versus 49.7 months, the 5‐year OS rates were 91% (95% CI, 81%–96%) versus 40% (95% CI, 27%–55%), p < .0001, respectively; and median PFS was not reached versus 23.5 months, the 5‐year PFS rates were 66% (95% CI, 55%–81%) versus 21% (95% CI, 15%–40%), p < .0001, respectively. Day 100 NKC/CD14+HLA‐DRDIM ratio was an independent predictor for OS and PFS in the multivariate analysis.ConclusionsDay 100 NKC/CD14+HLA‐DRDIM ratio is a prognostic immune‐biomarker in lymphoma patients post‐ APBHSCT.

Abstract The success of chimeric antigen receptor T‐cell (CAR‐T) therapy in hematologic malignancies has realized a longstanding effort toward harnessing the immune system to fight cancer in a truly personalized fashion. Second generation chimeric antigen receptors (CAR) incorporating co‐stimulatory molecules like 4‐1BB or CD28 were able to overcome some of the hindrances with initial CAR constructs resulting in efficacious products. Many second‐generation CAR‐T products have been approved in the treatment of relapsed/refractory hematologic malignancies including multiple myeloma (MM), non‐Hodgkin lymphoma (NHL), and acute lymphoblastic leukemia. However, challenges remain in optimizing the manufacturing, timely access, limiting the toxicity from CAR‐T infusions and improving sustainability of responses derived with CAR‐T therapy. Here, we summarize the clinical trial data leading to approval CAR‐T therapies in MM and NHL, discuss the limitations with current CAR‐T therapy strategies and review emerging strategies for overcoming these limitations.

PURPOSE In response to the COVID-19 pandemic, many cancer practices rapidly adopted telehealth services. However, there is a paucity of data regarding ongoing telehealth visit utilization beyond this initial response. The purpose of this study was to assess changes in variables associated with telehealth visit utilization over time. METHODS This is a cross-sectional, year-over-year, retrospective analysis of telehealth visits conducted across a multisite, multiregional cancer practice in the United States. Multivariable models examined the association of patient- and provider-level variables with telehealth utilization across outpatient visits conducted over three 8-week periods from July to August in 2019 (n = 32,537), 2020 (n = 33,399), and 2021 (n = 35,820). RESULTS The rate of telehealth utilization increased from <0.01% (2019) to 11% (2020) to 14% (2021). The most significant patient-level factors associated with increased telehealth utilization included nonrural residence and age ≤65 years. Among patients residing in rural settings, video visit utilization rates were significantly lower and phone visit utilization rates were significantly higher compared with patients from nonrural residences. Regarding provider-level factors, widening differences in telehealth utilization were observed at tertiary versus community-based practice settings. Increased telehealth utilization was not associated with duplicative care as per-patient and per-physician visit volumes in 2021 remained consistent with prepandemic levels. CONCLUSION We observed continuous expansion in telehealth visit utilization from 2020 to 2021. Our experiences suggest that telehealth can be integrated into cancer practices without evidence of duplicative care. Future work should examine sustainable reimbursement structures and policies to ensure accessibility of telehealth as a means to facilitate equitable, patient-centered cancer care.

Abstract Time to progression of disease (POD) after first-line (1L) therapy is prognostic in mantle cell lymphoma (MCL), although studies have included a broad range of 1L, second-line (2L), and subsequent lines of therapy. The purpose of this study was to evaluate the factors predicting outcomes in patients with relapsed/refractory (R/R) MCL exclusively initiating 2L Bruton’s tyrosine kinase inhibitors (BTKis) after 1L rituximab-containing therapy. Patients were accrued from 8 international centers (7 main, 1 validation cohort). Multivariable models evaluating the association between time to POD and clinical/pathologic factors were constructed and converted into nomograms and prognostic indexes predicting outcomes in this population. A total of 360 patients were included, including 160 in the main cohort and 200 in the validation cohort. Time to POD, Ki67 ≥ 30%, and MCL International Prognostic Index (MIPI) were associated with progression-free survival (PFS2) and overall survival (OS2) from the start of 2L BTKis. C-indexes were consistently ≥0.68 in both cohorts. Web/application-based calculators based on nomograms and prognostic indexes to estimate PFS2 and OS2 were constructed. The 2L BTKi MIPI identifies 3 groups with distinct 2-year PFS2, including high risk (14%), intermediate risk (50%), and low risk (64%). Time to POD, Ki67, and MIPI are associated with survival outcomes in patients with R/R MCL receiving 2L BTKis. Simple clinical models incorporating these variables may assist in planning for alternative therapies such as chimeric antigen receptor T-cell therapy, allogeneic stem cell transplantation, or novel agents with alternative mechanisms of action.

Abstract Non‐follicular low‐grade B‐cell lymphomas (LGBCL) are biologically diverse entities that share clinical and histologic features that make definitive pathologic categorization challenging. While most patients with LGBCL have an indolent course, some experience aggressive disease, highlighting additional heterogeneity across these subtypes. To investigate the potential for shared biology across subtypes, we performed RNA sequencing and applied machine learning approaches that identified five clusters of patients that grouped independently of subtype. One cluster was characterized by inferior outcome, upregulation of cell cycle genes, and increased tumor immune cell content. Integration of whole exome sequencing identified novel LGBCL mutations and enrichment of TNFAIP3 and BCL2 alterations in the poor survival cluster. Building on this, we further refined a transcriptomic signature associated with early clinical failure in two independent cohorts. Taken together, this study identifies unique clusters of LGBCL defined by novel gene expression signatures and immune profiles associated with outcome across diagnostic subtypes.

The field of malignant hematology is transforming with novel immunotherapeutic approaches. Unfortunately, quality of life, treatment efficacy, and life expectancy are negatively affected by cardiotoxic side effects of treatment. To date, the exact mechanism and incidence of cardiotoxicity associated with these therapies is unclear. These events are believed to be triggered or occur concurrently with cytokine release syndrome. Furthermore, there are no formal guidelines to provide evaluation, treatment, and surveillance. We aim to synthesize available literature with updates on the cardiotoxic effects of novel therapies used in malignant hematologic disorders, with a focus on chimeric antigen receptor T-cell therapy and bispecific T-cell engager therapy, along with a proposed algorithm that may guide pretreatment evaluation, monitoring during treatment, and post-treatment surveillance.

PURPOSE Brexucabtagene autoleucel (brexu-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory mantle cell lymphoma (MCL). This therapy was approved on the basis of the single-arm phase II ZUMA-2 trial, which showed best overall and complete response rates of 91% and 68%, respectively. We report clinical outcomes with brexu-cel in the standard-of-care setting for the approved indication. PATIENTS AND METHODS Patients who underwent leukapheresis between August 1, 2020 and December 31, 2021, at 16 US institutions, with an intent to manufacture commercial brexu-cel for relapsed/refractory MCL, were included. Patient data were collected for analyses of responses, outcomes, and toxicities as per standard guidelines. RESULTS Of 189 patients who underwent leukapheresis, 168 (89%) received brexu-cel infusion. Of leukapheresed patients, 79% would not have met ZUMA-2 eligibility criteria. Best overall and complete response rates were 90% and 82%, respectively. At a median follow-up of 14.3 months after infusion, the estimates for 6- and 12-month progression-free survival (PFS) were 69% (95% CI, 61 to 75) and 59% (95% CI, 51 to 66), respectively. The nonrelapse mortality was 9.1% at 1 year, primarily because of infections. Grade 3 or higher cytokine release syndrome and neurotoxicity occurred in 8% and 32%, respectively. In univariable analysis, high-risk simplified MCL international prognostic index, high Ki-67, TP53 aberration, complex karyotype, and blastoid/pleomorphic variant were associated with shorter PFS after brexu-cel infusion. Patients with recent bendamustine exposure (within 24 months before leukapheresis) had shorter PFS and overall survival after leukapheresis in intention-to-treat univariable analysis. CONCLUSION In the standard-of-care setting, the efficacy and toxicity of brexu-cel were consistent with those reported in the ZUMA-2 trial. Tumor-intrinsic features of MCL, and possibly recent bendamustine exposure, may be associated with inferior efficacy outcomes.

AbstractBackgroundIt is unknown whether serum procalcitonin (PCT) concentration monitoring can differentiate between bacterial infection or cytokine release syndrome (CRS) when chimeric antigen receptor T‐cell (CAR‐T) recipients present with a constellation of signs and symptoms that may represent both complications.ObjectiveThe objective of the study was to assess the utility of serum PCT concentrations as a biomarker of bacterial infection in CAR‐T recipients.Study designThis single‐center, retrospective, medical record review evaluated patients prescribed CAR‐T therapy until death or 30 days after infusion. Logistic regression modeling determined the association between elevated serum PCT concentrations within 48 h of fever onset and microbiologically confirmed infection. Secondary outcomes included clinically suspected infection, CAR‐T toxicity rates, and broad‐spectrum antibiotic usage. Predictive performance of PCT was assessed by area under the receiver operating characteristic curve (AUC).ResultsThe 98 included patients were a median age of 63 (IQR: 55–69) years old, 47 (48%) were male, and 87 (89%) were Caucasian. Baseline demographics and clinical characteristics were similar between patients with and without a bacterial infection. Serum PCT >0.4 ng/mL within 48 h of fever was significantly associated with a microbiologically confirmed bacterial infection (OR: 2.75 [95% CI: 1.02–7.39], p = 0.045). Median PCT values in patients with and without confirmed infections were 0.40 ng/mL (IQR: 0.26, 0.74) and 0.26 ng/mL (IQR: 0.13, 0.47), respectively. The AUC for PCT to predict bacterial infection was 0.62 (95% CI 0.48–0.76). All patients experienced CRS of some grade, with no difference in CRS severity based on elevated PCT. Broad‐spectrum antibiotics were used for a median of 45% and 23% of days in those with and without confirmed infection, respectively (p = 0.075).ConclusionElevated serum PCT concentrations above 0.4 ng/mL at time of first fever after CAR‐T infusion was significantly associated with confirmed bacterial infection. Furthermore, rigorous, prospective studies should validate our findings and evaluate serial PCT measurements to optimize antimicrobial use after CAR‐T therapy.

AbstractWaldenström macroglobulinemia (WM) is a rare, indolent lymphoma, that predominately affects the elderly. We report the outcomes of young WM patients, evaluated over five decades, compared to their older counterparts, matched for the time of diagnosis. Between January 1, 1960 and October 31, 2013, 140 (11.8%) WM patients were ≤50 years of age at diagnosis in our database, and their estimated 10‐year overall survival (OS) was 74%, with death attributable to WM in a higher proportion of patients compared to their older (≥65 years) counterparts (91% vs. 58%, p = .0001). Young patients were grouped into three cohorts based on the timing of the initiation of therapy: Group 1 (1960–1977, n = 12), Group 2 (1978–1995, n = 48), and Group 3 (1996–2013, n = 74). Among young patients, there was no disease‐specific survival (DSS) difference across the three periods, [median DSS at 13 years (95% CI 5–23), 16 years (95% CI 14–22), and 15 years (95% CI 10‐NR; p = .41), respectively]. However, DSS for the older cohort incrementally improved (Group 1, median 5.2 years, Group 2: 9.6 years, Group 3: 12 years; p = .05) over these periods. The estimated average years‐of‐life lost for the young cohort was 11.2 years from diagnosis, based on the expected survival for a normal age‐ and sex‐matched population. Despite a protracted disease course, nearly all young patients succumb to their disease. In contrast to the improved survival of the elderly patient population, the evolving treatment strategies in WM have not impacted the outcome of young patients; however, the impact of Bruton tyrosine kinase inhibitors on this unique patient population remains to be determined.