CD19-directed CART Therapy for T cell/Histiocyte Rich Large B-cell Lymphoma.

T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a rare histologic variant of LBCL. Limited data regarding CD19-directed chimeric antigen receptor T-cell (CART) therapy in relapsed/refractory (R/R) THRLBCL suggest poor efficacy. We investigated CART outcomes for R/R THRLBCL through the CIBMTR registry. A total of 58 adult patients with R/R THRLBCL who received commercial CD19-CART between 2018-2022 were identified. Most patients (67%) had early relapse of disease (45% primary refractory) with a median of 3 (range: 1-7) prior therapies and were treated with Axicabtagene ciloleucel (69%). At median follow-up of 23 months post-CART, 2-year overall and progression-free survival were 42% (95% CI: 27-57) and 29% (95% CI: 17-43), respectively. In univariable analysis, poor performance status pre-CART was associated with higher mortality (HR 2.35, 95%CI 1.02-5.5). The 2-year cumulative incidences of relapse/progression and non-relapse mortality were 69% and 2%, respectively. Grade ≥3 CRS and ICANS occurred in 7% and 15% of patients, respectively. In this largest analysis of CD19-CART for R/R THRLBCL, approximately 30% of patients were alive and progression-free 2 years post-CART. Despite a high incidence of progression (69% at 2 years), these results suggest a subset of patients with R/R THRLBCL may have durable responses with CART.

Anti-CD19 chimeric antigen receptor T-cell therapy in older patients with relapsed or refractory large B-cell lymphoma: A multicenter study.

Chimeric antigen receptor T-cell (CAR-T) therapy, despite being a potentially curative therapy in relapsed or refractory (RR) large B-cell lymphoma (LBCL), remains underutilized in older patients due to limited clinical data. We therefore studied the safety and efficacy of CAR-T therapy in older patients with RR LBCL in the real-world setting. Patients aged ≥65 years with RR LBCL, treated with anti-CD19 CAR-T therapy at 7 US institutions were included in this multicenter, retrospective, observational study. In total, 226 patients were included. Median age at infusion was 71 years (range 65-89). Best objective and complete response rates were 86% and 62%, respectively. Median follow-up after infusion was 18.3 months. The median progression-free survival (PFS) was 6.9 months, with 6- and 12-month PFS estimates of 54% and 44%, respectively. The nonrelapse mortality (NRM) rate was 10.9% at day 180, primarily due to infections, and not impacted by the age groups. Grade ≥3 cytokine release syndrome and neurotoxicity occurred in 7% and 26%, respectively. In univariate analysis, no significant difference in PFS was seen regardless of the age groups or CAR-T type, whereas ECOG PS ≥2, elevated LDH, bulky disease, advanced stage, extranodal involvement, the need for bridging therapy, and prior bendamustine exposure were associated with shorter PFS. These findings support the use of CAR-T in older patients, including those aged ≥80 years. The age at CAR-T therapy did not influence safety, survival, and NRM outcomes. Older patients should not be excluded from receiving CAR-T therapy solely based on their chronological age.

Change in alcohol consumption during the Covid-19 pandemic and associations with mental health and financial hardship: results from a survey of Wisconsin patients with cancer.

PURPOSE: Alcohol consumption increases health risks for patients with cancer. The Covid-19 pandemic may have affected drinking habits for these individuals. We surveyed patients with cancer to examine whether changes in drinking habits were related to mental health or financial effects of the pandemic. METHODS: From October 2020 to April 2021, adult patients (age 18-80 years at diagnosis) treated for cancer in southcentral Wisconsin were invited to complete a survey. Age-adjusted percentages for history of anxiety or depression, emotional distress, and financial impacts of Covid-19 overall and by change in alcohol consumption (non-drinker, stable, decreased, or increased) were obtained via logistic regression. RESULTS: In total, 1,875 patients were included in the analysis (median age 64, range 19-87 years), including 9% who increased and 23% who decreased drinking. Compared to stable drinkers (32% of sample), a higher proportion of participants who increased drinking alcohol also reported anxiety or depression (45% vs. 26%), moderate to severe emotional distress (61% vs. 37%) and viewing Covid-19 as a threat to their community (67% vs. 55%). Decreased (vs. stable) drinking was associated with higher prevalence of depression or anxiety diagnosis, emotional distress, and negative financial impacts of the pandemic. Compared to non-drinkers (36% of sample), participants who increased drinking were more likely to report emotional distress (61% vs. 48%). CONCLUSIONS: Patients with cancer from Wisconsin who changed their alcohol consumption during the Covid-19 pandemic were more likely to report poor mental health including anxiety, depression, and emotional distress than persons whose alcohol consumption was stable. IMPLICATIONS FOR CANCER SURVIVORS: Clinicians working with cancer survivors should be aware of the link between poor mental health and increased alcohol consumption and be prepared to offer guidance or referrals to counseling, as needed.

Critical gaps in understanding treatment outcomes in adolescents and young adults with lymphoma: A review of current data.

Adolescents and young adults (AYA) with lymphoma experience treatment-related effects in the short and long term that impact their quality of life and survivorship experience. The effort to improve outcomes for AYA lymphoma survivors requires understanding the available literature, identifying current knowledge deficits, designing better clinical trials incorporating the patient perspective, using novel tools to bridge data gaps and building survivorship guidelines that translate research to clinical practice. This review article summarizes the current state of lymphoma treatment-related outcomes in AYAs and provides future direction.

Efficacy of checkpoint inhibition after CAR-T failure in aggressive B-cell lymphomas: outcomes from 15 US institutions.

Checkpoint inhibitor (CPI) therapy with anti-PD-1 antibodies has been associated with mixed outcomes in small cohorts of patients with relapsed aggressive B-cell lymphomas after CAR-T failure. To define CPI therapy efficacy more definitively in this population, we retrospectively evaluated clinical outcomes in a large cohort of 96 patients with aggressive B-cell lymphomas receiving CPI therapy after CAR-T failure across 15 US academic centers. Most patients (53%) had diffuse large B-cell lymphoma, were treated with axicabtagene ciloleucel (53%), relapsed early (≤180 days) after CAR-T (83%), and received pembrolizumab (49%) or nivolumab (43%). CPI therapy was associated with an overall response rate of 19% and a complete response rate of 10%. Median duration of response was 221 days. Median progression-free survival (PFS) and overall survival (OS) were 54 and 159 days, respectively. Outcomes to CPI therapy were significantly improved in patients with primary mediastinal B-cell lymphoma. PFS (128 vs 51 days) and OS (387 vs 131 days) were significantly longer in patients with late (>180 days) vs early (≤180 days) relapse after CAR-T. Grade ≥3 adverse events occurred in 19% of patients treated with CPI. Most patients (83%) died, commonly because of progressive disease. Only 5% had durable responses to CPI therapy. In the largest cohort of patients with aggressive B-cell lymphoma treated with CPI therapy after CAR-T relapse, our results reveal poor outcomes, particularly among those relapsing early after CAR-T. In conclusion, CPI therapy is not an effective salvage strategy for most patients after CAR-T, where alternative approaches are needed to improve post-CAR-T outcomes.

Pre-Treatment Left Ventricular Ejection Fraction Assessment and Long-Term Cardiovascular Outcomes in Adolescent and Young Adult Lymphoma Survivors.

Purpose: Anthracyclines can cause long-term cardiovascular (CV) morbidity, especially in long-term Adolescent and Young Adult (AYA) lymphoma survivors. Pre-treatment left ventricular ejection fraction (LVEF) evaluation is recommended, although its utility in AYA is not established. We sought to determine the pre-treatment LVEF assessment practices in AYA lymphoma survivors treated with anthracyclines and factors associated with long-term cardiotoxicity. Methods: Through an electronic health records review, we retrospectively identified AYA lymphoma survivors with ≥5 years of follow-up postanthracycline treatment. Pre-treatment and follow-up data were abstracted. CV health conditions were defined as risk factors for CV disease and confirmed CV diagnoses. Survivors who had new CV health conditions at follow-up were compared to those who were not using descriptive statistics and logistic regression. Results: One hundred fifteen AYA lymphoma survivors met the study criteria. Pre-treatment LVEF assessment did not affect chemotherapy decisions. Survivors with pre-treatment CV evaluation had mean follow-up since diagnosis of 8 ± 3.3 years, while survivors without it had 10.3 ± 4.2 years, p < 0.05. Survivors with pre-treatment LVEF assessment received lower cumulative anthracycline dose (240.4 mg/m2 vs. 280.1 mg/m2, p < 0.05) and fewer cycles of chemotherapy (4.8 ± 1.5 vs. 5.6 ± 1.2, p < 0.05). Body mass index (BMI) category at diagnosis and follow-up, in addition to age were associated with development of new CV health conditions, pre-treatment LVEF evaluation was not. Conclusion: Pre-treatment LVEF assessment for AYA lymphoma survivors does not impact oncologic treatment decisions or development of CV health conditions. It may be more valuable to assess and modify CV risk factors such as BMI for CV disease prevention.

Cardio-Oncology Rehabilitation (CORE) Exercise Prescription and Programming: A PRACTICAL GUIDE.

BACKGROUND: Patients with cancer almost universally report diminished health-related quality of life. Many patients experience persistent fatigue and most have below-average exercise capacities. Despite the publication of exercise guidelines for cancer survivors that encourage physical activity, few patients exercise on a regular basis. Cardiovascular disease is a major cause of death in early-stage malignancies. Exercise training has been demonstrated to decrease cardiovascular events in patients with cancer. In addition, regular exercise improves exercise capacity, reduces fatigue, and improves quality of life in cancer survivors. CLINICAL CONSIDERATIONS: A 2019 American Heart Association scientific statement, endorsed by the American Cancer Society, provided a framework and rationale for partnering with existing multidimensional, interdisciplinary outpatient cardiac rehabilitation programs to provide supervised exercise training and risk factor control services for patients with cancer and cancer survivors: cardio-oncology rehabilitation. In addition, the American College of Sports Medicine has published recommendations for cancer exercise training. SUMMARY: This article provides practical suggestions for incorporating patients with cancer into cardiac rehabilitation and for patient-specific exercise prescription. Illustrative patient case examples are provided.

The association of health behaviors with quality of life in lymphoma survivors.

The impact of change in health behaviors (physical activity [PA], alcohol and smoking) on quality of life (QOL) in lymphoma survivors is not well understood. We evaluated the associations of health behaviors with QOL domains at diagnosis and at 3-year follow-up (FU3) in 2805 lymphoma survivors. We report clinically significant QOL score differences, defined as scores that exceeded a minimally important difference threshold and were statistically significant. Current smoking was associated with lower QOL at baseline (p < 0.01) and at FU3 (p < 0.01). Meeting the American Cancer Society PA guidelines was associated with better functional wellbeing and overall QOL at FU3 (p < 0.01). An increase in PA from baseline to FU3 was associated with improvement in physical, functional wellbeing and overall QOL at FU3 compared to baseline (p < 0.01). Thus, QOL in lymphoma survivors is associated with their health behaviors and active interventions to promote positive lifestyle changes in lymphoma survivors are needed.

Understanding Health-Related Quality of Life in Patients with Mantle Cell Lymphoma.

Mantle cell lymphoma (MCL) is a unique lymphoma that is heterogeneous in its clinical course, and lacks consensus treatment approaches. It is often treated with immunochemotherapy at diagnosis and chronic therapies in relapse. Despite significant advances in therapy, MCL remains incurable. Maintaining patients' health-related quality of life (HRQOL) is an important treatment goal. Assessment of HRQOL elucidates the impact of an illness and its treatment on patients' lives. This review highlights the relevance of HRQOL assessment in MCL, evaluates existing evidence, current knowledge gaps and challenges in HRQOL assessment, and defines future directions for improving HRQOL evaluation in MCL patients.

High level MYC amplification in B-cell lymphomas: is it a marker of aggressive disease?

While MYC translocations in B-cell lymphoma (BCL) have been extensively studied, the significance of MYC amplification (MYC amp) is poorly understood. This study characterizes BCL showing MYC amp, defined as uncountable FISH signals. Retrospective analysis of all BCL FISH for MYC aberrations performed at our institution (1/2010-2/2018) identified 44/9715 (0.45%) cases with MYC amp. MYC amp probe signals appeared in a cloud-like distribution (70%) or in a single homogenous-staining-region (30%). In total 59% also had MYC separation by breakapart probe indicating concurrent MYC translocation. The most common morphology was large cell (82%) and diagnosis was diffuse large BCL (DLBCL, 50%). In total 88% were germinal center B-cell-like by Hans algorithm. In total 12/42 (29%) cases were "double-hit" by WHO criteria (DHL/THL) in addition to having MYC amp. The estimated 2-year overall survival (OS) of DLBCL cases with MYC amp was 80%. There was no significant difference in OS between DLBCL and DHL/THL among cases with MYC amp, suggesting a poor prognostic impact of MYC amp. However, when compared to a larger cohort of DLBCL and DHL/THL, MYC amp did not have prognostic significance. In summary, MYC amp in BCL is rare, most commonly occurs in DLBCL, and was not associated with survival in our cohort.

Compliance with cancer screening and influenza vaccination guidelines in non-Hodgkin lymphoma survivors.

PURPOSE: Compliance with US Preventive Services Task Force (USPSTF) age-appropriate cancer screening and immunization guidelines in lymphoma survivors is not known. We sought to measure compliance in non-Hodgkin lymphoma (NHL) survivors and identify any differences based on patient, disease, and treatment characteristics. METHODS: Eligible NHL survivors were identified from the Molecular Epidemiology Resource (MER) prospective cohort study. Survivors self-reported colorectal, breast, and prostate cancer screening and influenza immunization in a questionnaire 3 years post-diagnosis (FU3). The USPSTF guidelines were used to define compliance. Chi-square tests were used to compare characteristics of compliant versus non-compliant survivors. RESULTS: A total of 1833 MER participants from 2005 to 2012 completed a FU3. Rates of breast and prostate cancer screening were 96% and 72%, respectively. No differences in compliance based on patient or disease characteristics or treatment were observed. Ninety-two percent of survivors were compliant with colorectal cancer screening. Older age, indolent lymphoma histology, and 2008-2012 year of diagnosis were associated with higher compliance. Eighty-two percent of survivors were compliant with influenza vaccination and older age was associated with higher compliance. CONCLUSION: NHL survivors have high compliance with USPSTF recommendations for cancer screening and immunization. Survivors who are younger or have aggressive lymphomas are less likely to meet the colorectal cancer screening guidelines. Older survivors are more likely to receive influenza vaccination. IMPLICATIONS FOR CANCER SURVIVORS: Measures to further improve preventive care for NHL survivors, especially those younger in age, are necessary.

Framingham Risk Score Is an Ineffective Screening Strategy for Coronary Heart Disease in Long-Term Allogeneic Hematopoietic Cell Transplant Survivors.

Long-term allogeneic hematopoietic cell transplant (allo-HCT) survivors suffer an elevated risk of coronary heart disease (CHD). We conducted a prospective, nonrandomized, cross-sectional study to screen asymptomatic survivors at a single allo-HCT center using cardiac computed tomography (CT) involving coronary CT angiography (CCTA) and the coronary artery calcium (CAC) score. Seventy-nine subjects with a median age of 39 years at allo-HCT and a median follow-up interval of 8 years were evaluated for CHD by Framingham Risk Score (FRS) and cardiac CT. CHD was detected in 33 of 79 (42%) subjects; 91% of lesions were nonobstructive, 19.5% of were noncalcified and 30% had associated valvular calcification. Overall, CAC was significantly superior to FRS in detecting early CHD in allo-HCT survivors [∆C = 0.25; P < 0.0001]. While both FRS and CAC were highly, >95% specific, FRS had a sensitivity, positive and negative predictive values of only 28% (95% CI, 14%-47%), 90% (95% CI, 55%-100%) and 60% (95% CI, 47%-73%), respectively. In contrast, the sensitivity, positive and negative predictive values of CAC were 78% (95% CI, 60%-91%), 96% (95% CI, 80%-100%) and 83% (95% CI, 69%-93%), respectively. Significantly, cardiac CT detected CHD in 23 of the 68 (34%) survivors deemed to have a low Framingham risk. Radiation exposure during cardiac CT was negligible, and there were no adverse events. In conclusion, CAC score with or without CCTA is a safe, feasible and sensitive screening technique for CHD. The FRS greatly underestimates CHD in allo-HCT survivors.

The association of physical activity before and after lymphoma diagnosis with survival outcomes.

The impact of physical activity (PA) on lymphoma survival is not known. The association of PA and change in PA with overall (OS), lymphoma-specific (LSS) and event-free (EFS) survival was evaluated in a prospective cohort of newly diagnosed lymphoma patients (2002-2012). We calculated Leisure Score Indexes (mLSI) from the self-reported usual adult PA (baseline) and at 3-years post-diagnosis (FU3), grouping patients by active vs insufficiently active by the American Cancer Society PA guidelines. Associations of PA with survival were assessed using hazard ratios (HRs) and 95% confidence intervals (CI) from Cox models stratified by lymphoma subtype, adjusted for age, sex, baseline BMI, and comorbidity score with change scores further adjusted for baseline PA. Three thousand sixty participants were evaluable at baseline and 1371 at FU3. Active patients had superior survival from baseline [HR (CI): OS 0.82 (0.72-0.94); LSS 0.74 (0.61-0.90); EFS 0.92 (0.82-1.02)] and FU3 [HR (CI): OS 0.64 (0.46-0.88); LSS 0.32 (0.18-0.59); EFS 0.82 (0.61-1.10)] compared to insufficiently active. An increase in mLSI from baseline to FU3 (vs stable mLSI) was associated with superior OS (HR = 0.70, CI 0.49-1.00) and LSS (HR = 0.49, CI 0.26-0.94).The continuous change in mLSI at FU3 was significantly associated with OS, LSS and EFS; maintained across subgroups and appeared linear. Higher PA among lymphoma patients at diagnosis and 3 years is significantly associated with OS, LSS, and EFS. Increasing PA after diagnosis is significantly associated with improved OS and LSS supporting an important role for PA in lymphoma survivorship and the need for intervention trials.

The Role of New Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia.

Imatinib mesylate was the first tyrosine kinase inhibitor (TKI) approved for the management of chronic myeloid leukemia. Imatinib produces acceptable responses in approximately 60% of patients, with approximately 20% discontinuing therapy because of intolerance and approximately 20% developing drug resistance. The advent of newer TKIs, such as nilotinib, dasatinib, bosutinib, and ponatinib, has provided multiple options for patients. These agents are more potent, have unique adverse effect profiles, and are more likely to achieve relevant milestones, such as early molecular responses (3-6 months) and optimal molecular responses (12 months). The acquisition of BCR-ABL kinase domain mutations is also reportedly lower with these drugs. Thus far, none of the randomized phase III clinical trials have shown a clinically significant survival difference between frontline imatinib versus newer TKIs. Cost and safety issues with the newer TKIs, such as vascular disease with nilotinib and ponatinib and pulmonary hypertension with dasatinib, have dampened the enthusiasm of using these drugs as frontline options. While the utility of new TKIs in the setting of imatinib failure or intolerance is clear, their use as frontline agents should factor in the age of the patient, additional comorbidities, risk stratification (Sokal score), and cost. Combination therapies and newer agents with potential to eradicate quiescent chronic myeloid leukemia stem cells offers future hope.

Radiation exposure from diagnostic procedures following allogeneic stem cell transplantation--how much is acceptable?

BACKGROUND: Frequent diagnostic radiology procedures in allogeneic stem cell transplantation (SCT) recipients raise concern about the potential harm from incidental radiation. OBJECTIVES: To determine the cumulative radiation dose from diagnostic studies in allogeneic SCT and its impact on clinical outcome. PATIENTS AND METHODS: This retrospective cohort study was conducted to determine the cumulative radiation dose from diagnostic studies following SCT. Sixty-four consecutive patients with hematological malignancies in a single tertiary care institution underwent total body irradiation (TBI)-based myeloablative conditioning followed by six of six human leukocyte antigen (HLA)-identical sibling allogeneic SCT. The median follow-up was 3 years. The cumulative effective dose in mSv from diagnostic radiological studies in the peri-transplant period from day -30 to day +200 was calculated for each patient and its impact on overall survival and non-relapse mortality was determined. RESULTS: The median cumulative radiation exposure from diagnostic radiological procedures was 92 mSv (range 1.2-300), representing about 30× the normal annual background radiation for the population and 10% of the 1200 cGy TBI dose used in conditioning. Sixty-five percent of the cumulative radiation exposure was delivered between day +1 and day 100 and computed tomography scans contributed 88%. In multivariate analysis, diagnostic procedures did not significantly impact clinical outcomes. CONCLUSIONS: While radiation exposure from diagnostic procedures did not impact clinical outcomes the risk of secondary cancers in long-term survivors is likely to be increased. Our results indicate that patients who are acutely ill for prolonged periods can receive clinically significant radiation doses during their hospital care. Our findings should prompt attempts to limit radiation exposure from diagnostic procedures in post-SCT recipients.

Repair of impaired pulmonary function is possible in very-long-term allogeneic stem cell transplantation survivors.

Both early- and late-onset noninfectious pulmonary injury are important contributors to the nonrelapse mortality seen after allogeneic stem cell transplantation (allo-SCT), particularly in subjects conditioned with high-dose total body irradiation (TBI). To characterize the kinetics of recovery from pulmonary injury in long-term survivors, we collected data on 138 subjects who survived > 3 years (median survival, 10.2 years) after predominantly TBI-based allo-SCT from their HLA-matched siblings. Baseline pulmonary function tests served as the reference for subsequent measurements at 3, 5, 10, and 15 years for each survivor. The only parameter showing a clinically and statistically significant decline post-transplant was adjusted diffusion capacity of lung for carbon monoxide (DLCO), which reached a nadir at 5 years but surprisingly normalized at the 10-year mark. Multivariable modeling identified chronic graft-versus-host disease (P < .02) and abnormal baseline-adjusted DLCO (P < .03) as the only significant factors associated with the decline in adjusted DLCO at 5 years but excluded smoking, conditioning intensity, baseline C-reactive protein level, TBI dose to the lungs, disease, and demographic variables. In conclusion, pulmonary injury as monitored by the adjusted DLCO continues to deteriorate in the first 5 years after allo-SCT but recovers at 10 years.

Male survivors of allogeneic hematopoietic stem cell transplantation have a long term persisting risk of cardiovascular events.

Long-term survivors of allogeneic stem cell transplantation (SCT) have increased risk of cardiovascular disease. We retrospectively studied cardiovascular risk factors (CVRFs) in 109 SCT survivors (62 males, 47 females; median age 34 years) five years or more after bone marrow (15) or T cell-depleted peripheral blood (94) SCT for CML (56), acute leukemia (29), MDS (13), and others (11). One death and two cardiovascular events were reported. At five and ten years after SCT, respectively, 44% and 52% had abnormal lipid profiles; 23% of 5-year survivors met the Adult Treatment Panel III threshold for dyslipidemia treatment, which is substantially higher than the age-matched general population. There were significant increases in prevalence of hypertension (p < 0.001), diabetes (p = 0.018), and body mass index (p = 0.044) after SCT compared with baseline. The Framingham general cardiovascular risk score (FGCRS) in males at five years after SCT projected a doubling (median 10.4% vs. 5.4%) in the 10-year risk of cardiovascular events. Females received HRT after SCT, and none had increased FGCRS. Chronic GVHD and C-reactive protein were not associated with CVRF at any time. All CVRFs stabilized between five and ten years after SCT. Thus, SCT survivors have sustained elevations in CVRFs. Males have a significantly increased risk of cardiovascular events in their second and third decade after SCT.