The current landscape of frontline large B-cell lymphoma trials.

At least 25-35% of patients with large B cell lymphoma (LBCL) are not cured with frontline treatment, with generally poor subsequent outcomes. This motivates ongoing and intense interest in improving the frontline treatment of this disease. R-CHOP has remained the standard of care for 20 years despite dozens of trials aiming to improve upon this regimen, and only recently has a novel regimen (Pola-R-CHP) challenged its supremacy. Fortunately, at least 15 promising randomized trials evaluating new treatments in frontline LBCL treatment are underway. They differ not only in the therapy evaluated in the experimental arm, but in the choice of control arm, primary endpoint, and patient selection strategy, with some targeting specific biologic subtypes, some focusing on specific high-risk patient populations, and others enrolling older or frail patients. Novel response-adapted strategies leveraging circulating tumor DNA are also underway. While this variety of approaches provides a welcome increase in the overall likelihood of success, it will also present challenges if several of these trials are successful and we must choose among multiple potential treatment options that were not all tested in the same fashion. In this review, we summarize the main ongoing frontline randomized trials and discuss some of the questions that we will face in interpreting and applying their results in clinical practice in the next few years.

Tafasitamab and lenalidomide in large B-cell lymphoma: real-world outcomes in a multicenter retrospective study.

ABSTRACT: In this real-world evaluation of tafasitamab-lenalidomide (TL) in relapsed or refractory LBCL, patients receiving TL had higher rates of comorbidities and high-risk disease characteristics, and substantially lower progression-free survival and overall survival, compared with the L-MIND registration clinical trial for TL.

Retrospective characterization of nodal marginal zone lymphoma.

Nodal marginal zone lymphoma (NMZL) is a rare non-Hodgkin B-cell lymphoma that has historically been difficult to define, though is now formally recognized by the World Health Organization Classification. To better characterize the clinical outcomes of patients with NMZL, we reviewed a sequential cohort of 187 patients with NMZL to describe baseline characteristics, survival outcomes, and time-to-event data. Initial management strategies were classified into five categories: observation, radiation, anti-CD20 monoclonal antibody therapy, chemoimmunotherapy, or other. Baseline Follicular Lymphoma International Prognostic Index scores were calculated to evaluate prognosis. A total of 187 patients were analyzed. The five-year overall survival was 91% (95% confidence interval [CI], 87-95), with a median follow-up time of 71 months (range, 8-253) among survivors. A total of 139 patients received active treatment at any point, with a median follow-up time of 56 months (range, 13-253) among survivors who were never treated. The probability of remaining untreated at five years was 25% (95% CI, 19-33). For those initially observed, the median time to active treatment was 72 months (95% CI, 49-not reached). For those who received at least one active treatment, the cumulative incidence of receiving a second active treatment at 60 months was 37%. Transformation to large B-cell lymphoma was rare, with a cumulative incidence of 15% at 10 years. In summary, our series is a large cohort of uniformly diagnosed NMZL with detailed analyses of survival and time to event analyses. We showed that NMZL commonly presents as an indolent lymphoma for which initial observation is often a reasonable strategy.

Personalized approaches for treatment-naïve mantle cell lymphoma.

INTRODUCTION: Mantle cell lymphoma (MCL) can have diverse disease presentations, which vary in aggressiveness and prognosis, and can occur in patients with varying ability to tolerate therapy. Additionally, the options for treatment of MCL have expanded rapidly in the last decade, translating to improved outcome for patients. AREAS COVERED: We review the initial evaluation of patients with MCL, identifying disease- and patient-specific prognostic factors, along with personalized therapies for patients with MCL. Specific scenarios include indolent and limited-stage MCL, advanced-stage disease in transplant-eligible and ineligible patients, and high-risk TP53 mutant disease. Ongoing trials and future directions in MCL treatment are also highlighted. EXPERT OPINION: Given the wide array of disease and patient presentations with MCL, a personalized therapeutic approach is needed to optimize outcomes. The best therapeutic strategy should incorporate disease prognostic factors, patient status and comorbidities, goals of care, and response to treatment.

Targeting the immune microenvironment in mantle cell lymphoma: implications for current and emerging therapies.

Mantle cell lymphoma (MCL) is a morphologically and phenotypically heterogeneous subtype of non-Hodgkin lymphoma, and has historically been associated with poor outcomes. However, recent advances in our understanding of this disease have yielded new targeted and immune-based therapies with promising activity. Immune-based therapies such as monoclonal antibodies, immunomodulators, and CAR T cells have significantly improved outcomes and are now standard of care in MCL. In this review, we describe our current understanding of the immune microenvironment of MCL, discuss current immunotherapeutic approaches, and highlight promising novel immune-based therapies and combination therapies that may further improve outcomes for patients with MCL.

Impaired humoral immunity is associated with prolonged COVID-19 despite robust CD8 T cell responses.

How immune dysregulation affects recovery from COVID-19 infection in patients with cancer remains unclear. We analyzed cellular and humoral immune responses in 103 patients with prior COVID-19 infection, more than 20% of whom had delayed viral clearance. Delayed clearance was associated with loss of antibodies to nucleocapsid and spike proteins with a compensatory increase in functional T cell responses. High-dimensional analysis of peripheral blood samples demonstrated increased CD8+ effector T cell differentiation and a broad but poorly converged COVID-specific T cell receptor (TCR) repertoire in patients with prolonged disease. Conversely, patients with a CD4+ dominant immunophenotype had a lower incidence of prolonged disease and exhibited a deep and highly select COVID-associated TCR repertoire, consistent with effective viral clearance and development of T cell memory. These results highlight the importance of B cells and CD4+ T cells in promoting durable SARS-CoV-2 clearance and the significance of coordinated cellular and humoral immunity for long-term disease control.

CD19-directed chimeric antigen receptor T cell therapy in Waldenström macroglobulinemia: a preclinical model and initial clinical experience.

BACKGROUND: Waldenström macroglobulinemia (WM) is an incurable disease and, while treatable, can develop resistance to available therapies and be fatal. Chimeric antigen receptor (CAR) T cell therapy directed against the CD19 antigen has demonstrated efficacy in relapsed or refractory B lymphoid malignancies, and is now approved for B cell acute lymphoblastic leukemia and certain B cell lymphomas. However, CAR T therapy has not been evaluated for use in WM. METHODS AND RESULTS: We performed preclinical studies demonstrating CAR T cell activity against WM cells in vitro, and developed an in vivo murine model of WM which demonstrated prolonged survival with use of CAR T therapy. We then report the first three patients with multiply relapsed and refractory WM treated for their disease with CD19-directed CAR T cells on clinical trials. Treatment was well tolerated, and observed toxicities were consistent with those seen in CAR T treatment for other diseases, and no grade 3 or higher cytokine release syndrome or neurotoxicity events occurred. All three patients attained at least a clinical response to treatment, including one minimal residual disease-negative complete response, though all three eventually developed recurrent disease between 3 and 26 months after initial treatment. CONCLUSIONS: This report summarizes preclinical and clinical activity of CD19-directed CAR T therapy in WM, demonstrating early tolerability and efficacy in patients with WM, and representing a possible treatment option in patients with heavily pretreated and relapsed or refractory WM. Larger studies evaluating CAR T therapy in WM are warranted, along with further evaluation into mechanisms of resistance to CAR T therapy.

Prospects in the management of patients with follicular lymphoma beyond first-line therapy.

The management of patients with relapsed or refractory follicular lymphoma has evolved markedly in the last decade, with the availability of new classes of agents (phosphoinositide 3-kinase inhibitors, immunomodulators, epigenetic therapies, and chimeric antigen receptor T cells) supplementing the multiple approaches already available (cytotoxic agents, anti-CD20 antibodies, radiation therapy, radioimmunotherapy, and autologous and allogeneic transplants). The diversity of clinical scenarios, the flood of data derived from phase II studies, and the lack of randomized studies comparing treatment strategies preclude firm recommendations and require personalized decisions. Patients with early progression require specific attention given the risk of histological transformation and their lower response to standard therapies. In sequencing therapies, one must consider prior treatment regimens and the potential need for future lines of therapy. Careful evaluation of risks and expected benefits of available options, which vary depending on location and socioeconomics, should be undertaken, and should incorporate the patient's goals. Preserving quality of life for these patients is essential, given the likelihood of years to decades of survival and the possibility of multiple lines of therapy. The current landscape is likely to continue evolving rapidly with other effective agents emerging (notably bispecific antibodies and other targeted therapies), and multiple combinations being evaluated. It is hoped that new treatments under development will achieve longer progression-free intervals and minimize toxicity. A better understanding of disease biology and the mechanisms of these different agents should provide further insights to select the optimal therapy at each stage of disease.

Lymphocyte-activation gene 3 in non-small-cell lung carcinomas: correlations with clinicopathologic features and prognostic significance.

Lymphocyte-activation gene 3 (LAG-3) modulates the tumor microenvironment through immunosuppressive effects. Its associations with clinicopathologic parameters and prognostic significance in non-small-cell lung carcinomas remain unclear. We examined LAG-3 expression in 368 resected non-small-cell lung carcinomas (including 218 adenocarcinomas and 150 squamous-cell carcinomas) using tissue microarrays, with normalization to CD8+ T-cell count (LAG-3/CD8 index), and correlated LAG-3, CD8, and LAG-3/CD8 index with clinicopathologic features, molecular status, and survival. LAG-3 expression in the immune cells (ranged 0.35-540.1 cells/mm²) was identified in 92% of non-small-cell lung carcinomas. In adenocarcinomas and squamous-cell carcinomas, LAG-3 expression correlated with CD8+ T-cell count and PD-L1 expression. In adenocarcinomas, high LAG-3 expression (defined as >median) was additionally associated with smoking history, high T stage, aggressive pathologic features (solid-predominant histologic pattern, lymphovascular invasion, and nodal metastasis), and lack of EGFR mutation. In the entire resected tumor cohort and in adenocarcinomas, high LAG-3 and LAG-3/CD8 index were each associated with worse overall survival. In squamous-cell carcinomas, high CD8 was associated with better overall survival. In an exploratory analysis of pretreatment samples from advanced non-small-cell lung carcinoma patients treated with pembrolizumab, high CD8 was predictive of improved overall and progression-free survival, while high LAG-3, but not high LAG-3/CD8 index, was associated with improved progression-free survival. In conclusion, the clinicopathologic correlations and prognostic impact of LAG-3 in non-small-cell lung carcinoma are histotype-dependent, highlighting differences in the immune microenvironment between adenocarcinomas and squamous-cell carcinomas. The predictive impact of LAG-3 warrants further investigation.

Optimizing CAR T cell therapy in lymphoma.

Chimeric antigen receptor (CAR) T cell therapy has significantly improved the outlook for patients with certain types of poor-risk lymphoma. Despite these advances, a majority of patients undergoing CAR T therapy will suffer progression or relapse of disease, and toxicity remains a concern. Additionally, the patients and disease subtypes that are most likely to benefit from CAR T have yet to be fully defined. Many ongoing trials are exploring novel CAR T approaches to address these concerns. In this review, we highlight some of the primary strategies and relevant studies aimed at improving the utility of CAR T therapy in lymphoma.

Positron emission tomography as an adjuvant diagnostic test in the evaluation of checkpoint inhibitor-associated acute interstitial nephritis.

BACKGROUND: Acute interstitial nephritis is an immune-related adverse event that can occur in patients receiving immune checkpoint inhibitor therapy. Differentiating checkpoint inhibitor-associated acute interstitial nephritis from other causes of acute kidney injury in patients with cancer is challenging and can lead to diagnostic delays and/or unwarranted immunosuppression. In this case report, we assess the use of 18F-flourodeoxyglucose positron-emission tomography imaging as an alternative diagnostic modality in the evaluation of potential acute interstitial nephritis. CASE PRESENTATION: A 55-year-old woman with metastatic vulvar melanoma underwent treatment with two cycles of ipilimumab plus nivolumab, followed by seven cycles of nivolumab combined with radiation therapy. During her treatment, she developed non-oliguric acute kidney injury to a creatinine of 4.5 mg/dL from a baseline of 0.5 mg/dL. A clinical diagnosis of acute interstitial nephritis was made, and steroids were initiated, with rapid improvement of her acute kidney injury. Retrospectively, four positron-emission tomography scans obtained for cancer staging purposes were reviewed. We found a markedly increased 18F-flourodeoxyglucose uptake in the renal cortex at the time acute interstitial nephritis was diagnosed compared to baseline. In three cases of acute kidney injury due to alternative causes there was no increase in 18F-flourodeoxyglucose uptake from baseline. CONCLUSIONS: To our knowledge, this is the first report describing increased 18F-flourodeoxyglucose uptake in the renal cortex in a patient with checkpoint inhibitor-associated acute interstitial nephritis. Our findings suggest that 18F-flourodeoxyglucose positron-emission tomography may be a valuable test for diagnosing immune-mediated nephritis, particularly in patients where timely kidney biopsy is not feasible.

Orthotopic heart transplant rejection in association with immunomodulatory therapy for AL amyloidosis: A case series and review of the literature.

Although end-organ damage caused by AL amyloidosis historically portends a poor prognosis, advances in therapy in combination with solid organ transplantation can lead to significant improvements in survival. Immunomodulatory agents (IMiDs), such as lenalidomide and pomalidomide, are an effective class of drugs in the treatment of AL amyloidosis. However, there is growing concern that these agents may precipitate acute transplant rejection via upregulation of interleukin-2 and inhibition of immune tolerance. This case series describes three patients who underwent orthotopic heart transplantation for AL amyloidosis and later had progression of their underlying plasma cell dyscrasia, leading to treatment with IMiD therapy. Two patients subsequently developed acute allograft rejection, including the first reported case of pomalidomide-associated allograft rejection. The third patient tolerated long-term therapy without signs of rejection: the first reported case of IMiD tolerability after heart transplant. These cases, together with a review of the literature, demonstrate variable outcomes and elucidate the potential risk of organ rejection associated with the use of IMiDs. When treatment with IMiDs is necessary, close surveillance and modification of immunosuppression may mitigate risks of rejection and complications.

Advances in risk assessment and prophylaxis for central nervous system relapse in diffuse large B-cell lymphoma.

Central nervous sytem recurrence of diffuse large B-cell lymphoma is an uncommon but devastating event, making identification of patients at high risk for relapse within the central nervous system essential for clinicians. Modern risk stratification includes both clinical and biological features. A validated clinical risk model employing the five traditional International Prognostic Index risk factors plus renal or adrenal involvement can identify a high-risk patient population with a central nervous system recurrence risk of greater than 10%. Lymphoma involvement of certain discrete extranodal sites such as the testis also confers increased risk, even in stage I disease. Adverse biological risk factors for central nervous system relapse include presence of translocations of MYC, BCL2 and/or BCL6, in so-called double- or triple-hit lymphoma. Immunohistochemically detectable co-expression of MYC and BCL2 in the absence of translocations also portends an increased risk of relapse within the central nervous system, particularly in the setting of the activated B-cell-like subtype of diffuse large B-cell lymphoma. The role, method, and timing of prophylactic therapy remain controversial based on the available data. We review both intrathecal and systemic strategies for prophylaxis in high-risk patients. Our preference is for systemic methotrexate in concert with standard chemoimmunotherapy in the majority of cases. Several novel agents have also demonstrated clinical activity in primary and secondary central nervous system lymphoma and warrant future investigation in the prophylactic setting.

Evolution of Body Composition Following Autologous and Allogeneic Hematopoietic Cell Transplantation: Incidence of Sarcopenia and Association with Clinical Outcomes.

Sarcopenia, the loss of muscle mass, has been identified as a potential risk factor for adverse outcomes in hematopoietic cell transplantation (HCT) recipients. However, much remains unknown about change in body composition following HCT. We retrospectively evaluated computed tomography (CT) imaging from 315 lymphoma patients undergoing HCT at our institution between 2000 and 2014. Cross-sectional areas of lean muscle, subcutaneous adipose tissue, and visceral adipose tissue were measured on CT at the level of the third lumbar vertebral body before HCT, 1-year post-HCT, and 2.5 years post-HCT. The incidence of sarcopenia before HCT was 47% in the autologous HCT (auto-HCT) cohort (n = 218) and 55% in the allogeneic HCT (allo-HCT) cohort (n = 97). Older age (odds ratio [OR], 1.04; 95% confidence interval [CI], 1.01 to 1.04; P < .001) and male sex (OR, 4.59; 95% CI, 1.42 to 4.93; P < .001) were associated with sarcopenia before HCT. Increasing body mass index (OR, .78; 95% CI, .73 to .84; P < .001) was protective against sarcopenia before HCT. A significant decline in total lean body mass (ß = 1.96; 95% CI, .79 to 3.13; P = .001) and increased sarcopenia incidence (OR, 1.72; 95% CI, 1.13 to 2.62, P = .012) was observed over time for patients in the allo-HCT cohort when compared with the trend in the auto-HCT cohort. Both auto-HCT and allo-HCT recipients experienced an increase in total body fat mass over time (ß = 3.75; 95% CI, 2.77 to 4.73; P < .001). In multivariate analysis of patients undergoing allo-HCT, the presence of sarcopenia on baseline imaging before HCT was associated with a lower risk of acute graft-versus-host disease (OR, .30; 95% CI, .09 to .98; P = .047). In conclusion, we found that total body fat mass increases after both auto-HCT and allo-HCT. Following allo-HCT, total lean body mass significantly decreases corresponding to increased incidence of sarcopenia. Future studies are needed to further characterize changes in body composition in HCT recipients and investigate its impact on HCT outcomes.

High-dose Thiotepa, Busulfan, Cyclophosphamide, and Autologous Stem Cell Transplantation as Upfront Consolidation for Systemic Non-Hodgkin Lymphoma With Synchronous Central Nervous System Involvement.

INTRODUCTION: Synchronous involvement of the central nervous system (CNS) at the diagnosis of systemic non-Hodgkin lymphoma (NHL) is associated with an increased risk for relapse despite complete remission to initial therapy. High-dose chemotherapy with a CNS-directed conditioning regimen followed by autologous stem cell transplantation (ASCT) holds promise as a consolidative approach. PATIENTS AND METHODS: We conducted a retrospective analysis of all patients with systemic B-cell NHL and synchronous CNS involvement who received upfront consolidation with high-dose chemotherapy with thiotepa, busulfan, cyclophosphamide, and ASCT while in first complete remission between July 2008 and June 2016 at 2 partner academic institutions. RESULTS: Twenty patients were identified through the transplant database. The median age at diagnosis was 53 years (range, 37-65 years). The majority had diffuse large B-cell lymphoma histology (n = 17; 85%). The sites of CNS involvement were parenchymal (n = 12; 60%) and leptomeningeal disease (n = 9; 45%). All patients received systemic and CNS-directed therapy prior to transplant, with the most common approaches being R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisolone) (n = 13; 65%) and high-dose intravenous methotrexate (n = 16; 80%), respectively. With a median follow up of 4.4 years after ASCT (range, 2 months-8.5 years), the Kaplan-Meier estimates of 4-year progression-free and overall survival were 77% (95% confidence interval, 48%-91%) and 82% (95% confidence interval, 54%-94%), respectively. CONCLUSION: CNS-directed high-dose chemotherapy and ASCT provides durable remission for patients with synchronous aggressive lymphoma and should be strongly considered as consolidative therapy for eligible patients with systemic NHL with CNS involvement in first complete remission.

Utility of magnetic resonance imaging in diagnosing cervical spine injury in children with severe traumatic brain injury.

BACKGROUND: Evaluation of children for cervical spine injuries (CSIs) after blunt trauma is complicated, particularly if the patient is unresponsive because of severe traumatic brain injury. Plain radiography and computed tomography (CT) are commonly used, but CT combined with magnetic resonance imaging (MRI) is still considered the gold standard in CSI detection. However, MRI is expensive and can delay cervical clearance. The purpose of this study is to determine the added benefit of MRI as an adjunct to CT in the clearance of children with severe head trauma. METHODS: We performed a retrospective chart review of pediatric head trauma patients admitted to the pediatric intensive care unit at St. Louis Children's Hospital from 2002 to 2012. Patients who received both cervical spine CT and MRI and presented with a Glasgow Coma Scale score of 8 or lower were included in the study. Imaging was analyzed by two pediatric trauma subspecialists and classified as demonstrating "no injury," "stable injury," or "unstable injury." Results were compared, and discrepancies between CT and MRI findings were noted. RESULTS: A total of 1,196 head-injured children were admitted to the pediatric intensive care unit between January 2002 and December 2012. Sixty-three children underwent CT and MRI and met Glasgow Coma Scale criteria. Seven children were identified with negative CT and positive MRI findings, but none of these injuries were considered unstable by our criteria. Five children were determined to have unstable injuries, and all were detected on CT. CONCLUSION: The results of this study suggest that MRI does not detect unstable CSIs in the setting of negative CT imaging. Given the limited patient population for this study, further and more extensive studies investigating the utility of MRI in the head-injured pediatric patient are warranted. LEVEL OF EVIDENCE: Diagnostic and care management study, level IV.