BET inhibition reforms the immune microenvironment and alleviates T cell dysfunction in chronic lymphocytic leukemia.

Redundant tumor microenvironment (TME) immunosuppressive mechanisms and epigenetic maintenance of terminal T cell exhaustion greatly hinder functional antitumor immune responses in chronic lymphocytic leukemia (CLL). Bromodomain and extraterminal (BET) proteins regulate key pathways contributing to CLL pathogenesis and TME interactions, including T cell function and differentiation. Herein, we report that blocking BET protein function alleviates immunosuppressive networks in the CLL TME and repairs inherent CLL T cell defects. The pan-BET inhibitor OPN-51107 reduced exhaustion-associated cell signatures resulting in improved T cell proliferation and effector function in the Eµ-TCL1 splenic TME. Following BET inhibition (BET-i), TME T cells coexpressed significantly fewer inhibitory receptors (IRs) (e.g., PD-1, CD160, CD244, LAG3, VISTA). Complementary results were witnessed in primary CLL cultures, wherein OPN-51107 exerted proinflammatory effects on T cells, regardless of leukemic cell burden. BET-i additionally promotes a progenitor T cell phenotype through reduced expression of transcription factors that maintain terminal differentiation and increased expression of TCF-1, at least in part through altered chromatin accessibility. Moreover, direct T cell effects of BET-i were unmatched by common targeted therapies in CLL. This study demonstrates the immunomodulatory action of BET-i on CLL T cells and supports the inclusion of BET inhibitors in the management of CLL to alleviate terminal T cell dysfunction and potentially enhance tumoricidal T cell activity.

Glofitamab stimulates immune cell infiltration of CNS tumors and induces clinical responses in secondary CNS lymphoma.

ABSTRACT: Although CD20×CD3 bispecific antibodies are effective against systemic B-cell lymphomas, their efficacy in central nervous system (CNS) lymphoma is unknown. Here, we report the CD20×CD3 bispecific glofitamab penetrates the blood-brain barrier, stimulates immune-cell infiltration of CNS tumors, and induces clinical responses in patients with secondary CNS.

Challenges in nodal peripheral T-cell lymphomas: from biological advances to clinical applicability.

T cell lymphomas are a heterogenous group with varying biological and clinical features that tend to have poor outcomes with a few exceptions. They account for 10-15% of all non-Hodgkin lymphomas (NHL), and 20% of aggressive NHL. There has been little change in the overall prognosis of T cell lymphomas over the last 2 decades. Most subtypes carry an inferior prognosis when compared to the B cell lymphomas, with a 5-year OS of 30%. Gene expression profiling and other molecular techniques has enabled a deeper understanding of these differences in the various subtypes as reflected in the latest 5th WHO and ICC classification of T cell lymphomas. It is becoming increasingly clear that therapeutic approaches that target specific cellular pathways are needed to improve the clinical outcomes of T cell lymphomas. This review will focus on nodal T cell lymphomas and describe novel treatments and their applicability to the various subtypes.

A Novel Triple-Action Inhibitor Targeting B-Cell Receptor Signaling and BRD4 Demonstrates Preclinical Activity in Chronic Lymphocytic Leukemia.

B-cell chronic lymphocytic leukemia (CLL) results from intrinsic genetic defects and complex microenvironment stimuli that fuel CLL cell growth through an array of survival signaling pathways. Novel small-molecule agents targeting the B-cell receptor pathway and anti-apoptotic proteins alone or in combination have revolutionized the management of CLL, yet combination therapy carries significant toxicity and CLL remains incurable due to residual disease and relapse. Single-molecule inhibitors that can target multiple disease-driving factors are thus an attractive approach to combat both drug resistance and combination-therapy-related toxicities. We demonstrate that SRX3305, a novel small-molecule BTK/PI3K/BRD4 inhibitor that targets three distinctive facets of CLL biology, attenuates CLL cell proliferation and promotes apoptosis in a dose-dependent fashion. SRX3305 also inhibits the activation-induced proliferation of primary CLL cells in vitro and effectively blocks microenvironment-mediated survival signals, including stromal cell contact. Furthermore, SRX3305 blocks CLL cell migration toward CXCL-12 and CXCL-13, which are major chemokines involved in CLL cell homing and retention in microenvironment niches. Importantly, SRX3305 maintains its anti-tumor effects in ibrutinib-resistant CLL cells. Collectively, this study establishes the preclinical efficacy of SRX3305 in CLL, providing significant rationale for its development as a therapeutic agent for CLL and related disorders.

NCCN Guidelines® Insights: Hematopoietic Growth Factors, Version 1.2022.

The NCCN Guidelines for Hematopoietic Growth Factors provide recommendations for the appropriate use of growth factors in the clinical management of febrile neutropenia (FN), chemotherapy-induced thrombocytopenia (CIT), and chemotherapy-induced anemia (CIA). Management and prevention of these sequelae are an integral part of supportive care for many patients undergoing cancer treatment. The purpose of these guidelines is to operationalize the evaluation, prevention, and treatment of FN, CIT, and CIA in adult patients with nonmyeloid malignancies and to enable the patient and clinician to assess management options for FN, CIT, and CIA in the context of an individual patient's condition. These NCCN Guidelines Insights provide a summary of the important recent updates to the NCCN Guidelines for Hematopoietic Growth Factors, with particular emphasis on the incorporation of a newly developed section on CIT.

T-Cell Lymphomas, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology.

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of lymphoproliferative disorders arising from mature T cells, accounting for about 10% of non-Hodgkin lymphomas. PTCL-not otherwise specified is the most common subtype, followed by angioimmunoblastic T-cell lymphoma, anaplastic large cell lymphoma, anaplastic lymphoma kinase-positive, anaplastic large cell lymphoma, anaplastic lymphoma kinase-negative, and enteropathy-associated T-cell lymphoma. This discussion section focuses on the diagnosis and treatment of PTCLs as outlined in the NCCN Guidelines for T-Cell Lymphomas.

Phase 1 trial of carfilzomib in relapsed/refractory peripheral T-cell lymphoma.

Peripheral T-cell lymphomas (PTCL) are a unique subset of lymphomas with a poor prognosis due to limited treatment options. We performed a phase 1 study of carfilzomib in patients with relapsed/refractory PTCL to determine the safety profile and the maximum tolerated dose (MTD) of this agent. The study was a classical 3 + 3 phase 1 design with intra-patient dose escalation allowed beginning on day 8 of cycle 1 and subsequently. Dose-limiting toxicity (DLT) was defined as the occurrence of any grade 3/4 adverse event. Carfilzomib was given on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Fifteen patients were enrolled from 3 centers. The median age of patients was 62. The median number of prior therapies for subjects on this trial was five. The MTD of carfilzomib was 36 mg/m2. Dose-limiting toxicities included anemia and sepsis. Serious adverse events were seen in 45% of patients. Single-agent carfilzomib leads to a complete response in one patient and a partial response in one patient. Overall, the drug was reasonably tolerated for a heavily pretreated population, but the limited response rate and short duration of response demonstrate a lack of promise for carfilzomib as a single agent in this patient population.

Single-route CNS prophylaxis for aggressive non-Hodgkin lymphomas: real-world outcomes from 21 US academic institutions.

Prophylaxis is commonly used to prevent central nervous sy stem (CNS) relapse in diffuse large B-cell lymphoma (DLBCL), with no clear standard of care. We retrospectively evaluated 1162 adult patients across 21 US academic centers with DLBCL or similar histologies who received single-route CNS prophylaxis as part of frontline therapy between 2013 and 2019. Prophylaxis was administered intrathecally(IT) in 894 (77%) and using systemic high-dose methotrexate (HD-MTX) in 236 (20%); 32 patients (3%) switched route due to toxicity and were assessed separately. By CNS-International Prognostic Index (IPI), 18% were considered low-risk, 51% moderate, and 30% high. Double-hit lymphoma (DHL) was confirmed in 243 of 866 evaluable patients (21%). Sixty-four patients (5.7%) had CNS relapse after median 7.1 months from diagnosis, including 15 of 64 (23%) within the first 6 months. There was no significant difference in CNS relapse between IT and HD-MTX recipients (5.4% vs 6.8%, P = .4), including after propensity score matching to account for differences between respective recipient groups. Weighting by CNS-IPI, expected vs observed CNS relapse rates were nearly identical (5.8% vs 5.7%). Testicular involvement was associated with high risk of CNS relapse (11.3%) despite most having lower CNS-IPI scores. DHL did not significantly predict for CNS relapse after single-route prophylaxis, including with adjustment for treatment regimen and other factors. This large study of CNS prophylaxis recipients with DLBCL found no significant difference in CNS relapse rates between routes of administration. Relapse rates among high-risk subgroups remain elevated, and reconsideration of prophylaxis strategies in DLBCL is of critical need.

Zilovertamab Vedotin Targeting of ROR1 as Therapy for Lymphoid Cancers.

BACKGROUND: Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncofetal protein present on many cancers. Zilovertamab vedotin (ZV) is an antibody­drug conjugate comprising a monoclonal antibody recognizing extracellular ROR1, a cleavable linker, and the anti-microtubule cytotoxin monomethyl auristatin E. METHODS: In this phase 1, first-in-human, dose-escalation study, we accrued patients with previously treated lymphoid cancers to receive ZV every 3 weeks until the occurrence of cancer progression or unacceptable toxicity had occurred. RESULTS: We enrolled 32 patients with tumor histologies of mantle cell lymphoma (MCL) (n=15), chronic lymphocytic leukemia (n=7), diffuse large B-cell lymphoma (DLBCL) (n=5), follicular lymphoma (n=3), Richter transformation lymphoma (n=1), or marginal zone lymphoma (n=1). Patients had received a median of four previous drug and/or cellular therapies. Starting dose levels were 0.5 (n=1), 1.0 (n=3), 1.5 (n=3), 2.25 (n=11), and 2.5 (n=14) mg per kg of body weight (mg/kg). Pharmacokinetic and pharmacodynamic data documented systemic ZV exposure and exposure-dependent ZV targeting of ROR1 on circulating tumor cells. As expected with an monomethyl auristatin E-containing antibody­drug conjugate, adverse events (AEs) included acute neutropenia and cumulative neuropathy resulting in a recommended ZV dosing regimen of 2.5 mg/kg every 3 weeks. No clinically concerning AEs occurred to suggest ROR1-mediated toxicities or nonspecific ZV binding to normal tissues. ZV induced objective tumor responses in 7 of 15 patients with MCL (47%; 4 partial and 3 complete) and in 3 of 5 patients with DLBCL (60%; 1 partial and 2 complete); objective tumor responses were not observed among patients with other tumor types. CONCLUSIONS: In heavily pretreated patients, ZV demonstrated no unexpected toxicities and showed evidence of antitumor activity, providing clinical proof of concept for selective targeting of ROR1 as a potential new approach to cancer therapy. (ClinicalTrials.gov number, NCT03833180.)

Outcomes of Richter's transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): an analysis of the SEER database.

Richter's transformation (RT) is a rare complication arising in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and is associated with an overall dismal outcome. The rarity of this entity poses many challenges in understanding its biology and outcomes seen and the optimal treatment approach. We utilized the SEER (Surveillance, Epidemiology and End Results) database to identify patients diagnosed with CLL/SLL between 2000 and 2016 and subsequently had a diagnosis of diffuse large B-cell lymphoma (DLBCL) or Hodgkin lymphoma (HL), thus capturing those who experienced an RT event. We compared the outcomes of those patients to those of patients in the database diagnosed with DLBCL without a preceding CLL/SLL diagnosis. We identified 530 patients who developed RT out of 74,116 patients diagnosed with CLL/SLL in the specified period. The median age at RT diagnosis was 66 years, and the median time from CLL/SLL diagnosis to RT development was roughly 4 years. Patients with RT had a dismal outcome with median overall survival of 10 months. We identified advanced Ann Arbor stage (III/IV) and prior treatment for CLL as predictors of worse outcome in patients with RT. Our study represents the largest dataset of patients with CLL/SLL and RT and adds to the existing literature indicating the poor outcomes for those patients.

Considerations for Use of Hematopoietic Growth Factors in Patients With Cancer Related to the COVID-19 Pandemic.

Hematopoietic growth factors, including erythrocyte stimulating agents (ESAs), granulocyte colony-stimulating factors, and thrombopoietin mimetics, can mitigate anemia, neutropenia, and thrombocytopenia resulting from chemotherapy for the treatment of cancer. In the context of pandemic SARS-CoV-2 infection, patients with cancer have been identified as a group at high risk of morbidity and mortality from this infection. Our subcommittee of the NCCN Hematopoietic Growth Factors Panel convened a voluntary group to review the potential value of expanded use of such growth factors in the current high-risk environment. Although recommendations are available on the NCCN website in the COVID-19 Resources Section (https://www.nccn.org/covid-19/), these suggestions are provided without substantial context or reference. Herein we review the rationale and data underlying the suggested alterations to the use of hematopoietic growth factors for patients with cancer in the COVID-19 era.

Contemporary strategies to improve outcomes for peripheral T-cell lymphoma patients following the failure of first-line therapy.

INTRODUCTION: T cell lymphomas are a heterogeneous group, with varying incidences, geographic patterns, and risk factors. Although until recently approached in a manner similar to B cell lymphomas, the treatment outcomes are poor and this disease is characterized by high relapse rates. The treatment advances in PTCL have been slow compared to B cell lymphomas. The outcomes of patients who progress following stem cell transplantation are worse. AREAS COVERED: This review focuses on the novel targeted agents that are approved and/or are under investigation for patients with relapsed/refractory PTCL. We conducted an electronic literature search of the studies using PubMed, clincaltrials.gov, MEDLINE, using the key words 'PTCL,' 'second line therapy,' and 'targeted agents.' Studies published before January 2020 were included in the search criteria. EXPERT OPINION: Development of newer therapies such as HDAC inhibitors and kinases are promising new agents with activity in relapsed/refractory PTCL. Combination therapy using novel agents may be the future for treatment of PTCL. Therapies in the next few years may take a more personalized approach taking into consideration not just the histology, but also the epigenomic landscape.

Academic Centers Compared With Nonacademic Centers for Patients With International Prognostic Index Risk-stratified Diffuse Large B-cell Lymphoma: A Survival Outcomes Analysis.

INTRODUCTION: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease associated with varying outcomes. The International Prognostic Index (IPI) has been the standard for the baseline prognostic assessment in these patients. The present study aimed to determine the effect of the treatment facility on the overall survival outcomes in patients with DLBCL stratified by IPI risk groups. MATERIALS AND METHODS: The National Cancer Database was used to identify patients with a diagnosis of DLBCL from 2004 to 2015. DLBCL was stratified by the IPI risk score from low- to high-risk disease, and the overall survival of those treated at academic centers was compared with that of those treated at nonacademic centers. RESULTS: Treatment at academic centers was associated with significantly improved overall survival for all patients with DLBCL (108.3 months) compared with those treated at nonacademic centers (74.5 months; P < .001). The median survival for patients with high-risk disease treated at academic centers (33.5 months) was more than twice that of high-risk patients treated at nonacademic centers (14.4 months; P < .001). The median survival for the other risk categories was similarly improved, although less pronounced in the lower IPI score groups. The long-term overall survival for all patients with DLBCL at academic centers was improved at 5 and 10 years (59% and 43% survival, respectively) compared with those treated at nonacademic centers (51% and 35% survival, respectively; P < .001). CONCLUSION: Patients with DLBCL treated at academic centers demonstrated improved survival compared with those treated at nonacademic centers, especially those with high-risk disease. Further investigations into the factors contributing to such disparities are required to help standardize care and improve outcomes.

Surveillance in Patients With Diffuse Large B Cell Lymphoma.

With improvement in the cure rates for diffuse large B cell lymphoma, the question of surveillance imaging in patients who achieve complete remission after the initial therapy has become relevant. Some of the clinical practice guidelines recommend surveillance scanning. However, several studies have reported no benefit in overall survival with scans. Moreover, studies have highlighted an increased risk for developing secondary malignancies because of exposure to ionizing radiation from the scans. Different international societies have contrasting guidelines for the role of surveillance computerized tomography scans in patients who achieve complete remission after first-line therapy. Any benefit of surveillance imaging must be balanced by the costs, risk of radiation exposure, and lack of survival benefit. The PubMed platform was searched using relevant keywords for English-language articles with no date restrictions. Search terms were cross-referenced with review articles, and additional articles were identified by manually searching reference lists. Results were reviewed by the authors and selected for inclusion based on relevance. We present a review of this current data available for surveillance imaging in patients with diffuse large B cell lymphoma.

NCCN Guidelines Insights: Hematopoietic Growth Factors, Version 1.2020.

Management of febrile neutropenia (FN) is an integral part of supportive care for patients undergoing cancer treatment. The NCCN Guidelines for Hematopoietic Growth Factors provide suggestions for appropriate evaluation, risk determination, prophylaxis, and management of FN. These NCCN Guidelines are intended to guide clinicians in the appropriate use of growth factors for select patients undergoing treatment of nonmyeloid malignancies. These NCCN Guidelines Insights highlight important updates to the NCCN Guidelines regarding the incorporation of newly FDA-approved granulocyte-colony stimulating factor biosimilars for the prevention and treatment of FN.