Bruton’s tyrosine kinase (BTK) inhibitors have revolutionized the landscape for the treatment of hematological malignancies, solid tumors, and, recently, autoimmune disorders. The BTK receptor is expressed in several hematopoietic cells such as macrophages, neutrophils, mast cells, and osteoclasts. Similarly, the BTK receptor is involved in signaling pathways such as chemokine receptor signaling, Toll-like receptor signaling, and Fc receptor signaling. Due to their unique mechanism, these agents provide a diverse utility in a variety of disease states not limited to the field of malignant hematology and are generally well-tolerated.

Secondary central nervous system (CNS) large B-cell lymphoma (SCNSL) occurs in the de novo setting, as a CNS-isolated relapse, or synchronous (concomitant CNS and systemic) relapse. SCNSL is a devastating event without therapeutic consensus. Thus, we aimed to evaluate treatment outcomes in an international cohort. Progression-free survival (PFS), overall survival (OS), and cumulative incidence of relapse (CIR, estimated using competing-risk models) were reported. Prognostic factors were identified in a 6-month landmark multivariate analysis. Outcomes after thiotepa autologous stem cell transplant (ASCT) and chimeric antigen receptor (CAR) T-cell therapy (CAR-T) delivered at relapse were compared after propensity score matching (PSM). A total of 1139 patients were included in the analysis (de novo: 537; relapsed SCNSL: 602). Two-year PFS estimates were 40.4%, 43.9%, and 16.2% for de novo SCNSL, CNS-isolated relapse, and synchronous relapse, respectively. Patients with CNS-isolated relapse demonstrated low rates of systemic recurrence (24-month CIR, 6%). Thiotepa-ASCT correlated with longer survival in de novo SCNSL (PFS: hazard ratio [HR], 0.57; P = .005; and OS: HR, 0.62; P = .023) and CNS-isolated relapses (PFS: HR, 0.55; P = .002; and OS: HR, 0.39; P< .0001). ASCT (thiotepa or no thiotepa) also associated with improved survival in synchronous relapses (PFS: HR, 0.57; P = .023; and OS: HR, 0.48; P = .019). Higher survival with thiotepa-ASCT than CAR-T was observed after PSM (PFS: HR, 0.45; P = .005 and OS: HR, 0.41; P = .014). These data support thiotepa-ASCT in eligible patients, particularly de novo disease and CNS-isolated relapses. CNS-isolated relapse was infrequently associated with systemic recurrence, supporting treatment regimens adopted from primary CNS lymphoma.

Non-Hodgkin lymphomas (NHLs) represent a diverse group of hematologic malignancies derived from various cells. B-cell NHLs represent the largest fraction of lymphomas diagnosed and treated in the United States. Standard chemo-immunotherapies with rituximab and multiagent cytotoxic regimens have proven to be effective in the management of these lymphoproliferative neoplasms; nonetheless, a considerable fraction of patients still experience relapse or have treatment-refractory disease. Therapeutic advances using novel immunotherapeutic agents as well as cell-based treatments, such as chimeric antigen receptor (CAR) T-cell therapies, have improved the outcomes of relapsed/refractory (R/R) B-cell NHL. Most of these new treatment strategies are not curative and most patients succumb to R/R disease, leaving this population with an unmet need for effective and well-tolerated therapeutic options. One of these up-and-coming options are bispecific antibodies (BsAb), either as single agent or in combination with other medications. Conclusion: BsAbs offer a novel “off the shelf” chemotherapy-free approach in the management of R/R B-cell NHL. Advancements in antibody construct design along with improved safety profile and clinical effectiveness of the most recent BsAbs suggest that these agents are a promising new option in the management of R/R B-cell NHL.

Introduction: Adult T-cell leukemia/lymphoma (ATLL) is a rare type of lymphoma that is often aggressive with poor survival. The majority of cases cluster in regions with high rates of endemic human T-lymphotropic virus type 1 (HTLV-1) because chronic infection is necessary for the development of ATLL. ATLL is rare in the US, with most cases occurring in immigrants from endemic regions. Although treatment data exist from Japan, some of the agents evaluated are not available in the US. Because of limited prospective data in the US, there is no well-defined standard of care. Brentuximab vedotin (BV) is a CD30-targeting antibody-drug conjugate that has been shown to be effective even in lymphomas with very low CD30 expression (Jagadeesh, JCO, 2019). Studies have shown 36% to 50% of ATLL cases will express CD30. CD30 may be associated with worse survival in acute ATLL, making it an important therapeutic target. BV has been studied in combination with a CHP (cyclophosphamide, doxorubicin, prednisone) backbone for the treatment of CD30 expressing PTCL. ATLL patients were eligible for the study, but only 7 patients were enrolled (Horwitz, Lancet, 2019). BV-CHEP has been studied in CD30 expressing PTCL and was shown to be safe and effective (Herrera, Blood, 2019). No ATLL patients were enrolled prior to the preliminary report. We developed a prospective, multicenter pilot study evaluating BV in combination with cyclophosphamide, doxorubicin, etoposide, and prednisone (BV-CHEP) for the treatment of ATLL. We report the interim safety and efficacy analysis of the first 8 patients treated on this study. Methods: Adult patients from 5 centers (UNC Chapel Hill, Boston Medical Center, Massachusetts General Hospital, Beth Israel Deaconess Medical Center, and Moffitt Cancer Center at Memorial Healthcare System) were enrolled from October 2017 until present. Newly diagnosed ATLL cases were eligible, including the acute, lymphomatous and chronic unfavorable subtypes. Patients did not have to express CD30 to be enrolled on the study. Patients could go on to frontline consolidation with allogeneic stem cell transplant per provider preference at any time after 2 cycles of BV-CHEP. Transplant-ineligible patients completed a total of 6 cycles of BV-CHEP and those who expressed CD30 were eligible for BV maintenance, whereas those without CD30 expression entered follow-up. Patients could receive prephase steroids and/or 1 cycle of CHOP-equivalent chemotherapy prior to enrollment. Prior antiviral therapy was allowed. Patients were treated with standard dosing every 21 days: BV 1.8 mg/kg on day 1, cyclophosphamide 750 mg/m2 on day 1, doxorubicin 50 mg/m2 on day 1, etoposide 100 mg/m2 days 1-3, and prednisone 100mg days 1-5. All patients received GCSF support. The primary endpoint was complete response (CR) by PET-CT after at least 2 cycles of therapy per adapted Lugano and ATLL criteria. Secondary endpoints were safety, overall response rate (ORR), progression free survival (PFS) and overall survival (OS). Results: 8 patients were enrolled and were evaluable for interim safety and efficacy analysis. All patients were HTLV-1 positive; 4 of 8 (50%) were acute type and 4 of 8 were the lymphomatous type. 4 of 8 patients had CD30 expression. The median age was 56 (range 38 to 68) and 7 of 8 (87.5%) were female. 6 of 8 patients identified as Black (Antigua and Barbuda N=1, Haiti N=4, US N=1), 1 identified as Asian (Japan) and 1 patient identified as Hispanic (Colombia). All patients were advanced stage (7 of 8 stage IV; 1 stage III). Five of 8 patients completed at least 4 cycles of treatment (median 4 cycles; range 2 to 6). After at least 2 cycles of BV-CHEP, 4 of 8 patients achieved a CR (50%). An additional 2 patients achieved a PR, for an ORR of 75%. The median PFS was 196 days (Fig.1) and the median OS was not reached (Fig.2). When CD30 expressing patients (N=4) were compared to non-expressing patients (N=4), there was no significant difference in median PFS or OS. The regimen was well-tolerated with grade 3 mucositis occurring in 3 patients, grade 3 hypertension in 2 patients, and grade 3 rash in 1 patient. No patients had to come off study due to toxicity. Three patients received consolidation allogeneic transplant. No patients received maintenance BV. Conclusions: In this interim analysis, BV-CHEP chemotherapy was safe and effective in the treatment of aggressive ATLL. We look forward to reporting the final results once the study completes accrual.