The CNS Relapse in T-Cell Lymphoma Index Predicts CNS Relapse in Patients with T- and NK-Cell Lymphomas.

Little is known about risk factors for central nervous system (CNS) relapse in mature T- and NK-cell neoplasms (MTNKN). We aimed to describe the clinical epidemiology of CNS relapse in patients with MTNKN and developed the CNS relapse In T-cell lymphoma Index (CITI) to predict patients at highest risk of CNS relapse. We reviewed data from 135 patients with MTNKN and CNS relapse from 19 North American institutions. After exclusion of leukemic and most cutaneous forms of MTNKN, patients were pooled with non-CNS relapse control patients from a single institution to create a CNS relapse-enriched training set. Using a complete case analysis (N=182), of whom 91 had CNS relapse, we applied a LASSO Cox regression model to select weighted clinicopathologic variables for the CITI score, which we validated in an external cohort from the Swedish Lymphoma Registry (N=566). CNS relapse was most frequently observed in patients with PTCL, NOS (25%). Median time to CNS relapse and median overall survival after CNS relapse was 8.0 months and 4.7 months, respectively. We calculated unique CITI risk scores for individual training set patients and stratified them into risk terciles. Validation set patients with low-risk (N=158) and high-risk (N=188) CITI scores had a 10-year cumulative risk of CNS relapse of 2.2% and 13.4%, respectively (HR 5.24, 95%CI 1.50-18.26, P=0.018). We developed an open-access web-based CITI calculator (https://redcap.link/citicalc) to provide an easy tool for clinical practice. The CITI score is a validated model to predict patients with MTNKN at highest risk of developing CNS relapse.

Post-infusion PD-1+CD8+CAR-T cells identify patients responsive to CD19-CAR-T therapy in non-Hodgkin's lymphoma.

Chimeric antigen receptor T cell therapy (CAR-T) has revolutionized treatment for relapsed/refractory (r/r) B-cell non-Hodgkin's lymphoma (NHL). Robust biomarkers and a complete understanding of CAR-T cell function in the post-infusion phase remain limited. Here we used a 37-color spectral flow cytometry panel to perform high dimensional single cell analysis of post-infusion samples in 26 patients treated with CD28 co-stimulatory domain containing commercial CAR-T (CD28-CAR-T) for NHL and focused on computationally gated CD8+ CAR-T cells. We found that the presence of post-infusion PD-1+ CD8+ CAR-T cells at the Day 14 timepoint highly correlated with the ability to achieve complete response (CR) by 6 months. Further analysis identified multiple subtypes of CD8+ PD-1+ CAR-T cells including PD-1+ TCF1+ stem-like CAR-T cells and PD-1+ TIM3+ effector-like CAR-T cells that correlated with improved clinical outcomes such as response and progression free survival. Additionally, we identified a subset of PD-1+ CD8+ CAR+ T cells with effector-like function that was increased in patients who achieved a CR and was associated with Grade 3 or higher immune effector cell-associated neurotoxicity syndrome. Here we identified robust biomarkers of response to CD28-CAR-T and highlight the importance of PD-1 positivity in CD8+ CAR-T cells post-infusion in achieving CR.

A US Multicenter Collaborative Study on Outcomes of Hematopoietic Cell Transplantation in Hepatosplenic T-Cell Lymphoma.

Hepatosplenic T-cell lymphoma (HSTCL) is a rare and aggressive type of peripheral T-cell lymphoma with median overall survival (OS) of approximately 1 year. Data on the effectiveness of hematopoietic cell transplantation (HCT) is limited, as is the choice between autologous HCT (auto-HCT) and allogeneic HCT (allo-HCT) in the treatment of this disease. To evaluate the outcome of patients with HSTCL who underwent either auto-HCT or allo-HCT, we performed a multi-institutional retrospective cohort study to assess outcomes of HCT in HSTCL patients. Fifty-three patients with HSTCL were included in the study. Thirty-six patients received an allo-HCT and 17 received an auto-HCT. Thirty-five (66%) were males. Median age at diagnosis was 38 (range 2 to 64) years. Median follow-up for survivors was 75 months (range 8 to 204). The median number of prior lines of therapy was 1 (range 1 to 4). Median OS and progression-free survival (PFS) for the entire cohort were 78.5 months (95% CI: 25 to 79) and 54 months (95% CI: 18 to 75), respectively. There were no significant differences in OS (HR: 0.63, 95% CI: 0.28 to 1.45, P = .245) or PFS (HR: 0.7, 95% CI: 0.32 to 1.57, P = .365) between the allo-HCT and auto-HCT groups, respectively. In the allo-HCT group, the 3-year cumulative incidence of relapse was 35% (95% CI: 21 to 57), while 3-year cumulative incidence of NRM was 16% (95% CI: 7 to 35). In the auto-HCT group, the 3-year cumulative incidence of relapse and NRM were 43% (95% CI: 23 to 78) and 14% (95% CI: 4 to 52), respectively. Both Auto-HCT and Allo-HCT are effective consolidative strategies in patients with HSTCL, and patients should be promptly referred for HCT evaluation.

Gemcitabine and liposomal doxorubicin (GemDox) for the treatment of relapsed and refractory T-cell lymphomas.

Aggressive T-cell lymphomas (TCL) account for 10-15% of non-Hodgkin lymphomas (NHL) with weaker responses and shorter durations to chemotherapy than other types of NHL. Current therapies for patients with relapsed/refractory Cutaneous T-cell lymphoma (CTCL) have limited efficacy, and short durations of response. Gemcitabine and liposomal doxorubicin have shown single-agent activity in TCL and combined have activity in relapsed B-cell lymphomas. We evaluated outcomes of 18 patients with relapsed/refractory aggressive TCL (13 CTCL, 5 PTCL) treated with a gemcitabine plus liposomal doxorubicin (GemDox) combination and evaluated outcomes with a specific focus on CTCL patients. Significant responses were observed in CTCL patients with an overall response rate of over 80%. In all patients, objective responses were seen in eight patients (50%), with six patients (5 CTCL) able to proceed to allogeneic stem cell transplant. Given limited treatment options for r/r CTCL, GemDox should be considered a therapeutic option in relapsed/refractory CTCL.

Targeted therapy with nanatinostat and valganciclovir in recurrent EBV-positive lymphoid malignancies: a phase 1b/2 study.

Lymphomas are not infrequently associated with the Epstein-Barr virus (EBV), and EBV positivity is linked to worse outcomes in several subtypes. Nanatinostat is a class-I selective oral histone deacetylase inhibitor that induces the expression of lytic EBV BGLF4 protein kinase in EBV+ tumor cells, activating ganciclovir via phosphorylation, resulting in tumor cell apoptosis. This phase 1b/2 study investigated the combination of nanatinostat with valganciclovir in patients aged ≥18 years with EBV+ lymphomas relapsed/refractory to ≥1 prior systemic therapy with no viable curative treatment options. In the phase 1b part, 25 patients were enrolled into 5 dose escalation cohorts to determine the recommended phase 2 dose (RP2D) for phase 2 expansion. Phase 2 patients (n = 30) received RP2D (nanatinostat 20 mg daily, 4 days per week with valganciclovir 900 mg orally daily) for 28-day cycles. The primary end points were safety, RP2D determination (phase 1b), and overall response rate (ORR; phase 2). Overall, 55 patients were enrolled (B-non-Hodgkin lymphoma [B-NHL], [n = 10]; angioimmunoblastic T-cell lymphoma-NHL, [n = 21]; classical Hodgkin lymphoma, [n = 11]; and immunodeficiency-associated lymphoproliferative disorders, [n = 13]). The ORR was 40% in 43 evaluable patients (complete response rate [CRR], 19% [n = 8]) with a median duration of response of 10.4 months. For angioimmunoblastic T-cell lymphoma-NHL (n = 15; all refractory to the last prior therapy), the ORR/CRR ratio was 60%/27%. The most common adverse events were nausea (38% any grade) and cytopenia (grade 3/4 neutropenia [29%], thrombocytopenia [20%], and anemia [20%]). This novel oral regimen provided encouraging efficacy across several EBV+ lymphoma subtypes and warrants further evaluation; a confirmatory phase 2 study (NCT05011058) is underway. This phase 1b/2 study is registered at www.clinicaltrials.gov as #NCT03397706.

Effective treatment with the selective cytokine inhibitor BNZ-1 reveals the cytokine dependency of T-LGL leukemia.

T-cell large granular lymphocytic leukemia (T-LGLL) is a clonal proliferation of cytotoxic T lymphocytes that can result in severe neutropenia, anemia, and bone marrow failure. Strong evidence from patients and mouse models demonstrate the critical role of interleukin-15 (IL-15) in T-LGLL pathogenesis. BNZ-1 is a pegylated peptide that selectively inhibits the binding of IL-15 and other γc cytokines to their cellular receptor complex, which has demonstrated efficacy in ex vivo T-LGLL cells and transgenic mice in preclinical studies. We conducted a phase 1/2 trial of BNZ-1 in patients with T-LGLL who had hematocytopenias (anemia or neutropenia) and required therapy. Clinical responses were assessed using hematologic parameters (improvement in hematocytopenias) based on response criteria from the Eastern Cooperative Oncology Group 5998 T-LGLL trial. BNZ-1 demonstrated clinical partial responses in 20% of patients with T-LGLL with minimal toxicity and the maximum tolerated dose was not reached. Furthermore, T-LGL leukemic cells showed significantly increased apoptosis in response to BNZ-1 treatment as early as day 2, including in clinical nonresponders, with changes that remained statistically different from baseline throughout treatment (P < .005). We report first-in-human proof that T-LGL leukemic cells are dependent on IL-15 and that intervention with IL-15 inhibition with BNZ-1 in patients with T-LGLL shows therapeutic effects, which carries important implications for the understanding of the pathogenesis of this disease. This trial was registered at www.clinicaltrials.gov as #NCT03239392.

The role of interleukin-15 in the development and treatment of hematological malignancies.

Cytokines are a vital component of the immune system that controls the activation and growth of blood cells. However, chronic overexpression of cytokines can trigger cellular events leading to malignant transformation. The cytokine interleukin-15 (IL-15) is of particular interest, which has been shown to contribute to the development and progression of various hematological malignancies. This review will provide an overview of the impact of the immunopathogenic function of IL-15 by studying its role in cell survival, proliferation, inflammation, and treatment resistance. We will also review therapeutic approaches for inhibiting IL-15 in blood cancers.

A Phase 2 Trial of Ibrutinib and Nivolumab in Patients with Relapsed or Refractory Classical Hodgkin's Lymphoma.

BACKGROUND: Relapsed or refractory classical Hodgkin lymphoma (cHL) remains a difficult treatment challenge. Although checkpoint inhibitors (CPI) have provided clinical benefit for these patients, responses are generally not durable, and progression eventually occurs. Discovering combination therapies which maximize the immune response of CPI therapy may overcome this limitation. We hypothesized that adding ibrutinib to nivolumab will lead to deeper and more durable responses in cHL by promoting a more favorable immune microenvironment leading to enhanced T-cell-mediated anti-lymphoma responses. METHODS: We conducted a single arm, phase II clinical trial testing the efficacy of nivolumab in combination with ibrutinib in patients ≥18 years of age with histologically confirmed cHL who had received at least one prior line of therapy. Prior treatment with CPIs was allowed. Ibrutinib was administered at 560 mg daily until progression in combination with nivolumab 3 mg/kg IV every 3 weeks for up to 16 cycles. The primary objective was complete response rate (CRR) assessed per Lugano criteria. Secondary objectives included overall response rate (ORR), safety, progression free survival (PFS), and duration of response (DoR). RESULTS: A total of 17 patients from two academic centers were enrolled. The median age of all patients was 40 (range 20-84). The median number of prior lines of treatment was five (range 1-8), including 10 patients (58.8%) who had progressed on prior nivolumab therapy. Most treatment related events were mild (

Targeting the Inducible T-cell Costimulator (ICOS) in Patients with Relapsed/Refractory T-follicular Helper Phenotype Peripheral T-cell and Angioimmunoblastic T-cell Lymphoma.

PURPOSE: Proliferation of T-follicular helper (TFH) CD4+ T cells is a postulated pathogenic mechanism for T-cell non-Hodgkin lymphomas (T-NHL). The inducible T-cell costimulator (ICOS) is highly expressed by TFH, representing a potential target. MEDI-570 is a monoclonal antibody against ICOS, which eliminates ICOS+ cells in preclinical models. PATIENTS AND METHODS: We report the safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of MEDI-570 in T-NHL. NCI-9930 is a phase I, first-in-human study of MEDI-570 in relapsed/refractory malignant T-NHL known to express ICOS. MEDI-570 was administered intravenously every 3 weeks for up to 12 cycles. Primary endpoints were safety, dose-limiting toxicities (DLT), and recommended phase II dose (RP2D). Secondary and exploratory endpoints included efficacy parameters and various correlative studies. This study is supported by the National Cancer Institute (NCT02520791). RESULTS: Twenty-three patients were enrolled and received MEDI-570 at five dose levels (0.01-3 mg/kg). Sixteen (70%) had angioimmunoblastic T-cell lymphoma (AITL); median age was 67 years (29-86) and the median prior lines of therapies was 3 (1-16). Most common grade 3 or 4 adverse events were decreased CD4+ T cells (57%), lymphopenia (22%), anemia (13%), and infusion-related reactions (9%). No DLTs were observed. The RP2D was determined at 3 mg/kg. Analysis of T-cell subsets showed reductions in CD4+ICOS+ T cells reflecting its effects on TFH cells. The response rate in AITL was 44%. CONCLUSIONS: MEDI-570 was well tolerated and showed promising clinical activity in refractory AITL. MEDI-570 resulted in sustained reduction of ICOS+ T lymphocytes.

Outcomes associated with allogeneic hematopoietic stem cell transplantation for relapsed and refractory Hodgkin lymphoma in the era of novel agents.

BACKGROUND: Relapsed or refractory Hodgkin lymphoma (R/R HL) is a challenging disease with limited treatment options beyond brentuximab vedotin and checkpoint inhibitors. Herein we present the time-trend analysis of R/R HL patients who received allogeneic hematopoietic cell transplantation (allo-HCT) at our center from 2001-2017. METHODS: The patients were divided into two distinct treatment cohorts: era1 (2001-2010), and era2 (2011-2017). The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), non-relapse mortality (NRM), and cumulative incidence of acute and chronic graft versus host disease (GVHD). RESULTS: Among the 51 patients included in the study, 29 were in era1, and 22 were in era2. There was decreased use of myeloablative conditioning in era2 (18% vs. 31%) compared to era1 and 95% of patients in era2 previously received brentuximab Vedotin (BV). Haploidentical donors were seen exclusively in era2 (0% vs. 14%) and more patients received alternative donor transplants (7% vs. 32%) in era2. The 4-year OS (34% vs. 83%, p < 0.001) and 4-year PFS (28% vs. 62%, p = 0.001) were significantly inferior in era1 compared to era2. The incidence of 1-year NRM was lower in era2 compared to era1 (5% vs. 34%, p = 0.06). The cumulative incidence of acute GVHD at day 100 was similar in both eras (p = 0.50), but the incidence of chronic GVHD at 1 year was higher in era2 compared to era1 (55% vs. 21%, p = 0.03). CONCLUSIONS: Despite the advent of novel therapies, allo-HCT remains an important therapeutic option for patients with R/R HL.

Longitudinal Survival Outcomes in Allogeneic Stem Cell Transplantation: An Institutional Experience.

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a potentially curative treatment for many hematological disorders, but is often complicated by relapse of the underlying disease, graft-versus-host disease (GVHD), and infectious complications. We conducted a retrospective analysis on patients undergoing allo-SCT from 1984 to 2018 to better understand how survival has changed longitudinally with therapeutic advancements made to mitigate these complications. Method: We analyzed data from 1943 consecutive patients who received allo-SCT. Patients were divided into groups (gps) based on the year (yr) of transplant. Primary endpoints were overall survival (OS), progression free survival (PFS), and GVHD-free relapse-free survival (GRFS). Secondary endpoints were the cumulative incidences of grade II−IV and grade III−IV acute GVHD (aGVHD), chronic GVHD (cGVHD), and non-relapse mortality (NRM). Results: Our study found statistically significant improvements in OS, PFS, and GRFS. Five-year PFS among the groups increased from 24% to 48% over the years. Five-year OS increased from 25% to 53%. Five-year GRFS significantly increased from 6% to 14%, but remained relatively unchanged from 2004 to 2018. Cumulative incidences of grade II−IV aGVHD increased since 2009 (p < 0.001). However, cumulative incidence of NRM decreased since 2004 (p < 0.001). Conclusions: Our data show improved OS, PFS, and GRFS post allo-SCT over decades. This may be attributed to advances in supportive care and treatments focused on mitigation of GVHD and relapse.

Outcomes of patients with diffuse large B-cell and high-grade B-cell lymphomas with synchronous CNS and systemic involvement at diagnosis treated with high-dose methotrexate and R-CHOP: a single-center retrospective study.

Background: The optimal treatment of patients with systemic diffuse large B-cell (DLBCL) or high-grade B-cell (HGBL) lymphomas with synchronous central nervous system (CNS) involvement at diagnosis is not well defined. High-dose methotrexate administered concurrently with R-CHOP (RM-CHOP) is a commonly used regimen, but data on outcomes achieved with this regimen are limited. Objective: To report our experience with RM-CHOP in patients with systemic DLBCL or HGBL with synchronous CNS involvement at diagnosis. Design: A single-center retrospective analysis. Methods: We identified consecutive patients with systemic DLBCL or HGBL with synchronous CNS involvement at diagnosis who were treated with RM-CHOP from January 2012 to January 2021. Results: Fifty patients were included with a median age of 62 years; 82% had DLBCL (n = 41) and 18% had HGBL (n = 9). Treatment with RM-CHOP was followed by consolidative autologous hematopoietic cell transplantation in 14 patients (28%). The complete response (CR) rate following RM-CHOP was 62%. With a median follow-up of 40 months, the median progression-free (PFS) and overall (OS) survivals were 16 and 58 months, and the 2-year PFS and OS were 41% and 57%, respectively. The 2-year cumulative incidence of CNS progression/relapse was 29%. Outcomes were particularly poor in HGBL, with median PFS and OS of 6 and 7 months, compared with median PFS and OS of 22 months and not reached in DLBCL, respectively. The outcomes of patients with relapsed/progressive disease were poor, with only 63% of patients receiving subsequent treatments and only 21% achieving CR to next subsequent treatment. Most patients (58%) with disease relapse/progression had CNS involvement which was associated with very poor outcomes (median OS of 2 months). Conclusion: CNS involvement in aggressive B-cell non-Hodgkin lymphoma at diagnosis dictates clinical outcomes and requires more effective treatment options.

Recent Advances in the Management of Relapsed and Refractory Peripheral T-Cell Lymphomas.

Peripheral T-cell lymphomas (PTCLs) are a group of heterogeneous lymphomas with poor overall prognosis, particularly in the setting of relapsed/refractory PTCL. Given the limited efficacy of current therapies, several different novel therapies encompassing multiple different mechanisms of action have been evaluated for relapsed and refractory PTCLs. In this review, we explore the current standard of care for relapsed/refractory PTCL, and evaluate in depth novel and emerging therapies, their scientific basis, and current trials for relapsed/refractory PTCL.

Pathogenesis and Treatment of T-Large Granular Lymphocytic Leukemia (T-LGLL) in the Setting of Rheumatic Disease.

A complex relationship exists between rheumatic diseases and cancer. This delicate balance between chronic inflammation and malignant cell transformation in hematologic neoplasms has been observed, but is not well defined. Large Granular Lymphocyte (LGL) leukemia is at the intersection of a clonal lymphoproliferative disease, chronic inflammation, and autoimmunity. The association between rheumatoid arthritis (RA) and the spectrum of Felty's Syndrome is well-known. Other rheumatic disorders have been reported including systemic lupus erythematosus (SLE), Sjogren's Syndrome (SS), vasculitis, Behcet's Disease (BD) and systemic sclerosis. The association between T-LGLL and rheumatic disease pathogenesis has been hypothesized, but has not yet been fully understood. Components of a shared pathogenesis includes chronic antigen stimulation, JAK-STAT pathway activation and overlap of various cytokines. We will summarize current knowledge on the molecular understanding between T-LGLL and rheumatic disease. There are many potential areas of research to help meet this need and lead to development of targeted therapeutic options.

Incidence, Treatment, and Survival of Patients With T-Cell Lymphoma, T-Cell Large Granular Leukemia, and Concomitant Plasma Cell Dyscrasias.

T-Cell malignancies are a group of heterogeneous disorders composed of primary cutaneous T-cell lymphomas (CTCLs), peripheral T-cell lymphomas (PTCLs), and T-cell leukemias, including T-cell large granular lymphocytic leukemia (T-LGLL). Cases of patients with combined T-cell malignancies and plasma cell dyscrasias (PCD) are reported in the literature, but these are mostly limited to case reports or small case series with <10 patients. Here, we described the clinical course of 26 patients and report baseline characteristics and clinical outcomes including overall survival (OS), progression-free survival (PFS), and objective response rates (ORRs) in this unique population. There was no survival difference in patients with CTCL or T-LGLL and concomitant PCD when treated with standard therapy directed at the T-cell malignancy when compared to historical controls. However, patients with PTCL and concomitant PCD had significantly inferior outcomes with rapid progression and worse OS and PFS at 1.7 years (p=0.006) and 4.8 months (p=0.08), respectively, when compared to historical controls for patients with PTCL, although the limited number of patients included in this analysis precludes drawing definitive conclusions. Treatment directed at the T-cell malignancy resulted in the eradication of the PCD clone in multiple patients (15.4%) including one with multiple myeloma (MM) who experienced a complete response after starting therapy directed at the T-cell malignancy. For patients with T-cell malignancies and concomitant PCD, treatment with standard T-cell-directed therapies is recommended based on this analysis with continued follow-up and monitoring of the concomitant PCD. Further studies are needed to definitively elucidate the increased risk of relapse in patients with PTCL and concomitant PCD, and larger, multi-center cohorts are needed to validate these findings across T-cell malignancies and PCDs.

Extranodal Natural Killer/T-Cell Lymphomas: Current Approaches and Future Directions.

Extranodal natural killer/T(NK/T)-cell lymphoma (ENKTL) is a rare subtype of non-Hodgkin lymphoma that typically presents with an isolated nasal mass, but a sizeable minority present with advanced stage disease and have a significantly poorer prognosis. Those with limited disease are standardly treated with chemotherapy and radiation while those with advanced stage disease are treated with L-asparaginase containing chemotherapy regimens. The addition of modern radiation therapy techniques and the incorporation of L-asparaginase into chemotherapy regimens have significantly improved outcomes in this disease, but relapses and death from relapsed disease remain frequent. Given the high rate of relapse, several novel therapies have been evaluated for the treatment of this disease. In this review, we explore the current standard of care for ENKTL as well as novel therapies that have been evaluated for its treatment and the biologic understanding behind these therapies.