Activity of the PI3K-δ,γ inhibitor duvelisib in a phase 1 trial and preclinical models of T-cell lymphoma.

Duvelisib (IPI-145) is an oral inhibitor of phosphatidylinositol 3-kinase (PI3K)-δ/γ isoforms currently in clinical development. PI3K-δ/γ inhibition may directly inhibit malignant T-cell growth, making duvelisib a promising candidate for patients with peripheral (PTCL) or cutaneous (CTCL) T-cell lymphoma. Inhibition of either isoform may also contribute to clinical responses by modulating nonmalignant immune cells. We investigated these dual effects in a TCL cohort from a phase 1, open-label study of duvelisib in patients with relapsed or refractory PTCL (n = 16) and CTCL (n = 19), along with in vitro and in vivo models of TCL. The overall response rates in patients with PTCL and CTCL were 50.0% and 31.6%, respectively (P = .32). There were 3 complete responses, all among patients with PTCL. Activity was seen across a wide spectrum of subtypes. The most frequently observed grade 3 and 4 adverse events were transaminase increases (40% alanine aminotransferase, 17% aspartate aminotransferase), maculopapular rash (17%), and neutropenia (17%). Responders and nonresponders had markedly different changes in serum cytokine profiles induced by duvelisib. In vitro, duvelisib potently killed 3 of 4 TCL lines with constitutive phospho-AKT (pAKT) vs 0 of 7 lines lacking pAKT (P = .024) and exceeded cell killing by the PI3K-δ-specific inhibitor idelalisib. Administration of duvelisib to mice engrafted with a PTCL patient-derived xenograft resulted in a shift among tumor-associated macrophages from the immunosuppressive M2-like phenotype to the inflammatory M1-like phenotype. In summary, duvelisib demonstrated promising clinical activity and an acceptable safety profile in relapsed/refractory TCL, as well as preclinical evidence of both tumor cell-autonomous and immune-mediated effects. This trial was registered at www.clinicaltrials.gov as #NCT01476657.

Incorporation of extracorporeal photopheresis into a reduced intensity conditioning regimen in myelodysplastic syndrome and aggressive lymphoma: results from ECOG 1402 and 1902.

BACKGROUND: Extracorporeal photopheresis (ECP) is an immunomodulatory cellular therapy which has been shown to induce a tolerogenic state in patients with acute and chronic graft-vs-host disease. ECOG-ACRIN explored the activity of ECP as a part of a reduced intensity conditioning regimen in two multicenter trials in patients with MDS (E1902) and lymphomas (E1402). While both studies closed before completing accrual, we report results in 23 patients (17 MDS and 6 lymphoma). STUDY DESIGN AND METHODS: Patients received 2 days of ECP followed by pentostatin 4 mg/m2 /day for two consecutive days, followed by 600 cGy of total body irradiation prior to stem cell infusion. Immunosuppression for aGVHD was infusional cyclosporine A or tacrolimus and methotrexate on day +1, +3, with mycophenolate mofetil starting on day 100 for chronic GVHD prophylaxis. RESULTS: All patients engrafted, with median time to neutrophil and platelet engraftment of 15-18 days and 10-18 days respectively. Grade 3 or 4 aGVHD occurred in 13% and chronic extensive GVHD in 30%. CONCLUSIONS: These studies demonstrate that ECP/pentostatin/TBI is well tolerated and associated with adequate engraftment of neutrophils and platelets in patients with lymphomas and MDS.

Incidence and outcomes of rare T cell lymphomas from the T Cell Project: hepatosplenic, enteropathy associated and peripheral gamma delta T cell lymphomas.

The T Cell Project was the largest prospective trial to explore the incidence, treatment patterns, and outcomes for T cell lymphomas. The rare subtypes of T cell lymphomas, including hepatosplenic T cell lymphoma (HSTCL), enteropathy associated T cell lymphoma (EATL), and peripheral gamma delta T cell lymphomas (PGDTCLs) are poorly represented in most studies and there is little data regarding treatment patterns. We report results from 115 patients with hepatosplenic (n = 31), enteropathy associated (n = 65), and PGDTCLs (n = 19). While anthracycline regimens were most commonly used as first line therapy, response rates ranged from 20%-40% and were suboptimal for all groups. Autologous stem cell transplantation was performed as a consolidation in first remission in a small number of patients (33% of HSTCL, 7% of EATL, and 12% of PGDTCL), and four patients with HSTCL underwent allogeneic stem cell transplantation in first remission. The progression free survival at 3 years ranged from 28%-40% for these rare subtypes, and the overall survival at 3 years was most favorable for PGDTCL (70%). These data highlight the need for novel treatment approaches for rare subtypes of T cell lymphomas and for their inclusion in clinical trials.

Outcomes for Relapsed and Refractory Peripheral T-Cell Lymphoma Patients after Front-Line Therapy from the COMPLETE Registry.

BACKGROUND: Outcomes for patients with peripheral T-cell lymphoma (PTCL) who fail to achieve complete response (CR) or relapse after front-line therapy are poor with lack of prospective outcomes data. OBJECTIVES: COMPLETE is a prospective registry of 499 patients enrolled at academic and community sites in the United States detailing patient demographics, treatment and outcomes for patients with aggressive T cell lymphomas. We report results for patients with primary refractory and relapsed disease. METHODS: Primary refractory disease was defined as an evaluable best response to initial treatment (induction ± maintenance or consolidation/transplant) other than CR, and included a partial response, progressive disease, or no response/stable disease. Relapsed disease was defined as an evaluable best response to initial treatment of CR, followed by disease progression at a later date, irrespective of time to progression. Patients were included in the analysis if initial treatment began within 30 days of enrollment and treatment duration was ≥4 days. RESULTS: Of 420 evaluable patients, 97 met the definition for primary refractory and 58 with relapsed disease. In the second-line setting, relapsed patients received single-agent therapies more often than refractory patients (52 vs. 28%; p = 0.01) and were more likely to receive single-agent regimens (74 vs. 53%; p = 0.03). The objective response rate to second-line therapy was higher in relapsed patients (61 vs. 40%; p = 0.04) as was the proportion achieving a CR (41 vs. 14%; p = 0.002). Further, relapsed patients had longer overall survival (OS) compared to refractory patients, with a median OS of 29.1 versus 12.3 months. CONCLUSIONS: Despite the availability of newer active single agents, refractory patients were less likely to receive these therapies and continue to have inferior outcomes compared to those with relapsed disease. PTCL in the real world remains an unmet medical need, and improvements in front-line therapies are needed.

The role of autologous stem cell transplantation in patients with nodal peripheral T-cell lymphomas in first complete remission: Report from COMPLETE, a prospective, multicenter cohort study.

BACKGROUND: The role of autologous stem cell transplantation (ASCT) in the first complete remission (CR1) of peripheral T-cell lymphomas (PTCLs) is not well defined. This study analyzed the impact of ASCT on the clinical outcomes of patients with newly diagnosed PTCL in CR1. METHODS: Patients with newly diagnosed, histologically confirmed, aggressive PTCL were prospectively enrolled into the Comprehensive Oncology Measures for Peripheral T-Cell Lymphoma Treatment (COMPLETE) study, and those in CR1 were included in this analysis. RESULTS: Two hundred thirteen patients with PTCL achieved CR1, and 119 patients with nodal PTCL, defined as anaplastic lymphoma kinase-negative anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma (AITL), or PTCL not otherwise specified, were identified. Eighty-three patients did not undergo ASCT, whereas 36 underwent consolidative ASCT in CR1. At the median follow-up of 2.8 years, the median overall survival was not reached for the entire cohort of patients who underwent ASCT, whereas it was 57.6 months for those not receiving ASCT (P = .06). ASCT was associated with superior survival for patients with advanced-stage disease or intermediate-to-high International Prognostic Index scores. ASCT significantly improved overall and progression-free survival for patients with AITL but not for patients with other PTCL subtypes. In a multivariable analysis, ASCT was independently associated with improved survival (hazard ratio, 0.37; 95% confidence interval, 0.15-0.89). CONCLUSIONS: This is the first large prospective cohort study directly comparing the survival outcomes of patients with nodal PTCL in CR1 with or without consolidative ASCT. ASCT may provide a benefit in specific clinical scenarios, but the broader applicability of this strategy should be determined in prospective, randomized trials. These results provide a platform for designing future studies of previously untreated PTCL.

Synergy of BCL2 and histone deacetylase inhibition against leukemic cells from cutaneous T-cell lymphoma patients.

The presence and degree of peripheral blood involvement in patients with cutaneous T-cell lymphoma (CTCL) portend a worse clinical outcome. Available systemic therapies for CTCL may variably decrease tumor burden and improve quality of life, but offer limited effects on survival; thus, novel approaches to the treatment of advanced stages of this non-Hodgkin lymphoma are clearly warranted. Mutational analyses of CTCL patient peripheral blood malignant cell samples suggested the antiapoptotic mediator B-cell lymphoma 2 (BCL2) as a potential therapeutic target. To test this, we developed a screening assay for evaluating the sensitivity of CTCL cells to targeted molecular agents, and compared a novel BCL2 inhibitor, venetoclax, alone and in combination with a histone deacetylase (HDAC) inhibitor, vorinostat or romidepsin. Peripheral blood CTCL malignant cells were isolated from 25 patients and exposed ex vivo to the 3 drugs alone and in combination, and comparisons were made to 4 CTCL cell lines (Hut78, Sez4, HH, MyLa). The majority of CTCL patient samples were sensitive to venetoclax, and BCL2 expression levels were negatively correlated (r = -0.52; P =018) to 50% inhibitory concentration values. Furthermore, this anti-BCL2 effect was markedly potentiated by concurrent HDAC inhibition with 93% of samples treated with venetoclax and vorinostat and 73% of samples treated with venetoclax and romidepsin showing synergistic effects. These data strongly suggest that concurrent BCL2 and HDAC inhibition may offer synergy in the treatment of patients with advanced CTCL. By using combination therapies and correlating response to gene expression in this way, we hope to achieve more effective and personalized treatments for CTCL.

Single agents vs combination chemotherapy in relapsed and refractory peripheral T-cell lymphoma: Results from the comprehensive oncology measures for peripheral T-cell lymphoma treatment (COMPLETE) registry.

Single agents have demonstrated activity in relapsed and refractory (R/R) peripheral T-cell lymphoma (PTCL). Their benefit relative to combination chemotherapy remains undefined. Patients with histologically confirmed PTCL were enrolled in the Comprehensive Oncology Measures for Peripheral T-cell Lymphoma Treatment (COMPLETE) registry. Eligibility criteria included those with R/R disease who had received one prior systemic therapy and were given either a single agent or combination chemotherapy as first retreatment. Treatment results for those with R/R disease who received single agents were compared to those who received combination chemotherapy. The primary endpoint was best response to retreatment. Fifty-seven patients met eligibility criteria. At first retreatment, 46% (26/57) received combination therapy and 54.5% (31/57) received single agents. At median follow up of 2 years, a trend was seen towards increased complete response rate for single agents versus combination therapy (41% vs 19%; P = .02). There was also increased median overall survival (38.9 vs 17.1 months; P = .02) and progression-free survival (11.2 vs 6.7 months; P = .02). More patients receiving single agents received hematopoietic stem-cell transplantation (25.8% vs 7.7%, P = .07). Adverse events of grade 3 or 4 occurred more frequently in those receiving combination therapy, although this was not statistically significant. The data confirm the unmet need for better treatment in R/R PTCL. Despite a small sample, the analysis shows greater response and survival in those treated with single agents as first retreatment in R/R setting, while maintaining the ability to achieve transplantation. Large, randomized trials are needed to identify the best strategy.

Peripheral T cell lymphoma, not otherwise specified (PTCL-NOS). A new prognostic model developed by the International T cell Project Network.

Different models to investigate the prognosis of peripheral T cell lymphoma not otherwise specified (PTCL-NOS) have been developed by means of retrospective analyses. Here we report on a new model designed on data from the prospective T Cell Project. Twelve covariates collected by the T Cell Project were analysed and a new model (T cell score), based on four covariates (serum albumin, performance status, stage and absolute neutrophil count) that maintained their prognostic value in multiple Cox proportional hazards regression analysis was proposed. Among patients registered in the T Cell Project, 311 PTCL-NOS were retained for study. At a median follow-up of 46 months, the median overall survival (OS) and progression-free survival (PFS) was 20 and 10 months, respectively. Three groups were identified at low risk (LR, 48 patients, 15%, score 0), intermediate risk (IR, 189 patients, 61%, score 1-2), and high risk (HiR, 74 patients, 24%, score 3-4), having a 3-year OS of 76% [95% confidence interval 61-88], 43% [35-51], and 11% [4-21], respectively (P < 0·001). Comparing the performance of the T cell score on OS to that of each of the previously developed models, it emerged that the new score had the best discriminant power. The new T cell score, based on clinical variables, identifies a group with very unfavourable outcomes.

The outcome of peripheral T-cell lymphoma patients failing first-line therapy: a report from the prospective, International T-Cell Project.

This analysis explored factors influencing survival of patients with primary refractory and relapsed peripheral T-cell lymphomas enrolled in the prospective International T-cell Project. We analyzed data from 1020 patients with newly diagnosed disease, enrolled between September 2006 and December 2015. Out of 937 patients who received first-line treatment, 436 (47%) were identified as refractory and 197 (21%) as relapsed. Median time from the end of treatment to relapse was 8 months (range 2-73). Overall, 75 patients (8%) were consolidated with bone marrow transplantation, including 12 refractory and 22 relapsed patients. After a median follow up of 38 months (range 1-96 months) from documentation of refractory/relapsed disease, 440 patients had died. The median overall survival (OS) was 5.8 months; 3-year overall survival rates were 21% and 28% for refractory and relapsed patients, respectively (P<0.001). Patients receiving or not salvage bone marrow transplantation had a 3-year survival of 48% and 18%, respectively (P<0.001). In a univariate Cox regression analysis, refractory disease was associated with a higher risk of death (HR=1.43, P=0.001), whereas late relapse (>12 months, HR 0.57, P=0.001) and salvage therapy with transplantation (HR=0.36, P<0.001) were associated with a better OS. No difference was found in OS with respect to histology. This study accurately reflects outcomes for patients treated according to standards of care worldwide. Results confirm that peripheral T-cell lymphomas patients had dismal outcome after relapse or progression. Patients with chemotherapy sensitive disease who relapsed after more than 12 months might benefit from consolidation bone marrow transplantation.

Duvelisib, an oral dual PI3K-δ,γ inhibitor, shows clinical and pharmacodynamic activity in chronic lymphocytic leukemia and small lymphocytic lymphoma in a phase 1 study.

Duvelisib (IPI-145), an oral, dual inhibitor of phosphoinositide-3-kinase (PI3K)-δ and -γ, was evaluated in a Phase 1 study in advanced hematologic malignancies, which included expansion cohorts in relapsed/refractory (RR) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and treatment-naïve (TN) CLL. Per protocol, TN patients were at least 65 years old or had a del(17p)/TP53 mutation. Duvelisib was administered twice daily (BID) in 28-day cycles at doses of 8-75 mg in RR patients (n = 55) and 25 mg in TN patients (n = 18.) Diarrhea was the most common nonhematologic AE (TN 78%, RR 47%); transaminase elevations the most frequent lab-abnormality AE (TN 33.3%, RR 30.9%); and neutropenia the most common ≥grade 3 AE (RR 44%, TN 33%). The overall response rates were 56.4% for RR patients (1.8% CR, 54.5% PR) and 83.3% for TN patients (all PRs); median response duration was 21.0 months in RR patients but was not reached for TN patients. Based upon phase 1 efficacy, pharmacodynamics, and safety, duvelisib 25 mg BID was selected for further investigation in a phase 3 study in RR CLL/SLL.

A prospective cohort study of patients with peripheral T-cell lymphoma in the United States.

BACKGROUND: Long-term survival in patients with aggressive peripheral T-cell lymphoma (PTCL) is generally poor, and there currently is no clear consensus regarding the initial therapy used for these diseases. Herein, the authors analyzed treatment patterns and outcomes in a prospectively collected cohort of patients with a new diagnosis of nodal PTCL in the United States. METHODS: Comprehensive Oncology Measures for Peripheral T-cell Lymphoma Treatment (COMPLETE) is a prospective multicenter cohort study designed to identify the most common prevailing treatment patterns used for patients newly diagnosed with PTCL in the United States. Patients with nodal PTCL and completed records regarding baseline characteristics and initial therapy were included in this analysis. All statistical tests were 2-sided. RESULTS: Of a total of 499 patients enrolled, 256 (51.3%) had nodal PTCL and completed treatment records. As initial therapy, patients received doxorubicin-containing regimens (41.8%), regimens containing doxorubicin plus etoposide (20.9%), other etoposide regimens (15.8%), other single-agent or combination regimens (19.2%), and gemcitabine-containing regimens (2.1%). Survival was found to be statistically significantly longer for patients who received doxorubicin (log-rank P = .03). After controlling for disease histology and International Prognostic Index, results demonstrated a trend toward significance in mortality reduction in patients who received doxorubicin compared with those who did not (hazard ratio, 0.71; 95% confidence interval, 0.48-1.05 [P = .09]). CONCLUSIONS: To the authors' knowledge, there is no clear standard of care in the treatment of patients with PTCL in the United States. Although efforts to improve frontline treatments are necessary, anthracyclines remain an important component of initial therapy for curative intent. Cancer 2017;123:1174-1183. © 2016 American Cancer Society.

Phase 1/2 study of mogamulizumab, a defucosylated anti-CCR4 antibody, in previously treated patients with cutaneous T-cell lymphoma.

This phase 1/2 study evaluated the efficacy of mogamulizumab, a defucosylated, humanized, anti-CC chemokine receptor 4 monoclonal antibody, in 41 pretreated patients with cutaneous T-cell lymphoma. No dose-limiting toxicity was observed and the maximum tolerated dose was not reached in phase 1 after IV infusion of mogamulizumab (0.1, 0.3, and 1.0 mg/kg) once weekly for 4 weeks followed by a 2-week observation. In phase 2, patients were dosed with 1.0 mg/kg mogamulizumab according to the same schedule for the first course followed by infusion every 2 weeks during subsequent courses until disease progression. The most frequent treatment-emergent adverse events were nausea (31.0%), chills (23.8%), headache (21.4%), and infusion-related reaction (21.4%); the majority of events were grade 1/2. There were no significant hematologic effects. Among 38 evaluable patients, the overall response rate was 36.8%: 47.1% in Sézary syndrome (n = 17) and 28.6% in mycosis fungoides (n = 21). Eighteen of 19 (94.7%) patients with ≥B1 blood involvement had a response in blood, including 11 complete responses. Given the safety and efficacy of mogamulizumab, phase 3 investigation of mogamulizumab is warranted in cutaneous T-cell lymphoma patients. This trial was registered at www.clinicaltrials.gov as #NCT00888927.

Resimmune, an anti-CD3ε recombinant immunotoxin, induces durable remissions in patients with cutaneous T-cell lymphoma.

Resimmune is a second-generation recombinant immunotoxin composed of the catalytic and translocation domains of diphtheria toxin fused to two single chain antibody fragments reactive with the extracellular domain of CD3ε. We gave intravenous infusions of Resimmune 2.5 - 11.25 µg/kg over 15 minutes to 30 patients (25 with cutaneous T-cell lymphoma, 3 with peripheral T-cell lymphoma, 1 with T-cell large granular lymphocytic leukemia and 1 with T-cell prolymphocytic leukemia) in an inter-patient dose escalation trial. The most common adverse events were fever, chills, hypotension, edema, hypoalbuminemia, hypophosphatemia, and transaminasemia. Among the 25 patients with cutaneous T-cell lymphoma, there were nine responses for a response rate of 36% (95% CI, 18%-57%) including four complete remissions (16%, 95% CI, 5%-36%). The durations of the complete remissions were 72+, 72+, 60+ and 38+ months. There were five partial remissions lasting 3, 3, 3+, 6+ and 14 months. Of 17 patients with a modified skin weighted assessment tool score <50, 17 patients with stage IB/IIB, and 11 patients with both a score <50 and stage IB/IIB, nine (53%), eight (47%), and eight (73%) had responses, respectively. Further studies of Resimmune in patients with low tumor burden, stage IB-IIB cutaneous T-cell lymphoma are warranted. This trial is registered at clinicaltrials.gov as #NCT00611208.

Phase 2 Trial of the Farnesyltransferase Inhibitor Tipifarnib for Relapsed/Refractory Peripheral T Cell Lymphoma.

A phase 2, international, open-label, non-randomized, single-arm trial was conducted to evaluate the efficacy and safety of tipifarnib, a farnesyltransferase inhibitor, as monotherapy for relapsed/refractory peripheral T-cell lymphoma (PTCL) and to evaluate tumor mutation profile as a biomarker of response. Adults with relapsed/refractory PTCL received tipifarnib 300 mg orally twice daily for 21 days in a 28-day cycle. The primary endpoint was objective response rate (ORR); secondary endpoints included ORR, progression-free survival (PFS), duration of response (DOR), and adverse events (AEs) in specific subtypes. Sixty-five patients with PTCL were enrolled: n=38 angioimmunoblastic T-cell lymphoma (AITL), n=25 PTCL not otherwise specified (PTCL-NOS), and n=2 other T-cell lymphomas. The ORR was 39.7% (95% CI, 28.1-52.5) in all patients and 56.3% (95% CI, 39.3-71.8) for AITL. Median PFS was 3.5 months overall (954% CI, 2.1-4.4), and 3.6 months (95% CI, 1.9-8.3) for AITL. Median DOR was 3.7 months (95% CI, 2.0-15.3), and greatest in AITL patients (7.8 months; 95% CI, 2.0-16.3). The median overall survival was 32.8 months (95% CI, 14.4 to not applicable). Tipifarnib-related hematologic AEs were manageable and included: neutropenia (43.1%), thrombocytopenia (36.9%), and anemia (30.8%); other tipifarnib-related AEs included nausea (29.2%) and diarrhea (27.7%). One treatment-related death occurred. Mutations in RhoA, DNMT3A, and IDH2 were seen in 60%, 33%, and 27%, respectively, in the AITL tipifarnib responder group vs 36%, 9%, and 9% in the non-responder group. Tipifarnib monotherapy demonstrated encouraging clinical activity in heavily pre-treated relapsed/refractory PTCL, especially in AITL, with a manageable safety profile. ClinicalTrials.gov NCT02464228.

Peripheral T-cell lymphoma.

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of clinically aggressive diseases associated with poor outcome. Studies that focus specifically on PTCL are emerging, with the ultimate goal of improved understanding of disease biology and the development of more effective therapies. However, one of the difficulties in classifying and studying treatment options in clinical trials is the rarity of these subtypes. Various groups have developed lymphoma classifications over the years, including the World Health Organization, which updated its classification in 2008. This article briefly reviews the major lymphoma classification schema, highlights contributions made by the collaborative International PTCL Project, discusses prognostic issues and gene expression profiling, and outlines therapeutic approaches to PTCL. These include the standard chemotherapeutic regimens and other modalities incorporating antifolates, conjugates, histone deacetylase inhibitors, monoclonal antibodies, nucleoside analogs, proteasome inhibitors, and signaling inhibitors. As this review emphasizes, the problem has now evolved into an abundance of drugs and too few patients available to test them. Collaborative groups will aid in future efforts to find the best treatment strategies to improve the outcome for patients with PTCL.

Acute toxicity and risk of infection during total skin electron beam therapy for mycosis fungoides.

BACKGROUND: Detailed rates of acute toxicity and skin infection during total skin electron beam therapy (TSEBT) for mycosis fungoides have not been reported in a large, modern series. OBJECTIVE: We sought to demonstrate the rates of acute toxicity and skin infection during TSEBT. METHODS: We retrospectively reviewed 89 consecutive courses of TSEBT. In all, 82 courses were prescribed a dose of 30 to 36 Gy and were included in the toxicity analysis. We recorded the types and grades of acute treatment toxicities and the incidence of infection during TSEBT for comparison with the previously documented baseline incidence of infection in mycosis fungoides. RESULTS: The most common toxicities included erythema/desquamation (76%), blisters (52%), hyperpigmentation (50%), and skin pain (48%). The worst reported toxicity grade per patient was grade 1 in 21%, grade 2 in 67%, and grade 3 in 10%, with no grade 4 or 5 toxicities. According to the previously reported rate, a total of 2.4 infections were expected for our cohort at baseline. The number with skin infection was 26 (32%) (relative risk 10.8, P < .01), and of these, 12 (15%) were culture confirmed (relative risk 5.0, P < .01). LIMITATIONS: This was a retrospective study design. CONCLUSION: The risk of cutaneous infection is significant during TSEBT.

Cost-effectiveness of chimeric antigen receptor T-cell therapy in adults with relapsed or refractory follicular lymphoma.

Follicular lymphoma (FL) is traditionally considered treatable but incurable. In March 2021, the US Food and Drug Administration approved the use of chimeric antigen receptor (CAR) T-cell therapy in patients with relapsed or refractory (R/R) FL after ≥2 lines of therapy. Priced at $373 000, CAR T-cell therapy is potentially curative, and its cost-effectiveness compared with other modern R/R FL treatment strategies is unknown. We developed a Markov model to assess the cost-effectiveness of third-line CAR T-cell vs standard of care (SOC) therapies in adults with R/R FL. We estimated progression rates for patients receiving CAR T-cell and SOC therapies from the ZUMA-5 trial and the LEO CReWE study, respectively. We calculated costs, discounted life years, quality-adjusted life years (QALYs), and the incremental cost-effectiveness ratio (ICER) of CAR T-cell vs SOC therapies with a willingness-to-pay threshold of $150 000 per QALY. Our analysis was conducted from a US payer's perspective over a lifetime horizon. In our base-case model, the cost of the CAR T-cell strategy was $731 682 compared with $458 490 for SOC therapies. However, CAR T-cell therapy was associated with incremental clinical benefit of 1.50 QALYs, resulting in an ICER of $182 127 per QALY. Our model was most sensitive to the utilities associated with CAR T-cell therapy remission and third-line SOC therapies and to the total upfront CAR T-cell therapy cost. Under current pricing, CAR T-cell therapy is unlikely to be cost-effective in unselected patients with FL in the third-line setting. Both randomized clinical trials and longer term clinical follow-up can help clarify the benefits of CAR T-cell therapy and optimal sequencing in patients with FL.

Integrated transcriptome and trajectory analysis of cutaneous T-cell lymphoma identifies putative precancer populations.

The incidence of cutaneous T-cell lymphoma (CTCL) increases with age, and blood involvement portends a worse prognosis. To advance our understanding of the development of CTCL and identify potential therapeutic targets, we performed integrative analyses of paired single-cell RNA and T-cell receptor (TCR) sequencing of peripheral blood CD4+ T cells from patients with CTCL to reveal disease-unifying features. The malignant CD4+ T cells of CTCL showed highly diverse transcriptomic profiles across patients, with most displaying a mature Th2 differentiation and T-cell exhaustion phenotype. TCR-CDR3 peptide prediction analysis suggested limited diversity between CTCL samples, consistent with a role for a common antigenic stimulus. Potential of heat diffusion for affinity-based trajectory embedding transition analysis identified putative precancerous circulating populations characterized by an intermediate stage of gene expression and mutation level between the normal CD4+ T cells and malignant CTCL cells. We further revealed the therapeutic potential of targeting CD82 and JAK that endow the malignant CTCL cells with survival and proliferation advantages.

The SALENTO prognostic model for limited-stage peripheral T-cell lymphoma from the International T-Cell Project Network.

The natural history of limited-stage peripheral T-cell lymphomas (PTCLs) remains poorly defined. We investigated outcomes and prognostic variables in patients registered in the T-Cell Project (TCP) (#NCT01142674) to develop a model to predict overall survival (OS) for the common nodal PTCL subtypes (PTCL-NOS, AITL, ALCL). The model was validated in an independent data set from Australian and Brazilian registries. 211 patients registered in the TCP between 2006-2018 were studied. The median age was 59 years (range 18-88) and median follow-up was 49 months. One hundred twenty-seven patients (78%) received anthracycline-based regimens, 5 patients (3%) radiotherapy alone (RT), 24 patients (15%) chemotherapy+RT. 5-year OS and PFS were 47% and 37%, respectively. Age >60 years, elevated LDH and low serum albumin were independent prognostic factors. The model identified 3 groups with low- (26%, score 0), intermediate- (41%, score 1), and high-risk (33%, score 2-3) with 5-year OS of 78% (95% confidence interval [95% CI], 29-127), 46% (95% CI, 24-68), and 25% (95% CI, 20-30), respectively (P < 0.001) and 5-year PFS of 66% (95% CI, 33-99), 37% (95% CI, 9-65), and 17% (95% CI, 9-25), respectively (P < 0.001). The model demonstrated greater discriminatory power than established prognostic indices and an analogous distribution and outcomes in the 3 groups in the validation cohort of 103 patients. The SALENTO Model (Limited Stage Peripheral T-Cell Lymphoma Prognostic Model) is an objective, simple and robust prognostic tool. The high-risk group has poor outcomes, comparable to advanced stage disease, and should be considered for innovative first-line approaches.

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.