Showing papers by "Julie M. Vose published in 2023"

Brexucabtagene Autoleucel for Relapsed or Refractory Mantle Cell Lymphoma in Standard-of-Care Practice: Results From the US Lymphoma CAR T Consortium

Abstract: PURPOSE Brexucabtagene autoleucel (brexu-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory mantle cell lymphoma (MCL). This therapy was approved on the basis of the single-arm phase II ZUMA-2 trial, which showed best overall and complete response rates of 91% and 68%, respectively. We report clinical outcomes with brexu-cel in the standard-of-care setting for the approved indication. PATIENTS AND METHODS Patients who underwent leukapheresis between August 1, 2020 and December 31, 2021, at 16 US institutions, with an intent to manufacture commercial brexu-cel for relapsed/refractory MCL, were included. Patient data were collected for analyses of responses, outcomes, and toxicities as per standard guidelines. RESULTS Of 189 patients who underwent leukapheresis, 168 (89%) received brexu-cel infusion. Of leukapheresed patients, 79% would not have met ZUMA-2 eligibility criteria. Best overall and complete response rates were 90% and 82%, respectively. At a median follow-up of 14.3 months after infusion, the estimates for 6- and 12-month progression-free survival (PFS) were 69% (95% CI, 61 to 75) and 59% (95% CI, 51 to 66), respectively. The nonrelapse mortality was 9.1% at 1 year, primarily because of infections. Grade 3 or higher cytokine release syndrome and neurotoxicity occurred in 8% and 32%, respectively. In univariable analysis, high-risk simplified MCL international prognostic index, high Ki-67, TP53 aberration, complex karyotype, and blastoid/pleomorphic variant were associated with shorter PFS after brexu-cel infusion. Patients with recent bendamustine exposure (within 24 months before leukapheresis) had shorter PFS and overall survival after leukapheresis in intention-to-treat univariable analysis. CONCLUSION In the standard-of-care setting, the efficacy and toxicity of brexu-cel were consistent with those reported in the ZUMA-2 trial. Tumor-intrinsic features of MCL, and possibly recent bendamustine exposure, may be associated with inferior efficacy outcomes.

ASCO Policy Statement on Biosimilar and Interchangeable Products in Oncology

Abstract: As the voice of cancer care clinicians and the patients they serve, ASCO has taken steps to elevate awareness about biosimilar products and their use in oncology. In 2018, ASCO released its Statement on Biosimilars in Oncology which was subsequently published in the Journal of Clinical Oncology to serve as an educational tool which highlighted and provided guidance on several topical areas surrounding biosimilars. At the time of its publication, the US Food and Drug Administration (FDA) had approved eight biosimilar products for use in the United States, including one product for use as a supportive care agent in the cancer setting and two products for use in the treatment for cancer. This number has risen dramatically (40 approvals), with a total of 22 cancer or cancer-related biosimilar products approved since 2015. Recently, the FDA also approved the four interchangeable biosimilar products for diabetes, certain inflammatory diseases, and certain ophthalmic diseases. Given the current market dynamics and the regulatory landscape, this ASCO manuscript now seeks to propose several policy recommendations across the scope of value, interchangeability, clinician barriers, and patient education and access. This policy statement is intended to guide ASCO's future activities and strategies and serves to affirm our commitment to providing education to the oncology community on the use of biosimilars in the cancer setting.

Final results of a phase II study of CHOEP plus lenalidomide as initial therapy for patients with stage II-IV peripheral T-cell lymphoma.

Abstract: There remains no one standard induction for nodal-based peripheral T-cell lymphoma (PTCL). We conducted a phase II study of lenalidomide plus CHOEP as a novel induction strategy. Patients received CHOEP at standard doses in combination with 10 mg of lenalidomide on days 1-10 of a 21-day cycle for six cycles of therapy followed by observation, high-dose therapy with autologous stem cell rescue, or maintenance lenalidomide per provider preference. Among 39 patients evaluable for efficacy, the objective response rate after six cycles was 69%, with complete response in 49%, partial response in 21%, stable disease in 0% and progressive disease in 13%. Thirty-two patients (82%) completed full induction, and seven patients (18%) discontinued for toxicity, primarily hematologic. Any grade hematologic toxicity occurred in over 50% of patients, with grade 3 or 4 febrile neutropenia occurring in 35% of patients despite mandated growth factors. With a median followup of surviving patients of 21.3 months, the estimated 2-year progression-free and overall survival were 55% (95% CI 37%-70%) and 78% (95% CI 59%-89%), respectively. In sum, six cycles of lenalidomide plus CHOEP resulted in a modest response rate primarily due to hematologic toxicity, which prevented all patients from completing planned induction.

Abstract 6396: BET inhibition alleviates T-cell dysfunction in chronic lymphocytic leukemia

Abstract: Background: The chronic lymphocytic leukemia (CLL) tumor microenvironment (TME) is laden with hyporesponsive T-cells that permit disease persistence. Yet, redundant TME immunosuppressive mechanisms and epigenetic maintenance of T-cell exhaustion limit the efficacy of T-cell targeted therapies in CLL. Bromodomain and extra-terminal (BET) proteins regulate key pathways contributing to CLL pathogenesis and TME interactions, including T-cell function and differentiation. We hypothesize that blocking BET protein function can reverse T-cell exhaustion to yield durable tumor elimination in CLL. Methods: WT C57BL/6 mice were engrafted with Eμ-TCL1 spleen-derived lymphocytes, then treated daily with the novel pan-BET inhibitor, OPN-51107 (OPN5; 20mg/kg PO) for up to 4 weeks. Splenic gene expression was evaluated with the NanoString PanCancer iO360 panel. T-cell differentiation status, immune inhibitory receptor (IR) expression, proliferation (72 h ex vivo α-CD3/α-CD28 stimulation), and cytokine production (6 h ex vivo PMA/ionomycin stimulation) was measured via flow cytometry. CLL patient and healthy donor PBMCs were used for validation studies and to assess T-cell transcription factor (TF) expression via flow cytometry. Evaluation of BRD4 occupancy at select T-cell TFs via ChIP qPCR is ongoing. Results: OPN5 significantly increased cytotoxic cell signatures and reduced exhaustion-associated cell signatures in leukemic mice through inhibition of T-cell exhaustion signaling, as well as activation of Th1, natural killer cell, and IL-7 signaling pathways. Correspondingly, T-cells from OPN5-treated mice demonstrated greater ex vivo proliferative capacity and effector response to stimuli. A greater proportion of CD8+ T-cells from OPN5-treated mice were classified as naïve, and OPN5 significantly reduced KLRG1 expression on antigen-experienced CD8+ T-cells. Importantly, OPN5 curtailed IR co-expression (PD-1, PD-L1, VISTA, CD244, CD160, and LAG3) on splenic T-cells. These findings were confirmed with primary CLL cells ex vivo. OPN5 also impaired expression of terminal differentiation-associated TFs in CLL patient-derived T-cells, enriching for a TCF1+ progenitor T-cell population. While BTK inhibitors are known to similarly improve T-cell function in CLL, ibrutinib treatment was inadequate to revert CLL T-cell terminal differentiation. Future ATAC-sequencing analysis will inform how BET inhibition alleviates exhaustion-associated chromatin organization in CLL T-cells. Conclusion: BET inhibition dismantles immunosuppressive mechanisms in the CLL TME, alleviating CLL-induced T-cell dysfunction and terminal differentiation. These findings suggest that BET inhibition may be a useful component of combination strategies for the treatment of CLL to yield lasting anti-cancer immune memory and prevent relapsed/refractory disease. Citation Format: Audrey L. Smith, Alexandria P. Eiken, Sydney A. Skupa, Christopher R. D'Angelo, Avyakta Kallam, Matthew A. Lunning, Gregory Bociek, Julie M. Vose, Ben Powell, Gideon Bollag, Dalia El-Gamal. BET inhibition alleviates T-cell dysfunction in chronic lymphocytic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6396.

Lenalidomide maintenance following high‐dose therapy and autologous haematopoietic stem cell transplantation in chemo‐resistant or high‐risk non‐Hodgkin lymphoma: A phase I/II study

Abstract: Improved maintenance treatments are needed for patients with relapsed/refractory aggressive lymphomas after autologous haematopoietic stem cell transplantation (ASCT). Several studies with lenalidomide have been found to have activity in the treatment of relapsed/refractory aggressive lymphomas. In the present phase I/II, single‐arm, open‐label study, 59 patients with high‐risk relapsed non‐Hodgkin lymphoma received pretransplant BEAM chemotherapy and ASCT followed by 12 months of maintenance lenalidomide once daily on Days 1–21 (28‐day cycles) beginning at post‐transplantation Day 100. The most common histologies were mantle cell lymphoma (56%) and diffuse large B‐cell lymphoma (24%). The maximum tolerated dose in the dose‐finding part of the study was 15 mg, but cytopenias led to the subsequent adoption of a 10 mg dose in the final study. Sixteen patients (27%) completed 12 cycles of lenalidomide maintenance. The most common reason for discontinuation was adverse events (31%). These were primarily haematologic, and 56% of patients experienced Grade 3–4 events. Two‐year PFS rates (95% CIs) were 70% (56%–80%), 45% (19%–68%) and 81% (66%–90%); 2‐year OS rates (95% CIs) were 91% (80%–96%), 93% (61%–99%) and 90% (76%–96%) in all patients, patients completing and patients not completing 12‐month maintenance respectively. These results do not support the use of lenalidomide maintenance in this setting.

Mature T and NK cell lymphomas classified according to 2016 WHO classification. A report of 741 cases registered in the International Prospective T‐cell Project 2.0.

Abstract: Introduction: Mature T and NK-cell lymphomas represent a heterogeneous group of rare lymphoid disorders arising from mature T cells of post-thymic origin. The T-cell Project 2.0 (TCP2) was launched in 2018 with the aim of better understanding this group of rare disorders, capturing a real-life snapshot of the evolving landscape of T-cell lymphoma biology, treatment strategies, and outcome. Here we report preliminary data on histotype distribution, disease characteristics, front line treatment, and short-term outcome of patients registered between 2018 and 2021. Methods: The TCP2 (ClinicalTrials.gov Identifier: NCT03964480) is a prospective, longitudinal, international, observational study of patients with Peripheral T-cell lymphoma (PTCL). For this analysis we considered cases based on the diagnosis made locally according to the WHO2016 classification. The study was approved by each participating center and required patients to sign informed consent. Results: Between October 2018 and December 2021, 741 eligible cases with newly diagnosed PTCLs were registered by 94 Institutions across 17 Countries. Overall, PTCL-NOS, AITL, ALCL ALK-, ALCL ALK+, ENKTCL, and ATLL resulted the most frequent 6 subtypes, accounting for 91% of cases, while the remaining 9% were represented by few cases of 13 different subtypes. Of note, only 16 cases (2.1%) were classified according to entities not considered in the previous WHO 2008 classification. The median age at diagnosis was 57 years (18–93), 56.5% of patients were male, the presence of systemic symptoms was reported in 30% of cases, 7.4% had ECOG-PS 3–4, 71% advanced disease and 36.6% bone marrow involvement. Overall, 88% were treated with combination chemotherapy and 28% of patients with advanced stage disease in complete or partial remission after chemotherapy were consolidated with high dose therapy and stem cell transplantation. After a median follow-up of 21 months, the 2-year PFS and OS of the whole series were 38% and 52%, respectively. At the same time point, the PFS and OS (in brackets) were: PTCL-NOS (24% and 43%); AITL (40% and 50%); ENKTL (44% and 53%); ALCL ALK- (52% and 67%); ALCL ALK+ (71% and 85%) and ATLL (14% and 27%). Comparing the distribution of cases enrolled in the present study with those in the previous TCP1 (2008–2018), we found a 6% and 3% decrease in the frequency of PTCL-NOS and EATL, respectively, whilst the frequency of other histotypes remained almost unchanged. Of note, no statistically significant differences emerged in terms of PFS and OS for the comparable histotypes of TCP1 and TCP2. Conclusions: Based on the analysis of this large series of cases of PTCL prospectively registered in the TCP2, it seems “Nothing new under the sun”: no improvement in terms of outcome and a very limited effect of the WHO2016 in classification of cases in the real world. The research was funded by: Angela Serra Association for Cancer Research Keywords: Aggressive T-cell non-Hodgkin lymphoma, Pathology and Classification of Lymphomas No conflicts of interests pertinent to the abstract.

Hematological Oncology journal women in lymphoma special issue: Latest updates in nodal peripheral T-cell lymphoma.

Abstract: In the last decade, there has been increased understanding of the pathologic features and biology of peripheral T cell lymphomas (PTCLs) through development of multi omics and molecular profiling techniques. In addition, international collaborations through multi center trials as well as prospective registry studies have improved our knowledge of host and tumor genomic factors and treatment factors affecting disease outcomes. In our review today, we aim to highlight the current epidemiology, latest advances in classification, disease biology and the evolving treatment landscape for nodal PTCLs.

Long term outcome of Peripheral T Cell Lymphomas: 10y follow‐up analysis of the International Prospective T Cell Project Network

Abstract: Introduction: Peripheral T cell lymphomas (PTCLs) are a rare, heterogeneous group of hematological malignancies with too often poor prognosis for almost all subtypes. The T-Cell Project (TCP; registered at clinicaltrials.gov identifier: 01142674) was a prospective cohort study aimed at better understanding clinical characteristics and outcome of patients with PTCL. Here we report the results of 10-year follow up, focused on late relapses and long term survival. Methods: The TCP started in September 2006 as a prospective registry of patients with mature PTCLs. Between December 2006 and March 2018, 1669 patients were registered and 1,553 patients were eligible in the study. Recently, a survey was launched asking for the willingness of the centers to provide long term follow up data. So far, out of 1,553 eligible patients, 713 were referred by Centers that provided information on long-term follow-up and have been included in the present analysis; 840 cases, referred by centers that did not participate to this long term survival analysis were excluded. However, both groups showed similar baseline characteristics and 5y OS (44% vs. 44%) and PFS (37% vs. 35%), thus minimizing selection biases Result: Out of these 713 patients, 255 patients (36%) had a diagnosis of PTCL NOS, 133 (19%) of AITL, 124 (17%) of ALCL ALK-, 62 (8%) of ACL ALK- and 13 (2%) of NKTCL. The median age at diagnosis was 56 years (range, 18–88 years), with a slight male predominance (55%). B symptoms were present in 44% and extranodal involvement in 56% of patients. Patients receiving chemotherapy alone and radiotherapy alone comprises 58% and 3% respectively; while the 18% received CHT+RT. Of evaluable patients, 60% received anthracycline-based chemotherapy, 24% anthracycline/etoposide and 12% etoposide alone. A minority (16%) of the total cohort underwent high-dose chemotherapy with autologous stem cell support as first-line consolidation. After a median follow-up of 82 months, 35 (12%) of patients had an event of progression or death beyond 5 years. The 5- and 10-year rates of both overall survival and progression-free have decreased from 44% and 40%, to 31% and 27%, respectively (Figure 1). For those patients alive at 5 years, the chance of surviving the subsequent 5 years was 83% (95% CI: 61–99). Furthermore, for patients progression free at 5 years the probability of being disease alive and free in the subsequent 5 years was 78% (95% CI: 60–96). Ten year OS and PFS rates for patients alive at 5 years were: 77% and 73% for PTCL NOS, 85% and 76% for AITL, 88% and 87% for ALCL ALK-, 100% and 100% for ALCL ALK+), and 78% and 80% (for NKTCL). Keyword: aggressive T-cell non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.