Purpose
Common variable immune deficiency (CVID) confers an increased risk of lymphoid neoplasms, but reports describing the precise WHO specification of the lymphoma subtypes and their immunological ...environment are lacking. We therefore classified lymphomas—occurring in a cohort of 21 adult CVID patients during a 17-year period at our center—according to the 2016 WHO classification and characterized the local and systemic immunological context
Results
The median time between the onset of CVID and lymphoma was 14 years. Patients showed a high prevalence of preceding immune dysregulation: lymphadenopathy (
n
= 13, 62%), splenomegaly (
n
= 18, 86%), autoimmune cytopenia (
n
= 14, 67%), and gastrointestinal involvement (
n
= 15, 71%). The entities comprised extranodal marginal zone lymphoma (
n
= 6), diffuse large B cell lymphoma (
n
= 7), plasmablastic lymphoma (
n
= 1), classic Hodgkin lymphoma (
n
= 4, including three cases with germline
CTLA
4 mutations), T cell large granular lymphocytic leukemia (
n
= 2), and peripheral T cell lymphoma, not otherwise specified (
n
= 1), but no follicular lymphoma. An Epstein-Barr virus association was documented in eight of 16 investigated lymphomas. High expression of PDL1 by tumor cells in five and of PDL1 and PD1 by tumor-infiltrating macrophages and T cells in 12 of 12 investigated lymphomas suggested a tolerogenic immunological tumor environment.
Conclusion
In summary, a diverse combination of specific factors like genetic background, chronic immune activation, viral trigger, and impaired immune surveillance contributes to the observed spectrum of lymphomas in CVID. In the future, targeted therapies, e.g., PD1/PDL1 inhibitors in CVID associated lymphomas with a tolerogenic environment may improve therapy outcome.
Abstract
Background: The pivotal PALOMA trials investigated the combination of the cyclin-dependent kinase 4/6 inhibitor palbociclib with letrozole as first-line treatment or with fulvestrant after ...prior endocrine therapy in patients with advanced HR+/HER2- breast cancer. Based on these trials, extended European approval was granted for this patient population to receive palbociclib in combination with any aromatase inhibitor or with fulvestrant after prior endocrine therapy. Methods: The prospective, multicenter phase 2 INGE-B trial was designed for patients with locally advanced or metastatic HR+/HER2- breast cancer to generate efficacy, safety and quality of life data on the combination of palbociclib with letrozole (first line) or fulvestrant (first and later line after prior endocrine therapy) in accordance with the PALOMA trials and to generate so far lacking trial data on the combination of palbociclib with letrozole (later line) and the combination of palbociclib with anastrozole or exemestane (first line) in Germany. This pre-planned interim analysis was conducted to evaluate data on patients receiving palbociclib plus anastrozole or exemestane as first-line therapy. The primary endpoint was the clinical benefit rate (CBR) in patients with measurable disease according to RECIST v1.1. Key secondary endpoints included the overall response rate (ORR), the CBR for all patients, the disease control rate (DCR), quality of life (QoL) and safety. Data will be analyzed for each group separately with descriptive statistics. Results: At the cut-off date of the interim analysis (June 30, 2019), 66 patients (pts) have been enrolled to receive palbociclib plus anastrozole (palbo+ana) and 64 pts have been enrolled to receive palbociclib plus exemestane (palbo+exe). Thereof, 60 and 58 pts were evaluable, respectively. Median age was 63.5 years (palbo+ana) and 65.0 years (palbo+exe), 100% (n=60) and 94.8% (n=55) of pts had an ECOG performance score of 0 or 1, respectively. 35% (n=21, palbo+ana) and 22.4% (n=13, palbo+exe) of pts presented with non-measurable bone-only disease. The primary endpoint CBR in pts with measurable disease was 73% with palbo+ana (27 of 37 pts) and 70% with palbo+exe (31 of 44 pts).Selected outcome data are depicted in Table 1.
Grade 3/4 adverse events experienced by at least 10% of pts were neutropenia (n=20, 33.3%) and leukopenia (n=9, 15.0%) in pts treated with palbo+ana and neutropenia (n=23, 39.7%), leukopenia and infections (both n=6, 10.3%) in pts treated with palbo+exe. Conclusions: This interim analysis of the INGE-B study will provide so far lacking trial data on the treatment of palbociclib in combination with anastrozole or exemestane. The data will be discussed with respect to results of the PALOMA trials and already published interim analysis results of the INGE-B trial.
Palbociclib + anastrozolePalbociclib + exemestaneMeasurable disease (RECIST v1.1) All pts (investigator assessment)Measurable disease (RECIST v1.1) All pts (investigator assessment)(N=37)(N=60)(N=44)(N=58)n% (95% CI)n% (95% CI)n% (95% CI)n% (95% CI)Overall response rate (ORR)1849 (32-66)2033 (22-47)1841 (26-57)1933 (21-46)Clinical benefit rate (CBR)2773 (56-86)4880 (68-89)3170 (55-83)4171 (57-82)Disease control rate (DCR)3081 (65-92)5388 (77-95)3784 (70-93)4679 (67-89)ORR=CR+PR, CBR=CR+PR+SD ≥ 24 weeks, DCR=CR+PR+SD
Citation Format: Manfred Welslau, Norbert Marschner, Ulrike Söling, Cosima Brucker, Oliver J. Stoetzer, Johannes Meiler, Pauline Wimberger, Steffen Dörfel, Jörg Sahlmann, Leonora Houet, Corinne Vannier, Karin Potthoff. Palbociclib in combination with anastrozole or exemestane as first-line therapy for patients with locally advanced, inoperable or metastatic HR+/HER2- breast cancer in Germany: Interim results of the INGE-B phase 2 study abstract. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-11-14.
Induction of tumor-antigen-specific T cells in active cancer immunotherapy is generally difficult due to the very low anti-tumoral precursor cytotoxic T cells. By improving tumor-antigen uptake and ...presentation by dendritic cells (DCs), this problem can be overcome. Focusing on MAGE-A3 protein, frequently expressed in many types of tumors, we analyzed different DC-uptake routes after additional coating the recombinant MAGE-A3 protein with either a specific monoclonal antibody or an immune complex formulation. Opsonization of the protein with antibody resulted in increased DC-uptake compared to the uncoated rhMAGE-A3 protein. This was partly due to Fcγ receptor-dependent internalization. However, unspecific antigen internalization via macropinocytosis also played a role. When analyzing DC-uptake of MAGE-A3 antigen expressed in multiple myeloma cell line U266, pretreatment with proteasome inhibitor bortezomib resulted in increased apoptosis compared to γ-irradiation. Bortezomib-mediated immunogenic apoptosis, characterized by elevated surface expression of hsp90, triggered higher phagocytosis of U266 cells by DCs involving specific DC-derived receptors. We further investigated the impact of antigen delivery on T-cell priming. Induction of CD8
+
T-cell response was favored by stimulating naïve T cells with either antibody-opsonized MAGE-A3 protein or with the bortezomib-pretreated U266 cells, indicating that receptor-mediated uptake favors cross-presentation of antigens. In contrast, CD4
+
T cells were preferentially induced after stimulation with the uncoated protein or protein in the immune complex, both antigen formulations were preferentially internalized by DCs via macropinocytosis. In summary, receptor-mediated DC-uptake mechanisms favored the induction of CD8
+
T cells, relevant for clinical anti-tumor response.
Owing to its heterogeneity and rarity, management of disseminated marginal zone B‐cell lymphoma (MZL) remains largely understudied. We present prospective data on choice of systemic treatment and ...survival of patients with MZL treated in German routine practice. Of 175 patients with MZL who had been documented in the prospective clinical cohort study Tumour Registry Lymphatic Neoplasms (NCT00889798) collecting data on systemic treatment, 58 were classified as extranodal MZL of mucosa‐associated lymphoid tissue (MALT) and 117 as non‐MALT MZL. We analyzed the most commonly used first‐line and second‐line chemo(immuno)therapies between 2009 and 2016 and examined objective response rate (ORR), progression‐free survival (PFS), overall survival (OS) and prognostic factors for survival. Compared to patients with MALT MZL, those with non‐MALT MZL more often presented with bone marrow involvement (43% vs. 14%), Ann Arbor stage III/IV (72% vs. 57%) and were slightly less often in good general condition (ECOG = 0; 41% vs. 47%). In German routine practice, rituximab‐bendamustine for a median of 6 cycles was the most frequently used first‐line (76%) and second‐line treatment (36%), with no major differences between MZL subtypes. The ORR for patients encompassing any positive response was 81%. For patients with MALT and non‐MALT MZL, respectively, 5‐years PFS was 69% (95% CI 52%–81%) and 66% (95% CI 56%–75%), 5‐years OS 79% (95% CI 65%–89%) and 75% (95% CI 66%–83%). Cox proportional hazards models showed a significantly increased risk of mortality for higher age in all patient groups. Our prospective real world data give valuable insights into the management and outcome of non‐selected patients with MZL requiring systemic treatment and can help optimize therapy recommendations.
Waldenström's macroglobulinaemia (WM) is a rare indolent B‐cell lymphoma for which only little prospective phase III evidence exists. Thus, real world data are important to provide insight into ...treatment and survival. We present here data on choice and outcome of systemic treatment of patients with WM treated in German routine practice. In total, 139 patients with WM who had been documented in the prospective clinical cohort study Tumour Registry Lymphatic Neoplasms (NCT00889798) were included into this analysis. We analysed the most frequently used first‐line and second‐line treatments between 2009 and 2017 and examined best response, progression‐free survival (PFS) and overall survival (OS). Bendamustine plus rituximab, with a median of six cycles, was by far the most frequently used first‐line treatment (81%). Second‐line treatment was more heterogenous and mainly based on bendamustine, cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP), fludarabine or ibrutinib, the latter approved in 2014. Three‐year PFS from start of first‐line treatment was 83% (95% confidence interval CI 74%‐88%), 3‐year OS was 87% (95% CI 80%‐92%). These prospective data give valuable insights into the management and outcome of non‐selected patients with WM treated in German routine practice. In the lack of prospective phase III clinical trials, real world data can help bridging the gap of evidence.
Clinical and genetic heterogeneity renders confirmation or exclusion of autoimmune lymphoproliferative syndrome difficult. To re-evaluate and improve the currently suggested diagnostic approach to ...patients with suspected FAS mutation, the most frequent cause of autoimmune lymphoproliferative syndrome, we prospectively determined 11 biomarkers in 163 patients with splenomegaly or lymphadenopathy and presumed or proven autoimmune cytopenia(s). Among 98 patients sequenced for FAS mutations in CD3(+)TCRα/β(+)CD4(-)CD8(-) "double negative" T cells, 32 had germline and six had somatic FAS mutations. The best a priori predictor of FAS mutations was the combination of vitamin B12 and soluble FAS ligand (cut-offs 1255 pg/mL and 559 pg/mL, respectively), which had a positive predictive value of 92% and a negative predictive value of 97%. We used these data to develop a web-based probability calculator for FAS mutations using the three most discriminatory biomarkers (vitamin B12, soluble FAS ligand, interleukin-10) of the 11 tested. Since more than 60% of patients with lymphoproliferation and autoimmune cytopenia(s) in our cohort did not harbor FAS mutations, 15% had somatic FAS mutations, and the predictive value of double-negative T-cell values was rather low (positive and negative predictive values of 61% and 77%, respectively), we argue that the previously suggested diagnostic algorithm based on determination of double-negative T cells and germline FAS sequencing, followed by biomarker analysis, is not efficient. We propose vitamin B12 and soluble FAS ligand assessment as the initial diagnostic step with subsequent decision on FAS sequencing supported by a probability-calculating tool.
Since myeloma cells express various potential target antigens, active immunotherapy is being investigated as a novel treatment modality for myeloma. Immunization against the clonal myeloma ...immunoglobulin (idiotype) elicits protective immunity in mouse models. Idiotype vaccination of myeloma patients can induce cellular immunity, albeit as yet without firm evidence for improved clinical outcome. Other tumour-associated antigens (including cancer/testis antigens) are expressed with various frequencies in myeloma. T cells with specificity for these antigens may exist in myeloma patients, and immunization trials with some of these antigens are ongoing. Future studies need to identify the best antigen, the optimal vaccine formulation and schedule, and the preferable clinical situation for vaccination with myeloma antigens. In addition, immunization of stem cell donors with myeloma antigens may improve the efficacy and outcome of allogeneic stem cell transplantation through transfer of idiotype-directed immunity to the patient, and has already shown promising clinical results.
The therapeutic value of donor lymphocyte infusions in patients who relapse with acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (HSCT) is limited by a low ...efficacy and the risk of graft-versus-host disease. We aimed at generating leukemia-reactive donor T cells for patients with AML.
Peripheral blood mononuclear cells of the donor were stimulated with mature donor dendritic cells, pulsed with irradiated patient leukemic blasts (LB), or directly with cytokine-treated LB. After 3 weekly stimulations, donor cells were tested for anti-leukemic reactivity in an IFNgamma Elispot.
In 5 of 6 donors, cells with reactivity against patient LB with low or absent reactivity against non-leukemic cells could be generated. T cell subset analyses in 2 donors indicated that specific anti-leukemic reactivity was mainly mediated by CD4+ T cells, which were also the predominant cell fraction in 4 of 6 donors. One leukemia-reactive donor T cell line was expanded with a recently developed system. One week of expansion resulted in a 10-fold increase in reactivity with sustained specificity of the resulting T cell line.
Our results show the feasibility of the in vitro generation of leukemia-reactive donor lymphocytes, rendering this method a promising tool for post-HSCT immunotherapy.
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