A multicenter real-world evidence study in the Swiss treatment landscape of chronic myeloid leukemia.

BACKGROUND: The real-world experience of Swiss chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKIs) is largely unknown, in particular with regard to achievement of response per European Leukemia Net (ELN) criteria and adherence to ELN recommendations. METHODS: This was a retrospective, non-interventional, multicenter chart review of patients with newly diagnosed CML who had received first-line TKI and were solely treated with TKIs between 2010 and 2015, with a minimum follow-up of 18 months, at six Swiss hospitals. Effectiveness was evaluated according to ELN 2013 milestone achievements at 3, 6, 12 and 18 months, and at last follow-up. RESULTS: Data from 63 patients (56% men; median age at diagnosis 55 years) were collected (first-line imatinib [n = 27], nilotinib [n = 27], dasatinib [n = 8], or ponatinib [n = 1]). TKI switches (49 times) and dosing changes (165 times) due to intolerance or insufficient response were frequent. Compared with patients receiving first-line imatinib, a higher proportion of patients receiving first-line nilotinib or dasatinib achieved optimal response at all timepoints, irrespective of subsequent TKI therapy, and a higher proportion of patients treated with first-line nilotinib and dasatinib reached deep molecular response (BCR-ABL1IS ≤ 0.01%) at 18 months (42 and 38%, respectively, versus 27%). Patients who received nilotinib or dasatinib switched therapies less frequently than patients treated with imatinib, irrespective of subsequent TKI therapy. CONCLUSIONS: Although patient numbers were small, this real-world evidence study with patients with CML confirms that ELN guidelines are generally implemented in Swiss clinical practice, with a large proportion of patients achieving ELN 2013 milestones. While TKI use involved all inhibitors approved at the time of the study, an unexpectedly high number of TKI therapy switches suggests a clear difference in TKI use between registration trials and clinical practice.

HLA ligandome analysis identifies the underlying specificities of spontaneous antileukemia immune responses in chronic lymphocytic leukemia (CLL).

The breakthrough development of clinically effective immune checkpoint inhibitors illustrates the potential of T-cell-based immunotherapy to effectively treat malignancies. A remaining challenge is to increase and guide the specificities of anticancer immune responses, e.g., by therapeutic vaccination or by adoptive T-cell transfer. By analyzing the landscape of naturally presented HLA class I and II ligands of primary chronic lymphocytic leukemia (CLL), we delineated a novel category of tumor-associated T-cell antigens based on their exclusive and frequent representation in the HLA ligandome of leukemic cells. These antigens were validated across different stages and mutational subtypes of CLL and found to be robustly represented in HLA ligandomes of patients undergoing standard chemo-/immunotherapy. We demonstrate specific immune recognition of these antigens exclusively in CLL patients, with the frequencies of representation in CLL ligandomes correlating with the frequencies of immune recognition by patient T cells. Moreover, retrospective survival analysis revealed survival benefits for patients displaying immune responses to these antigens. These results directly imply these nonmutant self-peptides as pathophysiologically relevant tumor antigens and encourages their implementation for cancer immunotherapy.

The antigenic landscape of multiple myeloma: mass spectrometry (re)defines targets for T-cell-based immunotherapy.

Direct analysis of HLA-presented antigens by mass spectrometry provides a comprehensive view on the antigenic landscape of different tissues/malignancies and enables the identification of novel, pathophysiologically relevant T-cell epitopes. Here, we present a systematic and comparative study of the HLA class I and II presented, nonmutant antigenome of multiple myeloma (MM). Quantification of HLA surface expression revealed elevated HLA molecule counts on malignant plasma cells compared with normal B cells, excluding relevant HLA downregulation in MM. Analyzing the presentation of established myeloma-associated T-cell antigens on the HLA ligandome level, we found a substantial proportion of antigens to be only infrequently presented on primary myelomas or to display suboptimal degrees of myeloma specificity. However, unsupervised analysis of our extensive HLA ligand data set delineated a panel of 58 highly specific myeloma-associated antigens (including multiple myeloma SET domain containing protein) which are characterized by frequent and exclusive presentation on myeloma samples. Functional characterization of these target antigens revealed peptide-specific, preexisting CD8(+) T-cell responses exclusively in myeloma patients, which is indicative of pathophysiological relevance. Furthermore, in vitro priming experiments revealed that peptide-specific T-cell responses can be induced in response-naive myeloma patients. Together, our results serve to guide antigen selection for T-cell-based immunotherapy of MM.