idelalisib and Leukemia--Prolymphocytic--T-Cell

Using next-generation sequencing (NGS), we recently documented T-cell oligoclonality in treatment-naïve chronic lymphocytic leukemia (CLL), with evidence indicating T-cell selection by restricted antigens.. Here, we sought to comprehensively assess T-cell repertoire changes during treatment in relation to (i) treatment type [fludarabine-cyclophosphamide-rituximab (FCR) versus ibrutinib (IB) versus rituximab-idelalisib (R-ID)], and (ii) clinical response, by combining NGS immunoprofiling, flow cytometry, and functional bioassays.. T-cell clonality significantly increased at (i) 3 months in the FCR and R-ID treatment groups, and (ii) over deepening clinical response in the R-ID group, with a similar trend detected in the IB group. Notably, in constrast to FCR that induced T-cell repertoire reconstitution, B-cell receptor signaling inhibitors (BcRi) preserved pretreatment clones. Extensive comparisons both within CLL as well as against T-cell receptor sequence databases showed little similarity with other entities, but instead revealed major clonotypes shared exclusively by patients with CLL, alluding to selection by conserved CLL-associated antigens. We then evaluated the functional effect of treatments on T cells and found that (i) R-ID upregulated the expression of activation markers in effector memory T cells, and (ii) both BcRi improved antitumor T-cell immune synapse formation, in marked contrast to FCR.. Taken together, our NGS immunoprofiling data suggest that BcRi retain T-cell clones that may have developed against CLL-associated antigens. Phenotypic and immune synapse bioassays support a concurrent restoration of functionality, mostly evident for R-ID, arguably contributing to clinical response.

Topics: Adenine; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Clonal Evolution; Cohort Studies; Cyclophosphamide; Disease-Free Survival; Female; Humans; Immunological Synapses; Immunophenotyping; Leukemia, Prolymphocytic, T-Cell; Male; Middle Aged; Piperidines; Purines; Quinazolinones; Rituximab; T-Lymphocytes; Vidarabine

B-cell (B-PLL) and T-cell (T-PLL) prolymphocytic leukemias are rare, poor-prognosis lymphoid neoplasms with similar presentation characterized by symptomatic splenomegaly and lymphocytosis. They can be distinguished from each other and from other T- and B-cell leukemias by careful evaluation of morphology, immunophenotyping, and molecular genetics. The clinical behavior is typically aggressive, although a subset of patients may have an indolent phase of variable length. First-line therapy for T-PLL is with intravenous alemtuzumab and for B-PLL is with combination purine analog-based chemo-immunotherapy. New B-cell receptor inhibitors, such as ibrutinib and idelalisib, may have a role in the management of B-PLL, especially for the patients harboring abnormalities of TP53. Allogenic stem cell transplantation should still be considered for eligible patients and may be the only current therapy capable of delivering a cure. In the past few years, many of the molecular mechanisms underlying disease pathogenesis and progression have been revealed and are likely to lead to the development of novel targeted approaches.

Topics: Adenine; Alemtuzumab; Antibodies, Monoclonal, Humanized; B-Lymphocytes; Disease Progression; Humans; Immunophenotyping; Immunotherapy; Leukemia, Prolymphocytic; Leukemia, Prolymphocytic, T-Cell; Mutation; Piperidines; Prognosis; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Recurrence; Stem Cell Transplantation; T-Lymphocytes; Treatment Outcome; Tumor Suppressor Protein p53