piperidines and Leukemia--Hairy-Cell

Hairy cell leukemia variant (HCLv) is a provisional disease in the 2016 WHO classification of lymphomas, characterized by unfavorable prognosis and early relapse following conventional purine analog-based regimens. In this study, we report 2 patients with relapsed HCLv treated with ibrutinib. The first patient achieved a partial response following ibrutinib treatment and received the drug for 16 months, without severe adverse events. However, at disease progression venetoclax was not clinically active. The second patient discontinued the drug early due to intolerance. Ibrutinib was active in our patients with HCLv and deserve further investigations.

Topics: Adenine; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Biopsy; Female; Humans; Immunohistochemistry; Immunophenotyping; Leukemia, Hairy Cell; Middle Aged; Piperidines; Protein Kinase Inhibitors; Retreatment; Tomography, X-Ray Computed; Treatment Outcome

Hairy cell leukemia (HCL) cells engage in complex cellular and molecular interactions with accessory cells, matrix proteins, and various cytokines in the bone marrow and spleen, collectively referred to as the tissue microenvironment. Chemokine receptors and adhesion molecules are critical players for homing and retention within these microenvironments. Engagement of B cell antigen receptors and CD40 on HCL cells promote survival and proliferation. In this chapter, we summarize the current knowledge about the cellular and molecular interactions between HCL cells and their supportive tissue microenvironment, and provide insight into new therapeutic approaches targeting B cell receptor signaling in HCL.

Topics: Adenine; Antineoplastic Agents; B-Lymphocytes; Bone Marrow; CD40 Antigens; Gene Expression Regulation, Leukemic; Humans; Intercellular Adhesion Molecule-1; Leukemia, Hairy Cell; Piperidines; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Receptors, Antigen, B-Cell; Receptors, CXCR4; Signal Transduction; Spleen; Tumor Microenvironment; Vascular Cell Adhesion Molecule-1

Hairy cell leukemia (HCL) is a rare B-cell malignancy, and there is a need for novel treatments for patients who do not benefit from purine analogs. Ibrutinib, an oral agent targeting Bruton tyrosine kinase in the B-cell receptor signaling pathway, is highly effective in several malignancies. Its activity in HCL was unknown, so we conducted a multisite phase 2 study of oral ibrutinib in patients with either relapsed classic or variant hairy cell leukemia. The primary outcome measure was the overall response rate (ORR) at 32 weeks, and we also assessed response at 48 weeks and best response during treatment. Key secondary objectives were characterization of toxicity and determination of progression-free survival (PFS) and overall survival (OS). Thirty-seven patients were enrolled at 2 different doses (24 at 420 mg, 13 at 840 mg). The median duration of follow-up was 3.5 years (range, 0-5.9 years). The ORR at 32 weeks was 24%, which increased to 36% at 48 weeks. The best ORR was 54%. The estimated 36-month PFS was 73% and OS was 85%. The most frequent adverse events were diarrhea (59%), fatigue (54%), myalgia (54%), and nausea (51%). Hematologic adverse events were common: anemia (43%), thrombocytopenia (41%), and neutropenia (35%). Ibrutinib can be safely administered to patients with HCL with objective responses and results in prolonged disease control. Although the initial primary outcome objective of the study was not met, the observation of objective responses in heavily pretreated patients coupled with a favorable PFS suggests that ibrutinib may be beneficial in these patients. This trial was registered at www.clinicaltrials.gov as #NCT01841723.

Topics: Adenine; Administration, Oral; Adult; Aged; Disease-Free Survival; Female; Follow-Up Studies; Humans; Leukemia, Hairy Cell; Male; Middle Aged; Piperidines; Survival Rate

Topics: Humans; Leukemia, Hairy Cell; Piperidines; Pyrazoles; Pyrimidines

Topics: Aged; Antineoplastic Agents; Azetidines; Drug Resistance, Neoplasm; Humans; Leukemia, Hairy Cell; Male; MAP Kinase Kinase 1; Piperidines; Prognosis; Salvage Therapy; Vemurafenib

Topics: Adenine; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Hairy Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Pyrazoles; Pyrimidines; Sulfonamides

Topics: Adenine; Aged; Aged, 80 and over; Antineoplastic Agents; Bendamustine Hydrochloride; Female; Humans; Leukemia, Hairy Cell; Male; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Rituximab

Topics: Adenine; Aged; Biopsy; Comorbidity; Drug Resistance, Neoplasm; Humans; Leukemia, Hairy Cell; Male; Neoplasm Staging; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Recurrence; Remission Induction; Retreatment; Treatment Outcome

B cell receptor (BCR) signalling plays a critical role in the progression of several B-cell malignancies, but its role in hairy cell leukaemia (HCL) is ambiguous. Bruton tyrosine kinase (BTK), a key player in BCR signalling, as well as B cell migration and adhesion, can be targeted with ibrutinib, a selective, irreversible BTK inhibitor. We analysed BTK expression and function in HCL and analysed the effects of ibrutinib on HCL cells. We demonstrated uniform BTK protein expression in HCL cells. Ibrutinib significantly inhibited HCL proliferation and cell cycle progression. Accordingly, ibrutinib also reduced HCL cell survival after BCR triggering with anti-immunoglobulins and abrogated the activation of kinases downstream of the BCR (PI3K and MAPK). Ibrutinib also inhibited BCR-dependent secretion of the chemokines CCL3 and CCL4 by HCL cells. Interestingly, ibrutinib inhibited also CXCL12-induced signalling, a key pathway for bone marrow homing. Collectively, our data support the clinical development of ibrutinib in patients with HCL.

Topics: Adenine; Adult; Agammaglobulinaemia Tyrosine Kinase; Aged; Antineoplastic Agents; Cell Proliferation; Cell Survival; Chemokine CCL3; Chemokine CCL4; Chemokine CXCL12; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Female; Humans; Leukemia, Hairy Cell; Male; Middle Aged; Mutation; Neoplasm Proteins; Phosphorylation; Piperidines; Protein-Tyrosine Kinases; Proto-Oncogene Proteins B-raf; Pyrazoles; Pyrimidines; Receptors, Antigen, B-Cell; Signal Transduction; Tumor Cells, Cultured

Topics: Aged; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents; Drug Resistance, Neoplasm; Flavonoids; Humans; Hyperkalemia; Interferons; Leukemia, Hairy Cell; Male; Pentostatin; Piperidines; Protein Kinase Inhibitors; Remission Induction; Rituximab; Splenectomy