pci-32765 and Leukemic-Infiltration

Central nervous system involvement (CNSi) is a rare and poorly reported complication of chronic lymphocytic leukaemia (CLL). Establishing cause and effect between the CLL and the neurological symptoms remains challenging. We have analysed a retrospective cohort of 30 CLL patients with CNSi, documented by lymphocytic infiltration either by flow cytometry of the cerebrospinal fluid (CSF; n = 29) or CNS biopsy (n = 1). Neurological symptoms were heterogeneous. At the time of CNSi, less than half of the patients had a progressive CLL and 20 had never been treated for CLL. Initial treatment with fludarabine-based immuno-chemotherapy, with or without intra-CSF therapy, led to durable response in eight out of nine untreated patients. In contrast, 50% patients receiving various prior treatments needed additional therapy within a median of 4 months (1-16). Ibrutinib led to complete response in 4/4 heavily pre-treated patients. From CNSi, 5-year overall survival was 72% and 48% for treatment-naïve and previously treated patients respectively (P = 0·06); 5-year progression-free survival (PFS) was 43% and 0% (P = 0·125). 17p deletion was significantly associated with poor PFS (P = 0·006). CNSi may be the only sign of progression of CLL and should be considered an initiation criterion of systemic treatment. Prognosis seemed to be related to CLL characteristics rather than to CNSi itself.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System; Cohort Studies; Disease Management; Disease-Free Survival; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemic Infiltration; Male; Middle Aged; Neoplasm Invasiveness; Piperidines; Prognosis; Pyrazoles; Pyrimidines; Remission Induction; Retrospective Studies; Survival Analysis; Vidarabine

B-cell receptor (BCR) signaling is a critical pathway in the pathogenesis of several B-cell malignancies, including chronic lymphocytic leukemia (CLL), and can be targeted by inhibitors of BCR-associated kinases, such as Bruton tyrosine kinase (Btk). PCI-32765, a selective, irreversible Btk inhibitor, is a novel, molecularly targeted agent for patients with B-cell malignancies, and is particularly active in patients with CLL. In this study, we analyzed the mechanism of action of PCI-32765 in CLL, using in vitro and in vivo models, and performed correlative studies on specimens from patients receiving therapy with PCI-32765. PCI-32765 significantly inhibited CLL cell survival, DNA synthesis, and migration in response to tissue homing chemokines (CXCL12, CXCL13). PCI-32765 also down-regulated secretion of BCR-dependent chemokines (CCL3, CCL4) by the CLL cells, both in vitro and in vivo. In an adoptive transfer TCL1 mouse model of CLL, PCI-32765 affected disease progression. In this model, PCI-32765 caused a transient early lymphocytosis, and profoundly inhibited CLL progression, as assessed by weight, development, and extent of hepatospenomegaly, and survival. Our data demonstrate that PCI-32765 effectively inhibits CLL cell migration and survival, possibly explaining some of the characteristic clinical activity of this new targeted agent.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Antineoplastic Agents; Cell Survival; Cells, Cultured; Chemotaxis, Leukocyte; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemic Infiltration; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, SCID; Mice, Transgenic; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Xenograft Model Antitumor Assays