pci-32765 and Lymphocytosis

Ibrutinib is a new first-line drug for treating chronic lymphocytic leukemia (CLL), and could change frontline treatment of CLL from traditional IV chemotherapy to oral targeted therapy. Lymphocytosis often worsens with initiation of ibrutinib, but typically resolves over 6 to 18 months. Though patients generally tolerate ibrutinib well, the drug can cause adverse reactions including hypertension, atrial fibrillation, bleeding, and infections such as fungal pneumonia.

Topics: Adenine; Administration, Oral; Antineoplastic Agents; Atrial Fibrillation; Hemorrhage; Humans; Hypertension; Leukemia, Lymphocytic, Chronic, B-Cell; Lung Diseases, Fungal; Lymphocytosis; Piperidines; Warfarin

Mantle cell lymphoma (MCL) is a heterogeneous and uncommon non-Hodgkin lymphoma that affects predominantly older patients and often is associated with an aggressive clinical course. MCL relies upon B-cell receptor signaling through Bruton tyrosine kinase (BTK); therefore, the development of the BTK inhibitors ibrutinib and acalabrutinib represents a therapeutic breakthrough. In this review, we provide a summary of the efficacy and safety data from the landmark trials of single-agent ibrutinib and acalabrutinib that led to US Food and Drug Administration approval of these agents for patients with relapsed or refractory MCL. Toxicities of interest observed with ibrutinib include bleeding, atrial fibrillation, and increased risk for infection. The selectivity of acalabrutinib for BTK is greater than that of ibrutinib, which mitigates the risk for certain off-target toxicities, including atrial fibrillation; however, these toxicities, along with frequent headaches, still occur. Ongoing clinical trials are investigating both alternate BTK inhibitors and BTK inhibitors in combination with chemo-immunotherapy or other targeted agents in an effort to enhance the depth and duration of response. Trials to evaluate the use of these agents in the frontline setting are emerging and are likely to build upon the success of BTK inhibitors in patients with MCL.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antigens, CD20; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Cardiovascular Diseases; Clinical Trials as Topic; Forecasting; Gastrointestinal Neoplasms; Hemorrhage; Humans; Immunologic Factors; Lymphocytosis; Lymphoma, Mantle-Cell; Molecular Targeted Therapy; Neoplasm Proteins; Opportunistic Infections; Piperidines; Protein Kinase Inhibitors; Pyrazines; Pyrazoles; Pyrimidines; Salvage Therapy

Ibrutinib is indicated in Europe for the treatment of several B-cell malignancies, including chronic lymphocytic leukaemia (CLL). However, despite the high efficacy and favourable toxicity profile of ibrutinib, recent data suggest that it is not always administered optimally in clinical practice, with an increased tendency for dose reduction and a higher frequency of discontinuation. An expert panel of European haematologists was convened to identify practical issues pertinent to physicians involved in the therapeutic management of ibrutinib-treated CLL patients and here we outline the findings. Practical management recommendations are given for treating patients with ibrutinib and clinical considerations for the management of adverse events (AEs) that can be associated with ibrutinib treatment are addressed. This article highlights that patients should be monitored for treatment emergent adverse events, most of which are mild, transient and generally occur early in therapy and that, even with more challenging AEs, patients can often be maintained on therapy with minimal disruption through careful management. The necessity to use the correct ibrutinib dose, along with increased awareness, vigilance, mitigation and management of AEs, are all recommended to maximise outcomes for CLL patients treated with ibrutinib.

Topics: Adenine; Anticoagulants; Antineoplastic Agents; Arthralgia; Atrial Fibrillation; Diabetes Mellitus, Type 1; Diarrhea; Drug Eruptions; Drug Interactions; Exanthema; Fatigue; Hemorrhage; Humans; Hypertension; Infections; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocytosis; Medication Adherence; Myalgia; Piperidines; Platelet Aggregation Inhibitors; Pyrazoles; Pyrimidines; Treatment Outcome

Inhibitors of the B cell receptor (BCR) represent an attractive therapeutic option for patients with chronic lymphocytic leukemia. Recently approved inhibitors of Bruton's tyrosine kinase (ibrutinib) and phosphatidylinositol 3-kinase (idelalisib), are promising agents because they are generally well tolerated and highly effective. These agents may be particularly important in the treatment of older patients who are less able to tolerate the myelosuppression (and infections) associated with chemoimmunotherapy. As a class of medications, BCR inhibitors have some unique side effects including redistribution lymphocytosis. Ibrutinib has specific toxicities including increased risk for bleeding and atrial fibrillation. Idelalisib also has some unique toxicities consisting of transaminitis, diarrhea and pneumonitis. Ongoing clinical trials are evaluating these agents in combination with antibodies, chemotherapy and other small molecules.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Age Factors; Atrial Fibrillation; Diarrhea; Hemorrhage; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocytosis; Neoplasm Proteins; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Piperidines; Pneumonia; Protein-Tyrosine Kinases; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Receptors, Antigen, B-Cell

Increased absolute lymphocyte count (ALC) is a key feature of chronic lymphocytic leukemia (CLL) but is also observed during treatment with B-cell receptor pathway inhibitors including ibrutinib, a first-in-class inhibitor of Bruton's tyrosine kinase. In patients with CLL treated with single-agent ibrutinib in two multicenter, open-label, randomized, phase 3 studies (RESONATE-2, NCT01722487; RESONATE, NCT01578707), lymphocytosis was observed in 77 of 136 (57%) patients treated in first-line and 133 of 195 (69%) relapsed/refractory patients. On treatment, lymphocytosis resolved in 95% of patients in the first-line and 94% in the relapsed/refractory setting. The median duration of lymphocytosis was 12 and 14 weeks in the first-line and relapsed/refractory settings, respectively. Lymphocytosis is a common and predictable pharmacodynamic effect of ibrutinib treatment, and in the absence of other signs of progression, does not represent disease progression. Lymphocytosis resolves in the majority of patients and does not require interruption or discontinuation of ibrutinib therapy.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Biomarkers; Follow-Up Studies; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocytosis; Molecular Targeted Therapy; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Treatment Outcome

Ibrutinib and other targeted inhibitors of B-cell receptor signaling achieve impressive clinical results for patients with chronic lymphocytic leukemia (CLL). A treatment-induced rise in absolute lymphocyte count (ALC) has emerged as a class effect of kinase inhibitors in CLL and warrants further investigation. Here we report correlative studies in 64 patients with CLL treated with ibrutinib. We quantified tumor burden in blood, lymph nodes (LNs), spleen and bone marrow, assessed phenotypic changes of circulating cells and measured whole-blood viscosity. With just one dose of ibrutinib, the average increase in ALC was 66%, and in>40% of patients the ALC peaked within 24 h of initiating treatment. Circulating CLL cells on day 2 showed increased Ki67 and CD38 expression, indicating an efflux of tumor cells from the tissue compartments into the blood. The kinetics and degree of the treatment-induced lymphocytosis was highly variable; interestingly, in patients with a high baseline ALC the relative increase was mild and resolution rapid. After two cycles of treatment the disease burden in the LN, bone marrow and spleen decreased irrespective of the relative change in ALC. Whole-blood viscosity was dependent on both ALC and hemoglobin. No adverse events were attributed to the lymphocytosis.

Topics: Adenine; Aged; Blood Viscosity; Female; Hemoglobins; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocyte Count; Lymphocytosis; Male; Models, Biological; Piperidines; Pyrazoles; Pyrimidines; Receptors, Antigen, B-Cell; Signal Transduction; Tumor Burden

Chronic lymphocytic leukemia (CLL) transformation to aggressive lymphoma, known as Richter's Transformation (RT), has a dismal prognosis. There are limited data evaluating risk of RT in patients treated with ibrutinib. We performed a retrospective analysis to determine prognostic variables associated with development of RT and overall survival (OS) at progression after treatment with ibrutinib. We identified 559 patients with CLL treated with ibrutinib from 2010-2019. After a median follow-up of 44.5 months from ibrutinib start, 179 patients progressed and were included in our analysis. After a median follow-up of 20.8 months from progression, 54 out of 179 patients developed RT. Progression on treatment (hazard ratio [HR] 4.01 [1.60-10.00], p = .003), higher LDH (HR 1.80 for 2-fold increase [1.33-2.43], p = .0001), and lymphadenopathy without lymphocytosis (HR 2.88 [1.15-7.20], p = .02) were independent prognostic variables for the development of RT at progression. Progression with lymphadenopathy without lymphocytosis continued to be an independent prognostic variable of worse OS post-progression. In a subset analysis of 50 patients who obtained a PET-CT at progression, the median SUV

Topics: Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphadenopathy; Lymphocytosis; Lymphoma, Large B-Cell, Diffuse; Positron Emission Tomography Computed Tomography; Retrospective Studies

Ibrutinib is indicated for the treatment of chronic lymphocytic leukemia (CLL). Absolute lymphocyte count (ALC) is a clinical criterion used for the monitoring of CLL. Ibrutinib has several effects on lymphocytes, and has highly variable pharmacokinetics (PK). The objective of this work was to build a PK-pharmacodynamic (PD) model describing ALC dynamics under ibrutinib treatment in patients with CLL. ALC observations before and after ibrutinib treatment initiation in patients with CLL were included in the analysis. A population PK-PD model was developed based on physio-pharmacological knowledge. Individual PK concentrations at each hospital visit were included in the model. The association between PD parameters and lymphocytosis, and between PD parameters and response to treatment were assessed. A total of 94 patients, 658 ALC and 1,501 PK observations were included in model development. The final PK-PD model accurately described ALC dynamics for different patient profiles. It consisted in two compartments (tissues and blood circulation) with ibrutinib plasmatic concentration inducing two drug effects: stimulation of lymphocyte redistribution and death. Patients with hyperlymphocytosis had significantly higher tissues to circulation baseline lymphocyte count ratio, and lower death effect. Patients who progressed under ibrutinib had significantly lower baseline lymphocyte counts in tissues (2-fold lower) and blood (3-fold lower). The first PK-PD model for ALC in patients with CLL under ibrutinib treatment was developed. This model suggests that estimated lymphocyte counts in tissues and blood could be used as an early predictor of response in patients with CLL.

Topics: Adenine; Adult; Aged; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocyte Count; Lymphocytes; Lymphocytosis; Male; Middle Aged; Models, Biological; Piperidines; Protein Kinase Inhibitors; Treatment Outcome

Topics: Adenine; Humans; Lymphocytosis; Lymphoma, Large B-Cell, Diffuse; Patient Acuity; Piperidines

The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, which antagonizes B cell receptor (BCR) signals, demonstrates remarkable clinical activity in chronic lymphocytic leukemia (CLL). The lymphocytosis experienced by most patients under ibrutinib has previously been attributed to inhibition of BTK-dependent integrin and chemokine cues operating to retain the tumor cells in nodal compartments. Here, we show that the VLA-4 integrin, as expressed by CD49d-positive CLL, can be inside-out activated upon BCR triggering, thus reinforcing the adhesive capacities of CLL cells. In vitro and in vivo ibrutinib treatment, although reducing the constitutive VLA-4 activation and cell adhesion, can be overcome by exogenous BCR triggering in a BTK-independent manner involving PI3K. Clinically, in three independent ibrutinib-treated CLL cohorts, CD49d expression identifies cases with reduced lymphocytosis and inferior nodal response and behaves as independent predictor of shorter progression-free survival, suggesting the retention of CD49d-expressing CLL cells in tissue sites via activated VLA-4. Evaluation of CD49d expression should be incorporated in the characterization of CLL undergoing therapy with BCR inhibitors.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Cell Adhesion; Humans; Immunoglobulin M; Integrin alpha4beta1; Kaplan-Meier Estimate; Leukemia, Lymphocytic, Chronic, B-Cell; Lymph Nodes; Lymphocytosis; Multivariate Analysis; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Piperidines; Progression-Free Survival; Proportional Hazards Models; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Receptors, Antigen, B-Cell

Ibrutinib, an irreversible inhibitor of Bruton tyrosine kinase (BTK), is a novel drug that has shown significant efficacy and survival benefit for treatment of various B-cell malignancies. The primary objective of the present study was to investigate the efficacy of ibrutinib therapy in various B-cell malignancies in the general community. The secondary objectives included studying the adverse effects, ibrutinib-induced peripheral lymphocytosis, and effect on immunoglobulin levels.. The present study was a retrospective observational cohort analysis conducted at Abington Jefferson Health. The clinical response was determined from the hematologist's assessment and evaluated independently using the response criteria for each B-cell malignancy. Adverse effects were graded according to the Common Terminology Criteria for Adverse Events, version 4.0. The Wilcoxon signed-rank test was used to compare immunoglobulin levels before and after ibrutinib. Forty five patients with B-cell malignancies and receiving ibrutinib therapy were eligible.. Ibrutinib is a highly effective and tolerable drug for B-cell malignancies in the general community. In contrast to the previously reported rate of 5% to 7%, we observed a higher rate (11%) of atrial fibrillation, which might have resulted from the smaller sample size in the present study and the multiple comorbidities. Nonetheless, this treatment-limiting side effect requires further elucidation. Paradoxical lymphocytosis at the outset of therapy was a common and benign finding. In conjunction with the reported trials, the IgG levels decreased in the first year of continued therapy. However, the IgA levels did not increase, even after 2 years of therapy.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Atrial Fibrillation; B-Lymphocytes; Disease-Free Survival; Female; Humans; Immunoglobulin G; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocytosis; Male; Middle Aged; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Retrospective Studies; Treatment Outcome; Waldenstrom Macroglobulinemia

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Antineoplastic Agents; Chromosome Aberrations; Female; Gene Expression; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocyte Count; Lymphocytosis; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines

Topics: Adenine; Adult; Aged; Aged, 80 and over; Chromosomes, Human, Pair 12; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocytosis; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Trisomy

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Bone Marrow; Humans; Lymphocytosis; Lymphoma, Mantle-Cell; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines

Ibrutinib leads to a transient lymphocytosis in patients with chronic lymphocytic leukemia (CLL) that develops within hours of starting drug and is due to the efflux of cells from lymphoid tissues into the blood. We therefore sought to investigate the in vivo effect of ibrutinib on migration and adhesion of CLL cells.. Patients received single-agent ibrutinib (420 mg daily) on an investigator-initiated phase II trial. Serial blood samples were collected pretreatment and during treatment for ex vivo functional assays.. Adhesion of CLL cells to fibronectin was rapidly (within hours) and almost completely inhibited (median reduction 98% on day 28, P < 0.001), while the effect on migration to chemokines was more moderate (median reduction 64%, P = 0.008) and less uniform. Although cell surface expression of key adhesion molecules such as CD49d, CD29, and CD44 were modestly reduced, this was only apparent after weeks of treatment. Stimulation of CLL cells from patients on ibrutinib with PMA, which activates PKC independent of BTK, restored the ability of the cells to adhere to fibronectin in a VLA-4-dependent manner. Finally, the addition of ibrutinib to CLL cells adhered to fibronectin in vitro caused the detachment of 17% of the cells, on average; consisten t with in vivo observations of an increasing lymphocytosis within 4 hours of starting ibrutinib.. Inhibition of BTK and VLA-4-dependent adhesion of CLL cells to stroma and stromal components provides a mechanistic explanation for the treatment-induced lymphocytosis and may reduce CD49d-dependent prosurvival signals in the tissue microenvironment.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Cell Adhesion; Female; Fibronectins; Humans; Integrin alpha4beta1; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocytosis; Male; Piperidines; Protein Kinase C; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines

The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has outstanding activity in patients with chronic lymphocytic leukemia. Most patients experience lymphocytosis, representing lymphocyte egress from nodal compartments. This resolves within 8 months in the majority of patients, but a subgroup has lymphocytosis lasting >12 months. Here we report a detailed characterization of patients with persistent lymphocytosis during ibrutinib therapy. Signaling evaluation showed that while BTK is inhibited, downstream mediators of B-cell receptor (BCR) signaling are activated in persistent lymphocytes. These cells cannot be stimulated through the BCR and do not show evidence of target gene activation. Flow cytometry for κ and λ expression, IGHV sequencing, Zap-70 methylation, and targeted gene sequencing in these patients are identical at baseline and later time points, suggesting that persistent lymphocytes do not represent clonal evolution. In vitro treatment with targeted kinase inhibitors shows that they are not addicted to a single survival pathway. Finally, progression-free survival is not inferior for patients with prolonged lymphocytosis vs those with traditional responses. Thus, prolonged lymphocytosis is common following ibrutinib treatment, likely represents the persistence of a quiescent clone, and does not predict a subgroup of patients likely to relapse early.

Topics: Adenine; Adult; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; CD40 Ligand; Disease-Free Survival; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocytes; Lymphocytosis; Male; Middle Aged; Phospholipase C gamma; Phosphorylation; Piperidines; Prognosis; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Receptors, Antigen, B-Cell; Signal Transduction; ZAP-70 Protein-Tyrosine Kinase

Topics: Adenine; Female; Humans; Lymphocytosis; Male; Piperidines; Pyrazoles; Pyrimidines