[A transient lymphocytosis after administration of tirabrutinib for leukemic Waldenström macroglobulinemia].

An 85-year-old woman was admitted to our hospital because of leukocytosis. Abnormal lymphocytic leukocytosis, including few plasmacytes, anemia, and thrombocytopenia, were observed. A diagnosis of primary macroglobulinemia was made based on immunoglobulin M-kappa monoclonal gammopathy, FACS of abnormal lymphocytes, and confirmed MYD88 L265P somatic mutation. Abnormal lymphocytes were markedly increased temporarily after the administration of tirabrutinib. However, the patient continued treatment after abdominal computed tomography showed that splenomegaly and lymphadenopathy had improved, and the patient recovered from leukocytosis. There are no reports that leukocytosis is a side effect of tirabrutinib; therefore, this case can be considered unique.

Dasatinib-induced spleen contraction leads to transient lymphocytosis.

The tyrosine kinase inhibitor dasatinib is approved for Philadelphia chromosome-positive leukemia, including chronic myeloid leukemia (CML). Although effective and well tolerated, patients typically exhibit a transient lymphocytosis after dasatinib uptake. To date, the underlying physiological process linking dasatinib to lymphocytosis remains unknown. Here, we used a small rodent model to examine the mechanism of dasatinib-induced lymphocytosis, focusing on lymphocyte trafficking into and out of secondary lymphoid organs. Our data indicate that lymphocyte homing to lymph nodes and spleen remained unaffected by dasatinib treatment. In contrast, dasatinib promoted lymphocyte egress from spleen with kinetics consistent with the observed lymphocytosis. Unexpectedly, dasatinib-induced lymphocyte egress occurred independently of canonical sphingosine-1-phosphate-mediated egress signals; instead, dasatinib treatment led to a decrease in spleen size, concomitant with increased splenic stromal cell contractility, as measured by myosin light chain phosphorylation. Accordingly, dasatinib-induced lymphocytosis was partially reversed by pharmacological inhibition of the contraction-promoting factor Rho-rho associated kinase. Finally, we uncovered a decrease in spleen size in patients with CML who showed lymphocytosis immediately after dasatinib treatment, and this reduction was proportional to the magnitude of lymphocytosis and dasatinib plasma levels. In summary, our work provides evidence that dasatinib-induced lymphocytosis is a consequence of drug-induced contractility of splenic stromal cells.

Development of Monoclonal B-cell Lymphocytosis Shortly After Treatment with Nivolumab and Subsequent Progression to Chronic Lymphocytic Leukemia.

INTRODUCTION: Immune checkpoint inhibitors, such as programmed death (PD)-1 inhibitor nivolumab, are currently widely used in treatment of various malignancies. Due to their widespread application, any new potential adverse effects due to these agents necessitate careful assessment. CASE REPORT: We report a case of an 81-year-old man with recurrent high-risk malignant melanoma who underwent a 12-month adjuvant treatment with nivolumab. Shortly after the course of nivolumab, he developed monoclonal B-cell lymphocytosis (MBL) which subsequently progressed to chronic lymphocytic leukemia (CLL). MANAGEMENT AND OUTCOME: The patient is currently doing clinically well in Rai stage 0. Malignant melanoma remains in remission. CONCLUSION: Considering the pathophysiologic plausibility of nivolumab inducing B-cell dysregulation via PD-1 inhibition, we suggest further studies on potential association between nivolumab and B-cell malignancies.

Eosinophilia during natalizumab treatment: Incidence, risk factors and temporal patterns.

Eosinophilia is common during natalizumab treatment for multiple sclerosis but risk factors are unknown. We aimed to identify demographic, clinical and laboratory characteristics predicting eosinophilia. Sustained eosinophilia occurred in 16.8%. Risk factors for sustained eosinophilia included baseline pre-treatment eosinophilia, medical conditions potentially associated with eosinophilia including allergies, and suboptimal compliance. One temporal profile was associated with the highest and most rapidly developing eosinophilia, and was less likely to resolve: in one such case, eosinophilia was symptomatic. Changes in eosinophil and lymphocyte counts were only weakly correlated, suggesting factors other than Very Late Antigen-4 (VLA-4) inhibition drive eosinophilia.

Selenite Downregulates STAT3 Expression and Provokes Lymphocytosis in the Liver of Chronically Exposed Syrian Golden Hamsters.

Arsenic is considered a worldwide pollutant that can be present in drinking water. Arsenic exposure is associated with various diseases, including cancer. Antioxidants as selenite and α-tocopherol-succinate have been shown to modulate arsenic toxic effects. Since changes in STAT3 and PSMD10 gene expression have been associated with carcinogenesis, the aim of this study was to evaluate the effect of arsenic exposure and co-treatments with selenite or α-tocopherol-succinate on the expression of these genes, in the livers of chronically exposed Syrian golden hamsters. Animals were divided into six groups: (i) control, (ii) chronically treated with 100 ppm arsenic, (iii) treated with 6 ppm α-tocopherol-succinate (α-TOS), (iv) treated with 8.5 ppm selenite, (v) treated with arsenic + α-TOS, and (vi) treated with arsenic + selenite. Urine samples and livers were collected after 20 weeks of continuous exposure. The urine samples were analyzed for arsenic species by atomic absorption spectrophotometry, and real-time RT-qPCR analysis was performed for gene expression evaluation. A reduction in STAT3 expression was observed in the selenite-treated group. No differences in PSMD10 expression were found among groups. Histopathological analysis revealed hepatic lymphocytosis in selenite-treated animals. As a conclusion, long-term exposure to arsenic does not significantly alter the expression of STAT3 and PSMD10 oncogenes in the livers of hamsters; however, selenite down-regulates STAT3 expression and provokes lymphocytosis.

Monoclonal B-cell Lymphocytosis Exacerbated by Prednisolone Therapy for Dermatomyositis.

Lymphoproliferative diseases have been associated with various autoimmune diseases. We experienced a case of non-chronic lymphocytic leukemia type monoclonal B-cell lymphocytosis (MBL) that was exacerbated by increasing prednisolone for dermatomyositis and then improved by decreasing the dosage. Because MBL is difficult to diagnose, cases like ours may not be rare. These findings will facilitate our understanding of the mechanism underlying lymphoproliferative diseases and autoimmune diseases.

The impact of lymphocytosis and CD4/CD8 ratio on the anti-JCV antibody index and clinical data in patients treated with natalizumab.

BACKGROUND: Natalizumab is an effective therapy in the treatment of relapsing-remitting multiple sclerosis; it induces lymphocytosis (NIL, natalizumab-induced lymphocytosis) and changes the peripheral lymphocyte pattern. METHODS: This study aims to evaluate NIL, peripheral blood lymphocyte subsets, CD4/CD8 ratio, and their impacts on JCV index and clinical data-No Evidence of Disease Activity (NEDA-3) and annualized relapse rate (ARR) in patients treated with natalizumab. RESULTS: Forty-one patients (33 women) were included in the study. The mean duration of follow-up on natalizumab treatment was 6.7 ± 3.2 years. Significant increases in relative lymphocytosis after 1 month, with a median of 40.4% (- 34.1 to + 145.5%) (p < 0.001), and after 1 year (49.0% (- 9.3 to + 127.6%)) (p < 0.001) were found. Significant differences were found after 1 month when comparing NIL between patients JCV-seroconverting (20.6% (- 17.7 to 72.7%)) and stable JCV-seronegative ones (43.5% (- 6.3 to +96.3%)) (p = 0.04). No significant difference NIL level was found between the patients exhibiting NEDA-3 status and those without it. ARR on natalizumab treatment correlated with CD4/CD8 ratio (r = 0.356; p = 0.021); patients who maintained NEDA-3 status over the whole treatment period exhibited a lower CD4/CD8 ratio (1.89 ± 1.08 vs. 2.5 ± 0.73; p < 0.04). CONCLUSION: This contribution reports the CD4/CD8 ratio as a possible biomarker for better clinical efficacy of natalizumab in patients exhibiting a lower CD4/CD8 ratio. NIL did not correlate with long-term therapeutic efficacy in patients treated with natalizumab, but was demonstrated as lower in patients JCV-seroconverting in the course of follow-up.

Rebound lymphocytosis in a patient with chronic lymphocytic leukemia after cessation of a CDK 4/6 inhibitor for concomitant breast cancer.

Herein, we present the case of a female with co-occurring chronic lymphocytic leukemia (CLL) and metastatic ER/PR-positive breast cancer, who when taken off palbociclib for severe neutropenia and infectious complications, experienced rebound lymphocytosis. Though this was ultimately a benign clinical outcome, it exemplifies how CDK4/6 inhibitors induce a cell cycle arrest by decreasing the proliferation of hematopoietic stem cells (HSC), in this case CLL cells, with recovery of counts once drug is stopped.

An oral drug for chronic lymphocytic leukemia.

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.

Bruton tyrosine kinase inhibitors for the treatment of mantle cell lymphoma: review of current evidence and future directions.

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.

Optimising outcomes for patients with chronic lymphocytic leukaemia on ibrutinib therapy: European recommendations for clinical practice.

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.

Differential effects of phototherapy, adalimumab and betamethasone-calcipotriol on effector and regulatory T cells in psoriasis.

BACKGROUND: Psoriasis is a chronic T-cell-mediated skin disease with marked social and economic burdens. Current treatments are unsatisfactory, with unpredictable remission times and incompletely understood modes of action. Recent advances in our understanding of the pathogenesis of psoriasis have identified the imbalance between CD4+ T effector cells, particularly the T helper (Th)17 subset, and regulatory T cells (Tregs) as key to the development of psoriatic lesions, and therefore a novel therapeutic target. OBJECTIVES: To quantify in patients the effects of three commonly used psoriasis treatment modalities on the Th1, Th2, Th17 and Treg subsets, and to test whether any change correlates with clinical response. METHODS: Flow cytometry was used to enumerate Th1, Th2, Th17 and Treg subsets in blood and skin of patients with psoriasis before and after receiving any of the following treatments: narrowband ultraviolet B (NB-UVB), adalimumab and topical betamethasone-calcipotriol combination (Dovobet® ) RESULTS: All patients responded clinically to the treatments. NB-UVB significantly increased the numbers of circulating and skin Tregs, while, by contrast, adalimumab reduced Th17 cells in these compartments, and Dovobet had dual effects by both increasing Tregs and reducing Th17 cells. CONCLUSIONS: The differential effects reported here for the above-mentioned treatment modalities could be exploited to optimize or design therapeutic strategies to overcome the inflammatory drivers more effectively and restore the Th17-Treg balance in psoriasis.

Analysis of Efficacy and Tolerability of Bruton Tyrosine Kinase Inhibitor Ibrutinib in Various B-cell Malignancies in the General Community: A Single-center Experience.

BACKGROUND: 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. PATIENTS AND METHODS: 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. RESULTS: The median age was 73 years (range, 49-96 years), and 84.4% of the patients had received ≥ 1 previous therapy. The best overall response rate of all cohorts combined was 63.8%. The greatest overall response rate was observed in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (76.1%), followed by those with Waldenström macroglobulinemia (75%). Of the 45 patients, 88.9% experienced adverse effects. Antiplatelet activity of ibrutinib was most commonly observed (30.5%). Of note, 5 patients (11%) developed new-onset atrial fibrillation after drug initiation. Peripheral lymphocytosis after drug initiation was observed in most patients, with a peak level at 1 month (median lymphocyte count, 2.7 × 103 cells/µL). Although the IgG levels at 3, 6, and 12 months had decreased (P = .01 for all) compared with the levels before ibrutinib, the IgA levels had not increased at 3, 6, 12, and 24 months (P = .6, P = .5, P = .3, and P = .9, respectively). CONCLUSION: 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.