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Introduction: Contrasting with the lymphopenia classically reported after administration of glucocorticoids, a lymphocytosis has been sometimes observed in patients after glucocorticoid administration. We here determine prospectively the timing and magnitude of methylprednisolone (mPDN)-induced lymphocytosis and study the effects of concomitant propranolol administration on lymphocyte count (Ly)., Methods: Ly was measured before and 24 to 72hours after initiating mPDN treatment in 20 patients with immune-mediated inflammatory disorders (IMID). After one week, patients with increased Ly were divided in two groups receiving, in addition to mPDN, either propranolol or a placebo; Ly was determined 4 days later. Lymphocyte subpopulations and mPDN plasma levels were determined in subsets of the patients. Values are expressed as median with 25%-75% interquartile range., Results: A 73.4% (37-305) increase of Ly was observed in 18/20 patients as soon as 48 (48-72) hours after initiating mPDN (32mg; 16-32). Lymphocytosis (Ly≥4000/μL) was observed in 7 patients and hyperlymphocytosis (Ly≥5000/μL) in 4 of them. The increase in Ly was noted both for B and T cells. Median mPDN plasma levels (n=13) were 97.4ng/mL (IQR 67-489) and 3.2 (IQR 2.1-5.1) respectively 8hours and 24hours after oral mPDN administration. No significant change in Ly was shown under propranolol (p=0.570)., Conclusion: A morning lymphocytosis observed during mPDN treatment occurs in the very first days of mPDN administration. Our results do not support the hypothesis of an increased adrenergic tone responsible for this phenomenon. Identifying this unexpected etiology of lymphocytosis could mitigate the need for unnecessary supplementary investigations in clinical practice., (Copyright © 2024 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

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., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

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.

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 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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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.

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.

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.

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., (© 2020 Wiley Periodicals LLC.)

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.

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.

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., (© 2018 British Association of Dermatologists.)

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., (© 2018 John Wiley & Sons Ltd.)

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 × 10 3 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., (Published by Elsevier Inc.)

An enhanced embryo-fetal development study was conducted in cynomolgus monkeys using pateclizumab, a humanized IgG1 monoclonal antibody (mAb) targeting lymphotoxin-alpha. Pateclizumab administration between gestation days (GD) 20 and 132 did not induce maternal or developmental toxicities. The ratio of fetal-to-maternal serum concentration of pateclizumab was 0.73% on GD 50 and 61% by GD 139. Decreased fetal inguinal lymph node-to-body weight ratio was present in the high-dose group without microscopic abnormalities, a change attributable to inhibition of lymphocyte recruitment, which is a pharmacologic effect of pateclizumab during late lymph node development. The effect was observed in inguinal but not submandibular or mesenteric lymph nodes; this was attributed to differential susceptibility related to sequential lymph node development. Placental transfer of therapeutic IgG1 antibodies; thus, begins during the first trimester in non-human primates. Depending on the potency and dose levels administered, antibody levels in the fetus may be pharmacologically or toxicologically relevant., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Transient acute reversible lymphopenia occurring within hours after glucocorticoid administration is a well-known phenomenon. The objective of this study was to establish the impact of chronic methylprednisolone (mPDN) administration on lymphocyte counts in patients with immune-mediated inflammatory disorders., Methods: The charts of 44 women and 17 men (median age, 59 years) with several immune-mediated inflammatory disorders receiving oral mPDN for at least 4 months were reviewed. Morning lymphocyte counts measured during treatment (LP) were compared with pretreatment values (LA). In addition, the acute effect of mPDN on lymphocyte counts was evaluated in 43 of these patients by quantifying lymphocyte subpopulations before and 8 hours after mPDN administration. Values are expressed as median with 25%-75% interquartile range., Results: The initial daily oral mPDN dose was 28 mg (12-32 mg). An increase in morning lymphocyte counts was detected 13 days (8.5-16 days) after initiation of mPDN treatment (LP: 2130/μL vs LA: 1650/μL; P = .0121) and persisted over time. Morning lymphocytosis (LP ≥4000/μL) was observed in 15 patients, including 7 with hyperlymphocytosis (LP ≥5000/μL). The increase in morning lymphocyte counts during treatment was most marked for CD4 T cells. In the subset of patients who agreed to a second blood test after mPDN absorption, a 49% decrease in the lymphocyte count (P <.0001) was transiently observed at the 8-hour time point., Conclusions: A significant increase of the morning lymphocyte count is frequently observed in patients with immune-mediated inflammatory disorders chronically treated with oral mPDN. Heightened awareness that the timing of blood sampling in corticosteroid-treated patients affects lymphocyte counts, with possible hyperlymphocytosis before absorption, should help avoid unnecessary investigations and worry., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Natalizumab is an effective therapy in relapsing-remitting multiple sclerosis (RRMS), as it reduces lymphocyte transmigration through the blood-brain barrier (BBB) and induces lymphocytosis., Objectives: To analyse natalizumab-induced lymphocytosis (NIL) as a biomarker of drug efficacy., Materials and Methods: We enrolled 50 relapsing-remitting (RR) and progressive-relapsing (PR) natalizumab-treated patients who had received at least 16 infusions and had been tested for lymphocyte count 24 hours before each administration. Clinical, MRI and hematological data were collected. Patients were divided into responders and sub-optimal responders according to the experience of at least one clinical and/or instrumental relapse during the treatment., Results: In 15 (30%) patients, an instrumental/clinical (14) or only instrumental (one) relapse occurred. We found a statistically significant difference in the mean percentage of the lymphocytes between the two groups over the first ten administrations (p=0.04). The comparison between the time-to-relapse in the groups with high and low levels of lymphocytes showed that the group with a low NIL had a greater risk of relapse (p=0.03)., Conclusions: We suggest that NIL could be a biomarker of therapeutic efficacy in patients with RRMS treated with natalizumab, and that the risk of relapse may be higher in patients with a lower-than-expected NIL., (© The Author(s), 2015.)

Background: The proliferation of clonal cytotoxic T-cells or natural killer cells has been observed after dasatinib treatment in small studies of patients with chronic myeloid leukemia (CML)., Methods: The incidence of lymphocytosis and its association with response, survival, and side effects were assessed in patients from 3 large clinical trials. Overall, 1402 dasatinib-treated patients with newly diagnosed CML in chronic phase (CML-CP), CML-CP refractory/intolerant to imatinib, or with CML in accelerated or myeloid-blast phase were analyzed., Results: Lymphocytosis developed in 32% to 35% of patients and persisted for >12 months. This was not observed in the patients who received treatment with imatinib. Dasatinib-treated patients in all stages of CML who developed lymphocytosis were more likely to achieve a complete cytogenetic response, and patients who had CML-CP with lymphocytosis were more likely to achieve major and deep molecular responses. Progression-free and overall survival rates were significantly longer in patients with CML-CP who were refractory to or intolerant of imatinib and had lymphocytosis. Pleural effusions developed more commonly in patients with lymphocytosis., Conclusions: Overall, lymphocytosis occurred and persisted in many dasatinib-treated patients in all phases of CML. Its presence was associated with higher response rates, significantly longer response durations, and increased overall survival, suggesting an immunomodulatory effect. Prospective studies are warranted to characterize the functional activity of these cells and to assess whether an immunologic effect against CML is detectable. Cancer 2016;122:1398-1407. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society., (© 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.)

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., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

This article describes the first reported case of dramatic lymphocytosis flare after initiation of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy for an indolent lymphoma. The study patient exhibited a marginal zone lymphoma with mild nodal involvement but packed infiltration of the bone marrow. After initiation of RCHOP therapy, lymphocyte count increased from 329 to 707 × 10⁹/L at day 7. Patient exhibited grade III infusion-related side effect during rituximab therapy. Lymphocyte flare was not accompanied with other clinical manifestation such as lymph node enlargement. Because patient's bone marrow aspirate showed a packed infiltration, it was hypothesized that lymphocytosis flare was a link to lymphocyte release from bone marrow and lymphocyte demargination. This report highlights the necessity to be vigilant after initiation of RCHOP therapy for lymphoma when pathologist notified a pack infiltration of the bone marrow.

Idelalisib is an inhibitor of the PI3Kδ isoform approved for treatment of patients with relapsed chronic lymphocytic leukemia and indolent non-Hodgkin lymphoma. Many patients develop gastrointestinal symptoms during idelalisib therapy; however, the pathologic effects of this drug have not been characterized. We identified 50 patients who received at least 3 months of idelalisib therapy. Clinical findings and symptoms were noted for each patient, and endoscopic findings were recorded for those who underwent colonoscopic examination. Hematoxylin and eosin-stained sections from colonic biopsy samples were evaluated for histologic patterns of injury. Twenty-three (46%) patients experienced diarrhea during treatment with idelalisib, including 8 with severe symptoms (≥7 stools/d above baseline and/or requiring hospitalization). Fourteen patients underwent colonoscopic examination with mucosal biopsy. Twelve (86%) of these had colitis characterized by intraepithelial lymphocytosis, crypt cell apoptosis, and neutrophilic infiltration of crypt epithelium. Eleven patients had symptoms severe enough to warrant drug withdrawal, including 9 who were also treated with corticosteroids. Idelalisib commonly causes diarrheal symptoms in patients undergoing therapy for B-cell neoplasia, which may be severe in nearly 20% of patients. Characteristic histologic features include the combination of intraepithelial lymphocytosis and crypt cell apoptosis, often accompanied by neutrophils. Discontinuation of the drug results in symptomatic improvement and resolution of histologic changes.

Dasatinib is one of the key treatment options for chronic myeloid leukemia (CML) patients. Increase in lymphocyte counts has been known to be predictive of a good treatment response under dasatinib treatment as a second line therapy. However, clinical significance of lymphocyte dynamics in the upfront setting has yet to be clarified. To investigate the significance of lymphocyte dynamics in newly diagnosed chronic phase (CP)-CML, patient data of D-First study (ClinicalTrials.gov NCT01464411) were analyzed. Fifty-two CML-CP patients enrolled to this study were treated with dasatinib (100 mg day(-1) ) and all were followed-up for 18 months. The incidence of lymphocyosis was observed in 14 (27%), but it was not associated with deep molecular response achievement. However, natural killer (NK) cell or cytotoxic T lymphocyte (CTL) counts at 1 month were significantly higher in patients with deep molecular response (DMR) by 18 months compared to those without DMR. When the patients were divided into two groups according to those calculated thresholds by receiver operating characteristic curve (407/μL for NK cells and 347/μL for CTLs), the cumulative DMR rates by 18 months were significantly better in higher value group compared to lower value group. In contrast, regulatory T cell counts were significantly lower at 12 and 15 months in patients achieved DMR. These results suggest the presence of dual effects of dasatinib on immune system through the cytotoxic lymphocytes activation and Treg deregulation in different periods in newly diagnosed CML-CP., (© 2015 Wiley Periodicals, Inc.)

We report 2 cases of CD4(+) large granular lymphocyte (LGL) lymphocytosis occurring in patients being treated with a monoclonal antibody against tumor necrosis factor α for underlying autoimmune disorders. CD4(+) LGL lymphocytosis is a rare subset of LGL disease that has previously only been described in patients without underlying autoimmune disorders, and most demonstrate uniform coexpression of CD56 on the atypical T cells. The clinical features, with both cases occurring in patients with autoimmune disease, and immunophenotypic features, with both cases showing dim CD8 coexpression without CD56 in the CD4(+) LGLs, suggest that the reported cases are distinct from those previously described and may represent a novel T-cell LGL lymphocytosis emerging from iatrogenic immune modulation of patients with underlying autoimmune disorders., (Copyright © 2015 Elsevier Inc. All rights reserved.)

A 73-year-old man was admitted in respiratory failure that had subacutely progressed after five weeks of dapsone treatment for a skin rash. He also presented with fever, systemic erythroderma and liver dysfunction. Chest computed tomography showed diffuse reticular shadows with ground-glass opacity and bilateral mediastinal lymphadenopathy. Lymphocytes, but not eosinophils, were increased in the bronchoalveolar lavage fluid. Moreover, reactivation of human herpes virus-6 was confirmed on a paired serum test. Finally, we diagnosed the patient with dapsone hypersensitivity syndrome (DHS), a rare adverse event of this drug. Lung injury unaccompanied by eosinophilia in the bronchoalveolar lavage fluid is even more rare as a DHS-related lung manifestation.

Spontaneous regression of methotrexate-related lymphoproliferative disorders (MTX-LPDs) occurs in some patients after withdrawal of MTX. However, the mechanisms by which MTX withdrawal contributes to the spontaneous regression of MTX-LPDs have not been fully elucidated. We herein show that spontaneous regression of MTX-LPDs is associated with the development of significant and transient T-cell large granular lymphocyte (T-LGL) lymphocytosis induced by MTX withdrawal. Since T-LGLs show strong cytotoxicity, their expansion may contribute to the spontaneous regression of lymphoma. Therefore, the development of T-LGL lymphocytosis maybe associated with a favorable prognosis in MTX-LPD patients.

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.

Dasatinib is a second generation tyrosine kinase inhibitor (TKI) approved for clinical use in patients with imatinib-resistant chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL). Large granular lymphocytes (LGLs) are medium to large cells with eccentric nuclei and abundant cytoplasm with coarse azurophilic granules. LGL lymphocytosis is caused by a proliferation of cytotoxic (CD8+) T cells and/or NK cells. In a proportion of CML and Ph(+) ALL patients, there is a significant expansion of LGLs during dasatinib therapy. LGL lymphocytosis is seen in some cases with fevers, colitis, and pleural effusions (PE), suggesting an aberrant immune response mediated by these LGLs. LGLs may participate in the elimination of the residual leukemic cells, and LGL clonal expansion is associated with excellent, long-lasting therapy responses in dasatinib-treated patients. For a more comprehensive analysis, we analyzed the morphologic, phenotypic, clinical, and functional features of the LGL subsets amplified in vivo during dasatinib therapy.

Dasatinib is a second generation tyrosine kinase inhibitor approved for clinical use in first line and imatinib-resistant chronic myeloid leukemia and Philadelphia positive (Ph+) acute lymphoblastic leukemia. In addition to BCR-ABL1, dasatinib inhibits TEC kinases and SRC family kinases and is more potent than imatinib in the treatment of Ph+ leukemias. In the last 3 years, increases in cytotoxic T and natural-killer cells in peripheral blood samples have been reported in cases treated by dasatinib. The awareness of the clonal expansion of large granular lymphocytes and beneficial effect of these clonal cells increased the interest to dasatinib in cases receiving this drug. Clonal expansion of large granular lymphocytes is an important effect of dasatinib therapy, shown to be an off-target phenomenon associated with pleural effusion and better clinical response. The benefit of dasatinib-induced lymphocytosis and its underlying mechanism of this are important points for clinicians working in hematology and oncology., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

This thesis describes the treatment of metastatic melanoma (MM) and non small-cell lung cancer (NSCLC) from an immunotherapeutic approach. The purpose of the first part of the thesis was to assess how treatment with Temozolomide (TMZ) chemotherapy affects the immune system in patients with metastatic MM. Our results showed that the number of T lymphocytes was significantly reduced after 3 treatment cycles. Furthermore, the induced lymphopenia was positive correlated to achievement of clinical benefit. We demonstrated that the proportion of CD4+ and Treg lymphocytes decreased whereas the CD8+ T cells increased. In particular, we demonstrated that mature CD8+ T cells increased during treatment. Analyses of peripheral blood before and after treatment showed that T cell responses against common viral epitopes were conserved despite chemotherapy. Surprisingly, we found a significant increase in T cell responses against well-known MM tumour specific antigens. Overall, we have verified that TMZ in addition to being an alkylating and cytotoxic chemotherapy, also possess immune modulatory effect in MM patients treated with standard dosage of TMZ. In the second part of the thesis we examined how treatment with Interferon alfa-2b and Interleukin 2 (IFNα/IL2) affects the immune system. We demonstrated a significant induced lymphocytosis during treatment. Furthermore, we showed that the percentage increase in lymphocytes was positively correlated to clinical outcome. Moreover, we have seen that IFNα/IL2 leads to significant increase in NK and Treg cells in both patients with and without clincal effect. In general, T cell responses against common viral epitopes and well-known melanoma tumour specific antigens were low. Furthermore, the study confirmed that elevated LDH is negatively correlated with both treatment response and median overall survival. Overall, we have characterized changes of immune cells and correlated them with clinical efficacy during the couse of IFNα/IL2 used in standard dosage. In the third part we investigated if vaccination with a peptide derived from IDO was feasible in patients with metastatic NSCLC. This "First in Man" trial was safe and showed modest side effects only. Since IDO was expressed in NSCLC tissues it was found to be a relevant target. One patient achieved significant regression of liver metastases (confirmed partial response) and another 6/15 patients achieved prolonged disease stabilization. Furthermore, median overall survival was 25.9 months demonstrating a better survival in vaccinated compared to non-vaccinated comparable NSCLC patients. The presence of IDO specific CD8+ T cells were detected by IFNy Elispot. In patients with clinical effect of the vaccine IDO-specific CD8+ T cells at pre-treatment was significanctly increased. Moreover, low-frequent IDO positive tetramer CD8+ T cells were detected and led to effective killing of an IDO+ HLA-A2 positive cancer cell line (SW480) in 1 patient. Moreover, flow cytometry was performed and in general no significant changes in CD8+ and CD4+ T cells were seen, although patients with clinical response showed a trend towards increased mature CD8+ T cells during treatment. In addition, we found lower levels of Tregs as well as an increased level of NK cells after 6 vaccinations. Elevated Kyn/Trp ratio is suggested to mirror IDO activity. In 8/11 patients the level after the 6th vaccine was stable compared to baseline. No differences between patients with clinical benefit (4/5) and patients with progressive disease (4/6) were demonstrated. Two patients had an increase in Kyn/Trp ration meanwhile demonstrating a high expression of IDO. In 2 patients with clinical response long-term stabilization of Kyn/Trp was observed. Overall, the vaccine was well tolerated with no adverse toxicity. Median overall survival was 25.9 months with long term disease stabilization achieved in 47% of the treated patients. Based on the promising clinical results achieved in the vaccine trial for NSCLC patients, we launched a new clinical trial for MM patients (ongoing patient recruitment) in June 2012. In order to enhance the immune response the vaccine comprises IDO plus Survivin peptide as well as the adjuvants Montanide, Aldara and GM-CSF. Finally, the vaccine is given in combination with TMZ. Patients are evaluated every 3rd month with PET-CT scan. Preliminary clinical data from the first 7/30 evaluable patients are presented. Two patients demonstrated a patial response with 57% and 45% tumour regression lasting for 10 months and 6+ months respectively, corresponding to a preliminary objective response rate of 29%. The vaccine has been manageable and without significant side effects.

Lymphocytosis predominantly due to natural killer (NK) cells has been reported in nearly a half of chronic myelogenous leukemia (CML) patients who were being treated with dasatinib. Besides, dasatinib-treated patients with lymphocytosis have a better prognosis than patients without lymphocytosis. In order to elucidate the effects of dasatinib on the proliferation of lymphocyte subset, dasatinib was added to the culture of peripheral blood mononuclear cells with IL-2 (lymphokine-activated killer culture) or a low dose of IL-2 with zoledronate (γδ T-cell culture). In both culture conditions, NK cells were increased in both percentage and absolute number in the culture with dasatinib compared with control culture without dasatinib. The increase of NK cells was dose dependent of dasatinib in the range of 2-25 nM. NK cell cytotoxicity of cultured cells with dasatinib was demonstrated to be superior to control cells without dasatinib in cytotoxicity assay using EGFP-transfected K562 cells as target cells. The present study suggested that lymphocytosis in dasatinib-treated CML patients is at least partly associated with a direct effect of dasatinib to stimulate the proliferation of NK cells. Favourable prognosis in patients with dasatinib-induced lymphocytosis might be associated with the effects of dasatinib to potentiate NK cytotoxicity in vivo., (Copyright © 2012 John Wiley & Sons, Ltd.)

Background: Multiple sclerosis (MS) patients discontinuing natalizumab treatment are at risk of disease reactivation. No clinical or surrogate parameters exist to identify patients at risk of post-natalizumab MS reactivation., Objective: To determine the role of natalizumab-induced lymphocytosis and of Akt polymorphisms in disease reactivation after natalizumab discontinuation., Methods: Peripheral leukocyte count and composition were monitored in 93 MS patients during natalizumab treatment, and in 56 of these subjects who discontinued the treatment. Genetic variants of the anti-apoptotic protein Akt were determined in all subjects because natalizumab modulates the apoptotic pathway and lymphocyte survival is regulated by the apoptotic cascade., Results: Natalizumab-induced peripheral lymphocytosis protected from post-natalizumab MS reactivation. Subjects who relapsed or had magnetic resonance imaging (MRI) worsening after treatment cessation, in fact, had milder peripheral lymphocyte increases during the treatment, largely caused by less marked T cell increase. Furthermore, subjects carrying a variant of the gene coding for Akt associated with reduced anti-apoptotic efficiency (rs2498804T) had lower lymphocytosis and higher risk of disease reactivation., Conclusion: This study identified one functionally meaningful genetic variant within the Akt signaling pathway that is associated with both lymphocyte count and composition alterations during natalizumab treatment, and with the risk of disease reactivation after natalizumab discontinuation.

Leukocytosis refers to an increase in leukocyte count above the normal range in the blood and is a common laboratory finding in patients. In many cases, the mechanisms underlying leukocytosis are not known. In this study, we examined the effects, the structural determinants, and the underlying mechanisms of heparin-induced leukocytosis, a side effect occurring in 0.44% of patients receiving heparin. We observed that heparin induced both lymphocytosis and neutrophilia, and the effects required heparin to be 6-O-sulfated but did not require its anticoagulant activity. Cell mobilization studies revealed that the lymphocytosis was attributable to a combination of blockage of lymphocyte homing and the release of thymocytes from the thymus, whereas the neutrophilia was caused primarily by neutrophil release from the bone marrow and demargination in the vasculature. Mechanistic studies revealed that heparin inhibits L- and P-selectin, as well as the chemokine CXCL12, leading to leukocytosis. Heparin is known to require 6-O-sulfate to inhibit L- and P-selectin function, and in this study we observed that 6-O-sulfate is required for its interaction with CXCL12. We conclude that heparin-induced leukocytosis requires glucosamine 6-O-sulfation and is caused by blockade of L-selectin-, P-selectin-, and CXCL12-mediated leukocyte trafficking.

We report two cases, one of a 52-year-old man and one of a 32-year-old man, who were treated with cefotaxime. On day 23 and day 28 of the treatment, respectively, the patients manifested clinically with fever, pruriginous skin rash, and facial edema. Blood tests showed marked eosinophilia and atypical lymphocytosis for both patients, and hepatic cytolysis only in the second patient. Cefotaxime was discontinued in both patients; the clinico-biological picture improved gradually and completely disappeared approximately 4 weeks later. Six weeks after complete recovery, both patients underwent intradermal testing which was positive to cefotaxime (2 mg/ml) at the 48-hour reading and negative to benzylpenicillin, amoxicillin, and cefazolin at the 20-minute and 48-hour readings. These clinical pictures suggest drug rash with eosinophilia and systemic symptoms (DRESS) induced by cefotaxime. To the best of our knowledge, only one case of cefotaxime-induced DRESS has been reported in the medical literature. Thus, we add two new cases of cefotaxime-induced DRESS and emphasize the usefulness and safety of intradermal testing in establishing the diagnosis.

The cellular profile of bronchoalveolar lavage fluid (BALF) in asbestos-exposed population remains controversial. We, therefore, aimed to investigate BALF in apparently healthy individuals that were exposed in asbestos-related work for a long period of time. Participants were selected among employees of a car brakes and clutches factory that used chrysotile asbestos. Selection criteria were an employment history of ≥ 15 years and the absence of severe respiratory disease. The total number and type of BALF cells, the existence of dust cells, iron-laden macrophages and asbestos bodies were assessed. Thirty-nine workers (25 men), with a mean age of 46.2 ± 4.2 years and a mean employment time of 23.5 ± 4 years, participated. Asbestos bodies were observed in 14 out of 39 (36%) specimens, dust cells in 37 and iron-laden macrophages in all. Those with asbestos bodies had at least 3 times higher probability to have lymphocytosis (lymphocytes > 11%: 64% vs 28%, p = 0.027) and had an increased percentage of iron-laden macrophages compared to those without asbestos bodies (median values: 42% vs 13%, p = 0.08). Smokers (36%) had less lymphocytes compared to non and ex-smokers (median values: 6% vs. 13%, p = 0.002), and iron-laden macrophages count had a positive relation (r = 0.31, p = 0.05) to lymphocyte count. Asbestos-exposed asymptomatic individuals with the presence of asbestos bodies in the BALF are more likely to have lymphocytic alveolitis while concurrent dust exposure and smoking habits hold a significant role.