Systemloesungen im kombinierten Verkehr: Rahmenbedingungen, Entwicklungen, Forderungen, Potentiale

Available from Bibliothek des Instituts fuer Weltwirtschaft, ZBW, Duesternbrook Weg 120, D-24105 Kiel C 177684 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

Corticosteroids Augment BRAF Inhibitor Vemurafenib Induced Lymphopenia and Risk of Infection

<div><p>We have previously demonstrated an impact of the BRAF inhibitor vemurafenib on patient lymphocyte counts. In the current study, the extent to which concomitant use of corticosteroids in BRAF inhibitor treated patients affects lymphocyte counts and predisposes to infection was investigated. A cohort of 102 patients receiving either the selective BRAF inhibitor vemurafenib or dabrafenib was analyzed. The amount of patients receiving either medication with or without systemic corticosteroids (dexamethasone) was determined and lymphocyte counts before and under therapy assessed. Additionally, the number and severity of infections occurring in these groups was analyzed. Vemurafenib treatment led to a considerable decrease in lymphocyte cell counts, with 62.3% of patients having lymphopenia. Dabrafenib treated patients only rarely demonstrated lymphopenia (12.5%). Dexamethasone co-administration further diminished lymphocyte counts. Lymphopenias were observed in 84.6% of patients receiving vemurafenib and dexamethasone. In our cohort, infections were noted in 9 patients, 4 of these were severe and 2 eventually fatal. All 9 cases with infections demonstrated lymphopenia, 8 of these had received dexamethasone and 7 of these a therapy with vemurafenib. Our findings demonstrate a significant lymphopenia in patients treated with the BRAF inhibitor vemurafenib, which is further augmented by dexamethasone and predisposes to infection. If validated in other studies, risk of infection should be considered when applying corticosteroids in combination with BRAF inhibitors, in particular vemurafenib.</p></div

Overview of patients’ characteristics with infections under therapy.

<p>LP = lymphopenia; grade 1–4 according to CTCAE criteria version 4.1; BRAFi = BRAF-inhibitor; VEM = vemurafenib; DAB = dabrafenib; DEX = dexamethasone; delta lymphocytes = difference between pretherapeutic lymphocyte count and lymphocyte count under therapy; severe infection = life-threatening infection.</p><p>Overview of patients’ characteristics with infections under therapy.</p

Distribution and degree of lymphopenia in treatment groups.

<p>Shown are the frequency and grade of lymphopenias in patients receiving BRAF inhibitor (vemurafenib or dabrafenib) monotherapy or those receiving both BRAF inhibitor and dexamethasone. VEM- vemurafenib; DAB- dabrafenib; DEX- dexamethasone; delta lymphocytes- difference between pretherapeutic lymphocyte count and lymphocyte count under therapy; CTCAE = Common Terminology Criteria of Adverse Events, version 4.0; corresponding symbols indicate statistically significant difference between groups (p < 0.05).</p

Frequency of lymphopenias in various treatment groups.

<p>Shown are the frequencies of lymphopenias patients treated receiving vemurafenib (VEM) or dabrafenib (DAB), with or without concomitant corticosteroid therapy (dexamethasone—DEX). * = p < 0.05 marking statistically significant differences between groups; n = number of patients</p

Mean lymphocyte counts before and during therapy.

<p>Shown are the mean overall lymphocyte counts before and during therapy according to treatment group. VEM- vemurafenib; DAB- dabrafenib; DEX- dexamethasone; delta lymphocytes = difference between pretherapeutic lymphocyte count and lymphocyte count under therapy; corresponding symbols (*, #, +, x, °) above bars indicate statistical significant difference between groups (p < 0.05).</p

Mean lymphocyte counts in patient groups with infections.

<p>VEM = vemurafenib; DAB = dabrafenib; DEX = dexamethasone; delta lymphocytes = difference between pretherapy lymphocyte count and lymphocyte count under therapy; severe infection = life-threatening infection.</p><p>Mean lymphocyte counts in patient groups with infections.</p

Images of infections occurring under BRAFi and DEX therapy.

<p>(A) The absolute number and percentage of patients developing infections in different treatment groups is shown. (B) Chest x-ray of a patient under therapy with vemurafenib and dexamethasone showing reticular pulmonary infiltrates (blue arrows). (C) CT scan of the thorax of a patient under therapy with vemurafenib and dexamethasone showing atypical pulmonary infiltrates (blue arrows). VEM = vemurafenib; DAB = dabrafenib; DEX = dexamethasone; * = p< 0.05 marking statistically significant difference between groups; n = number of patients.</p

Overview of basic patient characteristics sorted by groups.

<p>LP = lymphopenia; grades 1–4 according to CTCAE criteria version 4.1; BRAFi = BRAF inhibitor; VEM = vemurafenib; DAB = dabrafenib; DEX = dexamethasone; delta lymphocytes = difference between pretherapeutic lymphocyte count and lymphocyte count under therapy.</p><p>Overview of basic patient characteristics sorted by groups.</p