Idelalisib Rapidly Improves Platelets Function in Patients with Chronic Lymphocytic Leukemia (CLL)
Authors: Reda Gianluigi , Cassin Ramona , Artoni Andrea , Lecchi Anna , Fattizzo Bruno , La Marca Silvia , Bucciarelli Paolo , Peyvandi Flora , Cortelezzi Agostino 
Published: October 2019

Abstract
INTRODUCTION
Platelet function has never been studied systematically in patients with CLL. Novel drugs are now available for CLL treatment that may impact on platelet functions. Fifty per cent of patients treated with Ibrutinib suffered from minor bleedings and only 5% from major bleedings, partly caused by the drug driven inhibition of platelet glycoprotein VI signaling. No data on bleeding tendency has yet emerged on patient treated with Idelalisib, the first specific inhibitor of PI3K δ p110 approved for the treatment of relapsed/refractory CLL or for patients with del17p or TP53 as first line therapy. In animal models a reduction of p110δ on platelets (PLT) does not increase bleeding, causing only a slight reduction of platelet aggregation and activation. Knowledge about potential bleeding complications associated with the use of small molecules may be relevant in older patients and those at increased bleeding risk due to concomitant therapies.
PATIENTS AND METHODS
Ten patients with CLL (M/F: 6/4; median age: 71 years, range 47-82) who started therapy with Idelalisib were enrolled in a prospective observational pilot study. The Bleeding Severity Score (BSS), a validated questionnaire, was administrated to patients to estimate bleeding before and during idelalisib therapy. All patients underwent coagulation tests and platelet aggregation/secretion studies with different aggregating agents before starting therapy with Idelalisib, after 28 + 7 days and after 3 months. Patients with a platelet count less than 80.000/mm3, in antiplatelet or anticoagulant therapy, with recent use (within 7 days) of NSAIDs and a diagnosis of hereditary thrombocytopenia/pathy were excluded. We defined complete haematological remission (CHR) as Hb more than 11g/dl, PLT more than 100.000/mm3, lymphocyte less than 5.000/mm3 and partial haematological remission (PHR) as a response not fulfilling criteria for CHR.
RESULTS
No cases of hemorrhagic complications or increased bleeding tendency were observed in patients with CLL and no patients had a pathologic BSS (>5) at enrolment. All patients had coagulation tests within normal limits at baseline and after 28 days. Platelet count was below 100.000/mm3 in 5 patients. In 9 out of 10 patients platelet aggregation was pathological with at least 2 of the 4 aggregating agents tested. Platelet secretion before initiation of treatment with Idelalisib was particularly impaired with ADP (8/10 patients), while was pathological with collagen, a strong agonist, in only 2 patients. In 8 patients intraplatelet ATP/ADP ratio was pathological, as observed in delta storage pool disease. After 28 days of treatment 4 of 10 patients were in CHR and 3 in PHR. Platelets count was still below 100.000/mm3 in 2 subjects. At 28 days in 5 out of the 9 patients with pathological baseline test, platelet aggregation improved, while 3 remained unchanged and in one worsened. Even ADP secretion normalized in 4 patients. ATP/ADP ratio did not significantly change. At three months 7 patients reached CR and 2 reached PR. At three months platelets count was still below 100000/mm3 in 2 patients. In 3 patients platelet aggregation further ameliorated.
CONCLUSIONS
In this pilot study, treatment with idelalisib improved platelet aggregation tests in most of the CLL patients who presented a pathological test before starting therapy. It's unlikely that the drug has a direct effect on platelets, given their low expression of PI3Kδ; therefore our results are probably due to the rapid idealisib effect on CLL clone. Based on these preliminary data, Idelalisib seems to be safe in patients with an increased bleeding risk.

Disclosures
Reda: Roche: Membership on an entity's Board of Directors or advisory committees; Gilead: Research Funding. Peyvandi:Alexion: Other: research funding paid to Luigi Villa Foundation, Research Funding; Ablynx: Membership on an entity's Board of Directors or advisory committees, Other: research funding paid to Luigi Villa Foundation, Research Funding; CSL Behring: Speakers Bureau; Biotest: Other: research funding paid to Luigi Villa Foundation, Research Funding, Speakers Bureau; Octapharma: Consultancy; Kedrion Biopharma: Consultancy, Other: research funding paid to Luigi Villa Foundation, Research Funding; LFB: Consultancy; Grifols: Speakers Bureau; Novo Nordisk: Other: research funding paid to Luigi Villa Foundation, Research Funding, Speakers Bureau; SOBI: Speakers Bureau; Bayer: Speakers Bureau.