Contributions
Abstract: PB1881
Type: Publication Only
Background
Chronic Lymphocytic Leukemia (CLL) is characterized by immune disregulation, often including hypogammaglobulinemia, which contributes to a high rate of infections. Ibrutinib (IBR) seems to generate partial reconstitution of normal B cells and humoral immunity, expecially increase of IgA, in CLL. Frequent IBR associated side-effects are bleeding events, usually mild (Common Toxicity Criteria (CTC) grade1-2), rarely severe (grade3-4). A defect of platelet function, namely an inhibition of Btk-and Tec-mediated signaling downstream platelet glycoproteins GPVI and GPIb, has been hypothesized to cause these bleedings.
Aims
To investigate immune reconstitution and to characterize clinical and laboratory features of platelet dysfunction during IBR.
Methods
We report our monocentric retrospective study on immunological recovery and bleeding in CLL patients (pts) treated with IBR. From May 2014 to December 2017 we treated 27 pts with IBR for progressive naïve CLL if pts harboring del17p/TP53 mutation or with relapsed or refractory disease. In these pts before and 1, 3, 6, 9 and 12 months after beginning of therapy immunological reconstitution was investigated by measuring IgG, IgM, IgA levels, CD3 T lymphocytes, CD4 and CD8 T-helper and T-suppressor subset, B lymphocytes CD19+ and NK lymphocytes CD16/56+ by flow cytometry and platelet dysfunction was investigated by light transmission aggregometry using platelet-rich plasma and ADP, PAR1-AP, Collagen, Arachidonic Acid, ristocetin as platelet agonists. At each time point the grade of bleeding was measured by CTC score. No pts received concomitant antiplatelet or anticoagulant therapy.
Results
Immunoglobulin levels did not show any change during the study period. Median values were constantly belove the normal range during IBR. Immunological reconstitution showed a rapid increse of CD19+ lymphocytes above the normal range after 1 month of IBR and rapidly decreased to normal values. CD3+ lymphocytes remained into the normal from baseline to 12 months during IBR, the subset CD4+ decreased from months 3 to 12 with median values belove the normal range, on the contrary CD8 showed a progressive increase during the same period with median values into the normal range. CD16/56+ were into the normal range during the study period. We recorded CTC grade 1 or 2 bleedings (bruising, petechiae, conjunctival and retinal hemorrhage, rectal bleeding) in 18 pts; no pts needed IBR interruption or dose reduction. All pts displayed severe impairment of collagen induced aggregation during IBR. On the contrary, the aggregation by low-dose ADP significantly improved. The aggregation by PAR1-AP, ristocetin and arachidonic acid was unchanged before and under IBR. In 18 pts the vWF:Ag and RiCo were high at the onset of the disease and reduced up to normal values under IBR.
Conclusion
There was no improvement of humural immunity in our pts even after 12 months of IBR, after response to therapy. As expected, B-lymphocytes rapidly decreased up to the normal range after 1 month; T-cell compartment remained within normal values, with a trend toward an increase of T-Suppressor and a reduction of T-Helper after 12 months of treatment, which contributes to cellular immune reconstitution. Our study showed minor bleedings in pts treated with IBR. A severe impairment of collagen-induced aggregation was caused by IBR, which was counteracted by amelioration of ADP-induced aggregation. Finally, pts under anticoagulant or antiplatelet treatment might need be carefully monitored by clinical and laboratory evaluation.
Session topic: 6. Chronic lymphocytic leukemia and related disorders - Clinical
Keyword(s): Bleeding, Chronic Lymphocytic Leukemia, ibrutinib, Immune reconstitution
Abstract: PB1881
Type: Publication Only
Background
Chronic Lymphocytic Leukemia (CLL) is characterized by immune disregulation, often including hypogammaglobulinemia, which contributes to a high rate of infections. Ibrutinib (IBR) seems to generate partial reconstitution of normal B cells and humoral immunity, expecially increase of IgA, in CLL. Frequent IBR associated side-effects are bleeding events, usually mild (Common Toxicity Criteria (CTC) grade1-2), rarely severe (grade3-4). A defect of platelet function, namely an inhibition of Btk-and Tec-mediated signaling downstream platelet glycoproteins GPVI and GPIb, has been hypothesized to cause these bleedings.
Aims
To investigate immune reconstitution and to characterize clinical and laboratory features of platelet dysfunction during IBR.
Methods
We report our monocentric retrospective study on immunological recovery and bleeding in CLL patients (pts) treated with IBR. From May 2014 to December 2017 we treated 27 pts with IBR for progressive naïve CLL if pts harboring del17p/TP53 mutation or with relapsed or refractory disease. In these pts before and 1, 3, 6, 9 and 12 months after beginning of therapy immunological reconstitution was investigated by measuring IgG, IgM, IgA levels, CD3 T lymphocytes, CD4 and CD8 T-helper and T-suppressor subset, B lymphocytes CD19+ and NK lymphocytes CD16/56+ by flow cytometry and platelet dysfunction was investigated by light transmission aggregometry using platelet-rich plasma and ADP, PAR1-AP, Collagen, Arachidonic Acid, ristocetin as platelet agonists. At each time point the grade of bleeding was measured by CTC score. No pts received concomitant antiplatelet or anticoagulant therapy.
Results
Immunoglobulin levels did not show any change during the study period. Median values were constantly belove the normal range during IBR. Immunological reconstitution showed a rapid increse of CD19+ lymphocytes above the normal range after 1 month of IBR and rapidly decreased to normal values. CD3+ lymphocytes remained into the normal from baseline to 12 months during IBR, the subset CD4+ decreased from months 3 to 12 with median values belove the normal range, on the contrary CD8 showed a progressive increase during the same period with median values into the normal range. CD16/56+ were into the normal range during the study period. We recorded CTC grade 1 or 2 bleedings (bruising, petechiae, conjunctival and retinal hemorrhage, rectal bleeding) in 18 pts; no pts needed IBR interruption or dose reduction. All pts displayed severe impairment of collagen induced aggregation during IBR. On the contrary, the aggregation by low-dose ADP significantly improved. The aggregation by PAR1-AP, ristocetin and arachidonic acid was unchanged before and under IBR. In 18 pts the vWF:Ag and RiCo were high at the onset of the disease and reduced up to normal values under IBR.
Conclusion
There was no improvement of humural immunity in our pts even after 12 months of IBR, after response to therapy. As expected, B-lymphocytes rapidly decreased up to the normal range after 1 month; T-cell compartment remained within normal values, with a trend toward an increase of T-Suppressor and a reduction of T-Helper after 12 months of treatment, which contributes to cellular immune reconstitution. Our study showed minor bleedings in pts treated with IBR. A severe impairment of collagen-induced aggregation was caused by IBR, which was counteracted by amelioration of ADP-induced aggregation. Finally, pts under anticoagulant or antiplatelet treatment might need be carefully monitored by clinical and laboratory evaluation.
Session topic: 6. Chronic lymphocytic leukemia and related disorders - Clinical
Keyword(s): Bleeding, Chronic Lymphocytic Leukemia, ibrutinib, Immune reconstitution