scholarly journals Phosphatidylinositol 3-Kinase (PI3K) Inhibitors-Related Hematological Toxicities in Patients with Relapsed and Refractory Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5877-5877
Author(s):  
Bradley J. Grant ◽  
Anita Sultan ◽  
Nicholas D'Cunha ◽  
Chandler Graf ◽  
Sriman Swarup ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Adverse Effects ◽  
Febrile Neutropenia ◽  
B Cell ◽  
Selective Inhibitor ◽  
Lymphocytic Leukemia ◽  
Phosphatidylinositol 3 Kinase ◽  
Small Lymphocytic Lymphoma ◽  
Phase 3 ◽  
Pi3k Inhibitors

Introduction: Chronic lymphocytic leukemia is the most prevalent adult leukemia in western countries. Phosphatidylinositol 3-kinase (PI3K) is a kinase protein involved in downstream signaling for the B-cell receptor signaling pathway and has been shown to involve in the pathogenesis of chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL/ SLL) by promoting B-cell survival, proliferation and metabolism. Two prominent PI3K inhibitors, idelalisib (PI3Kδ-selective inhibitor) and duvelisib (PI3Kδ/γ-combinatorial inhibitor), have recently shown to improve survival in patients with relapsed and refractory CLL/ SLL. We undertook a systematic review and meta-analysis of phase 3 randomized controlled trials to determine the risk of hematological toxicities associated with PI3K inhibitors. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2019. Phase 3 RCTs utilizing PI3K inhibitors in patients with relapsed and refractory CLL/SLL that mention hematological toxicities as adverse effects were incorporated in the analysis. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Random effects model was applied. Results: Four phase 3 RCTs with a total of 1,216 patients with relapsed and refractory CLL/SLL were included. Studies compared ofatumumab vs idelalisib+ofatumumab, rituximab vs idelalisib+rituximab, bendamustine+ rituximab vs idelalisib+bendamustine+rituximab and ofatumumab vs duvelisib. The randomization ratio was 2:1 in Jones et al. study and 1:1 in other studies. The I2 statistic for heterogeneity was 49, suggesting some heterogeneity among RCTs. The RR of all-grade side effects were as follows: anemia, 1.39 (95% CI: 0.89 - 2.17; p = 0.15); neutropenia, 1.33 (95% CI: 1.06 - 1.67; p = 0.02); and thrombocytopenia, 1.23 (95% CI: 0.69 - 2.18; p = 0.48). The RR of high-grade adverse effects were as follows: anemia, 1.29 (95% CI: 0.62 - 2.67, p = 0.50); neutropenia, 1.51 (95% CI: 1.22 - 1.88; p = 0.0001); and thrombocytopenia, 1.21 (95% CI: 0.66 - 2.22; p = 0.53). The incidence of febrile neutropenia was 76 (11.69%) in study group vs 22 (3.92%) in control group with RR of 2.62 (95% CI: 1.27 -5.41, P = 0.009). Conclusions: PI3K inhibitors, idelalisib (PI3Kδ-selective inhibitor) and duvelisib (PI3Kδ/γ-combinatorial inhibitor), increased the risk of all grades of neutropenia and febrile neutropenia, with RR of 2.62 for febrile neutropenia, in patients with relapsed and refractory CLL/SLL. Vigilant monitoring is warranted, and proper supportive care and dose modifications should be followed. Disclosures No relevant conflicts of interest to declare.

scholarly journals Efficacy of Phosphatidylinositol 3-Kinase (PI3K) Inhibitors in Patients with Relapsed and Refractory Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5480-5480
Author(s):  
Anita Sultan ◽  
Bradley J. Grant ◽  
Donald P. Quick ◽  
Chandler Graf ◽  
Sriman Swarup ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Selective Inhibitor ◽  
Lymphocytic Leukemia ◽  
Phosphatidylinositol 3 Kinase ◽  
Small Lymphocytic Lymphoma ◽  
Phase 3 ◽  
Pi3k Inhibitors ◽  
Tp53 Status ◽  
Phosphatidylinositol 3

Introduction: Chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL/ SLL) is the most common adult lymphoproliferative disorder in western countries and the B-cell receptor signaling pathway has been shown to be involved in the pathogenesis of CLL/ SLL. Phosphatidylinositol 3-kinase (PI3K) is a kinase protein in downstream signaling for multiple pathways in B cells, promoting B-cell survival, proliferation and metabolism. Two prominent PI3K inhibitors, idelalisib (PI3Kδ-selective inhibitor) and duvelisib (PI3Kδ/γ-combinatorial inhibitor), are currently being studied in the treatment of relapsed and refractory CLL/ SLL. The purpose of our study is to explore and consolidate the efficacy of PI3K inhibitors in patients with relapsed and refractory CLL/SLL. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2019. Phase 3 RCTs utilizing PI3K inhibitors in patients with relapsed and refractory CLL/SLL were incorporated in the analysis. A generic inverse variance method was used to calculate the estimated pooled hazard ratio (HR) for progression-free survival (PFS) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q -statistic. Random effects model was applied. Results: Four phase 3 RCTs with a total of 1,216 patients with relapsed and refractory CLL/SLL were eligible for analysis. Studies compared ofatumumab vs idelalisib+ofatumumab, rituximab vs idelalisib+rituximab, bendamustine+ rituximab vs idelalisib+bendamustine+rituximab and ofatumumab vs duvelisib. The randomization ratio was 2:1 in the study by Jones et al. and 1:1 in other studies. The I2 statistic for heterogeneity was 82%, suggesting moderate heterogeneity among RCTs. The overall pooled HR for PFS was statistically significant at 0.30 (95% CI: 0.20- 0.47; P < 0.0001). The PFS benefit was observed across all ages and regardless of del 17p or TP53 status; age <65 (HR, 0.35; 95% CI: 0.27- 0.46; P < 0.0001), age ≥65 (HR, 0.32; 95% CI: 0.19- 0.54; P < 0.0001), either del 17p or TP53 cohort (HR, 0.33; 95% CI: 0.21- 0.52; P < 0.0001), and neither del 17p nor TP53 cohort (HR, 0.32; 95% CI: 0.19- 0.54; P < 0.0001). In the subset of patients with CLL treated with idelalisib, the pooled HR for PFS was statistically significant at 0.26 (95% CI: 0.18-0.37; P < 0.0001) and the PFS benefit was observed across all ages, and regardless of del17p or TP53 status and IGHV mutation status; age <65 (HR, 0.32; 95% CI: 0.24- 0.43; P < 0.0001), age ≥65 (HR, 0.26; 95% CI: 0.14- 0.47; P < 0.0001), either del17p or TP53 cohort (HR, 0.29; 95% CI: 0.15- 0.57; P = 0.0003), neither del17p nor TP53 cohort (HR, 0.26; 95% CI: 0.20- 0.35; P < 0.0001), IGHV mutated cohort (HR, 0.29; 95% CI: 0.17- 0.51; P < 0.0001), and IGHV unmutated cohort (HR, 0.25; 95% CI: 0.15- 0.40; P < 0.0001). Conclusions: Our study showed that PI3K inhibitors, idelalisib (PI3Kδ-selective inhibitor) and duvelisib (PI3Kδ/γ-combinatorial inhibitor), significantly improved PFS in patients with relapsed and refractory CLL/ SLL regardless of age and poor prognostic features such as del17p or TP53 and IGHV unmutated status, compared to control arm. The efficacy of these drugs must be balanced against the possible side effects. Disclosures No relevant conflicts of interest to declare.

scholarly journals Incidence of Serious Adverse Events, Pneumonitis, Infection and Sepsis in Patients with Relapsed and Refractory Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma Treated with Phosphatidylinositol 3-Kinase (PI3K) Inhibitors

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 798-798
Author(s):  
Sriman Swarup ◽  
Donald P. Quick ◽  
Anita Sultan ◽  
Myint Aung Win ◽  
Ei Moe Phyu ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Adverse Events ◽  
Lymphocytic Leukemia ◽  
Control Group ◽  
Study Group ◽  
Phosphatidylinositol 3 Kinase ◽  
Small Lymphocytic Lymphoma ◽  
Phase 3 ◽  
Serious Adverse Events ◽  
Pi3k Inhibitors

Introduction: Phosphatidylinositol 3-kinase (PI3K) is a kinase protein involved in downstream signaling for multiple pathways in B cells and is important for B cell survival, proliferation and metabolism. Hence, PI3K inhibitors have become an attractive therapeutic option for treatment of B cell malignancies. Two prominent PI3K inhibitors, (PI3Kδ-selective inhibitor) and duvelisib (PI3Kδ/γ-combinatorial inhibitor), are currently being studied in relapsed and refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) and have shown to improve survival in recent trials with notable toxicities. We analyzed phase 3 trials to assess the incidence of serious adverse events, pneumonitis, infection and sepsis associated with PI3K inhibitors in this susceptible population. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2019. Phase 3 RCTs utilizing PI3K inhibitors in patients with relapsed and refractory CLL/SLL that mention serious adverse events, pneumonitis, infection and sepsis as adverse effects were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR), and risk difference (RD) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Random effects model was applied. Results: Four phase 3 RCTs with a total of 1,216 patients with relapsed and refractory CLL/SLL were included in analysis. Studies compared ofatumumab vs idelalisib+ofatumumab, rituximab vs idelalisib+rituximab, bendamustine+ rituximab vs idelalisib+bendamustine+rituximab and ofatumumab vs duvelisib. The randomization ratio was 2:1 in Jones et al. study and 1:1 in other studies. The I2 statistic for heterogeneity was 49, suggesting some heterogeneity among RCTs. The incidence of serious adverse events was 479 (73.69%) in study group vs 252 (44.92%) in control group (RR, 1.58; 95% CI: 1.37 - 1.83; P &lt; 0.0001 and RD, 0.26; 95% CI: 0.13 - 0.40; P = 0.0002). Pneumonitis was noted in 20 (3.07%) vs 1 (0.18%) in control group with RR of 6.53 (95% CI: 1.74 -24.53; P = 0.005) and RD of 0.02 (95% CI: 0.01 - 0.04; P = 0.0004). The incidence of any-grade pneumonia was 107 (16.46%) in study group vs 54 (9.63%) in control group (RR, 1.61; 95% CI: 1.00 - 2.58; P = 0.05). High-grade pneumonia was reported in 81 (12.46%) in idelalisib arm versus 35 (6.24%) in control group with RR of 1.84 (95% CI: 0.82 - 4.13; P = 0.14). Pneumocystis jiroveci pneumonia (PJP) rate was 2.24% higher in study group compared to control arm (RR, 3.87; 95% CI: 1.22 - 12.29; P = 0.02). Any-grade upper respiratory tract infection (URTI) was 14% in study group versus 7.84% in control arm (RR, 1.65; 95% CI: 1.17 - 2.34; P = 0.005). Sepsis rate was 2.88% higher in idelalisib group compared to control arm and the pooled RR was statistically significant at 2.68 (95% CI: 1.19 - 6.04, P = 0.02). Treatment-related deaths were 64 (11.85%) in study arm vs 28 (6.17%) in control arm according to analysis of 3 trials. The pooled RR was also statistically significant at 1.87 (95% CI: 1.21 -2.88; P = 0.005). Conclusions: Our meta-analysis showed that the incidence of serious adverse events, pneumonitis, PJP pneumonia, any-grade URTI and sepsis was significantly higher in PI3K inhibitors group with RR of 1.58 for serious adverse events, RR of 6.53 for pneumonitis, RR of 3.87 for PJP pneumonia and RR of 2.68 for sepsis respectively. Moreover, patients on PI3K inhibitors experienced 5.68% higher incidence of treatment-related deaths with RR of 1.87, compared to control arm. Since treatment-related serious toxicities and deaths are higher amongst patients treated with these agents, extra caution should be observed and recommended with their use. Disclosures No relevant conflicts of interest to declare.

scholarly journals First-line treatment of chronic lymphocytic leukemia with ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab: final analysis of the randomized, phase 3 iLLUMINATE trial

Haematologica ◽  
2022 ◽  
Author(s):  
Carol Moreno ◽  
Richard Greil ◽  
Fatih Demirkan ◽  
Alessandra Tedeschi ◽  
Bertrand Anz ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Final Analysis ◽  
Lymphocytic Leukemia ◽  
Small Lymphocytic Lymphoma ◽  
First Line ◽  
Open Label ◽  
Phase 3 ◽  
First Line Therapy ◽  
Line Therapy ◽  
Open Label Phase

iLLUMINATE is a randomized, open-label phase 3 study of ibrutinib plus obinutuzumab (n=113) versus chlorambucil plus obinutuzumab (n=116) as first-line therapy for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma. Eligible patients were aged ≥65 years, or

scholarly journals COMPARISON OF CHROMOSOMAL REARRANGEMENTS IN BONE MARROW CELLS AND BLAST TRANSFORMED B-CELLS IN RELAPSE OF B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA/ SMALL LYMPHOCYTIC LYMPHOMA

2017 ◽  
Vol 39 (2) ◽  
pp. 141-144
Author(s):  
S V Andreieva ◽  
K V Korets ◽  
O E Ruzhinska ◽  
I M Skorokhod ◽  
O G Alkhimova
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Chromosomal Rearrangements ◽  
Lymphocytic Leukemia ◽  
Banding Technique ◽  
Small Lymphocytic Lymphoma ◽  
Detection Frequency ◽  
Cell Chronic Lymphocytic Leukemia

Aim: The genetic mechanisms of resistance to chemotherapy in B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CLL/SLL) are not clear. We aimed to determine the peculiarities of abnormal karyotype formation in bone marrow (BM) cells and peripheral blood (PB) blast transformed B-cells in relapse of B-CLL/SLL. Materials and Methods: Cytogenetic GTG banding technique and molecular cytogenetic in interphase cells (i-FISH) studies of BM cells and PB blast transformed B-lymphocytes were performed in 14 patients (10 males and 4 females) with B-CLL/SLL. Results: The results of karyotyping BM and PB cells revealed the heterogeneity of cytogenetic abnormalities in combined single nosological group of B-CLL/SLL. In PB B-cells, chromosome abnormalities related to a poor prognosis group were registered 2.5 times more often than in BM cells. Additional near tetraploid clones that occurred in 57.1% cases were the peculiar feature of BM cell karyotypes. Chromosomal rearrangements characteristic of the group of adverse cytogenetic prognosis were revealed in all cases from which in 2 cases by karyotyping BM cells, in 6 cases in PB B-cells and in 8 cases by the i-FISH method in BM cells, i.e. their detection frequency was 3 times higher in PB B-cells and 4 times higher when analyzing by i-FISH in BM cells. Conclusions: Mismatch in abnormal karyotypes in BM and PB B-cells by the presence of quantitative and structural chromosomal rearrangements may be indicative of simultaneous and independent processes of abnormal clone formation in the lymph nodes and BM hematopoietic cells. Accumulation the information about previously unidentified chromosomal rearrangements in relapse of the disease may help to understand the ways of resistance formation to chemotherapy.

CLO19-024: Risk of Atrial Fibrillation and Pulmonary Toxicities in Patients With Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma Treated With Ibrutinib

2019 ◽  
Vol 17 (3.5) ◽  
pp. CLO19-024
Author(s):  
Nimesh Adhikari ◽  
Myo H. Zaw ◽  
Sriman Swarup ◽  
Anita Sultan ◽  
Upama Sharma ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Relative Risk ◽  
Side Effects ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Respiratory Infections ◽  
Meta Analysis ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
Small Lymphocytic Lymphoma

Background: Bruton’s tyrosine kinase (BTK), a kinase downstream of the B-cell receptor, involves in the B cell survival and proliferation and has become an attractive therapeutic target. Ibrutinib is an oral potent, covalent inhibitor of BTK and hence employed in many hematologic malignancies. We performed a systematic review and pooled analysis of randomized controlled trials (RCTs) to determine the risk of atrial fibrillation (AF) and pulmonary toxicities among patients treated with ibrutinib. Methods: We performed a comprehensive literature search using MEDLINE, EMBASE databases, and meeting abstracts through September 2018. Phase 3 RCTs that mention AF and pulmonary toxicities as adverse effects were incorporated in the analysis. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio with 95% CI. Random effects model was applied. Results: 4 phase III RCTs with a total of 1,383 patients with chronic lymphocytic leukemia or small lymphocytic lymphoma were eligible. Studies comparing Ibrutinib (I) vs ofatumumab, I vs chlorambucil, I+ bendamustine (B)+ rituximab (R) vs placebo + B+ R, and I vs R were included in the analysis. The AF incidence was 41 (5.686%) in the ibrutinib group vs 8 (1.208%) in the control arm. The relative risk (RR) for AF was statistically significant at 3.825 (95% CI: 1.848–7.917; P<.0001) and RD was 0.041 (95% CI: 0.023–0.059; P<.0001). The RR of all-grade side effects was as follows: cough, 1.133 (95% CI: 0.724–1.773; P=.584); edema, 1.375 (95% CI: 0.943–2.006; P=.098); pneumonia, 1.227 (95% CI: 0.884–1.703; P=.221); and upper respiratory infections (URI), 1.075 (95% CI: 0.809–1.429; P=.616). The RR of high-grade side effects was as follows: cough, 0.373 (95% CI: 0.063–2.209; P=.277); edema, 1.232 (95% CI: 0.199–7.649; P=.822); pneumonia, 1.277 (95% CI: 0.847–1.926; P=.243); and URI, 1.555 (95% CI: 0.239–10.127; P=.644). Conclusion: Our meta-analysis demonstrated that patients on ibrutinib noted a significant increase in the risk of atrial fibrillation with a relative risk of 3.825. However, the risk of pulmonary toxicities was not statistically increased in the ibrutinib group.

Chronic Lymphocytic Leukemia with Bi-Nucleated Lymphocytes

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5285-5285 ◽  
Author(s):  
Amin Hrushik ◽  
Lisa Thomas ◽  
Qi Shi ◽  
Sudeep Ruparelia ◽  
Alfonso Zangardi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Lymph Node ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Lymphocyte Count ◽  
Morphological Feature ◽  
Inguinal Lymph Node ◽  
Absolute Lymphocyte Count ◽  
Lymphocytic Leukemia ◽  
Small Lymphocytic Lymphoma

Abstract Introduction: B-cell chronic lymphocytic leukemia is one of the common lymphoproliferative disorders in the adult patient population. It is very uncommon to find bi-nucleated lymphocytes as a morphological feature in this disorder. Our patient was diagnosed with CLL and was found to have bi-nucleated lymphocytes in the peripheral smear. The mechanism behind this type of morphological feature of lymphocytes is unknown in CLL, and whether it has prognostic value on disease outcome is undetermined. Case Description: 62 y/o man was referred to hematology oncology after diagnosis of small cell lymphocytic leukemia was made s/p a right inguinal lymph node biopsy. His CBC revealed a wbc count of 14,000, Rbc count of 4,360, Absolute lymphocyte count of 11,500 and Platelet count of 125,000. The patient did not have any B-symptoms. On physical exam, a pertinent finding was palpable right axillary adenopathy. The CT of abdomen /pelvic to evaluate these findings. This revealed extensive axillary, abdominal/pelvic lymphadenopathy, hepatosplenomegaly and cardio phrenic lymphadenopathy. The patient had a biopsy of the right inguinal lymph node as well as bone marrow biopsy. Biopsy results showed small lymphocytic cells, some of which show occasional large nucleoli were consistent with small lymphocytic lymphoma/chronic lymphocytic leukemia, and morphologic characteristics of the lymphocytes showed bi-nucleated lymphocytes in peripheral blood smear (figure A). Flow cytometric analysis confirmed a lymphocytic population with lambda light chain restriction, expressing CD5, CD19, CD20, and CD23 consistent with chronic lymphocytic leukemia/small lymphocytic lymphoma. Bone marrow biopsy showed a hypercellular marrow with 75 % cellularity mainly composed of mature lymphocytes with scattered macrophages and eosinophils, Flow cytometric analysis (Clarient FI11-041053) of the bone marrow is interpreted as chronic lymphocytic leukemia/small cell lymphoma with the abnormal B cells representing 56% of the viable white cells. FISH study showed deletion of the ATM gene (11q22-23), D13S319 (13q14) and TP53 (p53) were observed in 29%, 71% and 35.5% of the cells analyzed, respectively. A subset of cells with the 13q deletion (20.5% of the total cells) showed homozygous deletion of D13S319 (13q14). ATM deletion is associated with progressive disease and poor prognosis in cases of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).He did not have any other previous history of malignancy or hematologic disorder. Discussion: B-cell chronic lymphocytic leukemia is one of the common lymphoproliferative disorders in the adult patient population. To make a diagnosis requires absolute lymphocyte count >4x10 9 and lymphoid cell morphology. In CLL, leukemic cells are small and mature appearing lymphocytes, which have regular nuclear and cytoplasmic outlines and scant weakly basophilic cytoplasm. Surface markers that define a CLL cell are proteins such as antibody light chains (kappa or lambda) and CD proteins (CD5, CD19, CD20, and CD23). In our patient absolute lymphocyte count was 11.5x109 and lymphocytic population showed surface marker lambda light chain and CD proteins CD5, CD19, CD20 and CD23 which was consistent with CLL/SLL on inguinal lymph node biopsy, but morphology of lymphocytes was small and mature bi-nucleated lymphocytes, which is very uncommon. Although bi-nucleated lymphocytes are described in a disorder "Polyclonal chronic B-cell lymphocytosis with bi-nucleated lymphocytes". Detection of an extra chromosome for the long arm of chromosome 3 +i(3)(q10) has been considered a specific marker of Polyclonal B-cell lymphocytosis with binucleated lymphocytes (PPBL),which was not present in our case. One case study by Amouroux et al, included four patients with B-cell CLL who were found to have bi-nucleated lymphocytes. Disease course was stable in one patient, one patient had an indolent course and only one required treatment due to rapid doubling time of lymphocytes. Our patient initiated chemotherapy with Rituxan and Fludara, as he had progressive disease with hepatosplenomegaly, lymph nodes and bone marrow involvement. Conclusion: Bi -nucleated lymphocytes in B-cell CLL are very rare. Explanations as to the etiology of this morphological feature in B-cell CLL is unknown. There is no sufficient evidence that bi-nucleated lymphocytes in CLL has any impact on disease progression. Disclosures No relevant conflicts of interest to declare.

A Phase 3 Study to Evaluate the Efficacy and Safety of Dinaciclib Compared to Ofatumumab in Patients with Refractory Chronic Lymphocytic Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4171-4171 ◽  
Author(s):  
Paolo Ghia ◽  
Lydia Scarfo ◽  
Kumudu Pathiraja ◽  
Martha Derosier ◽  
Karen Small ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Febrile Neutropenia ◽  
Median Survival ◽  
Stock Options ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Cdk Inhibitors ◽  
Efficacy And Safety ◽  
Phase 3 ◽  
Grade 3

Abstract Introduction: Abnormalities of cell cycle regulation have an important role in the pathogenesis of cancers. Cyclin dependent kinase (CDK) inhibitors have shown potent activity in patients with chronic lymphocytic leukemia (CLL) and other cancers. Dinaciclib (MK-7965/SCH 727965) is a novel, selective inhibitor of CDK1, CDK2, CDK5, and CDK9. Prior studies show that dinaciclib has anti-leukemic activity against CLL. The present study compared the efficacy and safety of dinaciclib with ofatumumab in patients with refractory CLL. Methods: This Phase 3 randomized, open-label, active-controlled, balanced, multi-site, group sequential confirmatory trial evaluated the progression-free survival (PFS; primary objective), overall response rate and overall survival (secondary objectives), and safety of dinaciclib vs. ofatumumab in patients with refractory CLL. Patients with a confirmed diagnosis of CLL (based on 2008 International Workshop on CLL criteria) and fludarabine or chemoimmunotherapy refractory disease were enrolled if they had no central nervous system involvement, prior allogenic bone marrow transplant or uncontrolled autoimmune anemia or thrombocytopenia. Patients previously treated with dinaciclib, ofatumumab, or other CDK inhibitors were excluded. In Cycle 1, dinaciclib was administered intravenously (IV) over 2 hours at doses of 7 mg/m2 on Day 1, 10 mg/m2 on Day 8 and 14 mg/m2 on Day 15. In Cycle 2 and thereafter, dinaciclib was dosed at 14 mg/m2 on Days 1, 8, and 15 of each 28-day cycle for a total of 12 cycles. Ofatumumab was administered IV once-weekly for 8 weeks starting in Cycle 1 on Day 1, followed by 9 monthly doses as follows: 300 mg in Cycle 1 on Day 1; 2000 mg in Cycle 1 on Days 8, 15, and 22, Cycle 2 Days 1, 8, 15, and 22, and 5 weeks later on Day 1 of Cycles 4-12. Efficacy results are from the intent to treat (ITT) population, and safety results are from the all-subjects-as-treated population. Results: In total, 44 patients were randomized (ITT) and 42 were treated (20 dinaciclib and 22 ofatumumab) due to early study termination not attributed to safety. At study entry, the median age was 62 years (range, 43-77), 32/42 (76.2%) patients were male, 26/42 (62.0%) were RAI stage III-IV, 24/42 (57.1%) had bulky disease, 40/42 (95.2%) were ECOG ≤ 1, the median number of prior therapies was 3 (range, 1-20), and 39/42 (92.9%) patients received prior fludarabine. Deletion 17p (del 17p) was present in 17/42 (38.6%) patients, 7 dinaciclib and 10 ofatumumab. Median follow-up (range) was 16.7 (0.4-26.1) months. In the dinaciclib and ofatumumab groups, respectively, 11 (55.0%) and 17 (70.8%) patients had PFS events, and median (95% CI) PFS was 59.7 (45.0, 92.1) and 25.7 (9.3, 40.7) weeks. Overall response (all partial responses) was recorded for 8 (40.0%) dinaciclib and 2 (8.3%) ofatumumab patients. Stable disease was achieved by 7 (35.0%) dinaciclib and 11 (45.8%) ofatumumab patients. Median survival (95% CI) was 21.2 (16.6, NR) months with dinaciclib and 16.7 (2.3, 20.2) months with ofatumumab; 6 (30.0%) and 11 (45.8%) patients have died in each group, respectively. There were 2 treatment-related deaths in the dinaciclib arm (pneumonia and febrile neutropenia) and none in the ofatumumab arm. Median survival (95% CI) in the del 17p population was 21.2 (1.4, 21.2) months with dinaciclib and 5.4 (0.4, NR) months with ofatumumab. Overall, 17 (85.0%) dinaciclib and 13 (59.0%) ofatumumab patients had a grade 3-5 adverse event (AE). The most common grade ≥ 3 AEs with dinaciclib and ofatumumab, respectively, were neutropenia, 7 (35.0%) vs. 2 (9.1%); thrombocytopenia, 4 (20.0%) vs. 2 (9.1%); decreased neutrophil count, 4 (20.0%) vs. 1 (4.5%); pneumonia, 1 (5.0%) vs. 3 (13.6%); sepsis, 1 (5.0%) vs. 3 (13.6%); and febrile neutropenia, 2 (10.0%) vs. 1 (4.5%). One dinaciclib patient developed tumor lysis syndrome that was deemed not treatment-related. Ten (50.0%) dinaciclib and 13 (54.2%) ofatumumab patients discontinued from the study for the following reasons: AE, 3 (15.0%) vs. 1 (4.2%); disease progression, 4 (20.0%) vs. 4 (16.7%); death, 1 (5.0%) vs. 5 (20.8%); and other/unknown, 2 (10.0%) vs. 4 (16.7%). Conclusion: The limited data from this study demonstrate potential anti-cancer activity and tolerability of dinaciclib compared with ofatumumab in patients with refractory CLL. Based on these results and given the distinct mechanism of action, combinations of dinaciclib with other novel therapies should be explored. Disclosures Ghia: Janssen: Consultancy; Acerta Pharma BV: Research Funding; Adaptive: Consultancy; Pharmacyclics: Consultancy; Roche: Consultancy, Research Funding; AbbVie: Consultancy; Gilead: Consultancy, Research Funding, Speakers Bureau; GSK: Research Funding. Pathiraja:Merck & Co., Inc.: Employment, Other: stock/stock options. Derosier:Merck & Co., Inc.: Employment, Other: stock/stock options. Small:Merck & Co., Inc.: Employment, Other: stock/stock options.

scholarly journals CD160 signaling mediates PI3K-dependent survival and growth signals in chronic lymphocytic leukemia

Blood ◽  
2010 ◽  
Vol 115 (15) ◽  
pp. 3079-3088 ◽  
Author(s):  
Feng-Ting Liu ◽  
Jerome Giustiniani ◽  
Timothy Farren ◽  
Li Jia ◽  
Armand Bensussan ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Cycle Progression ◽  
Lymphocytic Leukemia ◽  
Cytochrome C Release ◽  
Pi3k Inhibitors ◽  
Phosphoinositide 3 Kinase ◽  
Dose Dependent

Abstract B-cell chronic lymphocytic leukemia (CLL) expresses CD160, a glycosylphosphatidylinositol-linked receptor found on normal natural killer (NK) and T cells, but not B cells. CD160 is a multifunctional molecule in normal lymphocytes, but its role in CLL biology is unknown. In vitro, CLL cells undergo rapid spontaneous apoptosis, which CD160 activation protected against—mean cell viability increased from 67% to 79% (P < .001). This was associated with up-regulation of Bcl-2, Bcl-xL, and Mcl-1, but not Bax. As expected from these changes in Bcl-2/Bax and Bcl-xL/Bax ratios, CD160 triggering reduced mitochondrial membrane potential collapse and cytochrome c release. CD160 stimulation also induced DNA synthesis, cell cycle progression, and proliferation. B-cell antigen receptor (BCR)–induced CLL proliferation was generally greater than with CD160, but marked variation was seen. Both BCR and CD160 signaling led to CLL secretion of interleukin-6 (IL-6) and IL-8, although CD160 induced greater increases of IL-6 (51-fold) and IL-8 (15-fold). Survival and activation signals mediated by CD160 showed dose-dependent suppression by phosphoinositide-3 kinase (PI3K) inhibitors. Thus, in vitro, CLL cells can use the CD160 pathway for survival and activation, mimicking CD160 signaling in normal NK and CD8+ T cells. Establishing the pathophysiologic relevance of these findings may reveal new therapeutic targets.

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