Ibrutinib plus Obinutuzumab as Frontline Therapy for Chronic Lymphocytic Leukemia Is Associated with a Lower Rate of Infusion-Related Reactions and with Sustained Remissions after Ibrutinib Discontinuation: A Single-Arm, Open-Label, Phase 1b/2 Clinical Trial NCT0231576.

Ibrutinib-based therapies are costly and require continuous administration. We hypothesized combining BTK inhibition with anti-CD20 monoclonal antibodies would yield deep remissions allowing discontinuation. We enrolled 32 therapy-naïve CLL patients to receive ibrutinib plus obinutuzumab, followed by single-agent ibrutinib. Patients could discontinue ibrutinib after 36 months with sustained complete response (CR). We evaluated treatment safety, efficacy, and outcomes after ibrutinib discontinuation. The overall response rate was 100%, 28% achieved a CR, and 12.5% achieved bone marrow undetectable minimal residual disease. At a three-year median follow-up, 91% remain in remission with 100% overall survival. Five patients in sustained CR stopped ibrutinib and have not progressed. Eight non-CR patients discontinued for other reasons, with only two progressing. The treatment was safe, with a lower IRR rate. All patients responded to treatment with longer time-to-progression after discontinuation of ibrutinib. Our data support the evaluation of ibrutinib discontinuation strategies in more extensive clinical trials (https://Clinicaltrials.gov Identifier https://clinicaltrials.gov/ct2/show/NCT02315768).

Prognostic Testing and Treatment Patterns in Chronic Lymphocytic Leukemia in the Era of Novel Targeted Therapies: Results From the informCLL Registry.

INTRODUCTION: The therapeutic landscape for chronic lymphocytic leukemia (CLL) has significantly shifted with the approval of novel agents. Understanding current prognostic testing and treatment practices in this new era is critical. Beginning enrollment in 2015, informCLL is the first United States-based real-world, prospective, observational registry that initiated enrollment after approval of novel agents. PATIENTS AND METHODS: Eligible patients were age ≥ 18 years, started CLL treatment within 30 days of enrollment, and provided consent. For this planned interim analysis, treatments were classified into 5 groups: ibrutinib, chemoimmunotherapy, chemotherapy, immunotherapy, and other novel agents. RESULTS: Frequency of prognostic testing and treatment patterns are reported among 840 patients (459 previously untreated; 381 relapsed/refractory), enrolled largely (96%) from community practice settings. Testing for chromosomal abnormalities by fluorescence in situ hybridization, TP53 mutation, or IGHV mutation status occurred infrequently among all patients (31%, 11%, and 11%, respectively). Chemoimmunotherapy was the most common treatment in previously untreated patients (42%), whereas ibrutinib was the most common treatment among relapsed/refractory patients (51%). Of patients who tested positive for del(17p) or TP53 mutation, 34% and 26% received chemoimmunotherapy, respectively. Among patients who did not have fluorescence in situ hybridization or TP53 mutation testing prior to enrollment, 33% and 32% received chemoimmunotherapy, respectively. CONCLUSION: Our findings indicate that prognostic testing rates were poor, and approximately one-third of high-risk patients (del[17p] and TP53) received chemoimmunotherapy, which is not aligned with current CLL treatment recommendations. This represents an opportunity to educate and alert health care professionals about the necessity of prognostic testing to guide optimal CLL treatment decisions.

Targeting the CXCR4 pathway using a novel anti-CXCR4 IgG1 antibody (PF-06747143) in chronic lymphocytic leukemia.

BACKGROUND: The CXCR4-CXCL12 axis plays an important role in the chronic lymphocytic leukemia (CLL)-microenvironment interaction. Overexpression of CXCR4 has been reported in different hematological malignancies including CLL. Binding of the pro-survival chemokine CXCL12 with its cognate receptor CXCR4 induces cell migration. CXCL12/CXCR4 signaling axis promotes cell survival and proliferation and may contribute to the tropism of leukemia cells towards lymphoid tissues and bone marrow. Therefore, we hypothesized that targeting CXCR4 with an IgG1 antibody, PF-06747143, may constitute an effective therapeutic approach for CLL. METHODS: Patient-derived primary CLL-B cells were assessed for cytotoxicity in an in vitro model of CLL microenvironment. PF-06747143 was analyzed for cell death induction and for its potential to interfere with the chemokine CXCL12-induced mechanisms, including migration and F-actin polymerization. PF-06747143 in vivo efficacy was determined in a CLL murine xenograft tumor model. RESULTS: PF-06747143, a novel-humanized IgG1 CXCR4 antagonist antibody, induced cell death of patient-derived primary CLL-B cells, in presence or absence of stromal cells. Moreover, cell death induction by the antibody was independent of CLL high-risk prognostic markers. The cell death mechanism was dependent on CXCR4 expression, required antibody bivalency, involved reactive oxygen species production, and did not require caspase activation, all characteristics reminiscent of programmed cell death (PCD). PF-06747143 also induced potent B-CLL cytotoxicity via Fc-driven antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity activity (CDC). PF-06747143 had significant combinatorial effect with standard of care (SOC) agents in B-CLL treatment, including rituximab, fludarabine (F-ara-A), ibrutinib, and bendamustine. In a CLL xenograft model, PF-06747143 decreased tumor burden and improved survival as a monotherapy, and in combination with bendamustine. CONCLUSIONS: We show evidence that PF-06747143 has biological activity in CLL primary cells, supporting a rationale for evaluation of PF-06747143 for the treatment of CLL patients.

Biomarkers in chronic lymphocytic leukemia: Clinical applications and prognostic markers.

Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with a variable clinical course. The Rai and Binet staging systems are often used to predict survival. However, they do not take into account other biological characteristics of CLL cells that may influence the disease course and response to treatment. Prognostic factors such as chromosome abnormalities (trisomy 12, 11q deletions and 17p deletions), ß2 microglobulin, thymidine kinase, CD38 and ZAP-70 expression, IGHV mutation status, and mutations in genes such as NOTCH1, MYD88, SF3B1, and ATM are also predictors of prognosis. These biological markers have enabled the development of multiparameter risk models to predict overall survival. In addition, these models are useful for treatment decisions, as they can identify patients that could be treated with clinical trials vs. standard of care therapies. This chapter will review the most important prognostic markers that have been described in CLL and their application in clinical practice.

Ulocuplumab (BMS-936564 / MDX1338): a fully human anti-CXCR4 antibody induces cell death in chronic lymphocytic leukemia mediated through a reactive oxygen species-dependent pathway.

The CXCR4 receptor (Chemokine C-X-C motif receptor 4) is highly expressed in different hematological malignancies including chronic lymphocytic leukemia (CLL). The CXCR4 ligand (CXCL12) stimulates CXCR4 promoting cell survival and proliferation, and may contribute to the tropism of leukemia cells towards lymphoid tissues. Therefore, strategies targeting CXCR4 may constitute an effective therapeutic approach for CLL. To address that question, we studied the effect of Ulocuplumab (BMS-936564), a fully human IgG4 anti-CXCR4 antibody, using a stroma--CLL cells co-culture model. We found that Ulocuplumab (BMS-936564) inhibited CXCL12 mediated CXCR4 activation-migration of CLL cells at nanomolar concentrations. This effect was comparable to AMD3100 (Plerixafor--Mozobil), a small molecule CXCR4 inhibitor. However, Ulocuplumab (BMS-936564) but not AMD3100 induced apoptosis in CLL at nanomolar concentrations in the presence or absence of stromal cell support. This pro-apoptotic effect was independent of CLL high-risk prognostic markers, was associated with production of reactive oxygen species and did not require caspase activation. Overall, these findings are evidence that Ulocuplumab (BMS-936564) has biological activity in CLL, highlight the relevance of the CXCR4-CXCL12 pathway as a therapeutic target in CLL, and provide biological rationale for ongoing clinical trials in CLL and other hematological malignancies.

Respuesta inflamatoria en pacientes con un primer ataque cerebrovascular isquémico: evaluación por género / Inflammatory response in a first ischemic stroke: differences by gender

Introducción. Se han descrito diferencias por género en la incidencia, la severidad y mortalidad asociadas al ataque cerebrovascular isquémico. Objetivo. Describir el comportamiento de la respuesta inflamatoria en hombres y mujeres con un primer episodio de ACV isquémico. Material y Métodos. Se incluyeron 50 mujeres postmenopáusicas mayores de 45 años y 50 hombres mayores de 45 años con un primer episodio de ataque cerebrovascular isquémico. Se evaluaron y analizaron diferencias en la presentación de síntomas, antecedentes, severidad, respuesta inflamatoria y mortalidad entre ambos géneros. Resultados. Las mujeres tuvieron un promedio de edad mayor al momento de presentar un primer ataque cerebrovascular isquémico (72,9 ± 9,8 años vs. 69,7 ± 9,03 años; p= 0,09), sin diferencias en la severidad del evento (mediana NIHSS 10,4 ± 7,61 en mujeres vs. 10,46 ± 4,96 en hombres), con mayores niveles de colesterol total (216,39 ± 50,61 vs. 188,76 ± 49,56; p=0,007), LDL (140,40 ± 39,57 vs. 121,3 ± 45,36; p=0,032), HDL (44,69 ± 15,52 vs. 37,67 ± 12,23; p= 0,013), triglicéridos (158,03 ± 74,65 vs. 144,05 ± 55,64; p=0,291) y glicemia (142,77 ± 71,60 vs. 138,16 ± 115,75; p=0,826), menor respuesta inflamatoria evaluada por PCR ultrasensible, IL-6 y TNFα, y mortalidad hospitalaria que los hombres (6,52% vs. 14%; p=0,231). Conclusión. Se propone que las diferencias por género en el comportamiento del ACV isquémico observadas en este estudio podrían ser explicadas por la protección cardiovascular hormonal extendida o la existencia de factores inherentes en las mujeres que les confieren un estado de protección ante un ACV isquémico.

Introduction. Controversy persists regarding gender differences in the incidence, severity and mortality associated with ischemic stroke. Objective. To describe the inflematory response in patients with a first ischemic stroke behavior in women and men over 45 year-old. Materials and Methods. 50 postmenopausal women and 50 men, over 45 years old with a first-ever ischemic stroke were included. Differences in symptoms, medical history, severity, inflammatory response and mortality were evaluated and analyzed among both genders. Results: Postmenopausal women were older at the first-ever ischemic stroke (72,9 + 9,8 years vs. 69,7 + 9,03 years, p=0,09), with no differences in stroke severity (NIHSS median score 10,4 + 7,61 in women vs. 10,46 + 4,96 in men), with higher levels of total cholesterol (216,39 + 50,61 vs. 188,76 + 49,56; p=0,007), LDL cholesterol (140,40 + 39,57 vs. 121,3 + 45,36; p=0,032), HDL cholesterol (44,69 + 15,52 vs. 37,67 + 12,23; p= 0,013), triglycerides (158,03 + 74,65 vs. 144,05 + 55,64; p=0,291) and blood glucose (142,77 + 71,60 vs. 138,16 + 115,75; p=0,826); less inflammatory response assessed by CRP, IL-6 and TNF-α, and hospital mortality than men (6,52% vs. 14%, p=0,231). Conclusion. Gender differences in ischemic stroke behavior observed in this study could be explained by the cardiovascular protection of premenopausal hormonal factors or inherent factors in women that confers a protection state against ischemic stroke.