Diagnosis and management of complications of chronic lymphocytic leukemia/small lymphocytic lymphoma

Chronic lymphocytic leukemia (CLL) causes early-onset immune dysregulation increasing the risk of infection, second malignancies, and autoimmune complications by poorly understood mechanisms. Targeted therapy has improved therapeutic outcomes but persistent immune deficiency remains an unresolved problem. Severe infections (20/100 patient-years) cause or contribute to over 35% of CLL-related deaths. Most identified infections are bacterial (~70%) with the commonest blood isolates being , and aureus. Viral infections (~25%) are disproportionately caused by Herpes viruses and influenza. Most common infection sites are lower respiratory tract, skin, and urogenital tract. CLL patients have an increased risk (~2-fold) of second malignancies with the commonest being squamous and basal cell skin cancer, melanoma, and lung cancer. There is a significantly increased risk of additional clonal and non-clonal non-Hodgkin lymphomas and Hodgkin lymphoma. Autoimmune cytopenias affect ~10% of CLL patients causing anemia (hemolysis and red cell aplasia), thrombocytopenia, and neutropenia. Nonhematological autoimmune complications are rare. Management of these complications requires a comprehensive multidisciplinary approach including education, preventative medicine, active monitoring, and early diagnosis and treatment. Research to better understand CLL-related immune defects and determine how to reverse them is essential for improved clinical care

Hexamerization-enhanced CD20 antibody mediates complement-dependent cytotoxicity in serum genetically deficient in C9

We examined complement-dependent cytotoxicity (CDC) by hexamer formation-enhanced CD20 mAb Hx-7D8 of patient-derived chronic lymphocytic leukemia (CLL) cells that are relatively resistant to CDC. CDC was analyzed in normal human serum (NHS) and serum from an individual genetically deficient for C9. Hx-7D8 was able to kill up to 80% of CLL cells in complete absence of C9. We conclude that the narrow C5b-8 pores formed without C9 are sufficient for CDC due to efficient antibody-mediated hexamer formation. In the absence of C9, we observed transient intracellular increases of Ca2 + during CDC (as assessed with FLUO-4) that were extended in time. This suggests that small C5b-8 pores allow Ca2 + to enter the cell, while dissipation of the fluorescent signal accompanying cell disintegration is delayed. The Ca2 + signal is retained concomitantly with TOPRO-3 (viability dye) staining, thereby confirming that Ca2 + influx represents the most proximate mediator of cell death by CDC

Differentiation of Chronic Lymphocytic Leukemia B Cells into Immunoglobulin Secreting Cells Decreases LEF-1 Expression

Lymphocyte enhancer binding factor 1 (LEF-1) plays a crucial role in B lineage development and is only expressed in B cell precursors as B cell differentiation into mature B and plasma cells silences its expression. Chronic lymphocytic leukemia (CLL) cells aberrantly express LEF-1 and its expression is required for cellular survival. We hypothesized that modification of the differentiation status of CLL cells would result in loss of LEF-1 expression and eliminate the survival advantage provided by its aberrant expression. In this study, we first established a methodology that induces CLL cells to differentiate into immunoglobulin (Ig) secreting cells (ISC) using the TLR9 agonist, CpG, together with cytokines (CpG/c). CpG/c stimulation resulted in dramatic CLL cell phenotypic and morphologic changes, expression of cytoplasmic Ig, and secretion of light chain restricted Ig. CpG/c stimulation also resulted in decreased CLL cell LEF-1 expression and increased Blimp-1 expression, which is crucial for plasma cell differentiation. Further, Wnt pathway activation and cellular survival were impaired in differentiated CLL cells compared to undifferentiated CLL cells. These data support the notion that CLL can differentiate into ISC and that this triggers decreased leukemic cell survival secondary to the down regulation of LEF-1 and decreased Wnt pathway activation

Toxicities and outcomes of 616 ibrutinib-treated patients in the United States: a real-world analysis

Clinical trials that led to ibrutinib’s approval for the treatment of chronic lymphocytic leukemia showed that its side effects differ from those of traditional chemotherapy. Reasons for discontinuation in clinical practice have not been adequately studied. We conducted a retrospective analysis of chronic lymphocytic leukemia patients treated with ibrutinib either commercially or on clinical trials. We aimed to compare the type and frequency of toxicities reported in either setting, assess discontinuation rates, and evaluate outcomes. This multicenter, retrospective analysis included ibrutinib-treated chronic lymphocytic leukemia patients at nine United States cancer centers or from the Connect® Chronic Lymphocytic Leukemia Registry. We examined demographics, dosing, discontinuation rates and reasons, toxicities, and outcomes. The primary endpoint was progression-free survival. Six hundred sixteen ibrutinib-treated patients were identified. A total of 546 (88%) patients were treated with the commercial drug. Clinical trial patients were younger (mean age 58 versus 61 years, P=0.01) and had a similar time from diagnosis to treatment with ibrutinib (mean 85 versus 87 months, P=0.8). With a median follow-up of 17 months, an estimated 41% of patients discontinued ibrutinib (median time to ibrutinib discontinuation was 7 months). Notably, ibrutinib toxicity was the most common reason for discontinuation in all settings. The median progression-free survival and overall survival for the entire cohort were 35 months and not reached (median follow-up 17 months), respectively. In the largest reported series on ibrutinib- treated chronic lymphocytic leukemia patients, we show that 41% of patients discontinued ibrutinib. Intolerance as opposed to chronic lymphocytic leukemia progression was the most common reason for discontinuation. Outcomes remain excellent and were not affected by line of therapy or whether patients were treated on clinical studies or commercially. These data strongly argue in favor of finding strategies to minimize ibrutinib intolerance so that efficacy can be further maximized. Future clinical trials should consider time-limited therapy approaches, particularly in patients achieving a complete response, in order to minimize ibrutinib exposure

Complement Activation in the Treatment of B-Cell Malignancies

Unconjugated monoclonal antibodies (mAb) have revolutionized the treatment of B-cell malignancies. These targeted drugs can activate innate immune cytotoxicity for therapeutic benefit. mAb activation of the complement cascade results in complement-dependent cytotoxicity (CDC) and complement receptor-mediated antibody-dependent cellular phagocytosis (cADCP). Clinical and laboratory studies have showed that CDC is therapeutically important. In contrast, the biological role and clinical effects of cADCP are less well understood. This review summarizes the available data on the role of complement activation in the treatment of mature B-cell malignancies and proposes future research directions that could be useful in optimizing the efficacy of this important class of drugs