INTRODUCTION: The impact of chemoimmunotherapy (CIT) on immunoglobulin (Ig) quantities in patients with chronic lymphocytic leukemia (CLL) has not been extensively studied. METHODS: We analyzed Ig levels in 45 stable patients with indolent CLL (without indication for treatment) and 87 patients with progressive disease before first-line treatment. Fifty-five patients were evaluated again after the treatment with CIT. RESULTS: We observed significantly lower levels of all Ig classes and subclasses in patients with progressive disease compared to patients with indolent disease. After treatment, median IgA increased from 0.59 g/L to 0.74 g/L (p = 0.0031). In stable patients, lower IgA2 was associated with shorter time to first treatment, although it did not reach statistical significance (p = 0.056). Shorter overall survival was observed in patients with progressive disease and lower IgG2 (p = 0.043). Surprisingly, among the patients with progressive CLL, unmutated IGHV genes were associated with higher levels of IgG, IgG1 and IgM, while TP53 mutation and/or 17p deletion were associated with higher levels of IgA and IgA1. CONCLUSIONS: CIT may lead to increase in IgA levels. Hypogammaglobulinemia is more common in patients with progressive CLL and unmutated IGHV or TP53 dysfunction.

• Keywords
• CLL, chemoimmunotherapy, immunoglobulin, immunosuppression, infections, prognosis,
• MeSH
• Leukemia, Lymphocytic, Chronic, B-Cell * drug therapy   blood   immunology   mortality   MeSH
• Adult MeSH
• Immunoglobulin A * blood   MeSH
• Immunotherapy methods   MeSH
• Middle Aged MeSH
• Humans MeSH
• Disease Progression MeSH
• Antineoplastic Combined Chemotherapy Protocols therapeutic use   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Immunoglobulin A * MeSH

This is the first large-scale cross-country analysis of patients with chronic lymphocytic leukemia (CLL) aimed to evaluate the incidence, types, and key prognostic factors of secondary malignancies, and to assess the impact on overall survival based on retrospective claims data from three Central European countries. We analyzed 25,814 newly diagnosed CLL patients from Czechia, Hungary, and Poland; 10,312 (39.9%) patients were treated for CLL in study periods between 2004 and 2016. Out of the treated patients, 1986 (19.3%) received the FCR therapy in the first line and 779 (7.6%) received FCR in subsequent lines. We observed that 33.7% of treated patients developed secondary malignancies during the study. Based on country estimates, the probability to develop a secondary malignancy within 4 years since starting the first-line FCR therapy ranged between 28.0% and 36.8%. We found the age at diagnosis, male gender, any malignancy prior to the CLL diagnosis, and the CLL treatment to be the key risk factors for developing secondary malignancies. Specifically, the FCR therapy was a statistically significant (p < 0.001) prognostic factor for risk increase with the hazard ratio between 1.46 and 1.60. Across the three Central European countries, we observed consistent results indicating FCR increased the risk of secondary malignancies in CLL patients. We conclude that secondary malignancies are clearly an undervalued burden for CLL patients, caregivers, and the healthcare system. When evaluating new therapies in regulatory and reimbursement decision making, the factor of secondary malignancies deserves deeper considerations.

• Keywords
• CLL population, FCR therapy, secondary malignancy, survival,
• MeSH
• Leukemia, Lymphocytic, Chronic, B-Cell * drug therapy   epidemiology   MeSH
• Cyclophosphamide therapeutic use   MeSH
• Humans MeSH
• Disease-Free Survival MeSH
• Antineoplastic Combined Chemotherapy Protocols adverse effects   MeSH
• Retrospective Studies MeSH
• Rituximab therapeutic use   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Europe epidemiology   MeSH
• Names of Substances
• Cyclophosphamide MeSH
• Rituximab MeSH

The paradigm of first-line treatment of chronic lymphocytic leukaemia (CLL) is currently undergoing a radical change. On the basis of several randomised phase III trials showing prolongation of progression-free survival, chemoimmunotherapy is being replaced by treatment based on novel, orally available targeted inhibitors such as Bruton tyrosine kinase inhibitors ibrutinib and acalabrutinib or bcl-2 inhibitor venetoclax. However, the use of these agents may be associated with other disadvantages. First, with the exception of one trial in younger/fit patients, no studies have so far demonstrated benefit regarding the ultimate endpoint of overall survival. Second, oral inhibitors are extremely expensive and thus currently unavailable due to the absence of reimbursement in some countries. Third, treatment with ibrutinib and acalabrutinib necessitates long-term administration until progression; this may be associated with accumulation of late side effects, problems with patient compliance, and selection of resistant clones. Therefore, the identification of a subset of patients who could benefit from chemoimmunotherapy would be ideal. Current data suggest that patients with the mutated variable region of the immunoglobulin heavy chain (IGHV) achieve fairly durable remissions, especially when treated with fludarabine, cyclophosphamide, and rituximab (FCR) regimen. This review discusses current options for treatment-naïve patients with CLL.

• Keywords
• acalabrutinib, chemoimmunotherapy, chronic lymphocytic leukaemia, direct inhibitors, ibrutinib, obinutuzumab, prognosis, rituximab, venetoclax,
• Publication type
• Journal Article MeSH
• Review MeSH

Revolutionary progress has recently changed the landscape of chronic lymphocytic leukemia (CLL). Powerful prognostic factors, especially p53 mutation and/or deletion and IGHV mutation status, have refined individual patient prognosis. Purine analogs and monoclonal antibodies paved the way from palliative treatment to chemoimmunotherapy capable of eradication of minimal residual disease and prolongation of survival. Obinutuzumab (GA-101) and ofatumumab have been recently approved for the treatment of comorbid patients. Bendamustine is available for first-line treatment of patients ineligible for fludarabine, cyclophosphamide, and rituximab (FCR). High-dose glucocorticoids combined with rituximab represent a promising option for refractory CLL; ofatumumab is approved for fludarabine- and alemtuzumab-refractory patients. Allogeneic stem cell transplantation is the only curative option but is feasible in a highly selected group of patients only. The novel small molecule inhibitors ibrutinib and idelalisib have been recently approved for relapsed/refractory CLL. This review provides practical advice for diagnosis, prognostication and treatment of CLL.

• Keywords
• chronic, drug therapy, ibrutinib, idelalisib, leukemia, lymphocytic, obinutuzumab, ofatumumab, prognosis,
• Publication type
• Journal Article MeSH

Introduction of targeted agents revolutionized the treatment of chronic lymphocytic leukemia (CLL) in the past decade. Addition of chimeric monoclonal anti-CD20 antibody rituximab to chemotherapy significantly improved efficacy including overall survival (OS) in untreated fit patients; humanized anti-CD52 antibody alemtuzumab and fully human anti-CD20 antibody ofatumumab lead to improvement in refractory disease. Novel small molecule inhibitors such as ibrutinib and idelalisib demonstrated excellent activity and were very recently licensed in relapsed/refractory CLL. Obinutuzumab (GA101) is the newest monoclonal antibody approved for the treatment of CLL. This novel, glycoengineered, type II humanized anti-CD20 antibody is characterized by enhanced antibody-dependent cellular cytotoxicity and direct induction of cell death compared to type I antibodies. Combination of obinutuzumab and chlorambucil yielded significantly better OS in comparison to chlorambucil monotherapy in untreated comorbid patients. These results led to approval of obinuzutumab for the treatment of CLL. Numerous clinical trials combining obinutuzumab with other cytotoxic drugs and novel small molecules are currently under way. This review focuses on the role of obinutuzumab in the treatment of CLL.

• Keywords
• anti-CD20 antibodies, chlorambucil, chronic lymphocytic leukemia, obinutuzumab, ofatumumab, overall survival, rituximab,
• Publication type
• Journal Article MeSH
• Review MeSH