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

BACKGROUND: In chronic lymphocytic leukemia (CLL), changes in the peripheral blood lymphocyte subsets play an important role in disease progression and infectious complications. The impact of chemoimmunotherapy (CIT) on these changes has not been extensively studied METHODS: We used multi-color flow cytometry, to prospectively measure absolute and relative numbers of CD4+ and CD8+ T-cells and their subsets in 45 patients with indolent untreated CLL, 86 patients indicated for first-line treatment, and 34 healthy controls. In 55 patients, we analyzed the impact of CIT RESULTS: CLL patients had a significant increase in most cell populations in comparison to controls. Progression of CLL was characterized by significantly elevated counts with the exception of a lower percentage of naïve T-cells. After treatment, the percentage of naïve T-cells further decreased at the expense of effector memory T-cells (TEM). In patients with indolent CLL, higher percentages of naïve CD4+ (p = 0.0026) and naïve CD8+ (p = 0.023) T-cells were associated with a longer time to first treatment (TTFT). The elevation of CD4+ central memory T-cells (TCM) (p = 0.27) and TEM (p = 0.003) counts and a higher percentage of CD4+ TEM (p = 0.0047), were linked with shorter TTFT. In treated patients, increased regulatory T-cells count was associated with shorter time to next treatment (TTNT) (p = 0.042), while higher CD4+ TCM count with shorter TTNT (p = 0.035) and shorter overall survival (p = 0.041). CONCLUSION: Our results indicate that naïve cell depletion and CD4+ TCM and TEM increases are detrimental to CLL patients' prognosis.

• Keywords
• CLL, chemoimmunotherapy, immunosuppression, infections, lymphocyte subset, prognosis,
• MeSH
• CD4-Positive T-Lymphocytes MeSH
• CD8-Positive T-Lymphocytes MeSH
• Leukemia, Lymphocytic, Chronic, B-Cell * MeSH
• Humans MeSH
• Lymphocyte Subsets MeSH
• Prognosis MeSH
• T-Lymphocytes, Regulatory MeSH
• T-Lymphocyte Subsets MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't 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

We report final analysis outcomes from the phase 3 HELIOS study (NCT01611090). Patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma without deletion 17p (n = 578) were randomized 1:1 to 420 mg daily ibrutinib or placebo plus ≤6 cycles of bendamustine plus rituximab (BR), followed by ibrutinib or placebo alone. Median follow-up was 63.7 months. Median investigator-assessed progression-free survival was longer with ibrutinib plus BR (65.1 months) than placebo plus BR (14.3 months; hazard ratio [HR] 0.229 [95% confidence interval (CI) 0.183-0.286]; p < .0001). Despite crossover of 63.3% of patients from the placebo plus BR arm to ibrutinib treatment upon disease progression, ibrutinib plus BR versus placebo plus BR demonstrated an overall survival benefit (HR 0.611 [95% CI 0.455-0.822]; p = .0010; median not reached in either arm). Long-term follow-up data confirm the survival benefit of ibrutinib plus BR over BR alone. Safety profiles were consistent with those known for ibrutinib and BR.

• Keywords
• 5-year follow-up, HELIOS phase 3 trial, Ibrutinib, overall survival, relapsed chronic lymphocytic leukemia,
• MeSH
• Adenine analogs & derivatives   MeSH
• Bendamustine Hydrochloride therapeutic use   MeSH
• Leukemia, Lymphocytic, Chronic, B-Cell * drug therapy   MeSH
• Humans MeSH
• Piperidines MeSH
• Antineoplastic Combined Chemotherapy Protocols adverse effects   MeSH
• Rituximab therapeutic use   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Randomized Controlled Trial MeSH
• Names of Substances
• Adenine MeSH
• Bendamustine Hydrochloride MeSH
• ibrutinib MeSH Browser
• Piperidines MeSH
• Rituximab MeSH

Limited information is available on the efficacy of front-line bendamustine and rituximab (BR) in chronic lymphocytic leukemia (CLL) with reduced renal function or coexisting conditions. We therefore analyzed a cohort of real-world patients and performed a matched adjusted indirect comparison with a cohort of patients treated with ibrutinib. One hundred and fifty-seven patients with creatinine clearance (CrCl) <70 mL/min and/or CIRS score >6 were treated with BR. The median age was 72 years; 69% of patients had ≥2 comorbidities and the median CrCl was 59.8 mL/min. 17.6% of patients carried TP53 disruption. The median progression-free survival (PFS) was 45 months; TP53 disruption was associated with a shorter PFS (P = 0.05). The overall survival (OS) at 12, 24, and 36 months was 96.2%, 90.1%, and 79.5%, respectively. TP53 disruption was associated with an increased risk of death (P = 0.01). Data on 162 patients ≥65 years treated with ibrutinib were analyzed and compared with 165 patients ≥65 years treated with BR. Factors predicting for a longer PFS at multivariable analysis in the total patient population treated with BR and ibrutinib were age (HR 1.06, 95% CI 1.02-1.10, P < 0.01) and treatment with ibrutinib (HR 0.55, 95% CI 0.33-0.93, P = 0.03). In a post hoc analysis of patients in advanced stage, a significant PFS advantage was observed in patient who had received ibrutinib (P = 0.03), who showed a trend for OS advantage (P = 0.08). We arrived at the following conclusions: (a) BR is a relatively effective first-line regimen in a real-world population of unfit patients without TP53 disruption, (b) ibrutinib provided longer disease control than BR in patients with advanced disease stage.

• Keywords
• bendamustine, chronic lymphocytic leukemia, ibrutinib, real-world analysis, unfit patients,
• MeSH
• Adenine adverse effects   analogs & derivatives   therapeutic use   MeSH
• Antineoplastic Agents, Alkylating adverse effects   therapeutic use   MeSH
• Bendamustine Hydrochloride adverse effects   therapeutic use   MeSH
• Time Factors MeSH
• Leukemia, Lymphocytic, Chronic, B-Cell diagnosis   drug therapy   mortality   MeSH
• Progression-Free Survival MeSH
• Protein Kinase Inhibitors adverse effects   therapeutic use   MeSH
• Middle Aged MeSH
• Humans MeSH
• Piperidines adverse effects   therapeutic use   MeSH
• Disease Progression MeSH
• Antineoplastic Agents, Immunological adverse effects   therapeutic use   MeSH
• Antineoplastic Combined Chemotherapy Protocols adverse effects   therapeutic use   MeSH
• Retrospective Studies MeSH
• Rituximab adverse effects   therapeutic use   MeSH
• Aged MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Comparative Study MeSH
• Geographicals
• Europe MeSH
• United States MeSH
• Names of Substances
• Adenine MeSH
• Antineoplastic Agents, Alkylating MeSH
• Bendamustine Hydrochloride MeSH
• ibrutinib MeSH Browser
• Protein Kinase Inhibitors MeSH
• Piperidines MeSH
• Antineoplastic Agents, Immunological MeSH
• Rituximab MeSH

We report follow-up results from the randomized, placebo-controlled, phase 3 HELIOS trial of ibrutinib+bendamustine and rituximab (BR) for previously treated chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) without deletion 17p. Overall, 578 patients were randomized 1:1 to either ibrutinib (420 mg daily) or placebo, in combination with 6 cycles of BR, followed by ibrutinib or placebo alone. Median follow-up was 34.8 months (range: 0.1-45.8). Investigator-assessed median progression-free survival (PFS) was not reached for ibrutinib+BR, versus 14.3 months for placebo+BR (hazard ratio [HR] [95% CI], 0.206 [0.159-0.265]; P < 0.0001); 36-month PFS rates were 68.0% versus 13.9%, respectively. The results are consistent with the primary analysis findings (HR = 0.203, as assessed by independent review committee, with 17-month median follow-up). Median overall survival was not reached in either arm; HR (95% CI) for ibrutinib+BR versus placebo: 0.652 (0.454-0.935; P = 0.019). Minimal residual disease (MRD)-negative response rates were 26.3% for ibrutinib+BR and 6.2% for placebo+BR (P < 0.0001). Incidence of treatment-emergent adverse events (including grades 3-4) were generally consistent with the initial HELIOS report. These long-term data support improved survival outcomes and deepening responses with ibrutinib+BR compared with BR in relapsed CLL/SLL.

• MeSH
• Adenine analogs & derivatives   MeSH
• Bendamustine Hydrochloride administration & dosage   MeSH
• Leukemia, Lymphocytic, Chronic, B-Cell drug therapy   pathology   MeSH
• Adult MeSH
• Double-Blind Method MeSH
• Middle Aged MeSH
• Humans MeSH
• Survival Rate MeSH
• Adolescent MeSH
• Young Adult MeSH
• Follow-Up Studies MeSH
• Piperidines MeSH
• Prognosis MeSH
• Antineoplastic Combined Chemotherapy Protocols therapeutic use   MeSH
• Pyrazoles administration & dosage   MeSH
• Pyrimidines administration & dosage   MeSH
• Rituximab administration & dosage   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Randomized Controlled Trial MeSH
• Names of Substances
• Adenine MeSH
• Bendamustine Hydrochloride MeSH
• ibrutinib MeSH Browser
• Piperidines MeSH
• Pyrazoles MeSH
• Pyrimidines MeSH
• Rituximab MeSH

Chronic lymphocytic leukemia is associated with a highly heterogeneous disease course in terms of clinical outcomes and responses to chemoimmunotherapy. This heterogeneity is partly due to genetic aberrations identified in chronic lymphocytic leukemia cells such as mutations of TP53 and/or deletions in chromosome 17p [del(17p)], resulting in loss of one TP53 allele. These aberrations are associated with markedly decreased survival and predict impaired response to chemoimmunotherapy thus being among the strongest predictive markers guiding treatment decisions in chronic lymphocytic leukemia. Clinical trials demonstrate the importance of accurately testing for TP53 aberrations [both del(17p) and TP53 mutations] before each line of treatment to allow for appropriate treatment decisions that can optimize patients' outcomes. The current report reviews the diagnostic methods to detect TP53 disruption better, the role of TP53 aberrations in treatment decisions and current therapies available for patients with chronic lymphocytic leukemia carrying these abnormalities. The standardization in sequencing technologies for accurate identification of TP53 mutations and the importance of continued evaluation of TP53 aberrations throughout initial and subsequent lines of therapy remain unmet clinical needs as new therapeutic alternatives become available.

• MeSH
• Chromosome Deletion * MeSH
• Leukemia, Lymphocytic, Chronic, B-Cell diagnosis   genetics   therapy   MeSH
• Humans MeSH
• Chromosomes, Human, Pair 17 genetics   MeSH
• Mutation * MeSH
• Tumor Suppressor Protein p53 genetics   MeSH
• Disease-Free Survival MeSH
• Prognosis MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Tumor Suppressor Protein p53 MeSH

We performed an observational study on the efficacy of ben-damustine and rituximab (BR) as first salvage regimen in chronic lymphocytic leukemia (CLL). In an intention-to-treat analysis including 237 patients, the median progression-free survival (PFS) was 25 months. The presence of del(17p), unmutated IGHV and advanced stage were associated with a shorter PFS at multivariate analysis. The median time-to-next treatment was 31.3 months. Front-line treatment with a chemoimmunotherapy regimen was the only predictive factor for a shorter time to next treatment at multivariate analysis. The median overall survival (OS) was 74.5 months. Advanced disease stage (i.e. Rai stage III-IV or Binet stage C) and resistant disease were the only parameters significantly associated with a shorter OS. Grade 3-5 infections were recorded in 6.3% of patients. A matched-adjusted indirect comparison with ibrutinib given second-line within Named Patient Programs in the United Kingdom and in Italy was carried out with OS as objective end point. When restricting the analysis to patients with intact 17p who had received chemoimmunotherapy in first line, there was no difference in OS between patients treated with ibrutinib (63% alive at 36 months) and patients treated with BR (74.4% alive at 36 months). BR is an efficacious first salvage regimen in CLL in a real-life population, including the elderly and unfit patients. BR and ibrutinib may be equally effective in terms of OS when used as first salvage treatment in patients without 17p deletion.

• MeSH
• Adenine analogs & derivatives   MeSH
• Survival Analysis MeSH
• Bendamustine Hydrochloride administration & dosage   MeSH
• Leukemia, Lymphocytic, Chronic, B-Cell diagnosis   drug therapy   mortality   MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Biomarkers, Tumor MeSH
• Retreatment MeSH
• Piperidines MeSH
• Prognosis MeSH
• Antineoplastic Combined Chemotherapy Protocols adverse effects   therapeutic use   MeSH
• Pyrazoles administration & dosage   adverse effects   therapeutic use   MeSH
• Pyrimidines administration & dosage   adverse effects   therapeutic use   MeSH
• Rituximab administration & dosage   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Treatment Outcome MeSH
• Salvage Therapy MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Comparative Study MeSH
• Geographicals
• Italy MeSH
• United Kingdom MeSH
• Names of Substances
• Adenine MeSH
• Bendamustine Hydrochloride MeSH
• ibrutinib MeSH Browser
• Biomarkers, Tumor MeSH
• Piperidines MeSH
• Pyrazoles MeSH
• Pyrimidines MeSH
• Rituximab MeSH