Evidence indicates that there are significant alterations in gut microbiota diversity and composition in patients with hematological malignancies. The present study investigated the oral and intestinal microbiome in patients with chronic lymphocytic leukemia (CLL) (n=81) and age-matched healthy volunteers (HVs; n=21) using 16S ribosomal RNA next-generation sequencing. Changes in both oral and gut microbiome structures were identified, with a high abundance of Proteobacteria and depletion of Bacteroidetes in CLL as compared to HVs. Oral and stool samples of patients with CLL revealed a significant change in the abundance of short-chain fatty acid-producing genera in comparison with HVs. Furthermore, the relative abundance of oral and intestine Bacteroidetes was significantly decreased in patients with CLL with negative prognostic features, including unmutated immunoglobulin heavy chain gene (IGHV). Notably, an increased abundance of gut Firmicutes was found to be associated with high expression of CD38. Finally, the present study suggested the log Firmicutes/Bacteroidota ratio as a novel intestinal microbiome signature associated with a shorter time to first treatment in individuals with CLL. The findings indicate that oral and gut microbial diversity in CLL might point to the inflammatory-related modulation of the clinical course of the disease.

Topic: 5. Chronic lymphocytic leukemia and related disorders - Biology & Translational Research Background: Growing evidence suggests the impact of structural changes in the intestinal microbiota on the development of hematologic malignancies, including chronic lymphocytic leukemia (CLL). Therefore, investigating the role of microbiome changes in CLL might unveil predictive signatures, which could facilitate precision-medicine approaches, thus improving treatment outcome. Aims: As dysregulation of human microbiota is involved in carcinogenesis and host response against immunotherapy, the aim of our study was to characterize the nasopharynx and stool microbiome changes in CLL patients compared to age-matched healthy donors. In addition, we investigated the microbiota composition of samples collected from CLL patients concerning the independent prognostic factors. Methods: The study included 92 newly diagnosed and untreated CLL patients and 21 healthy volunteers (HVs). The microbiota composition of 85 stool samples and 76 oral samples from these cases were determined by 16S rRNA next-generation sequencing. Results: Alpha-diversity analysis showed that oral samples from CLL patients exhibit lower richness and evenness than oral samples from HVs (Chao1 index p=0.049 and Shannon index p=0.006, respectively), especially regarding to women cohort (Chao1 index p=0.021 and Shannon index p<0.05). Furthermore, higher richness and evenness were observed in CLL patients with stage 1-2 Rai in comparison to stage 0 (Shannon index p=0.043). However, these metrics showed no significant differences in richness and evenness in fecal probes between CLL and HVs samples. At the phylum level, a significant increase in the relative abundance of Proteobacteria was observed in oral and stool samples from CLL patients compared to HVs (p=0.028 and p<0.032, respectively). Intriguingly, Proteobacteria was significantly more abundant in oral samples collected from CLL patients with stereotypical IGHV status (p=0.033), del11q (p=0.0049), and the presence of 2 or more cytogenetic aberrations (p=0.0096). The abundance of Bacteroidota was lower in both oral and fecal samples collected from CLL patients in comparison to HVs (p=0.002 and p<0.016, respectively). Moreover, the Firmicutes/Bacteroidota (F/B) ratio was found to be significantly higher in oral and fecal samples collected from CLL patients in comparison to HVs (p<0.0001 and p<0.0001, respectively). Regarding oral samples, CLL patients with higher F/B ratio (upper quartile of the log F/B ratio, values >4.612) exhibited a significantly shorter time to first treatment than subjects with lower F/B ratio (p<0.05) (Figure 1). Interestingly, a noteworthy higher F/B ratio was observed in both oral and fecal samples from CLL patients with stage Binet B compared to stage Binet A (p=0.0265 and p=0.0159, respectively). Furthermore, there was a tendency to the increased F/B ratio in oral samples from CLL patients with unmutated IGHV than CLL patients with mutated IGHV (p=0.0689). At the family level, we observed a higher abundance of short-chain fatty acids (SCFAs)-producing bacteria Ruminococcaceae and Lachnospiraceae in fecal samples collected from CLL patients in comparison to HVs (p=0.01 and p<0.009, respectively). Summary/Conclusion: The oral and gut microbiome of CLL patients show lower diversity and specific alterations in comparison to a healthy microbiome. Firmicutes/Bacteroidota (F/B) ratio might modulate survival of CLL patients.Figure 1. Time to first treatment (TTFT) curves of CLL patients with respect to the quartiles of the log Firmicutes/Bacteroidota ratio. Funding: Polish National Science Center (NCN 2018/29/B/NZ5/02706). Keywords: Chronic lymphocytic leukemia, Inflammation

Background: For the last years it has been speculated that immunologic and inflammatory factors, including antigen stimulation, could be involved in the pathogenesis of chronic lymphocytic leukemia (CLL). With increasing evidence that the activation of cellular proinflammatory signaling pathways driven by somatic mutations and an increased release of proinflammatory cytokines is associated with CLL development, it seems relevant to investigate the role of chronic inflammation in the pathogenesis of this disease. Recent studies have revealed that the intestinal microbiota could modulate the activity of immune system through creating an imbalance between cell proliferation and apoptosis. Thus, the relationship of microbial dysbiosis and specific taxon abundances with CLL biology and clinical outcome should be examined. Aims: As it was reported that the activity of human microbiome is involved in cancer development and host response against anticancer therapy, the aim of this study was to investigate the stool and oral microbiome alterations in CLL patients with respect to selected prognostic and predictive markers. Methods: The study included 92 patients with untreated CLL. Microbiota composition of 85 stool samples and 76 oral samples from these cases were determined by 16S rRNA next-generation sequencing and analyzed with respect to the Binet stage, IGHV and TP53 mutation status, CD38 and ZAP-70 expression, and cytogenetic aberrations. The species richness and evenness were analyzed using Shannon and Chao1 indexes, respectively. The DADA2 tool was used to classify sequences into appropriate taxonomic groups. The differences in taxonomic profiles and species diversity in oral and stool samples with distinct prognostic features were investigated using the Wilcoxon or Kruskall-Wallis tests. Results: Alpha-diversity analysis indicates that there were no significant differences in richness and evenness between probes with distinct CLL features in both fecal and oral samples. However, at phylum level, an increase in Proteobacteria, a common feature of gut dysbiosis, was observed in stool samples from patients with stage Binet C compared to stage Binet A (p=0.042), and in oral samples with del11q compared to samples with no del11q (p=0.021). The abundance of Bacteroidota was higher in fecal samples collected from patients with stage Binet A in comparison to stage Binet B (p=0.051) and C (p=0.009). Moreover, Bacteroidota was relatively more abundant in oral samples from patients with stage Binet A in comparison to stage Binet C (p=0.008). Bacteroidota was significantly less abundant in stool samples from patients with unmutated IGHV compared to samples with mutated IGHV (p=0.029). Stool samples from patients with CD38+ exhibited decreased abundance of Bacteroidota and increased abundance of Firmicutes in comparison to CD38- cases (p=0.031 and p=0.022, respectively). Furthermore, fecal samples from patients with del6q showed a higher abundance of Firmicutes and lower abundance of Bacteroidota compared to samples with no del6q (p=0.006 and p=0.018, respectively). Additionally, a relative increase in Actinobacteriota and Firmicutes was found in oral samples with tri12 in comparison to samples with no tri12 (p=0.039 and p=0.016, respectively). Image:Summary/Conclusion: Our findings provide new insights into oral and gut microbial diversity which is related to distinct prognostic features in CLL and might point to the inflammatory-related modulation of the clinical course of disease.

Chronic lymphocytic leukemia (CLL) is a disease of the elderly, with a median age at diagnosis of approximately 70 years. The natural course of the disease varies greatly, and patients with nonprogressive and asymptomatic leukemia do not require treatment. The results of CLL treatment have improved significantly in recent years, mainly due to the introduction of new, more effective drugs, including BCR inhibitors and BCL2 inhibitors. The new drugs are used continuously, while venetoclax in combination with anti-CD20 antibodies is used for 24 (rituximab) or 12 (obinutuzumab) months, depending on the type of antibody and line of therapy. The choice of treatment protocol should largely depend on the assessment of 17p deletion/ TP53 mutation and immunoglobulin variable heavy chain (IGVH) mutation status, which correlate with a worse response to immunochemotherapy. The role of immunochemotherapy, which until recently was the mainstay of CLL treatment, has now significantly decreased. In the first-line, it is recommended only in patients without 17p deletion/ TP53 mutation, with mutated IGVH . Other patients should receive novel targeted therapies. However, at the time of the preparation of these recommendations, these therapies are not available in the firs-line of treatment in Poland. Novel targeted therapies play a major role in the treatment of refractory/relapsed CLL, and immunochemotherapy is recommended primarily in patients with a long-term response to first-line therapy. In this article, we present an update of the guidelines for the diagnosis and treatment of CLL, including the treatment of autoimmune complications, as well as the prophylaxis and treatment of infections, developed by the Polish Society of Haematologists and Transfusiologists and PALG-CLL Working Group.

Anti-CD20 monoclonal antibodies (mAbs) in combination with chemotherapies have changed the treatment landscape for chronic lymphocytic leukemia (CLL) [1]. Rituximab added to fludarabine with cyclop...

Chronic lymphocytic leukemia (CLL) treatment is improving; however, some patients do not respond to therapy. Due to the high heterogeneity in disease development, there is an urgent need for personalization of therapy. In the present study, the response of leukemic mononuclear cells to anticancer drugs used for CLL treatment (cladribine + mafosfamide; CM or CM combined with rituximab; RCM) was compared with the response to new cyclin-dependent kinase (CDK) inhibitors: BP14 and BP30. Viable apoptotic and necrotic cells were quantified by flow cytometry using propidium iodide and Yo-Pro stains. CDK inhibitors were studied in several doses to determine the reduction of necrosis and simultaneous increase of apoptosis in leukemic cell incubations with anticancer agents. The distinct cell response to applied doses/anticancer agents was observed. Results obtained in the current manuscript confirmed that modulation of doses is important. This was particularly indicated in results obtained at 24 h of cells incubation with anticancer agent. While an important time for analysis of anticancer response efficacy (monitoring of apoptosis induction potential) seems to be 48 h of cells exposition to anticancer agents. High variability in response to the drugs revealed that both the nature and the dose of the anticancer agents could be important in the final effect of the therapy. The present findings support the thesis that personalized medicine, before drug administration in the clinic, could be important to avoid the application of ineffective therapy.

We studied whether bendamustine (BENDA) alone or with rituximab (RIT) modifies in vitro expression of apoptosis-involved genes and proteins of chronic lymphocytic leukemia (CLL) cells depending on IGVH mutational status. Circulating lymphocytes from 34 untreated patients (18 IGVH-MUT and 16 IGVH-UNMUT) were incubated with above drugs to evaluate proteins expression. Microarray analysis of 93 genes was performed in 14 patients. BENDA and BENDA+RIT increased expression of BAX and BBC3 in IGVH-MUT and IGVH-UNMUT groups, and significant differences in expression of above genes after BENDA+RIT were observed between both groups. Additionally, BENDA+RIT decreased NFB and BCL-2 genes in IGVH-UNMUT patients and increased expression of P53, BAX and PUMA proteins in IGVH-MUT and UNMUT subjects. However, no significant differences were found between these groups. In conclusion, BENDA+RIT modified gene expression profile in CLL cells and affected expression of some apoptosis-regulating proteins in vitro. Expression of BAX and BBC3 depends on action of drugs and IGVH mutational status.

Introduction: COMPLEMENT 2 is a phase III, randomized, open-label study, which compared the efficacy of ofatumumab (OFA) in combination with fludarabine and cyclophosphamide (FC) vs FC therapy alone in patients (pts) with relapsed chronic lymphocytic leukemia (CLL). In a previous interim analysis (2015) performed based on 194 progression-free survival (PFS) events, OFA+FC showed significant improvement of PFS and was well tolerated compared to FC in pts with relapsed CLL. Here, we report the 5-year follow-up of overall survival (OS) and safety profile of the drugs evaluated in this study. Methods: Based on stratification factors (number of prior CLL therapies and Binet stage), pts with relapsed CLL were randomized 1:1 to Arm A (OFA+FC) and Arm B (FC alone). Arm A received OFA intravenously (IV) (300 mg on day 1, cycle [c] 1; 1000 mg on day 8, c1; and 1000 mg on day 1, c2-6) in addition to FC (F [IV]: 25 mg/m2 and C [IV]: 250 mg/m2 on days 1-3, c1-6). Arm B received FC only. Pts who had achieved a complete response or partial response following at least 1 prior CLL therapy, but whose disease had progressed after >6 months (mo) were included in the present study. The primary endpoint was PFS. Key secondary endpoints were OS, time to next treatment (TTNT), and safety. During the primary analysis for PFS, all the type 1 error (1-sided alpha 0.025) was spent, resulting in no alpha remaining for inferential interpretation of the final analysis for OS. The final analysis results will be used for descriptive and supportive purposes only. Results: A total of 365 pts were randomly assigned to receive OFA+FC (n=183) or FC (n=182) in the final analysis. Overall, 119 (65%) and 102 (56%) pts completed the scheduled OFA+FC and FC treatments, respectively. Adverse events (AEs) were the main reason for treatment discontinuation in both treatment arms (50 [27%] pts in the OFA+FC arm and 52 [29%] in the FC arm). A total of 332 (91%) pts entered the follow-up phase, 172 (94%) from the OFA+FC arm and 160 (88%) from the FC arm. The follow-up phase for the OFA+FC and FC arms was approximately 41 mo and 23 mo, respectively. Baseline characteristics were similar in both arms. Median PFS was not assessed for the final analysis because the final results for the primary endpoint of PFS were reported as part of the primary analysis. PFS was 28.9 mo for OFA+FC and 18.8 mo for FC (hazard ratio [HR]=0.67, 95% confidence interval [CI]: 0.51, 0.88; p=0.0032). The final OS analysis was performed based on 82 events in the OFA+FC arm and 83 events in the FC arm. Median OS was 62.6 mo (95% CI: 44.58, NA) and 46.2 mo (95% CI: 37.72, 56.57) for the OFA+FC and FC arms, respectively (HR=0.80, 95% CI: 0.59, 1.09; p=0.143) (Figure 1). Median TTNT in the OFA+FC and FC arms was 53 mo and 40.1 mo, respectively (HR=0.77, 95% CI: 0.55, 1.08; p=0.114). As per the primary analysis, the overall response rate (95% CI) by independent review committee assessment (IRC) was 84% (77%, 89%) for OFA+FC and 68% (60%, 74%) for FC (p=0.0003). Other secondary endpoints (in mo) for OFA+FC vs FC were IRC-assessed median time to response (1 vs 1; HR=1.08, 95% CI: 0.85, 1.37; p=0.45), median duration of response (29.6 vs 24.9; HR=0.77, 95% CI: 0.56, 1.05; p=0.09), and median time to progression (42.1 vs 26.8; HR=0.63, 95% CI: 0.45, 0.87; p=0.004). All AEs and AEs of grade 3, 4, and 5 by preferred term (≥10%) are presented in Table 1. Serious drug-related AEs (≥2%) in the OFA+FC arm were pneumonia (8%), neutropenia and febrile neutropenia (7% each), and thrombocytopenia, pancytopenia, and pyrexia (2% each). Myelodysplastic syndrome was the most frequently reported secondary malignancy observed in ≥1% of pts (OFA+FC, 3 [2%]; FC, 2 [1%]). A total of 82 (45%) and 83 (47%) pts died during the study in the OFA+FC and FC arms, respectively; 2 (1%) and 6 (3%) died up to 60 days after the end of treatment, and 74 (41%) and 69 (39%) after >60 days. Three (2%) on-treatment deaths were reported in the OFA+FC arm and 4 (2%) in the FC arm. Conclusion: This final analysis confirmed the results of the primary analysis that addition of OFA to FC resulted in improvement of OS and TTNT by approximately 16 mo and 13 mo, respectively, compared to FC alone. Of note, the trend in the OS improvement seems to be maintained in the present long-term follow-up at 5 years. No new safety concerns have emerged in the long-term follow-up after treatment with OFA+FC, and the treatment was well tolerated. Grosicki: Affimed: Research Funding. Lech-Maranda:Roche: Consultancy; Jansen-Cilag: Consultancy; Novartis: Consultancy; BMS: Consultancy; Amgen: Consultancy. Loscertales:Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Homenda:Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Rigel: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Acerta: Consultancy, Honoraria. Blonski:Novartis: Consultancy. Stefanelli:Novartis: Employment, Equity Ownership. Vincent:Novartis: Employment. Banerjee:Novartis: Employment. Robak:AbbVie, Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy.

OBJECTIVES:PALG CLL4 is the first, randomized, phase IIIb study with rituximab, cladribine, and cyclophosphamide (RCC) induction and subsequent maintenance with rituximab in previously untreated chronic lymphocytic leukemia (CLL) patients. METHODS:The induction treatment consisted of 6 RCC cycles regimen. Patients with complete response (CR) or partial response (PR) after an induction phase were randomized into a maintenance arm with rituximab or an observational arm. RESULTS:In the intention-to-treat population, 97 patients completed the induction phase with an overall response rate (ORR) of 73.2% (CR 22.7%, PR 50.5%). Subsequently, 66 patients were randomized into the rituximab maintenance arm (n = 33) or the observational arm (n = 33). CR rates were 57.1% in the maintenance group vs 50% in the observational group. PFS was significantly longer in the rituximab maintenance vs the observational arm (P = .028). The multivariate Cox model indicated that del17p (P = .006) and elevated beta-2-microglobulin (P = .015) significantly increased the hazard ratio (HR) of progression, whereas the presence of CD38 (P = .013) significantly decreased it; maintenance therapy with rituximab (P < .0001) significantly decreased the HR of disease progression. CONCLUSIONS:The study confirmed the high efficacy and acceptable safety profile of induction therapy with RCC and maintenance therapy with rituximab in previously untreated patients with CLL.

Randomized phase 3 study of lenalidomide versus chlorambucil as first-line therapy for older patients with chronic lymphocytic leukemia (the ORIGIN trial)

There is individual variation in the course of disease development and response to therapy of patients with chronic lymphocytic leukemia (CLL). Novel treatment options for CLL include a new generation of purine analogs, antibodies and inhibitors of specific cell signaling pathways, which typically induce apoptosis or necrosis. A prospective analysis of patient blood samples revealed that a combination of four tests allowed the most appropriate and effective type of treatment to be selected prior to drug administration, and for the analysis of leukemic cell sensitivity to anticancer drug(s) during disease development. The comparative analysis of blood from the stable and progressive form of CLL in an individual patient revealed diversity in the response to anticancer agents. CLL peripheral blood mononuclear cells were incubated with cladribine + mafosfamide (CM), fludarabine + mafosfamide, CM + rituximab, rituximab alone (Rit) or kinetin riboside (RK). A combination of cell viability, differential scanning calorimetry (DSC) profiles of nuclear preparations and poly(ADP-ribose) polymerase 1 (PARP-1) protein expression analysis of the leukemic cells was performed to evaluate the anticancer effects of the tested agents during CLL development. The results of the present study indicate that such studies are effective in determining the most appropriate anticancer drug and could monitor disease progression on an individual level. In addition, the results of the current study suggest that CLL progression leads to diversification of the cellular drug response. The most efficient apoptosis inducer for the patient was purine analog RK when the disease was stable, while the CM combination was the most effective agent for the progressive form of disease.

Chronic lymphocytic leukemia (CLL) is an incurable disease. Quality of life during treatment and periods of subsequent remission is therefore vital. Health-related quality of life (HRQoL) was compared in relapsed CLL during and after treatment with ofatumumab combined with fludarabine and cyclophosphamide versus fludarabine and cyclophosphamide alone. The European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 v3 and QLQ-CLL16 were used to assess HRQoL in this open-label, phase 3 study. Improvements in prespecified domains of patient-reported outcomes (Global Health Status [GHS]/HRQoL and B symptom scores) were recorded in both treatment arms after three cycles and were sustained after 18 months of follow-up. The two treatment arms were not significantly different at the nominal 0.05 level for GHS/HRQoL (p = .7278) or B symptoms (p = .5968). Small improvements in quality of life were maintained after therapy. The addition of ofatumumab was without any adverse impact on HRQoL (NCT00824265).

Thymidine kinase (TK) activity is a marker of biological activity that allows the indolent and aggressive forms of chronic lymphocytic leukemia (CLL) to be distinguished. The aims of the study were to determine the relationship between TK activity and clinical status and prognosis, as well as to compare its activity with that of other prognostic and predictive factors. TK activity was measured in patient sera at the time of diagnosis using the DiviTum method, with the mean value being 439 Du/L. A correlation was found between TK activity and risk of disease progression (p=0.045). The optimal discriminative value of TK activity in the prediction of CLL progression was found to be 600 Du/L. TK activity significantly differed between the patients who achieved complete remission and those who only partially responded to therapy. In 93% of patients without any response to treatment and 18 out of 20 patients with progressive disease, TK activity over 600 Du/L was noted. In addition, all of the 10 patients with 17p13 deletion displayed TK activity of over 600 Du/L (p=0.0004). High TK activity also correlated with elevated levels of LDH (p=0.001) and β2‑microglobulin (p=0.03) in the study group. The results of the study indicated the importance of TK activity as a prognostic factor in patients with CLL.

A series of adenosine derivatives bearing a boron cluster were synthesized and evaluated for their cytotoxicity against primary peripheral mononuclear cells from the blood of 17 patients with leukemias (16 CLL and 1 very rare PLL), as well as from 5 healthy donors used as a control. Among the tested agents, two, i.e., compounds 1 and 2, displayed high in vitro cytotoxicity and proapoptotic potential on leukemic cells, with only scarce activity being seen against control cells. Biological tests related to apoptosis revealed the activation of the main execution apoptotic enzyme, procaspase-3, in CLL and PLL cells exposed to compounds 1 and 2. Moreover, the above compounds indicated high activity in the proteolysis of the apoptotic markers PARP-1 and lamin B1, fragmentation of DNA, and the induction of some changes in the expression of the Mcl-1, protein apoptosis regulator in comparison with control cells.

The development of non-chemotherapeutic agents, including monoclonal antibodies (mAbs) and other targeted drugs, makes chemotherapy-free treatment an attractive option for chronic lymphocytic leukemia (CLL). The classical mAb, rituximab, has been authorized for use in both first-line and second-line therapy for CLL. New mAbs directed against CD20, ofatumumab, and obinutuzumab (GA-101) have also been approved for the treatment of this disease. Recently, several new mAbs with potential benefits over the approved anti-CD20 antibodies have been developed for use in CLL. Anti-CD37, anti-CD19, and anti-CD40 mAbs are in early clinical trials and show promise in treating CLL. In addition, the combination of mAbs with B-cell receptor signaling pathway inhibitors and immunomodulatory drugs makes the chemotherapy-free option a reality today. Combinations of antibodies with targeted drugs like ibrutinib, idelalisib, or lenalidomide are expected to replace chemotherapy-based combinations for treating CLL in the near future. However, phase III trials should confirm the benefit of these new treatment strategies and establish their exact place in the therapeutic armamentarium for CLL.

In this multicenter, open-label, phase III study, patients with relapsed chronic lymphocytic leukemia (CLL) were randomized (1:1) to receive ofatumumab plus fludarabine and cyclophosphamide (OFA + FC) or FC alone; the primary endpoint being progression-free survival (PFS) assessed by an independent review committee (IRC). Between March 2009 and January 2012, 365 patients were randomized (OFA + FC: n = 183; FC: n = 182). Median IRC-assessed PFS was 28.9 months with OFA + FC versus 18.8 months with FC (hazard ratio = 0.67; 95% confidence interval, 0.51-0.88; p = .0032). Grade >= 3 adverse events (<= 60 days after last dose) were reported in 134 (74%) OFA + FC-treated patients compared with 123 (69%) FC-treated patients. Of these, neutropenia was the most common (89 [49%] vs. 64 [36%]). OFA + FC improved PFS with manageable safety for patients with relapsed CLL compared with FC alone, thus providing an alternative treatment option for patients with relapsed CLL.

The management of patients with chronic lymphocytic leukaemia (CLL) is currently undergoing improvements, particularly because of novel therapies. Purine analogs based immuno-chemotherapy, especially fludarabine combined with cyclophosphamide and rituximab (FCR), is still the current standard of care for first line therapy in younger, fit patients. However, its use in older, co-morbid patients is limited, particularly due to high toxicity. In fit patients older than 65 years or/and with previous infections bendamustine and rituximab (BR) should be considered instead of FCR. Recently, in patients with relevant comorbidities chlorambucil and anti CD20 monoclonal antibodies (rituximab, obinutuzumab or ofatumumab) are recommended as the first-line treatment. In addition, in 2014, two novel agents targeting the B cell receptor (BCR) signaling pathway, ibrutinib and idelalisib, were approved for patients with 17p deletion and/or p53 mutations and in the relapsed situation because of high efficacy and a favorable toxicity. Subsequently, ibrutinib has been approved to treat CLL patients regardless of their treatment history. Thus far it is recommended to treat patients with these agents until progression or unacceptable toxicity. The BCL-2 antagonist venetoclax is another oral drug with very promising preliminary data in patients refractory to immunochemotherapy as well as patients harboring del 17p. In 2014, the PTHiT and PALG-CLL group defined guidelines for the diagnosis, prognosis and treatment of CLL. In this article, we present updated recommendations for therapy of CLL.

It has been previously revealed that statins used at high concentrations display antileukemic potential towards chronic lymphocytic leukemia (CLL) cells. However, their usage alone in clinical practice may be limited due to possible side effects of high doses of these drugs. On the other hand, combined treatment of leukemia with statins and the conventional chemotherapeutics is questionable because of unknown influence of the first on the standard treatment results. This study has revealed thatin vitroatorvastatin increases the proapoptotic potential of cladribine and mafosfamide in CLL cells isolated from peripheral blood of patients. Moreover, a preincubation with the above statin sensitizes leukemic cells to CM-induced apoptosis even at small concentrations of the drug. The usage of atorvastatin together with or followed by the conventional chemotherapy should be considered as therapeutic option for the treatment for this leukemia. Interestingly, CM-resistant patients might have the biggest benefits from atorvastatin administration.