REVIEW ARTICLE. Paula Cramer 1, Petra Langerbeins 1, Barbara Eichhorst 1, Michael Hallek 1,2

European Journal of Haematology 96 (9 18) REVIEW ARTICLE Advances in first-line treatment of chronic lymphocytic leukemia: current recommendations on management and first-line treatment by the German CLL Study Group (GCLLSG) Paula Cramer 1, Petra Langerbeins 1, Barbara Eichhorst 1, Michael Hallek 1,2 1 Department I of Internal Medicine, Center of Integrated Oncology Cologne-Bonn and German CLL Study Group, University of Cologne, Cologne, Germany; 2 CECAD - Cologne Cluster of Excellence in Cellular Stress Responses in Aging-associated Diseases, University of Cologne, Cologne, Germany Abstract The management of patients with CLL is undergoing significant changes; during the last decade, the outcome of first-line therapies has been markedly improved with the addition of anti-cd20 antibodies to chemotherapy. Today, chemoimmunotherapy for physically fit patients 65 years should consist of fludarabine, cyclophosphamide, and rituximab (FCR). The combination of bendamustine and rituximab (BR) should be considered in physically fit patients >65 years and in patients with a higher risk of infections. Patients with reduced fitness and/or relevant comorbidity should receive chlorambucil with a CD20 antibody, preferably obinutuzumab. Regardless of their fitness, patients with CLL carrying genetic aberrations such as del(17p) and/or TP53 mutation poorly respond to chemoimmunotherapy and therefore require different therapeutic approaches. An increasing understanding of the disease biology has led to the development of targeted drugs for the treatment of CLL, such as the BTK inhibitor ibrutinib and PI3K inhibitor idelalisib. These agents have shown efficacy in high-risk and relapsed/refractory patients and are currently being evaluated in clinical trials for first-line therapy. It is anticipated that these compounds and further other novel agents will profoundly change the therapy of CLL. Key words CLL; first-line treatment; high-risk Correspondence Paula Cramer, Department I of Internal Medicine and Center of Integrated Oncology Cologne-Bonn, German CLL Study Group (GCLLSG), University of Cologne, Kerpener Str. 62, 50942 Cologne, Germany. Tel: +49-221-478-88220; Fax: +49-221-478-86886; e-mail: paula.cramer@uk-koeln.de Accepted for publication 27 August 2015 doi:10.1111/ejh.12678 Management of patients with CLL With an age-adjusted incidence of 4.1/100 000 inhabitants in the United States, chronic lymphocytic leukemia (CLL) is the most common type of leukemia in Western countries (1 4). CLL affects mainly older and male patients as the median age at initial diagnosis lies between 67 and 72 years and the male-to-female ratio is 1.7 : 1 (1,2,5). Because the incidence rate rises with age (4), it is projected that the prevalence of CLL will further increase in the forthcoming decades due to the demographic changes in society. In addition, more frequent use of blood testing in routine practice leads to a diagnosis of CLL and also its precursor the monoclonal B-cell lymphocytosis (MBL) in a higher proportion of younger, asymptomatic patients (6,7). According to IWCLL guidelines (8), the diagnosis of CLL is established by a blood count showing a lymphocytosis with 5.000/lL clonal B-lymphocytes, a peripheral blood smear with small, morphologically mature lymphocytes and an immunophenotype that is characterized by the coexpression of the T-cell antigen CD5 and B-cell surface antigens CD19, CD20, and CD23, as well as the expression of either kappa or lambda immunoglobulin light chains. These clonal mature B cells accumulate in the peripheral blood and bone marrow, as well as the secondary immune tissues, and thereby lead to enlargement of lymph nodes, liver, and spleen. 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 9

Advances in the first-line treatment of CLL Cramer et al. The clinical staging systems by Binet (9) and Rai (10) were introduced decades ago and are still widely used as simple and inexpensive tools to distinguish between three prognostic groups and to define which patients should be treated or managed with a watch and wait approach (see Fig. 1). Both staging systems require a clinical examination of the lymph nodes, liver, and spleen plus a blood count including hemoglobin and platelets. Treatment should be initiated in patients with advanced CLL, that is, Binet stage C/Rai stages III/IV, which are defined by a thrombocytopenia and/or anemia, which are mostly related to bone marrow infiltration. In addition, treatment is indicated in case of constitutional symptoms, such as weight loss ( 10% within 6 months), night sweats, or fever without evidence of infection, as well as a rapid lymphocyte doubling time and massive or symptomatic enlargement of lymph nodes or spleen (8). The clinical course of patients with CLL is very variable, and both staging systems lack the accuracy to predict outcome on an individual basis. Therefore, a plethora of molecular and biological factors were proposed for prediction of disease progression and survival (11). Continuously, attempts are made to define the most relevant factors and establish a prognostic score for patients with CLL (12 14). However, such prognostic factors and scores should not be assessed routinely in patients without an indication for treatment, as unfavorable results might increase the psychological stress of these patients, who were diagnosed with a leukemia and are managed with a watch and wait approach (11). The presence of a deletion of the short arm of chromosome 17 [del(17p)] or mutation of the TP53 gene is associated with a poor prognosis (15) and resistance to most chemotherapeutic agents used in the treatment of CLL, as they mediate cell death through DNA damage and p53-dependent apoptosis (16 18). Therefore, the detection of a del(17p) or a TP53 mutation is crucial for the choice of treatment, and these analyses should be repeated ahead of every treatment decision, as clonal evolution leads to an accumulation of genetic aberrations during the course of disease (18 21). In addition to these two genetic abnormalities, the patient s physical fitness, burden of comorbidities, and concomitant medications must be taken into consideration for treatment decisions. Three groups of elderly patients with cancer can be distinguished based on their physical constitution, comorbidities, and estimated life expectancy regardless of the diagnosis of cancer (22 24): First, physically fit patients without or with mild comorbidities that do not adversely impact on the patient s life expectancy, who should be treated with standard therapies. Second, patients with relevant comorbidities that have impact on life expectancy, who should receive dose-reduced or modified therapies for disease control. Third, patients with a markedly reduced life expectancy due to multiple and / or severe comorbidities or frailty, who should be treated with Therapeu c algorithm of the GCLLSG (August 2015) (ini al) diagnosis of CLL (re-) evalua on of treatment requitrement 1 Binet A/B without B-symptoms Binet A/B with B-symptoms Binet C irrespec ve of B-symptoms watch & wait Evalua on of physical fitness and comorbidity² go go slow go no go Evalua on of del(17p)/tp53 mut. Evalua on of del(17p)/tp53 mut. go go without del (17p)/TP53 mut FCR, consider BR if >65 years and risk of infec on go go with del (17p)/TP53 mut Ibrut., Idela. + Ritux, discuss allohsct slow go without del (17p)/TP53 mut Clb + CD20 mab (GA101, Ofa, Ritux) slow go with del (17p)/TP53 mut Ibrut., Idela. + Ritux References: 1) Hallek et al., Blood 2008 2) Gribben, Blood 2009 Figure 1 Therapeutic algorithm of the GCLLSG. 10 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Cramer et al. Advances in the first-line treatment of CLL best supportive care. For these three patient groups, different therapeutic goals should be pursued. The aim for the first group is to achieve a long-term-remission and a prolongation of survival, whereas for the second and third group disease control and symptom control/palliation should be sought. The management of these three groups can be summarized with the mnemonic principles of action go go, slow go, and no go (Fig. 1) (25 27). To allocate a patient to the group of go go or slow go patients, the German CLL Study Group (GCLLSG) uses the cumulative illness rating scale (CIRS) score (28) and the creatinine clearance, as they reflect the biological age rather than the calendar age of a patient. The CIRS rates the burden and severity of comorbidities in 14 organ systems with up to four points in each category. A total CIRS score of six is used as a cutoff to distinguish slow go patients from go go patients, who are eligible for a more intensive chemoimmunotherapy. Treatment of physically fit patients (so-called go go patients) Different chemotherapeutic agents, for example fludarabine and cyclophosphamide (FC), were combined for the treatment of younger patients with CLL and led to an improvement of overall and complete response rates, as well as progression-free survival (PFS) (29 31). Treatment outcome, including response rates, PFS, and overall survival (OS), was further improved with the addition of the monoclonal anti- CD20 antibody rituximab to FC chemotherapy (32 35). Hence, chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) became the standard of care for physically fit patients. An update of the CLL8 data in 2012 showed that after a median observation time of 4.9 years, 69.4% of patients treated with FCR remained alive compared to 62.3% in the FC arm (hazard ratio [HR] = 0.68, 95% Cl 0.535 0.858, P = 0.001) (36). Interestingly, the median PFS was still not reached in FCR-treated patients with an unmutated IGHV status and their Kaplan Maier PFS curve appeared to level off to a plateau, raising expectations that a subgroup of patients treated with FCR might achieve not only long-term remissions but also a cure from the disease (37). Long-term results from the first trial evaluating FCR at the MD Anderson Cancer Center showed a 6-year overall and failure-free survival of 77% and 51%, respectively (38). However, FCR is associated with a high incidence of adverse events, especially cytopenias and infections, for example, in the CLL8-trial CTC III-IV leukopenias and neutropenias occurred in 24% and 34% of patients treated with FCR and 25% experienced CTC III-IV infections (32). Attempts to reduce the toxicity of chemoimmunotherapy were made with either a dose reduction of the chemotherapeutic drugs (FCR light) and with the substitution of fludarabine by the other purine analogues pentostatin or cladribine or substitution of fludarabine and cyclophosphamide with bendamustine. The combination of cladribine with cyclophosphamide and rituximab (RCC) yielded an ORR of 78% in relapsed/refractory patients; however, the RCC regimen was not evaluated in first-line treatment (39). In 65 previously untreated patients, the combination of pentostatin, cyclophosphamide, and rituximab (PCR) achieved overall and complete response rates of 91% and 41%, respectively (40). In a randomized comparison of PCR and FCR in 184 previously untreated or minimally pretreated patients, no differences in response rates, PFS, and OS, but also no difference in the incidence of infections were documented (41). The combination of pentostatin and rituximab without cyclophosphamide (PR) yielded only an ORR and CR rate of 76% and 27%, respectively (42). In a historical comparison, these response rates and PFS were worse for the PR regimen compared with PCR regimen. The authors concluded that the addition of cyclophosphamide to purine-analogue-based chemoimmunotherapy is necessary for a better efficacy. Experience from the use of single agent bendamustine in routine practice and results from phase-ii trials evaluating the combination of bendamustine and rituximab (BR)(43,44) were promising, with especially a lower incidence of CTC III-IV neutropenias and infections (10.3% and 6.8% of patients receiving BR as first-line treatment). The CLL10 trial of the GCLLSG therefore prospectively evaluated whether the BR regimen was indeed equally effective and less toxic compared to the current standard first-line treatment FCR. A total of 564 physically fit patients (defined as a CIRS score 6 and a creatinine clearance >70 ml/min) without del(17p) were randomized to receive up to 6 cycles of either FCR or BR (45). Overall response rates were 97.8% in both arms, but patients treated with FCR achieved a higher rate of complete remissions (40.7% vs. 31.5%, P = 0.026), more MRD negativity (74.1 vs. 62.9%, P = 0.024), and a longer median PFS (53.7 vs. 43.2 months, HR = 1.589, 95% CI 1.25 2.079, P = 0.001). However, a distribution bias of IGHV status (55% of FCR- and 68% of BR-treated patients had an unmutated IGHV status, P = 0.003) and age (14% vs. 22% aged >70 years, P = 0.020) unfavors the BR arm. The mean number of treatment cycles was lower in patients receiving FCR (5.27 vs. 5.41 courses, P = 0.017). Significantly more CTC III-IV neutropenias and infections occurred with FCR (87.7% vs. 67.8%, P < 0.001 and 39.8% vs. 25.4%, P = 0.001), especially in patients >65 years old (48.4% vs. 26.8%, P = 0.001). The incidence of anemia and thrombocytopenia, as well as treatment-related mortality did not differ significantly between both treatment arms (3.9% vs. 2.1%). With these results demonstrating a higher efficacy with regard to CR rate, MRD negativity and PFS, FCR remains the standard of care in the first-line treatment of physically fit patients. However, as FCR is associated with a higher risk for severe neutropenias and infections in older patients, BR should be considered in elderly fit patients with 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 11

Advances in the first-line treatment of CLL Cramer et al. a high risk of infections as alternative frontline therapy, although it is likely inferior to FCR. Also, anti-infective prophylaxis should be re-evaluated during treatment with FCR or BR and follow-up. The combination of fludarabine and cyclophosphamide with two different dose levels of ofatumumab, another anti- CD20 antibody (FCO), yielded an ORR of 77% and 73% and CR rates of 32% and 50% in the two cohorts receiving either 500 mg or 1000 mg ofatumumab for first-line therapy (46). A higher proportion of high-risk features in these patients might explain the fact that these response rates are lower than usually observed with FCR. The combination of pentostatin, cyclophosphamide, and ofatumumab (PCO) achieved an ORR and CR rate of 96% nd 46%, as well as 18% MRD negativity in 48 previously untreated patients (47). Even if the response rates documented with PCO are comparable to the results achieved with FCR, further followup and a randomized comparison are needed. The substitution of rituximab within the FCR regimen by the anti-cd52 antibody alemtuzumab was not only associated with a high efficacy but also increased toxicity with especially cytopenias and infections. In an international phase-iii trial by the HOVON group, the combination of fludarabine, cyclophosphamide, and subcutaneous alemtuzumab (FCA) led to a higher frequency of opportunistic infections, without an increase in treatment-related mortality compared to FC alone. FCA increased overall and complete response rate as well as MRD negativity and prolonged PFS but not OS as compared to FC (48). Another phase-iii trial by the French group comparing first-line treatment with FCR and FCA was prematurely stopped due to higher toxicity and treatment-related mortality as well as a slightly lower efficacy with FCA (49). Further attempts to increase the efficacy of the FCR regimen were made with the addition of other compounds to the FCR regimen, for example, alemtuzumab (CFAR regimen) (50), the anthracycline mitoxantrone (FCM-R) (51,52), or the immune modulatory agent lenalidomide (FCR-L or FCR 2 ) (53,54). In most of these trials, a relevant increase of toxicity was observed preventing the wider use of these regimen. Without randomized comparisons to the FCR regimen, a broader use of these regimen cannot be recommended. Also, the use of the novel agents ibrutinib or idelalisib requires further investigation to define whether these should be used in patients without high-risk genetic features in the frontline setting. Treatment of patients with relevant comorbidities (so-called slow go patients) Over decades, chlorambucil was the standard treatment for CLL, especially in older patients with relevant comorbidities (55 57). In several clinical trials evaluating more potent agents, higher ORR and CR rates, as well as a prolongation of PFS, were achieved compared to chlorambucil, but no improvement of OS could be demonstrated (58 60). In the CLL5 trial of the GCLLSG comparing single agent chlorambucil and fludarabine in first-line treatment of patients aged 65 years and older, also no statistically significant differences in OS were found (57). Surprisingly, the median OS was 68.1 months in patients receiving chlorambucil and only 49.8 months in patients treated with fludarabine (61). The worse outcome of these elderly patients treated with fludarabine may be explained by the fact that they were treated less often in case of relapse (55% vs. 71%, P = 0.03) and experienced more secondary neoplasias (26% vs. 15%, P = 0.07), including skin tumors (11% vs. 2%, P = 0.07) and Richter 0 s transformations (9% vs. 2%, P = 0.05). The addition of an anti-cd20 antibody to chlorambucil was successfully tested in the CLL11-trial (62): 781 patients with coexisting medical conditions (defined as a CIRS score >6 and/or creatinine clearance <70 ml/min) were ran-domized to receive single agent chlorambucil (Clb) or chlorambucil with either rituximab (R-Clb) or obinutuzumab (GA101 [G-Clb]), a type-ii antibody with increased direct cell killing and antibody-dependent cellular cytotoxicity (ADCC) (63). The incidence of infusion-related reactions (IRRs) in general and especially severe IRRs was higher with G-Clb than with R-Clb (CTC I-IV and III-IV: 66% and 20% vs. 38% and 4%); however, with certain safety precautions for prevention of IRRs, such as adequate premedication, dose-splitting of the first dosage, and prophylactically withholding antihypertensive medications, these were manageable and limited to the first administration of obinutuzumab. Also, cytopenias, especially neutropenias, were more common with G-Clb and R-Clb compared to single agent chlorambucil (neutropenia CTC III-IV: 33% and 28% vs. 10%), but did not lead to a higher rate of infections (infection CTC III-IV: 12%, 14% and 14%). As expected, overall and complete response rate was highest with the combination of chlorambucil and obinutuzumab (ORR: 77.3%, incl. 22.3% CRs), followed by chlorambucil with rituximab (65.6% and 7.3%) and was worst with single agent chlorambucil (31.4%, no CRs). With G-Clb, a significant proportion of responding patients even achieved a MRD negativity in peripheral blood and bone marrow (37.6% and 19.5%). The median PFS was only 11.1 months in patients receiving single agent chlorambucil and was significantly improved to 16.3 months with the addition of rituximab (P < 0.0001). The combination of G-Clb further improved the median PFS to 26.7 months (P < 0.0001) and also improved the median OS in comparison to single agent chlorambucil (P = 0.0022). These and the updated results of the CLL11 trial (64) are in line with the experience of a phase-ii trial evaluating chlorambucil with rituximab in 100 patients with a median age of 70 years and a median of seven comorbidities, which achieved an ORR of 84% including 10% CRs and a median PFS of 23.5 months (65). 12 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Cramer et al. Advances in the first-line treatment of CLL The combination of chlorambucil and ofatumumab (O- Clb), another anti-cd20 antibody, which might have a higher complement-dependent cytotoxicity (CDC) than rituximab (63,66), was compared to single agent chlorambucil in a total of 447 patients with treatment-na ıve CLL, who were considered inappropriate for fludarabine-based therapy due to their age or comorbidities (67). Overall and complete response rate was significantly higher with the addition of ofatumumab compared to chlorambucil alone (82% incl. 12% CRs vs. 69% incl. 1%, P < 0.001), which translated into an improvement in the median PFS of 9 months (22.4 vs. 13.1 months, P < 0.001). So far, no randomized head-tohead comparison of ofatumumab and the other anti-cd20 antibodies was performed. However, the results achieved with O-Clb in this trial compare favorably to those achieved with R-Clb in the CLL11-trial but are not as good as with G-Clb. In a trial evaluating bendamustine plus ofatumumab (BO) in previously untreated and relapsed CLL, the investigatorassessed overall and complete response rate was 95% and 43% in the 44 patients included for first-line treatment with BO (68). CTC III/IV adverse events occurred in 34% and 23% of first-line patients, including 16% and 20% III/IV neutropenias, 5% CTC III skin reactions, and 11% CTC III/ IV infections. However, another trial evaluating first-line treatment with BO was prematurely closed due to unexpected toxicity (IRRs, infections and neurological toxicity) (69). To maintain the efficacy but reduce the toxicity of chemoimmunotherapy with FCR, different dose-reduced FCR treatment schedules were designed. The so-called FCR- Lite regimen contains a reduced dosage of fludarabine and cyclophosphamide (F: 20 mg/m² instead of 25 mg/m², C: 150 mg/m² instead of 250 mg/m²) and an increased frequency of rituximab infusions (d1 & d15 of each cycle), followed by 3-monthly rituximab administrations as a maintenance treatment until progression (70,71). The overall and CR rate of 65 previously untreated patients was 94% and 73%, respectively, and the median PFS was 5.8 years, which compared favorably to results achieved with FCR. The incidence of CTC III/IV cytopenias and infections was only 11% and 6%, respectively, which is lower than documented for the normal FCR regimen. However, the median age of patients was only 58 years. Four cycles of the FCR- Lite regimen with an oral administration of fludarabine and cyclophosphamide and an intensification of rituximab in the first two cycles was evaluated by the French study group and yielded an ORR of 93.6% with 19.7% CRs and 36.7% MRD negativity in physically fit patients >65 years (72). Overall survival at 36 months was 87.4%. The addition of lenalidomide with a slow dose escalation from 5 mg to 15 mg lenalidomide to the above-described FCR-Lite regimen (FCR-L or FCR 2 ) followed by a maintenance with lenalidomide was also successfully tested in 20 previously untreated patients. After only four cycles of FCR² with a routinely administration of pegfilgastrim, an ORR and CR rate of 95% and 75% was achieved, CTC III/IV neutropenias and infections occurred in 52% and 8%, respectively (54). The FCR3 and FCR5 regimen designed by the Australian group consisted of either three or 5 days of orally administered fludarabine and cyclophosphamide and the FR5 regimen of 5 days of single agent fludarabine (F: 24 mg/m², C: 150 mg/m² p.o.) combined with the usual dosage of rituximab (73). The regimen were tested in a randomized trial with 120 previously untreated patients aged 65 years; the ORR and CR rates were 95% and 51% with FCR3, 97% and 79% with FCR5 and 95% and 38% with FR5, respectively. Toxicity was mostly hematological AEs and manageable. However, 34% of patients treated with FCR5 had to terminate treatment due to toxicity and only 44% of the patients receiving FCR5 completed six cycles of therapy, which might explain a shorter PFS with FCR5. In an observation study of the Czech study group, 108 patients with a median age of 69 years and a median CIRS score of 5 received FCR with a dose reduction by 50% for fludarabine and cyclophosphamide and the full dosage of rituximab [Q- Lite], ORR was 81% with 37% clinical CRs; however, median PFS was only 28 months and OS was 79% at 2 years (74). Thus, these different dose-reduced FCR regimen proved to be feasible and less toxic, but might also be less effective than the conventional FCR regimen. The lower efficacy might be compensated with a more dose-dense administration of rituximab or addition of lenalidomide. However, the patient collective included in the trials evaluating the dose-reduced FCR regimen was somewhat older with more comorbidities, but was still younger and more physically fit than the elderly patient collective with relevant coexisting conditions evaluated in the CLL11 trial. Therefore, the standard of care in the first-line treatment of patients with relevant comorbidities is a chlorambucil-based chemoimmunotherapy. The combination with obinutuzumab achieved the longest progression-free survival times so far documented in this patient group and furthermore led to an improvement of overall survival. But so far, only data from a head-to-comparison of chlorambucil and GA101 with chlorambucil and rituximab is available. So far, no comparison with ofatumumab or other regimen such as the dose-reduced FCR regimen is available. Treatment of patients with del(17p)/tp53 mutation Patients with a del(17p) and/or a TP53 mutation have more rapid course of disease, which sometimes even resembles an acute leukemia and often poorly responds to chemotherapy (15,17,18,20,21). Until recently, the anti-cd52 antibody alemtuzumab was the only efficacious therapy and the mainstay of treatment in these patients despite it s risk of serious infectious complications due to T-cell depletion (75). 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 13

Advances in the first-line treatment of CLL Cramer et al. Another possibly curative therapeutic option for these patients with p53 abnormalities is the allogeneic hematopoietic stem cell transplantation (HSCT) (76), which is feasible only in a minority of patients due to their age, fitness, and burden of comorbidities, because of patient s refusal to undergo a procedure with significant mortality and morbidity or due to lack of a matching donor. Treatment of patients with CLL and especially of patients with del(17p) and/or TP53 mutations was markedly improved with the introduction of novel drugs targeting kinases downstream the B-cell receptor signaling pathway, namely Bruton s tyrosine kinase (BTK) and phosphatidylinositol-3-kinase (PI3K), which act independently of the p53 pathway (77 79). Both the BTK inhibitor ibrutinib and the PI3K inhibitor idelalisib (formerly CAL-101) were found to induce high response rates and promising progression-free and overall survival times as single agents and in combination with rituximab (80 82). However, del(17p) and TP53 mutations appear to retain their adverse prognostic impact as the treatment outcome is inferior with regard to quality and duration of response compared to patients without these genetic abnormalities (80 84). Nevertheless, the treatment outcomes achieved with these drugs are the best ever reported in patients with del(17p)/tp53 mutations (83,84). The BCL-2 antagonist venetoclax (ABT-199) is another oral drug with very promising preliminary data in patients refractory to fludarabine as well as patients harboring a del(17p) or an unmutated IGHV status, which is further investigated especially for the use in high-risk CLL (85 88). Both, ibrutinib and idelalisib, were recently approved by the American and European health authorities for the use in patients with relapsed CLL and in Europe also for treatmentna ıve patients with a del(17p) or TP53 mutation, if considered unsuitable for chemoimmunotherapy which one can argue is the case in all patients with these genomic alterations due to their inability to respond to chemotherapy. With these drugs available, the indication and optimal timing for an allogeneic HSCT needs to be redefined (89). Previously, most eligible and willing patients with del(17p)/tp53 mutations underwent this procedure in the first remission as recommended by the guidelines of the European Society for Blood and Marrow Transplantation (EBMT) (76). Nowadays, these patients are treated with one of the new drugs until achievement of a maximum response and the allogeneic HSCT may be performed at the time point of maximum response or alternatively treatment with kinase inhibitors may be continued and the allogeneic HSCT can be deferred to the time point of relapse. A consensus article by EBMT and the European Research Initiative on CLL (ERIC)(89) recommends to weigh the risks of the disease (cytogenetics and relapsed/refractory situation) and the transplantation (patient s age and comorbidities, donor match) and also to consider the patient s wish and expectations. Whenever possible, patients should be offered the participation in a clinical trial to increase the knowledge in medicine; however, this is particularly important for patient groups without a defined therapeutic standard. Therefore, clinical trials for patients with del(17p) and TP53 mutations are urgently needed to further evaluate the novel agents ibrutinib, idelalisib, and especially venetoclax and redefine the indication for allogeneic HSCT. Current therapeutic algorithm of the GCLLSG and possible future treatment principles in CLL First-line treatment with chemoimmunotherapy is an es-tablished therapeutic standard for patients without del(17p)/ TP53 mutations. FCR is the standard of care in physically fit patients without or with mild comorbidities (CIRS 6), while BR can be considered in fit elderly patients and in patients with a higher risk of infections. Patients with relevant coexisting conditions (CIRS >6) should receive chlorambucil with a CD20 antibody, preferably obinutuzumab. As a therapeutic principle for CLL, it seems advisable to administer the most efficacious treatment upfront, as a survival benefit could be demonstrated with FCR chemoimmunotherapy only in the first-line but not in the relapse situation (32,33). Also, in 30 comorbid patients, who failed to respond or relapsed early after single agent chlorambucil in the CLL11-trial and received obinutuzumab as salvage treatment, the outcome was worse compared to patients treated with G-Clb in the first-line situation. Even if the response rate (86.6%) was comparable, the median PFS from start of crossover treatment was shorter (17.2 months) (90), which also supports the use of the most effective treatment upfront. Fit and unfit CLL patients with del(17p)/tp53 mutations should be treated with a kinase inhibitor and an allogeneic HSCT should be considered in suitable patients with a matching donor. However, the use of these novel agents in the first-line treatment of CLL patients without these highrisk features needs to be defined. It is uncertain whether these drugs should be added to chemoimmunotherapy to increase the efficacy or whether they should be used to rather reduce or even omit the chemotherapeutic agents to decrease the risk for toxicities. Another important, but so far unanswered question is, whether these agents should be administered until progression or if a termination of treatment is possible in case of a deep remission (e.g., achievement of MRD negativity). Thus far, it is recommended to treat patients with these agents until progression or unacceptable toxicity, but this will almost certainly lead to issues with the patient s adherence to treatment after a longer time period and further yet unknown problems with medication interactions or long-term toxicities, for example due to immunosuppression leading to infections or secondary neoplasias. 14 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Cramer et al. Advances in the first-line treatment of CLL In order to use the opportunities of these innovative drugs and to redefine the treatment of CLL, the German CLL Study Group (GCLLSG) proposed a tailored and targeted treatment aiming for a total eradication of MRD (91). This so-called sequential triple-t concept consists of a debulking treatment with up to two cycles of a mild chemotherapy with bendamustine or fludarabine, followed by 6- to 12- month induction treatment with an antibody and a kinase inhibitor or BCL-2 antagonist, followed by a MRD-tailored maintenance. A series of phase-ii trials evaluating different combinations of antibodies (obinutuzumab or ofatumumab) and novel drugs (idelalisib, ibrutinib or venetoclax) is currently performed to evaluate the feasibility of this concept in an all-comer population including first-line, relapsed, and refractory patients, fit and unfit patients, as well as patients with and without adverse prognostic parameters such as del (17p) and TP53 mutations. These and several other trials are designed chemo-free or with reduced dosages of chemotherapy and appear to have more favorable toxicity profiles and promising efficacy. Therefore, patients with and without comorbidities might be treated with the same regimen with the therapeutic goal of a deep and long-lasting remission. Thus, the distinction of go go and slow go patients might become less relevant. Instead, the treatment will become more personalized, for example with an optional debulking in case of a high tumor load and the duration of treatment tailored to the patient s response. Furthermore, attempts are made to define biological parameters, which are predictive of the patients response to certain treatment options to guide therapeutic decisions. Conclusion The management of patients with CLL is undergoing significant changes; during the last decade, the outcome of firstline therapies was markedly improved by the addition of CD20-antibodies to well-established chemotherapies. Whereas in physically fit patients rituximab is combined with either fludarabine and cyclophosphamide (FCR)(32,45) or bendamustine (BR, to be considered in case of an age >65 years and higher risk of infections) (44,45), in patients with relevant comorbidities obinutuzumab (alternatively ofatumumab or rituximab) should be added to chlorambucil (Fig. 1). In addition to the patient 0 s age and comorbidities, the presence of a del(17p)/tp53 mutation needs to be taken into account for treatment decisions, as these chemoimmunotherapies lack efficacy in patients with these high-risk features. In 2014, two novel agents targeting the BCR signaling pathway were approved for the first-line treatment of patients with del(17p)/tp 53 mutations as well as for relapsed patients because of high efficacy and a favorable toxicity. These and other novel agents may enable further advances and may revolutionize the treatment of CLL. Disclosures The authors received research funding and honoraria for scientific talks and advisory boards from the following pharmaceutical companies: Celgene, Gilead, GlaxoSmithKline, F. Hoffmann LaRoche, Janssen-Cilag, and Mundipharma. References 1. Morton LM, Wang SS, Devesa SS, Hartge P, Weisenburger DD, Linet MS. Lymphoma incidence patterns by WHO subtype in the United States, 1992-2001. Blood 2006;107:265 76. 2. 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