Guideline for the treatment of chronic lymphocytic leukaemia (2018)

This guideline was compiled according to the British Society for Haematology (BSH) process at http://www.b-s-h.org.uk/guidelines/proposing-and-writing-a-new-bsh-guideline/. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at http://www.gradeworkinggroup.org. The guideline group was selected to be representative of UK medical experts and patients. Recommendations are based on a review of the literature using Medline/Pubmed searches under the heading, chronic lymphocytic leukaemia AND phase III AND (Ibrutinib OR Idelalisib OR Venetoclax OR Obinutuzumab OR Ofatumumab OR Bendamustine OR Rituximab OR Fludarabine OR Cyclophosphamide OR Chlorambucil). Only English language publications from 1 August 2011 to 22 March 2018 were included in the literature search. Titles and/or abstracts of publications obtained from the database searches described were manually reviewed. The writing group produced the draft guideline, which was revised by members of the UK Chronic Lymphocytic Leukaemia (CLL) Forum Executive, including patient representatives of the CLL Support Association and Leukaemia Care. The manuscript was reviewed by the BSH Haemato-Oncology Taskforce, placed on the members’ section of the BSH website for comment, and approved by the BSH guidelines executive committee. The objective of this guideline is to provide healthcare professionals with clear guidance on the management of patients with chronic lymphocytic leukaemia. In all cases, individual patient circumstances may dictate an alternative approach. The significant developments in the treatment of chronic lymphocytic leukaemia (CLL) in recent years demand an update of the British Committee for Standards in Haematology Guidelines for CLL (Oscier et al, 2012) with a focus on therapy. The guidance in this document refers to treatment outside clinical trials. However, the basic principle remains that, wherever possible, treatment of patients with CLL should be delivered within the context of a clinical trial. Chronic lymphocytic leukaemia is a chronically relapsing and remitting leukaemia. It is therefore particularly important that patients are able to establish trust with the clinician managing their disease over the years. The diagnosis is often overwhelming for patients and their families and it can be difficult for the patient to understand the complexities of treatments and the concept of ‘watch and wait’. Patients will expect and are entitled to be honestly informed about their disease. The majority of patients benefit from, and should be offered, information about CLL. All patients should be supported by a Clinical Nurse Specialist with experience in CLL. The national patient support associations are also a valuable resource for patients and have internet sites and booklets with reliable information (Bloodwise: https://bloodwise.org.uk/info-support/chronic-lymphocytic-leukaemia/what; CLLSA: https://www.cllsupport.org.uk/; Leukaemia Care: https://www.leukaemiacare.org.uk/; Macmillan: https://www.macmillan.org.uk/information-and-support/leukaemia/chronic-lymphocytic). Any treatment decision has to take into account the wishes of the patient and the desired treatment outcome (disease control or remission induction). The indications for treatment of CLL patients are outlined in the International Working Group CLL (IWCLL) criteria and include progressive lymphadenopathy, hepatosplenomegaly and/or splenomegaly, deteriorating blood counts and constitutional symptoms (Hallek et al, 2008, 2018). The expertise of the clinician, the performance status of the patient and characteristics of disease biology are important determinants of outcome, even for patients receiving identical therapy (Shanafelt et al, 2012; Goede et al, 2014a). Given that almost 90% of CLL patients have one or more co-morbidities, the potential risks and benefits of a particular treatment need to be fully assessed in each individual patient by an experienced CLL clinician and discussed at the multi-disciplinary team (MDT) meeting (Thurmes et al, 2008). The optimal strategy to determine fitness for chemotherapy remains undetermined and there is no agreement on the use of a specific formal co-morbidity assessment tool. Poor performance status might be disease-related and should not lead per se to a reduction in therapy intensity, especially not in patients with rapidly progressing disease. In the relapsed/refractory setting, the choice of approved targeted agent might depend on their respective specific toxicity profile (i.e. anticoagulation, cardiac history, etc.). Pre-treatment assessment of disease status (e.g. role of bone marrow assessment, computed tomography scans) remains as per current guidelines (Oscier et al, 2012). Chemoimmunotherapy is ineffective in patients with TP53 disruption, defined by either deletion of chromosome 17p or mutation in the TP53 gene. As alternative agents are available, it is therefore essential that all patients are tested for the presence of both deletions AND mutations of TP53 before each line of therapy (Furman et al, 2014; Farooqui et al, 2015; Rossi et al, 2015; Roberts et al, 2016). As small TP53 disrupted subclones have been shown to impact on clinical outcome (Rossi et al, 2013; Landau et al, 2015; Nadeu et al, 2016), the results of TP53 testing should be interpreted in light of the sensitivity of the diagnostic methodologies used. The definition of test sensitivity should always be established as part of the clinical laboratory accreditation process and sensitivity thresholds should be included in the diagnostic report. Retrospective studies have suggested that the sub-group of patients with mutated IGHV genes experience prolonged remissions with chemoimmunotherapy (Lucas et al, 2015; Fischer et al, 2016; Thompson et al, 2016). While these results require independent validation, testing for IGHV mutation status should be considered for patients eligible to receive chemoimmunotherapy to provide information for the likelihood of long-term progression-free-survival following chemoimmunotherapy (Rossi et al, 2015; Fischer et al, 2016). The pivotal German CLL8 study showed that the addition of rituximab (R) to the chemotherapy backbone (fludarabine and cyclophosphamide, FC) improved not just progression-free survival (PFS) but also overall survival (OS) of fit patients with CLL (Hallek et al, 2010). Subsequently, both the UK's ARCTIC and ADMIRE trials (Howard et al, 2017; Munir et al, 2017) and the German CLL10 trial (Eichhorst et al, 2016) provided further evidence that FCR remains the treatment of choice for fit patients. In addition, the ARCTIC, ADMIRE and Cancer Trials Ireland studies demonstrated that rituximab with oral administration of FC yields high rates of response and rates of minimal residual disease (MRD) negativity compared to historical series using intravenous FC (Appleby et al, 2017; Howard et al, 2017; Munir et al, 2017). In the German CLL10 trial, which compared FCR × 6 versus bendamustine with rituximab (BR) × 6, FCR proved superior in terms of overall response rate (ORR), achievement of MRD-negative remissions and duration of first remission in young fit patients. Although the BR arm of the trial had a statistically higher proportion of older and IGHV unmutated patients, patients in the FCR arm experienced more serious adverse events (SAE), particularly neutropenia and serious infections. OS remained similar in both arms. A retrospective sub-group analysis of the trial suggested that elderly patients (>65 years old) are more likely to experience toxicity with intensive therapy, and current US National Cancer Control Network guidelines do not recommend fludarabine for patients aged >70 years (Wierda et al, 2017). However, there is no international consensus on a specific age restriction for fludarabine-based chemotherapy (Martell et al, 2002; Michallet et al, 2013). Due to the age distribution of CLL, two-thirds of patients are likely to have at least one significant co-morbidity and higher risk disease (Truger et al, 2015). The considerable clinical heterogeneity seen between patients should be considered when planning treatment (Goede & Hallek, 2011). Co-morbidity scores, such as the Cumulative Illness Rating Scale (CIRS) (Linn et al, 1968; Baumann et al, 2014), are not routinely recommended, but have been used in clinical trials to define fitness objectively. As with fit patients, testing for TP53 deletions and mutations should be standard practice. Two major randomised clinical trials, CLL11 by the German CLL Study Group (GCLLSG) and COMPLEMENT-1, included older patients and patients with significant co-morbidities and led to approval of combinations of chlorambucil (Clb) with obinutuzumab (Obin) or ofatumumab (Ofa), respectively (Goede et al, 2014b; Lee et al, 2014; Hillmen et al, 2015). In addition to demonstrating the superiority of Clb-R over Clb alone, the CLL11 study confirmed a significant PFS and time-to-next treatment (TTNT) benefit with Clb-Obin over Clb-R and an OS benefit compared to Clb. Of note, the lower limit of creatinine clearance permitted was 30 ml/min. Infusional reactions (IR) with Obin, although manageable, were significantly higher than with rituximab (grade 3–4 IR 20% vs. 4%) (Goede et al, 2014b, 2015). The COMPLEMENT-1 study demonstrated a significantly prolonged PFS with Clb-Ofa compared to Clb alone, but no difference in OS. Grade 3–4 IRs were reported at 10% with Ofa (Hillmen et al, 2015). Comparison between the two studies is hampered, amongst other factors, by differences in the dose and schedule of Clb (0·5 mg/kg on days 1 + 15 in CLL11 and 10 mg/m2 days 1–7 in COMPLEMENT-1). A randomised comparison of BR with Clb-R for fludarabine-ineligible treatment-naïve patients showed a complete response rate after Cycle 6 of 24% vs. 9%; respectively (P = 0·002) and a median PFS of 40 months vs. 30 months (P = 0·003). The ORR and OS were not different. In first-line patients with a complete response, MRD negativity was higher with BR than Clb-R (66% vs. 36%) (Michallet et al, 2018). Clb-R is not routinely recommended as two of these randomised trials showed inferior PFS compared to either BR or Clb-Obin. Ibrutinib is licensed for front-line use in patients without TP53 disruption as excellent responses and a significant improvement in OS were demonstrated compared to Clb in a randomised phase 3 study of older patients without TP53 deletion (RESONATE-2) (Burger et al, 2015). Main trials summarised in table 1. While extremely frail patients may tolerate mild oral chemotherapy (chlorambucil), they may find additional antibody therapy unacceptable, with the requirement for intravenous infusions and more frequent hospital attendance. Best supportive care was recommended for this group before the advent of B-cell receptor signalling pathway inhibitors (BCRi), preserving quality of life and concentrating on infection prevention, pain management and transfusion support. The introduction of non-chemotherapy agents has expanded options for extremely frail patients: the newer therapies are more effective, have a different side-effect profile from chemotherapy and are administered orally. However, all clinical trials have excluded very frail patients because of performance status, number of co-morbidities and/or renal function and therefore there is no evidence on how to manage CLL in extremely frail patients. As with all patients, the goal of treatment in this group should be determined in discussion with each patient. Extremely frail patients could be offered a brief trial of treatment that includes clear guidance on when to stop and should be very closely monitored. Our recommendations are therefore the summary of different expert opinions. A minority of patients (5–10%) will have evidence of TP53 disruption at time of first treatment. 4% of cases are identified by fluorescence in situ hybridisation (FISH) for deletions of chromosome 17p. Using Sanger sequencing, an additional 4–6% of patients carry mutations in TP53. This percentage increases further when using more sensitive next generation sequencing. Treatment of TP53-disrupted patients with standard chemotherapy is associated with significantly inferior disease response, duration of response and OS compared with patients who do not have TP53 disruption (Dohner et al, 2000; Tam et al, 2008; Zenz et al, 2008). Compelling data has been published on the treatment of patients with TP53 disruption with BCRi, namely idelalisib with rituximab or or the (Furman et al, 2014; Farooqui et al, 2015; et al, 2016; et al, 2016). Although the majority of TP53-disrupted patients in these studies were at high ORR and superior PFS were in the patients with TP53-disrupted CLL in led to the current of these for front-line treatment of TP53-disrupted CLL, and to National for and approval of and idelalisib with rituximab for this However, a higher risk of infection and with idelalisib therapy than et al, 2016), the to review for and to recommend idelalisib for treatment of CLL in the presence of 17p deletion or TP53 mutation in patients who are not eligible for other The guidance also recommended that all patients should and randomised trials of antibody therapy in CLL have been published et al, 2013; et al, 2015; et al, 2016). has been following FCR and other chemoimmunotherapy et al, et al, 2016; et al, 2017). The data that patients on therapy may benefit in terms of but no OS has been with to the potential toxicity of therapy in CLL and further and analysis of these trials are therapy be recommended in CLL. As for front-line therapy, the criteria for treatment as defined by the guidelines (Hallek et al, 2008, 2018). patients with but CLL can be with no therapy for a of the time of treatment testing for the presence of TP53 disruption by and should be Chemoimmunotherapy is not in patients who have not to within months of intensive chemoimmunotherapy with FCR or or have TP53 disruption guidance on PFS In addition, patients with co-morbidities who after a chlorambucil and and patients who remissions with front-line chemoimmunotherapy but have co-morbidities are no eligible for further on randomised trials in these patient significant in OS compared to licensed treatment options include in with bendamustine and or idelalisib in with either rituximab or ofatumumab et al, 2014; et al, 2014; et al, 2016; et al, 2017; et al, 2017). or idelalisib with rituximab is for an individual patient on a of factors, including toxicity profile and of The of bendamustine to either or idelalisib rituximab is that the median PFS was similar for the respective with or without the addition of bendamustine et al, 2016; et al, 2017). Of note, patients who were or who had experienced a prolonged first remission with chemoimmunotherapy were excluded from randomised trials of both idelalisib rituximab have been chemoimmunotherapy in the The decision to with chemoimmunotherapy on the time to the of therapy and the of TP53 In the and Cancer patients were FCR and FCR or FCR with an at to a median PFS of months et al, et al, et al, and included patients with to FCR et al, 2014; et al, 2015). Treatment was more but the median PFS was under years. with chemoimmunotherapy may be more in patients with remissions et al, Fischer et al, Tam et al, The evidence for BR in the relapsed/refractory from the control of both the and studies et al, 2016; et al, similar PFS of 1 to the phase study of Fischer et is data on patients who on BCRi, including patients with TP53 It is important to that an in response to the agents and disease patients who on BCRi, a number of studies a outcome in the of alternative treatment et al, 2015; Forum et al, 2017). studies of patients who on one and were to an alternative targeted agent a PFS et al, 2016). A phase study and a data of patients who on either or idelalisib et al, 2016; et al, 2017) of in this setting, which is also in TP53-disrupted disease et al, 2016). Venetoclax is licensed for use in patients with CLL who have or are for therapy and either have a TP53 disruption or a of The benefit of in with rituximab over BR for patients with relapsed/refractory CLL was demonstrated by the independent review PFS and proportion of patients blood MRD negativity vs. et al, 2018). Although of the study is it that is likely to a for relapsed/refractory CLL. Only of the patients into the study were to Main trials summarised in table published guidelines (Hallek et al, 2008, used response criteria that were in the of therapy. may not always be in the of In patients receiving often have improvement in lymphadenopathy, and constitutional symptoms of therapy, but a in to of from et al, 2013; et al, 2014; et al, that can for over a The guideline the that is not a of treatment (Hallek et al, 2018). This should be in patients are not to be defined as a response to therapy, and risk treatment was considered as the standard of care for selected patients with as defined by response to therapy of than 6 TP53 disruption or and can remission in patients with disease Society for 2013). The decision to should be based on remission status, patient performance status, co-morbidity and patient status and of alternative In the of disease on current therapy, discussion with a is recommended & 2015). The of is in patients with performance status, no significant a and disease at the time of However, is associated with and long-term toxicity et al, 2014; et al, 2017; et al, 2017). The of CLL the of in patients and role in the management of CLL has more been into with the advent of targeted therapies & 2015). Although patients with CLL and TP53 disruption benefit significantly from compared to historical patients within 3 years et al, 2014; et al, 2015; et al, 2016; et al, 2017) and the optimal treatment for patients who is patients with at remains very and remains the standard of care for patients remission to chemotherapy et al, 2016). Chronic lymphocytic leukaemia is by reduction in and the of & 2010). This can be by chemoimmunotherapy et al, In addition, treatment are associated with et al, et al, and counts × are significantly associated with such as patients with CLL from and the administration of and targeted agents in this has been associated with infections. Patients with CLL therefore require therapy and for at least 6 months & 2016; and 2017). All patients should be for evidence of or infection to therapy. of has been described following therapy et al, 2017; et al, 2017). CLL patients with evidence of infection should be with a (Hallek et al, 2008; et al, 2015). and infection can co-morbidities and may lead to disease such as et al, et al, However, in of CLL patients with antibody responses to can be found et al, 2015). to this risk include therapy and therapy et al, Patients with CLL should be offered and disease et al, 2014; et al, 2017). The of and the Committee on and specific recommendations on additional for patients at risk of from including CLL patients. with is recommended for all CLL patients, by at least months of 2018). However, patients, even with CLL, are to a response to et al, guidelines use of that patients with CLL should have to to and at least 3 months of therapy. dose of of intravenous is recommended and levels should be et al, 2011). This the need to and document response to In line with the such as and are not The and use of targeted agents has led to a of patients no to the associated with may experience of and and for the of and for idelalisib and and patients to to A of risks and benefits is essential and should be considered on an individual use of with that or or other should be and should be with and not be with Patients on may or have or therapy. patients on who require therapy, risk may be by to a oral and dose reduction risk benefit therapy such as inhibitors may be patients on therapy following of one of these agents should be considered in with the et al, 2017; et al, 2017). Due to the of and in patients on all patients should be closely for cardiac symptoms 2017). alternative agent should be considered In patients with a significant cardiac can and Patients with or co-morbidities should therefore be considered for In the advent of or the should be and and/or therapy can be with oral et al, 2015). Patients on also require for and have also been reported in patients with it is that patients receiving idelalisib should receive and for is a significant risk of when therapy with et al, 2016). over of patients for dose and including laboratory are following In the study of in CLL, which included patients, in of patients their disease and the diagnosis of CLL in of cases 2008; et al, 2008; et al, 2011). patients have no indications to the CLL and can be with with supportive as in et al, 2017). to of CLL patients have a test at but A or of is not a to chemoimmunotherapy et al, patients with and CLL before therapy. are no studies to chemoimmunotherapy choice in CLL patients with and are from with fludarabine and chlorambucil can and is in this is for patients with a that and or are for the treatment of patients who experienced et al, et al, A of has been reported for in the front-line study and also in a series from et al, 2016; et al, 2017). of and progressive CLL also results with & 2016). CLL patients when not receiving treatment et al, 2008). of cases also have a of to first-line treatment with or intravenous is 2008). rituximab for is an treatment. The and have shown response in & remains a treatment for cases and may a long-term response in to of patients, although response is lower in or chronic and neutropenia are with an of are of The treatment is the as for While the and information in this guidance is to be and at the time of to the the BSH the for the of this The to their to the patients who valuable into writing these guidelines on of Leukaemia and on of the UK CLL Support The BSH Haemato-Oncology members at the time of writing this guideline were and and The to the BSH and the BSH guidelines for their support in this The BSH the the writing of this All have a of to the BSH and which may be on The UK CLL Forum is a that from a number of including and This was by the of the writing group will the writing group evidence that the strength of the recommendations in this document or it The document will be reviewed by the and the literature will be 3 years to for evidence that may have been The document will be and from the BSH current guidelines website it recommendations are an will be published on the BSH guidelines website of Tam Hillmen for the Ibrutinib versus Ofatumumab in Chronic with