Guideline for the treatment of chronic lymphocytic leukaemia.

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Recent changes to the commissioned regimens and the COVID-19 pandemic necessitate an update of the 2018 British Society of Haematology guidance on chronic lymphocytic leukaemia (CLL).1 Here we discuss: (1) considerations prior to treatment; (2) front-line treatment recommendations; (3) management of relapsed or refractory disease; (4) management of intolerance to Bruton tyrosine kinase inhibitors (BTKi); and (5) guidance for vaccinations and prophylaxis. We focus particularly on therapies approved for use in the UK at the time of writing. Guidance on initial approach to patient management, indications for treatment, molecular assessment prior to treatment, assessment of response to treatment, supportive care, and autoimmune cytopenia remain unchanged. In addition to this CLL treatment update, we have published recent guidance on management of cardiovascular complications secondary to treatment with BTKi2 and Good Practice Guidance on the management of Richter transformation (RT) of CLL.3 These guidelines were compiled according to the BSH process (https://b-s-h.org.uk/media/16732/bsh-guidance-development-process-dec-5-18.pdf). 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. Recommendations are based on a review of the literature using Medline/Pubmed. Search terms included; CLL treatment, randomised, clinical trial, FCR, TP53 disruption, Bruton tyrosine kinase inhibitor, BCL2 inhibitor, rituximab, obinutuzumab, vaccination, Covid19. The search was limited to English-language publications and conference abstracts from the date of publication of the previous CLL guideline in 2018 to July 2021. Titles/abstracts obtained were curated and manually reviewed by the writing group who conducted additional searches, using subsection heading terms. Review of the manuscript was performed by the BSH Guidelines Committee Haemato-Oncology Task Force, the BSH Guidelines Committee and the Haemato-Oncology sounding board of the BSH. It was also posted on the members section of the BSH website for comment. This guideline has also been reviewed by patient representatives from the UK CLL Support Association (https://www.cllsupport.org.uk) and Leukaemia Care (https://www.leukaemiacare.org.uk). Choosing the optimal therapy for a patient with CLL requires consideration of both patient-related factors (such as comorbidities, concomitant medication, patient preference) and disease-related factors (prognostic and predictive). In addition, previous responses and toxicities from prior therapies and the impact of treatment on cellular and humoral immunity will also influence therapy choices. The availability of targeted agents provides effective therapy for older patients for whom palliative chemoimmunotherapy was previously the only option. However, differences in the side effect profiles of first- and second-generation BTKi and B-cell lymphoma-2 inhibitors (BCL2i), phosphoinositide 3-kinase inhibitors (PI3Ki), and the option of fixed-duration venetoclax-including regimens versus continuous BTKi therapy all impact on the choice of therapy for individual patients. Screening for TP53 disruption (i.e. del 17p13.1 and/or TP53 mutation) prior to each line of treatment is recommended as patients with these genetic abnormalities remain a high-risk group, even in the era of targeted therapy. IGHV gene mutation analysis should be performed to identify a subgroup of patients who often fare particularly well and may be functionally cured with fludarabine, cyclophosphamide and rituximab (FCR) (fit, younger patients) and have excellent, durable responses with 12 months' fixed-duration venetoclax–obinutuzumab (VenO) (older patients). Since the last BSH CLL guidelines were published in 2018, targeted pathway inhibitors have challenged the role of chemoimmunotherapy (CIT) and represent a paradigm shift in front-line treatment. Criteria for initiating treatment remain as defined by the iwCLL.4 Given the natural CLL age distribution, the majority of patients fall into the category of 'less fit', with almost 90% having comorbidities.5 Prior to the approval of targeted agents, the German CLL Study Group (DCLLSG) CLL11 trial established chlorambucil with obinutuzumab (CO) as an international standard of care for this patient cohort.6 Three major randomised clinical trials in unfit patients7-9 have since shown an improved progression-free survival (PFS) with targeted inhibitors using either a BTKi or BCL2i in combination with obinutuzumab, compared to CO (Table 1), but no overall survival benefit to date. Ibrutinib Chlorambucil 73 72 136 133 92/30 37 NR (78% 6.5 years) NR (68% 5 years) – – Ibrutinib: Hypertension (26%) AF (16%) Major haemorrhage (11%) Ibrutinib Ibrutinib-Rituximab Bendamustine-Rituximab 71 71 70 182 183 183 93 94 81 NR (87% 2 years) NR (88% 2 years) NR (74% 2 years) 0.38 (0.250–0.59) IR vs BR 1.00 (0.62–1.62) I vs IR NR (90% 2 years) NR (94% 2 years) NR (95% 2 years) – – – 1 4 8 ≥G3 neutropenia-I (15%), IR (21%), BR (40%) AF-I (9%), IR (6%), BR (3%) Hypertension >G3-I (29%), IR (34%), BR (15%) Ibrutinib-obinutuzumab Chlorambucil-obinutuzumab 70 72 113 116 88 73 NR (76% 36 m) 22 m 0.251 (0.160–0.395) NR (86% 40 m) NR (85% 30 m) – – 35 25 Acalabrutinib Acalabrutinib-obinutuzumab Chlorambucil-obinutuzumab 70 70 71 179 179 177 86 94 79 NR (78% 4 years) NR (87% 4 years) 27.8 m – – – NR (88% 4 years) NR (93% 4 years) NR (88% 4 years) – – – – – – AF-A (4%), AO (3%), CO (1%) Hypertension ≥G3 A (2%), AO (3%), CO (3%) Bleeding >G3 A & AO (2%) Venetoclax-obinutuzumab Chlorambucil-obinutuzumab 72 72 216 216 85 71 NR (74% 4 years) 36.4 m NR (85.3% 4 years) NR (83.1% 4 years) 76 35 ECOG-ACRIN E1912 Ibrutinib-rituximab FCR 56.7 56.7 354 175 96 81 NR (89% 3 years) NR (73% 3 years) NR (99% 3 years) NR (92% 3 years) 8 59 Neutropenia ≥G3 IR (25.6), FCR (44.9%) AF-IR (7.4%), FCR (3.2%) Ibrutinib was the first-in-class BTKi to be licensed in CLL. The phase 3 RESONATE-2 study compared indefinite ibrutinib with ≤12 cycles of chlorambucil in untreated patients over 65 years old without del17p13.1.10 After seven years of follow-up, the ibrutinib arm displayed superior survival: PFS 61% vs 9%, and overall survival (OS) at five years of 83% vs 68% (78% of ibrutinib-treated patients were estimated to be alive at 6.5 years). Ibrutinib was well tolerated in this older population with 47% of patients remaining on treatment at this timepoint. Continued ibrutinib also improved depth of response with complete remission/complete remission with incomplete count recovery (CR/CRi) increasing from 11% at 18 months to 34% after a median follow-up of seven years.11, 12 The ALLIANCE A041707 study demonstrated an improved two-year PFS for ibrutinib with or without rituximab, compared to bendamustine–rituximab (87% vs 88% vs 74%, hazard ratio [HR] 0.38; 95% confidence interval [CI] 0.25–0.59).13 Notably, there was no additional benefit in adding rituximab to ibrutinib. Most common/clinically relevant adverse events (AEs) are included in Table 1. In the ELEVATE-TN study, acalabrutinib, the second-generation BTKi, in combination with obinutuzumab or as monotherapy improved the four-year PFS compared to chlorambucil–obinutuzumab (87% vs 78% vs 25%). An ad hoc analysis showed the addition of obinutuzumab to acalabrutinib improved PFS, but at the expense of an increased rate of ≥grade 3 infection (23.6% vs 16.2%, compared with 8.3% with chlorambucil–obinutuzumab), neutropenia rate (30.9% vs 11.2% vs 41.4%), and infusion-related reactions (2.8% vs 0 vs 5.9%)14 (see Table 1 for more information on AEs). The DCLLSG CLL14 study, which compared venetoclax in combination with obinutuzumab (VenO) to CO, showed improved four-year PFS (74% vs 35%).15 The improved PFS of CO, compared to that in the CLL11 study,6 is possibly explained by longer chlorambucil treatment (12 vs 6 cycles). VenO has some potential advantages over BTKi combinations, offering a fixed-duration treatment of one year, and high rates of minimal residual disease (MRD)-negative (<10−4) response (75.5% MRD-negative in peripheral blood and 56.9% in bone marrow). Additionally, there was a significantly lower incidence of subsequent clonal evolution than in the CO arm. Specific mutations associated with venetoclax resistance were not detected, such as mutations in BCL2, BIM, BAX, BCL-XL and MCL1). Grade ≥3 neutropenia occurred in 52.8% of VenO-treated patients, but precautions (use of adequate prophylaxis, initial debulking with obinutuzumab, and the well-established weekly venetoclax ramp-up dosing schedule) resulted in significant reduction of tumour lysis syndrome (TLS). FCR was previously the standard of care for front-line treatment of fit patients with CLL and intact TP53. The phase 3 ECOG-ACRIN 1912 trial randomised patients to receive either ibrutinib and rituximab (IR) for six cycles, followed by ibrutinib until disease progression or unacceptable toxicity, or six cycles of FCR.16 The IR cohort had a superior survival compared to FCR (three-year PFS 89.4% vs 72.9%, HR 0.35; 95% CI 0.22–0.56, with three-year OS 98.8% vs 91.5% HR 0.17; 95% CI 0.05–0.54). A subgroup analysis of patients with unmutated IGHV showed a PFS of 90.7% vs 62.5% at three years in favour of IR; whereas among those with mutated IGHV, PFS was comparable (87.7% vs 88.0%). The overall incidence of grade ≥3 AEs was similar; however, grade ≥3 infections were less common (10.5% vs 20.3%) in the IR group. Acalabrutinib Investigator's choice (BR/IdelaR) 68 67 155 155 81/0 76/2 NR (88% 1 year) 16.5 (68% 1 year) NR (90% 1 year) NR (88% 1 year) N/A N/A MURANO (Seymour et al.35) (Kater et al.37) VenR BR 64 66 194 195 92.3/26.8a 72.3/8.2a 53.6 17 NR (82% 5 years) NR (62% 5 years) X°62.4 13.3 Ibrutinib Ofatumumab 67 71 195 196 44.1 8.1 67.7 65.2 N/A N/A GS-US-312-0116 (Furman et al.31) (Sharman et al.82) IdelaR Rituximab 71 71 110 110 85.5/0 17/0 19.4 6.5 40.6 34.6 N/A N/A Among patients with mutated IGHV who receive front-line FCR and obtain a MRD-negative remission, extremely durable responses can be achieved leading to 'functional cure' in about 50% of patients with mutated IGHV,17 while the very long-term durability of responses to targeted inhibitors is as yet unknown. FCR therefore remains a viable option for fit, younger patients with mutated IGHV and intact TP53. However, this indication for FCR may change once longer-term follow-up data exist for the targeted inhibitors. Currently, front-line BTKi with ibrutinib or acalabrutinib does not have NICE approval for use in fit, younger patients without TP53 disruption, although the E1912 study showed an OS advantage of ibrutinib compared to FCR in this patient group. Prospective data from a phase 1b study of 32 patients indicates that VenO may be equally effective in fit patients.18 NICE TA633 permits use, via the Cancer Drugs Fund (CDF) in England and Northern Ireland, and through a different funding stream in Wales, of up-front VenO for fit patients lacking TP53 disruption, while more data are collected in this group. NICE-approved front-line treatment options for all patients with CLL and TP53 disruption include VenO, ibrutinib, acalabrutinib and venetoclax monotherapy where BTKi is contra-indicated (Figure 1). A growing body of evidence suggests that BTKi and BCL2i with or without anti-CD20 antibodies are highly effective front-line combination treatment. The phase 2 CAPTIVATE19 trial of venetoclax combined with ibrutinib (VI) in previously untreated CLL, included patients who were fit, under 65 years, but had at least one of: del(17p), TP53 mutation, del(11q) or unmutated IGHV. After 12 cycles of combined treatment, 88% of patients had CR/CRi, and 61% were MRD-negative in bone marrow, leading to FDA approval. The most common grade 3/4 AE across cohorts was neutropenia.20 In the less fit populations (over 65 years old or younger patients with a cumulative illness rating scale (CIRS) score of >6 or creatinine clearance <70 ml/min) efficacy and safety of fixed-duration VI is being evaluated in a phase 3 trial, GLOW. Improved PFS with VI (76% at 27.7 months) compared with CO (29%) (HR for progression or death 0.216; 95% CI 0.131–0.357) was consistent across predefined subgroups, including patients with unmutated IGHV. High-risk patients with known TP53 disruption were excluded. Undetectable bone-marrow (BM) MRD rates by next-generation sequencing (NGS) were significantly higher for VI at three months after the end of treatment compared with CO (51.9% vs 17.1% respectively, p = 0.0259). The most common grade 3/4 AE in both treatment groups was neutropenia (VI 34.9% vs CO 49.5%), infections (17% vs 11.4%), and diarrhoea (10.4% vs 1%); 22.6% participants discontinued VI.21 The relatively high incidence of early treatment-related mortality in VI patients compared with the control arm and VI patients in the CAPTIVATE trial suggests this combination should be used with caution in older/more comorbid patients and should be limited to fit patients with high-risk CLL. The pivotal studies described above have demonstrated superior long-term efficacy and tolerability of targeted therapy over CIT in the front-line setting for patients over 65 or with CIRS scores of >6. As result, both continuous therapy with acalabrutinib monotherapy and 12 months' fixed-duration VenO are now NICE-approved in the UK. The decision on which regimen to choose has to be based on a number of different factors including CLL-specific risk factors, past medical history, concomitant medication and patients' choice. Front-line ibrutinib monotherapy is NICE-approved and funded in the UK for patients with TP53 disruption but not routinely for all other front-line patients at the time of writing. There is no evidence directly comparing targeted agents in TP53 aberrant to recommend one over the other. Long-term follow-up of CLL14 shows that the small proportion of patients with TP53 disruption have a shorter PFS compared to those with wild-type (WT) TP53 following fixed-duration VenO. A similar patient population receiving continuous ibrutinib plus obinutuzumab in the Illuminate trial had a PFS of 72% at 36 months (HR 0.162; 95% CI 0.096–0.275).22 There is long-term benefit with ibrutinib monotherapy despite lack of undetectable MRD: Ahn et al. reported a six-year PFS in CLL patients with TP53 aberrations of 61% (95% CI 46–80) and an OS of 79% (95% CI 67–94).23 Zanubrutinib, a selective, second-generation covalent BTK inhibitor, had been tested in 109 TP53-deleted naïve patients with overall response rates of 94.5%, 18-months PFS of 88.6% (95% CI, 79.0–94.0) and an OS of 95.1% (95% CI, 88.4–98).24 With respect to IGHV mutational status, ibrutinib and acalabrutinib with or without anti-CD20 showed broadly equal responses for IGHV-mutated and unmutated patients,7, 13, 16 whereas IGHV-unmutated patients have an inferior PFS compared to those with mutated IGHV following VenO in CLL14.9 Whether IGHV status should be used to determine use of BTKi- or BCL2i-based treatment remains unclear. Longer-term sequencing studies may provide further guidance in this area in the future. Impact of past medical history such as cardiovascular comorbidities, use of anticoagulation, and bleeding risk on choice of front-line therapy is covered by related guidance.2 Here, the use of a more selective BTKi, such as acalabrutinib, with fewer cardiovascular side effects may be preferable.25 Alternatively, a combination is a for this patient group. with a history of disease should be obinutuzumab also treatment with BCL2 inhibitors requires adequate and patients with clearance and ml/min) should only be for venetoclax benefit with for the increased risk of for patients with high tumour and/or chronic BTKi may be a option. on the of treatment, medication should be with to or inhibitors which should be or by other of for all targeted inhibitors is are with and inhibitors. to the of for guidance on management of therapy to the BSH on management of cardiovascular complications of Bruton tyrosine kinase A of the and of fixed-duration therapy and continuous therapy should patient age patients, fixed-duration treatment may be and the effect of treatment on of should be In addition, the long-term of secondary should be with younger patients with mutated IGHV, CLL where FCR is being and side effects is treatment but is particularly relevant in the months following of a data demonstrated a rate of ibrutinib with subsequent also a rate of at 17 Acalabrutinib rates were for acalabrutinib with obinutuzumab and for acalabrutinib Most side effects with time with the of and The licensed therapies in relapsed CLL are BTKi and BCL2i monotherapy or in combination with and phosphoinositide 3-kinase inhibitors and After one or cycles of and BCL2 or in combination with anti-CD20 standard treatment options for relapsed CLL, of or of TP53 randomised evidence has compared BTKi versus in CLL after are into patient and There are also data on the sequencing patients following targeted agents (Table a patient is on a targeted treatment should be for as as the patient clinical benefit until the subsequent targeted therapy is as there is a risk of progression once therapy is Acalabrutinib monotherapy demonstrated benefit in relapsed CLL over choice or in the With a median follow-up of patients with acalabrutinib showed an overall response rate of and a PFS of 88% compared to 68% on the choice. Acalabrutinib also improved PFS in and unmutated IGHV There were no safety for acalabrutinib and the rate of to AEs was fixed-duration venetoclax and rituximab for CLL demonstrated PFS and OS benefit compared to BR in MURANO with a four-year PFS of and (HR 95% CI A proportion of patients peripheral blood MRD at the end of treatment vs 37 patients had previously been to VenR was in unmutated IGHV patients and in those with TP53 Ibrutinib showed superior efficacy in CLL compared to in follow-up demonstrated an of and a rate of of therapy was months with on ibrutinib at study PFS was 44.1 months for the ibrutinib arm and 8.1 months for the arm. and were in and In a phase 3 trial of patients unfit for standard IdelaR demonstrated an of a PFS of 19.4 months and an OS of 40.6 months compared to rituximab The IdelaR subgroup of showed a similar median PFS of However, IdelaR remains a less used treatment option to and data exist to the sequencing of targeted with pivotal randomised trials performed in targeted patients after A phase 2 35 of venetoclax monotherapy in patients an of and a progression-free survival of patients who prior showed an of and a estimated PFS of patients demonstrated an of 50% and a of monotherapy is further by studies provide evidence for sequencing with Recent evidence suggests that BTKi provide high in patients including those previously to and more than in this monotherapy is licensed for relapsed CLL patients who have or are for monotherapy remains a option for following venetoclax evidence for this approach remains 1). The BTKi has efficacy in patients to both covalent BTKi and but is not yet approved in The majority of data on BTKi intolerance from of with ibrutinib and small clinical demonstrated that acalabrutinib is effective in patients ibrutinib to A phase 2 trial of found an of and a two-year PFS of AEs were diarrhoea and Prospective trial data that long-term are for patients who a BTKi for intolerance than but there are no data on responses to subsequent In subgroup 95% CI of 30 patients who had discontinued ibrutinib therapy of AEs had an overall response with compared with 95% CI of patients who had discontinued ibrutinib of disease of acalabrutinib and ibrutinib showed that acalabrutinib is tolerated with similar efficacy to ibrutinib in previously patients, but has lower of common AEs and treatment In cardiovascular events were less A phase 2 trial has demonstrated that the selective is and effective in BTKi and British Society of and and indications for in CLL remain as defined in This therapy to be an option for patients with high-risk such as TP53 disruption and treatment The decision to patients with high-risk disease should be based on remission status, patient status, and patient status and availability of Given the evolution of targeted treatment options the of treatment that indicates remains unclear. the time of patients who are refractory to CIT and/or TP53 disruption, and following at least one targeted should be targeted inhibitors not to impact the safety of and survival are similar of number of agents prior chemoimmunotherapy or targeted inhibitors prior to therapies to are including therapy which has been evaluated in clinical trials the last years following initial reported in A of and with ibrutinib have been or are in phase 1 and 2 response rates of to 95% of patients have been with rates of to in patients. These may be to of has also limited the use of to the of patients with CLL who not have Long-term follow-up data are lacking and such treatment remains an option only through clinical It is of that a number of trials of cellular licensed for other B-cell have either been using or are not using remains a very of CLL for which therapy may have a the management of to the recent BSH is a treatment option for patients with high-risk CLL defined by A of CLL is by responses to vaccination, including and We patients to a (see the is followed at least months by the response to should be in those with a history of or The is and should not be should with who have the for seven The is for patients with and is in the UK for those years of age should be for all patients with a history of or Most patients with disease from secondary patients BTKi is recommended either therapy or for at least the 12 months the risk of infection to be patients on fixed-duration regimen may be for at least six months after the end of treatment or until from the and on in patients with BTKi in a front-line setting and use of is We recommend for the of BTKi therapy in those on combination therapy or for patients with significant and a history of or of infection are and limited to those with is not routinely recommended with BTKi or BCL2i to potential There are of infections on patients receiving BTKi and the and of with targeted therapy should be each other on the individual risk is a common in patients with therapy is for patients (1) or infections despite six months of continuous (2) have a and (3) have to to of therapy that can be may be more for patients and can be used as an to A of is recommended with according to the In a small the resulted in higher levels and patient of improved in to In addition, a reduction in the number of AEs were with This information on to for the information found The COVID-19 pandemic has for patients with CLL and It is that the secondary associated with CLL a higher risk of COVID-19 disease but no data exist to the risk compared with An early the of COVID-19 in patients with CLL was similar to that in the population but associated with a high mortality rate in those with infection to be and rates were similar patients and those on including those on In a where CLL patients were for COVID-19 infection the mortality was lower but this included a number of who have from COVID-19 infection have lower rates in without and this is most in those with The of to patients with CLL by the COVID-19 is lower than that of An initial study from found responses to the COVID-19 of compared with for The response rate for untreated patients was compared with in those on BTKi therapy. patient 12 months of anti-CD20 therapy a response to The UK study patients who had either the and vaccination, with an interval the Here, an response rate of was compared to in This increased to 79% those on and response rates were in those on BTKi therapy or with Notably, the which was in the UK at the time of study, were compared to a further in those with The of from COVID-19 disease with levels remains unknown. response to COVID-19 is and cellular which are to in However, recent that cellular responses to are also in CLL compared to and compared to rates and to with subsequent of should be recommended to all patients and particularly for those to the inferior response rates patients with CLL, a followed at least three months by a is now patients who COVID-19 treatment options have been and are now for patients with CLL in the has been shown to the risk of and death in high-risk patients by to is to patients who for infection and have the last five are for use as a treatment option. an is associated with a reduction in the risk of or and is with the criteria and where of therapy is not or contra-indicated CLL Support Association Leukaemia Care and other groups provide to CLL patients. After of and initial we recommend that patients are to these and also of the where can receive on a treatment patients should be using the or to the writing of the The to members of the UK CLL for and review of the to to Richter and who reviewed the and to the members of the BSH The BSH the the writing of this have a of to the BSH and Task which may be on The is not for the or of information by the than should be to the for the