Interim statement from the BCSH CLL Guidelines Panel

Interim statement from the BCSH CLL Guidelines Panel George A Follows 1, Adrian Bloor 2, Claire Dearden 3, Steve Devereux 4, Christopher P Fox 5, Peter Hillmen 6, Ben Kennedy 7, Helen McCarthy 8, Nilima Parry-Jones 9, Piers EM Patten 4, Anna Schuh 10, Renata Walewska 8. 1. Cambridge University Hospitals NHS Foundation Trust, Cambridge 2. Christie NHS Foundation Trust, Manchester 3. Royal Marsden NHS Foundation Trust, Sutton 4. Kings College Hospital NHS Foundation Trust, London 5. Nottingham University Hospitals NHS Trust, Nottingham 6. Leeds Teaching Hospitals NHS Trust, Leeds 7. University Hospitals of Leicester NHS Trust, Leicester 8. Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust, Bournemouth 9. Nevill Hall Hospital, Abergavenny 10. Oxford University Hospitals NHS Trust, Oxford Email for correspondence: george.follows@addenbrookes.nhs.uk Conflicts of interest statements provided in appendix 2 Considering the significant developments in the treatment of CLL in the last 18 months, the BCSH Guidelines group have asked the CLL Guidelines Panel to provide an interim update for the BCSH guidelines website. This interim statement has not been peer-reviewed, but it is anticipated that a definitive rewriting of the CLL Guidelines will be completed before the end of 2015. The guidance in this document refers to treatment outside clinical trials. However, the basic principle remains that if possible or practical, treatment of CLL patients should be delivered within the context of a clinical trial. The current national trials of choice for the treatment of first line CLL are the FLAIR trial (http://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trialibrutinib-rituximab-chronic-lymphocytic-leukaemia-flair) for fit patients and RIAltO (http://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-looking-ofatumumabpeople-chronic-lymphocytic-leukaemia-who-cannot-have-more-intensive-treatment-rialto)for less fit patients. First line therapy The indications as to which patients meet criteria for treatment have not changed, i.e. the introduction of new therapies for first line and relapsed CLL does not alter the basic principle that

early stage CLL patients who have no symptoms attributable to their disease and no significant cytopenias, should be observed without therapy. Assessment of patients prior to treatment Pre-treatment assessment of disease status and biology (eg. role of bone marrow assessment, CT scans, TP53 disruption) remains as per current guideline. Note that CLL with lost TP53 function either by 17p deletion, assessed by FISH, or TP53 mutation, assessed by sequencing, does not respond well to genotoxic therapies. These will be referred to as cases with TP53 disruption throughout this document. Pre-treatment assessment of patient fitness remains as per current guideline [Oscier et al., 2012]. It remains broadly useful to separate patients into one of 3 groups based on their co-morbidity profile, as this will help decide on appropriate first line therapy: The mostfit patients (so-called go-go ), the less fit ( slow-go ) and frail ( no-go ). The optimal strategy to determine fitness for chemotherapy has not been determined and there is no obligation to use a formal co-morbidity assessment tool (such as CIRS), but some clinicians may find this useful. Initial treatment of fit patients with no TP53 disruption The German CLL10 trial has provided further evidence that fludarabine / cyclophosphamide / rituximab (FCR) x 6 cycles remains the treatment of choice for fit patients [Eichhorst et al., 2014]. In this randomised trial of FCR x6 vs bendamustine / rituximab (BR) x 6 in young fit patients, FCR proved superior in terms of overall response rate, achievement of MRD negative remissions and duration of first remission, although the BR arm of the trial had a statistically higher proportion of patients who were older and were IgVH unmutated. FCR was more toxic in terms of SAEs, particularly neutropenia and serious infections and with a median of 3 years follow-up, there have been 6 cases of MDS / AML in FCR treated patients compared with 1 case in BR treated patients. Overall survival remains inseparable between both arms of the trial. Retrospective sub-group analysis of the trial has suggested that elderly patients (>65 years old) are more likely to suffer toxicity with more intensive therapy and current US NCCN guidelines do not recommend fludarabine chemotherapy for patients aged >70. However, there is no international consensus on a specific age restriction for fludarabine chemotherapy and, within the current UK national FLAIR trial, patients are eligible for FCR up to age 75 if the patients meet other criteria for FCR. Recommendation FCR is recommended as initial therapy for previously untreated fit patients outside clinical trials (GRADE A1) BR is an acceptable alternative for fit patients in whom FCR is contra-indicated due to renal impairment, more advanced age or patient preference. (GRADE A1) Initial treatment of less fit patients with no TP53 disruption

Two large prospective randomised trials have now been presented with different therapeutic strategies for the less fit patient group. The German CLL11 trial has been presented and published [Goede et al., 2014]. In this trial, less fit patients were randomised to either chlorambucil (CBL) monotherapy (note German dosing schedule of treatment on D1 and D15 of a 28 day cycle), CBL + rituximab or CBL + obinutuzumab. The obinutuzumab dosing was higher in the first month ( front loaded ) than the rituximab dose. Cross over from the CBL monotherapy arm was permitted for patients who progressed within 1 year of starting therapy. The trial has shown acceptable toxicity and compared with CBL monotherapy, addition of either rituximab or obinutuzumab resulted in a clear improvement in overall response, depth of response, duration of first remission and time to next leukaemia therapy. Patients randomised to CBL + obinutuzumab had a statistically improved overall response, depth of response, duration of first remission and time to next leukaemia therapy compared with CBL + rituximab. In addition, the CBL+ obinutuzumab cohort also had a statistically improved overall survival compared with patients randomised to CBL monotherapy. CLL patients treated with obinutuzumab had a 20% chance of grade 3 or 4 infusion reactions, and it is essential that staff delivering this therapy are trained in managing this complication. The CBL + rituximab combination has also been assessed in a non-randomised phase 2 UK trial [Hillmen et al., 2014]. In this trial the CBL dosing was higher (Standard UK MRC dosing 10mg/m2 D1-7) than the dose used in the CLL11 trial, while the rituximab schedule was the same. The reported PFS for the combination with the higher chlorambucil dose was 23.5 months compared with the reported PFS of 15 months for CBL + rituximab from CLL11. The second randomised trial in this patient group randomised patients to receive either CBL monotherapy (Standard UK MRC dosing 10mg/m 2 D1-7) or CBL + ofatumumab and has now been published [Hillmen et al., 2015]. The trial has shown acceptable toxicity and compared with CBL monotherapy, addition of ofatumumab resulted in a clear improvement in the primary end-point for progression free survival and key secondary end-points of overall response, depth of response and duration of first remission. The significant gain in progression free survival through the addition of antibody therapy to CBL as first line therapy is compelling. The approved license indications are slightly different: Rituximab has a first line license to treat CLL in combination with chemotherapy, obinutuzumab is licensed specifically in combination with CBL (note intermittent dosing of CBL in the CLL11 trial; obinutuzumab has not been studied in combination with CBL dosed at 10mg/m 2 D1-7), and ofatumumab is licensed in combination with either CBL or bendamustine. Owing to differences in trial design (CBL and antibody dosing, patient selection etc), it is not possible to make a clear comparison of antibody efficacy between trials. Recommendation Chlorambucil therapy is recommended in combination with either ofatumumab or obinutuzumab as initial therapy for previously untreated less fit patients (GRADE A1)

Chlorambucil therapy in combination with rituximab is an alternative if access to ofatumumab or obinutuzumab is restricted (GRADE A1) Initial treatment of particularly frail patients If clinicians feel there is no realistic chance of a patient benefiting in terms of symptom control and / or remission duration from the addition of antibody therapy to CBL, then it remains entirely reasonable for patients to be treated with CBL with palliative intent. Bendamustine monotherapy is also licensed for use in this context. Equally, some patients will not want to consider intravenous therapy and these patients may derive benefit from CBL monotherapy Recommendation Chlorambucil therapy remains the treatment of choice for palliating frail patients with CLL, but bendamustine monotherapy may be appropriate for certain patients (GRADE A1) Initial treatment of patients with TP53 disruption A small minority of patients (5 10%) will have TP53 disruption at time of first treatment. This is most commonly identified using FISH for 17p deletion, but approximately half of cases will be due to TP53 mutation [Zenz et al., 2010]. In standard practice, 17p deletion in >20% of cells assessed by FISH has been considered significant and this level precludes entry into the current national UK FLAIR trial. Treatment of TP53-disrupted patients with standard chemotherapy is associated with significantly worse outcomes in terms of disease response, duration of response and overall survival compared with patients who do not have TP53 disruption. The current BCSH guidelines and ESMO guidelines (http://www.esmo.org/guidelines/haematological-malignancies/chronic-lymphocytic-leukemia) recommend the use of alemtuzumab +/- steroids in these patients as this combination appears to deliver a better overall response rate and PFS compared with patients treated with standard chemotherapy, although this has not been tested prospectively with a randomised trial. Treatment with alemtuzumab +/- steroids can be associated with significant toxicities and it is standard practice for this therapy to be delivered by clinicians / teams familiar with the use of this drug. Compelling data has now been presented and published treating patients with TP53 disruption with B cell receptor (BCR) signalling pathway inhibitors, namely Idelalisib + rituximab or ibrutinib [Furman et al., 2014, O'Brien et al., 2014]. Although the majority of TP53-disrupted patients have been treated at relapse, similar high levels of response have been observed in the few patients with TP53- disrupted CLL treated as first line. The response rates and duration of remissions have been strikingly good compared with historical controls, and this has led to the current licensing of these drugs, which includes treatment of first line CLL in patients who are shown to have TP53 disruption. At the time of writing, there is no nationally agreed funding for first line use of either idelalisib+rituximab or ibrutinib in front-line TP53-disrupted CLL. However, there is currently a scheme in place permitting

compassionate access to idelalisib in the UK managed by Idis Parma (idelalisib@idispharma.com). If access to ibrutinib or idelalisib can be secured, then either of these approaches would be considered the preferred first line therapy. Deciding between the two approaches may depend on a range of factors discussed in the relapse section of this interim statement. If either of these drugs cannot be obtained, then alemtuzumab with steroids remains the treatment of choice in patients, who are considered fit enough to receive this combination. Note that the previous recommendations for allogeneic transplant in CLL are less clear. Previously, fit patients with TP53-disrupted CLL would be offered an allogeneic transplant in first remission following alemtuzumab therapy. However, these recommendations need to be reassessed in the light of new data with idelalisib and ibrutinib. Patients in first remission after alemtuzumab may have other options for re-treatment with a BCR-pathway inhibitor at relapse, and may prefer this strategy rather than allogeneic transplant in first remission. However, this is a very challenging area and it is strongly recommended that such patients are discussed early in their treatment algorithm with a tertiary centre with expertise in both CLL and allogeneic stem cell transplantation. Recommendation Treatment with either idelalisib + rituximab or ibrutinib is the treatment of choice for first line therapy for patients with TP53 disruption (GRADE B1) If either idelalisib + rituximab or ibrutinib are not available then treatment with alemtuzumab +/- corticosteroids remains preferable to chemotherapy (GRADE B1) MAINTENANCE THERAPY Two prospective randomised trials of anti-cd20 antibody maintenance therapy in CLL were presented at in December 2014 in abstract form [Greil et al., 2014, van Oers et al., 2014]. The data suggest that patients who receive maintenance therapy may benefit in terms of PFS, but no OS benefit has been presented. There remain concerns with regards to potential toxicity of maintenance therapy in CLL, and further follow-up and analysis of these trials are required. At present, maintenance therapy cannot be recommended in CLL. However, patients who become MRD positive within 2 years of completing chemo-immunotherapy are eligible for the randomised Phase III NCRI GALACTIC trial testing the role of obinutuzumab consolidation against observation. RELAPSE THERAPY Two large prospective randomised trials have now been presented and published, evaluating B-cell receptor pathway antagonists in the setting of relapsed / refractory CLL [Furman et al., 2014, Byrd et al., 2014]. With very heavily pre-treated frail patients, idelalisib + rituximab has been shown to be superior to monotherapy rituximab in terms of response rate, depth of remission, duration of remission and overall survival [Furman et al., 2014]. Similar striking benefit has also been shown for

ibrutinib compared with ofatumumab in the relapse / refractory setting [Byrd et al., 2014]. Therefore, relapsed / refractory patients who meet appropriate criteria should be considered for treatment with either idelalisib+ rituximab or ibrutinib. The NHS England CDF panel has included these drugs in the CDF as long as specific inclusion criteria are met. These are based on the entry criteria for the respective trials which are included in appendix 1. Deciding whether ibrutinib or idelalisib + rituximab is most appropriate for an individual patient will depend on a range of factors. The trial inclusion criteria for treatment were not overlapping, so certain patients will only meet treatment criteria for one drug. The side effect profile and the convenience of delivery is different between the regimens and this may influence clinician / patient choice. High-risk CLL has traditionally been defined as those patients with a demonstrable TP53 disruption and/or those who relapsed within 2 years of fludarabine-based immunochemotherapy. For these patients, if remissions could be established, use of allogeneic transplant has in the past been recommended by UK, European and US guidelines. With access to BTK and / or PI3K inhibitors, defining which patients are high-risk becomes more challenging and, consequently, the role of allogeneic transplant in CLL has become less clear. These challenges have been the subject of a recently published review [Dreger et al., 2014]. Unfortunately, it remains likely that many patients with TP53 disruption will relapse after a period of time on one of the novel therapies. Clinicians are, therefore, encouraged to discuss these patients with tertiary centres with expertise in CLL allogeneic transplantation and CLL clinical trials. Of note, patients who were less heavily pre-treated, or who had experienced a prolonged first remission with immunochemotherapy were excluded from both the ibrutinib and idelalisib randomised relapse trials. Furthermore, neither ibrutinib nor idelalisib + rituximab have been evaluated prospectively against immunochemotherapy in the relapse setting. We, therefore, do not know whether patients relapsing after a prolonged first remission will benefit more from earlier treatment with a BCR pathway inhibitor, rather than re-treatment with immunochemotherapy. Although, retrospective subgroup analysis of the RESONATE trial has suggested that patients treated after fewer lines of therapy appear to have a prolonged PFS compared with the patients treated later in their disease [Brown et al., 2014], interpreting this retrospective data needs caution, as there will be inherent bias in favour of better outcomes for the less heavily pre- treated patients. Therefore, with particular reference to patients relapsing after a prolonged first remission it is less likely that they will meet criteria for treatment with either idelalisib+ rituximab or ibrutinib. For these patients, treatment with chemotherapy or immunochemotherapy, as per the existing BCSH guidelines remains recommended. Unfortunately the quality of data from relapsed trials with immunochemotherapy is poor, and choice of chemotherapy regimen will depend on previous therapy and co-morbidities. For patients treated with more intensive intent this is likely to be FCR or BR, while more palliative patients may be re-treated with CBL.

As the data stands, no firm recommendations can be made as to how patients relapsing after treatment with ibrutinb or idelalisib+rituximab should be managed. The NHS England CDF has specifically excluded funding of patients crossing from one therapy to another, although clarification is awaited to confirm that this exclusion does not apply if the first therapy was delivered within a clinical trial. Data on the use of eitheridelalisib + rituximab or ibrutinib as a bridge to allogeneic transplant is very limited and individual cases would need to be discussed with specialist transplant centres to assess suitability. Recommendation Idelalisib + rituximab or ibrutinib is the treatment of choice for patients with relapsed CLL who meet specific criteria see appendix 1 (GRADE A1) Patients with relapsed CLL who do not meet the treatment criteria for either idelalisib + rituximab or ibrutinib should be treated with chemotherapy+/- rituximab, most likely BR or FCR although the quality of data to support this choice is limited. CBL is an option where a more palliative approach is required (GRADE B2) References Brown JR, Hillmen P, O'Brien S et al., Updated Efficacy Including Genetic and Clinical Subgroup Analysis and Overall Safety in the Phase 3 RESONATE TM Trial of Ibrutinib Versus Ofatumumab in Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Abstract 3331, ASH 2014 Byrd JC, Brown JR, O'Brien S et al., RESONATE Investigators.Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia.n Engl J Med. 2014 Jul 17;371(3):213-23. doi: 10.1056/NEJMoa1400376. Epub 2014 May 31. Dreger P, Schetelig J, Andersen N et al., European Research Initiative on CLL (ERIC) and the European Society for Blood and Marrow Transplantation (EBMT).Managing high-risk CLL during transition to a new treatment era: stem cell transplantation or novel agents? Blood. 2014 Dec 18;124(26):3841-9. doi: 10.1182/blood-2014-07-586826. Epub 2014 Oct 9. Review. Eichhorst B, Fink A, Busch R et al., Frontline Chemoimmunotherapy with Fludarabine (F), Cyclophosphamide (C), and Rituximab (R) (FCR) Shows Superior Efficacy in Comparison to Bendamustine (B) and Rituximab (BR) in Previously Untreated and Physically Fit Patients (pts) with Advanced Chronic Lymphocytic Leukemia (CLL): Final Analysis of an International, Randomized Study of the German CLL Study Group (GCLLSG) (CLL10 Study). Abstract 19, ASH 2014 Furman RR, Sharman JP, Coutre SE et al., Idelalisib and rituximab in relapsed chronic lymphocytic leukemia.n Engl J Med. 2014 Mar 13;370(11):997-1007. doi: 10.1056/NEJMoa1315226. Epub 2014 Jan 22

Goede V, Fischer K, Busch R, et al.,obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions.n Engl J Med. 2014 Mar 20;370(12):1101-10. doi: 10.1056/NEJMoa1313984. Epub 2014 Jan 8. Greil R, Obrtlikova P, Smolej L et al., Rituximab Maintenance after Chemoimmunotherapy Induction in 1 st and 2 nd Line Improves Progression Free Survival: Planned Interim Analysis of the International Randomized AGMT- CLL8/a Mabtenance Trial. Abstract 20, ASH 2014 Hillmen P, Gribben JG, Follows GA et al., Rituximab plus chlorambucil as first-line treatment for chronic lymphocytic leukemia: Final analysis of an open-label phase II study. J Clin Oncol. 2014 Apr 20;32(12):1236-41. doi: 10.1200/JCO.2013.49.6547. Epub 2014 Mar 17. Hillmen P, Robak T, Janssens A et al., COMPLEMENT 1 Study Investigators.Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open-label phase 3 trial.lancet. 2015 May 9;385(9980):1873-83. doi: 10.1016/S0140-6736(15)60027-7. Epub 2015 Apr 14. O'Brien S, Jones JA et al., Efficacy and Safety of Ibrutinib in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Leukemia with 17p Deletion: Results from the Phase II RESONATE -17 Trial Abstract 327, ASH 2014 van Oers MHJ, Kuliczkowski K, Smolej K et al., Ofatumumab (OFA) Maintenance Prolongs PFS in Relapsed CLL: Prolong Study Interim Analysis Results. Abstract 21, ASH 2014 Oscier D, Dearden C, Eren E et al., British Committee for Standards in Haematology.Br J Haematol. 2012 Dec;159(5):541-64. doi: 10.1111/bjh.12067. Epub 2012 Oct 11. No abstract available. Erratum in: Br J Haematol. 2013 Mar;160(6):868. Dosage error in article text. Br J Haematol. 2013 Apr;161(1):154. Erem, Sharman JP, Coutre SE, Furman RR et al., Second Interim Analysis of a Phase 3 Study of Idelalisib (ZYDELIG ) Plus Rituximab (R) for Relapsed Chronic Lymphocytic Leukemia (CLL): Efficacy Analysis in Patient Subpopulations with Del(17p) and Other Adverse Prognostic Factors. Abstract 330, ASH 2014 Zenz T, Eichhorst B, Busch R et al.,tp53 mutation and survival in chronic lymphocytic leukemia.j Clin Oncol. 2010 Oct 10;28(29):4473-9. doi: 10.1200/JCO.2009.27.8762. Epub 2010 Aug 9. Appendix 1 Idelalisib + rituximab inclusion criteria from Furman et al NEJM 2014 1. CLL that had progressed within 24 months after their last treatment 2. Previous treatment must have included either a CD20 antibody based regimen or at least two previous cytotoxic regimens.

3. Not able to receive cytotoxic agents for one or more of the following reasons: a. severe neutropenia or thrombocytopenia caused by cumulative myelotoxicity from previous therapies, b. an estimated creatinine clearance of less than 60 ml per minute, c. a score on the Cumulative Illness Rating Scale (CIRS) of more than 6 for coexisting illnesses not related to CLL. d. 17p deletion or mutation (added by CDF) Ibrutinib inclusion criteria from Byrd et al NEJM 2014 1. Must have received at least one prior therapy for CLL/SLL and not be appropriate for treatment or retreatment with purine analog based therapy, defined by at least one of the following criteria: a. Failure to respond (stable disease or disease progression on treatment), or a progression-free interval of less than 3 years from treatment with a purine analog based therapy and anti-cd20 containing chemoimmunotherapy regimen after at least two cycles. b. Age 70 years, or age 65 and the presence of comorbidities (Cumulative Illness Rating Scale [CIRS] 6 or creatinine clearance <70 ml/min) that might place the patient at an unacceptable risk for treatment-related toxicity with purine analog based therapy, provided they have received one or more prior treatment including at least two cycles of an alkylating agent based (or purine analog based) anti-cd20 antibody containing chemoimmunotherapy regimen. CIRS score can be determined using a web-based tool. c. History of purine analog associated autoimmune anemia or autoimmune thrombocytopenia. d. Fluorescent hybridization showing del17p in 20% of cells (either at diagnosis or at any time before study entry) either alone or in combination with other cytogenetic abnormalities, provided the patient has received at least one prior therapy. Appendix 2 Conflicts of interest UK CLL Forum is a registered charity that receives funding from a number of pharmaceutical companies including Roche, GSK, Janssen, Gilead, Napp GAF: advisory board / paid speaker engagements with Roche, GSK, Janssen, Gilead, Napp AB: advisory board / speaker / consultant: Janssen / GSK / Roche / Gilead / NAPP CD: advisory board / paid speaker engagements with Roche, GSK, Janssen, Gilead, Napp, Infinity

SD: advisory board / paid speaker engagements with Roche, GSK, Janssen, Gilead, Napp CPF: advisory board/paid speaker engagements with Roche, Janssen, Gilead, Napp PH: advisory board/paid speaker from Roche, GSK, Janssen, Gilead, Pharmacyclics, Abbvie BK: advisory board/paid speaker with Roche, Janssen, Gilead HM: advisory board/paid speaker with Roche, Janssen NP-J: No conflicts to declare NP-J: No conflicts to declare PEMP: advisory board / paid speaker engagements with Roche, GSK, Janssen, Gilead AS: advisory board/paid speaker from Roche, GSK, Janssen, Gilead, Pharmacyclics, Napp RW: Gilead conference grants