Long‐term Follow‐up of 415 Patients with Chronic Lymphocytic Leukemia Treated with Fludarabine and Cyclophosphamide‐based Chemoimmunotherapy in the Frontline ADMIRE and ARCTIC Trials: A Comprehensive Assessment of Prognostic Factors

American Journal of HematologyVolume 97, Issue 5 p. E168-E171 CORRESPONDENCEFree Access Long-term follow-up of 415 patients with chronic lymphocytic leukemia treated with fludarabine and cyclophosphamide-based chemoimmunotherapy in the frontline ADMIRE and ARCTIC trials: A comprehensive assessment of prognostic factors David John Allsup, Corresponding Author David John Allsup [email protected] orcid.org/0000-0001-6159-6109 Centre for Atherothrombosis and Metabolic Disease, Hull York Medical School, Hull, UK Correspondence David John Allsup, Centre for Atherothrombosis and Metabolic Disease, Hull York Medical School, Hull, UK. Email: [email protected]Search for more papers by this authorZoe Craig, Zoe Craig Clinical Trials Research Unit, University of Leeds, Leeds, UKSearch for more papers by this authorDavid Cairns, David Cairns Clinical Trials Research Unit, University of Leeds, Leeds, UKSearch for more papers by this authorDena Howard, Dena Howard Clinical Trials Research Unit, University of Leeds, Leeds, UKSearch for more papers by this authorAnna Hockaday, Anna Hockaday Clinical Trials Research Unit, University of Leeds, Leeds, UKSearch for more papers by this authorAdrian Bloor, Adrian Bloor The Christie NHS Foundation Trust, Manchester, UKSearch for more papers by this authorZarni Soe, Zarni Soe St James Institute of Oncology, Leeds, UKSearch for more papers by this authorChristopher Pepper, Christopher Pepper Clinical and Experimental Medicine, Brighton and Sussex Medical School, Brighton, UKSearch for more papers by this authorValter Gattei, Valter Gattei Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano (PN), ItalySearch for more papers by this authorAntonella Zucchetto, Antonella Zucchetto orcid.org/0000-0003-3678-5957 Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano (PN), ItalySearch for more papers by this authorPauline Robbe, Pauline Robbe Laboratory for Transcriptome Technology, RIKEN Centre for Integrative Medical Sciences, Yokohama, JapanSearch for more papers by this authorRuth Clifford, Ruth Clifford Department of Haematology, University Hospital Limerick, Limerick, IrelandSearch for more papers by this authorAnna Schuh, Anna Schuh Department of Oncology, University of Oxford, Oxford, UKSearch for more papers by this authorTalha Munir, Talha Munir St James Institute of Oncology, Leeds, UKSearch for more papers by this authorAndrew Rawstron, Andrew Rawstron Haematological Malignancy Diagnostic Service, St James Hospital, Leeds, UKSearch for more papers by this authorPeter Hillmen, Peter Hillmen St James Institute of Oncology, Leeds, UK Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UKSearch for more papers by this author David John Allsup, Corresponding Author David John Allsup [email protected] orcid.org/0000-0001-6159-6109 Centre for Atherothrombosis and Metabolic Disease, Hull York Medical School, Hull, UK Correspondence David John Allsup, Centre for Atherothrombosis and Metabolic Disease, Hull York Medical School, Hull, UK. Email: [email protected]Search for more papers by this authorZoe Craig, Zoe Craig Clinical Trials Research Unit, University of Leeds, Leeds, UKSearch for more papers by this authorDavid Cairns, David Cairns Clinical Trials Research Unit, University of Leeds, Leeds, UKSearch for more papers by this authorDena Howard, Dena Howard Clinical Trials Research Unit, University of Leeds, Leeds, UKSearch for more papers by this authorAnna Hockaday, Anna Hockaday Clinical Trials Research Unit, University of Leeds, Leeds, UKSearch for more papers by this authorAdrian Bloor, Adrian Bloor The Christie NHS Foundation Trust, Manchester, UKSearch for more papers by this authorZarni Soe, Zarni Soe St James Institute of Oncology, Leeds, UKSearch for more papers by this authorChristopher Pepper, Christopher Pepper Clinical and Experimental Medicine, Brighton and Sussex Medical School, Brighton, UKSearch for more papers by this authorValter Gattei, Valter Gattei Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano (PN), ItalySearch for more papers by this authorAntonella Zucchetto, Antonella Zucchetto orcid.org/0000-0003-3678-5957 Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano (PN), ItalySearch for more papers by this authorPauline Robbe, Pauline Robbe Laboratory for Transcriptome Technology, RIKEN Centre for Integrative Medical Sciences, Yokohama, JapanSearch for more papers by this authorRuth Clifford, Ruth Clifford Department of Haematology, University Hospital Limerick, Limerick, IrelandSearch for more papers by this authorAnna Schuh, Anna Schuh Department of Oncology, University of Oxford, Oxford, UKSearch for more papers by this authorTalha Munir, Talha Munir St James Institute of Oncology, Leeds, UKSearch for more papers by this authorAndrew Rawstron, Andrew Rawstron Haematological Malignancy Diagnostic Service, St James Hospital, Leeds, UKSearch for more papers by this authorPeter Hillmen, Peter Hillmen St James Institute of Oncology, Leeds, UK Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UKSearch for more papers by this author First published: 02 February 2022 https://doi.org/10.1002/ajh.26483Citations: 1 David John Allsup and Zoe Craig co-first authors. Funding information: Health Technology Assessment Programme; Associazione Italiana Ricerca Cancro, Grant/Award Number: IG-21687; Progetto Ricerca Finalizzata, Grant/Award Numbers: RF-2018-12365790, PE-2016-02362756; Core Clinical Trials Unit Infrastructure, Grant/Award Number: C7852/A25447; Roche Products Ltd AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL To the Editor: Chemoimmunotherapy (CIT) with fludarabine, cyclophosphamide, and rituximab (FCR) has been the mainstay treatment of previously untreated chronic lymphocytic leukemia (CLL) for many years.1 A minority of FCR-treated patients are identified as a favorable risk group by the presence of mutated immunoglobulin heavy chain variable genes (M-IGHV), weak CD49d expression, long telomeres and post-therapy assessment of minimal residual disease (MRD).2-4 Most patients treated with FCR relapse, and this has driven the development of efficacious therapies targeting the B-cell receptor (BCRi) but exposes patients to risks such as hypertension and other cardiovascular toxicities.5 Therefore, there may remain a case for CIT in untreated patients with CLL with favorable features. We report the outcomes of previously untreated patients with CLL after prolonged follow-up following fludarabine and cyclophosphamide-based CIT in two phase II randomized controlled trials, ADMIRE and ARCTIC. ADMIRE compared FCR with fludarabine, cyclophosphamide, mitoxantrone, and rituximab (FCMR), while ARCTIC compared FCR with fludarabine, cyclophosphamide mitoxantrone, and reduced dose rituximab (FCM-minR). In addition to reporting long-term outcomes, we assessed a range of factors reported to be prognostic to identify robust markers associated with favorable outcomes. Treatment-related toxicities and premature discontinuation of therapy may be associated with inferior outcomes, so we assessed how these events impact patient outcomes. Methods including trial design and assessment of prognostic factors are presented as Supporting information Appendix S1. ADMIRE/ARCTIC provided outcome data on 415 previously untreated patients with CLL recruited between July 2009 and September 2012 (Supporting information Tables 1 and 2). Median follow-up is 84 months (interquartile range [IQR]: 72–94 months), median progression-free survival (PFS) is 66 months (95% confidence interval [CI] 56–72 months), and median overall survival (OS) is 108 months (95% CI 101 months-not reached) (Supporting information Figure 1A and B). There is no difference in PFS or OS between FCR and FCM-R (PFS adjusted hazard ratio [aHR] 1.09, 95% CI 0.80–1.49; OS aHR 0.95, 95% CI 0.62–1.47). For FCR and FCM-miniR, a small difference was observed for PFS but not OS (PFS aHR 1.35, 95% CI 1.00–1.84; OS aHR 1.01, 95% CI 0.65–1.57) (Supporting information Figures 2A and B). Five years postrandomization, 68.9% (95% CI 60.6%–75.9%) of patients with M-IGHV CLL were progression-free and 83.0% were alive (95% CI 75.8%–88.3%). Unadjusted Cox regression analysis found unmutated IGHV (UM-IGHV) is associated with shortened PFS and OS (PFS HR 2.62, 95% CI 1.92–3.57; OS HR 1.65, 95% CI 1.09–2.48) (Supporting information Figure 3A and B). Three months posttreatment, 169 patients (40.7%) were bone marrow (BM) MRD positive, 84.0% had a PFS event and 40.2% had an OS event during follow-up, compared to 36.6% and 21.0% who were MRD negative (n = 186). Unadjusted Cox regression analysis of MRD found that MRD positivity is associated with shortened PFS and OS (PFS HR 4.49, 95% CI 3.33–6.04; OS HR 2.35, 95% CI 1.59–3.47) (Supplementary Figure 4A and B). The combination of MRD positivity and UM-IGHV resulted in highly shortened PFS and OS compared to M-IGHV and MRD negativity (PFS HR 11.1, 95% CI 6.76–18.22; OS HR 3.45, 95% CI 1.94–6.13) (Supporting information Figure 5A and B). Univariable Cox regression analysis of PFS revealed UM-IGHV, 17p/11q deletion, TP53 mutations (mutTP53), and increasing international prognostic index for CLL (CLL-IPI) are associated with shortened PFS (Supporting information Table 3A). Increasing CD38 (% positive cells), CD49d (% positive cells), and decreasing CD20 (mean fluorescence intensity [MFI]), CCR6 (MFI and % positive cells) and LAIR1 (MFI) are also associated with shortened PFS (Supporting information Table 3B). Multivariable penalized Cox regression found IGHV, MRD, standardized CD49d (% positive cells) and deletion 17p (d17p) and/or mutTP53 are, in combination, most prognostic of PFS (Supporting information Table 3C). Univariable Cox regression analysis of OS found age greater than 65 years, positive direct coombes' test (DCT), UM-IGHV, d17p, mutTP53, and increasing CLL-IPI are associated with shortened OS (Supporting information Table 4A). Increasing CD49d (% positive cells), decreasing CCR6 (MFI), and LAIR1 (MFI) are associated with shortened OS (Supporting information Table 4B). Mutations in ATM, BIRC3, NOTCH1, and SF3B1 are not independently associated with PFS or OS. Multivariable penalized Cox regression found MRD, age, CD49d (% positive cells), DCT and d17p, and/or mutTP53 are, in combination, most prognostics of OS (Table 1). TABLE 1. Multivariable penalized Cox regression analysis of OS Parameter estimate Standard error Hazard ratio and 95% CI Number of times variable selected out of the 42 imputed data sets 3-month posttreatment BM MRD status Positive vs. negative 0.39 0.18 1.48 (1.04 to 2.1) 42 Age at randomization >65 vs. ≤65 years 0.129 0.15 1.14 (0.847 to 1.53) 42 Standardized CD49d (% of positive cells) 0.0737 0.0686 1.08 (0.941 to 1.23) 36 Direct Coombs test Positive vs. negative 0.0496 0.147 1.05 (0.788 to 1.4) 24 Deletion 17p and/or mutated TP53 Yes vs. no 0.098 0.146 1.1 (0.828 to 1.47) 24 Standardized LAIR1 −0.000638 0.0407 0.999 (0.923 to 1.08) 5 Mutated BIRC3 Yes vs. no 0.00785 0.0725 1.01 (0.874 to 1.16) 3 Mutated ATM Yes vs. no 0.00426 0.0316 1 (0.944 to 1.07) 1 Mutated NOTCH1 Yes vs. no 0.000673 0.0477 1 (0.911 to 1.1) 1 Note: Variables frequently selected from the imputed data sets by the penalized Cox model are more predictive of the outcome than those not selected or selected infrequently. Each selected variable contributes to predicting the outcome in combination with the other selected variables, even if it is not significantly associated with the outcome itself. Abbreviations: BM, bone marrow; MRD, minimal residual disease; OS, overall survival. The proportion of PFS and OS events is higher in those who experienced any grade 3 or 4 adverse event (AE), a hematological-related grade 3 or 4 AE, or an infection-related grade 3 or 4 AE (Supporting information Table 5), but the presence of any grade 3 or 4 AE or hematological-related grade 3 or 4 AEs are not associated with shortened PFS or OS (Supporting information Table 6A and B). However, the presence of infection-related grade 3 or 4 AEs are associated with both shortened PFS and OS (PFS aHR 1.52, 95% CI 1.07–2.27: OS HR 1.64, 95% CI 1.02–2.63) (Supporting information Figure 6A and B). Baseline IgA and IgG levels are not associated with grade 3 or 4 AEs, a hematological or an infection grade 3 or 4 AE (Supporting information Table 7A–C). One hundred twenty-two second cancers were diagnosed in 102 of the 415 patients and comprised Richter's transformations 12 (2.9%), acute myeloid leukemia/myelodysplasia (AML/MDS) 19 (4.6%), skin (nonmelanoma) 37 (8.9%), skin (melanoma) 9 (2.2%), and solid tumors 35 (8.4%). In those diagnosed with a second cancer, the median time to diagnosis from randomization was 34.5 months (IQR: 22, 60 months). For patients developing Richter's, there was no preponderance of poor prognostic features (Supporting information Table 8). In patients who developed AML/MDS, this was not associated with trial therapy and occurred at a median of 34.9 months (IQR: 23, 46 months) post-therapy. Of patients who developed AML/MDS three had received more than one line of therapy (Supporting information Table 9). Patients who receive three or less treatment cycles tend to be older, more likely to have d17p and more likely to be MRD positive (Supporting information Table 10). Receiving three or less treatment cycles is associated with shorter PFS, and OS (PFS aHR 2.66, 95% CI 1.73–4.07; OS aHR 2.62, 95% CI 1.65–4.17) (Supporting information Figure 7A and B). For PFS, only patients who prematurely discontinued therapy due to toxicity, without progression, were included in the analysis. Of 192 patients who experienced disease progression, 79 (41.1%) received further treatment with 70 (88.6%) receiving one line, 8 (10.1%) receiving two lines, and 1 (1.3%) receiving three lines of subsequent treatment. Of these, 46.3% received CIT, 37.5% received BCRi, 5% received BCRi with a BCL2 inhibitor, 13.8% received a monoclonal antibody and 3.8% received steroids. The proportion of patients treated with novel agents at relapse increased over the duration of follow-up with a corresponding decrease in CIT (Supporting information Figure 8). We report excellent long-term outcomes in patients with CLL treated with FC-based CIT in two UK clinical trials. With a median follow-up of 84 months, the PFS and OS are 65 and 108 months. Patients with favorable factors such as M-IGHV and nondisrupted TP53 have prolonged survival outcomes following FC-based CIT and the incorporation of BM-MRD following therapy further refines the identification of a cohort with prolonged survival. We assessed all available parameters previously described as prognostic in similar patient populations and identified multiple factors predictive of PFS and OS in univariable analysis. However, the parameters most predictive of PFS on multivariable analysis were CD49d, d17p, and mutTP53 combined with posttreatment BM-MRD. Likewise, multivariable analysis revealed age, DCT, and d17P/mutTP53 combined with posttreatment BM-MRD were most predictive for OS. Thus, a relatively simple combination of prognostic factors and MRD can identify a cohort with prolonged survival. Our results complement those of others who demonstrate that IGHV, d17p, mutTP53, and posttreatment MRD are prognostic following CIT and facilitate the identification of patients with prolonged survival.2, 4 In addition to assessing the prognostic power of established biomarkers we sought to assess the role of patient specific factors in responses to FC-based CIT. Our finding that infection-related AEs were associated with shortened survival could reflect the impact of infectious events in an immunosuppressed patient population or could be a surrogate for other comorbidities not captured within our data collection. It is likely that a combination of reduced dose intensity due to premature discontinuation of therapy with associated suboptimal disease control and the consequences of grade 3/4 infections could contribute to inferior outcomes for a subset of patients. CLL is associated with an increased risk of second malignancies, a risk exacerbated by treatment with regimens such as FC. After prolonged follow-up of around 10 years 25% of patients were diagnosed with at least one new malignancy. Our results confirm that second malignancies remain a significant concern in FC-treated patients and support the role of health promotion interventions known to reduce cancer. In conclusion, we find that treatment of CLL with FC-based CIT is associated with excellent long-term outcomes. We show that the main markers for long-term progression-free and overall survival are MRD, age, IGHV, CD49d, DCT, d17p, and mutTP53. The results presented in this paper further aid in the consideration of which patients with CLL may benefit from initial treatment with FCR as opposed to targeted therapy and who may need less intensive follow-up following completion of therapy. ACKNOWLEDGMENTS ADMIRE was a National Institute for Health Research (NIHR) Portfolio Study developed in association with the NCRI CLL Subgroup and funded by Roche Products Ltd. ARCTIC was funded by the NIHR Health Technology Assessment program. This work was also supported by Core Clinical Trials Unit Infrastructure from Cancer Research UK (C7852/A25447). We also acknowledge funding from Progetto Ricerca Finalizzata PE-2016-02362756 (to Valter Gattei), and RF-2018-12365790 (to Antonella Zucchetto), Italian Ministry of Health, Rome, Italy; Associazione Italiana Ricerca Cancro, Investigator Grant IG-21687 (to Valter Gattei). CONFLICT OF INTERESTS David John Allsup reports personal fees and research funding from Roche Pharmaceuticals. Peter Hillmen received research funding and speakers' fees from Roche Pharmaceuticals. Andrew Rawstron reports personal fees from Roche Pharmaceuticals. Dr. Munir reports personal fees from Roche Pharmaceuticals. Adrian Bloor reports personal fees, consultancy/advisory fees and speakers' fees from Roche Pharmaceuticals. Dena Howard is an employee of Roche Pharmaceuticals. ETHICS STATEMENT Both trials were approved by relevant institutional ethical committees and regulatory review bodies and were conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. TRIAL REGISTRATION ADMIRE was registered as an International Standard Randomized Controlled Trial (ISRCTN42165735) and on the European Clinical Trials Database (EudraCT: 2008-006342-122-25). ARCTIC was registered as an International Standard Randomized Controlled Trial (ISRCTN16544962) and on the European Clinical Trials Database (EudraCT: 2009-010998-20). Supporting Information Filename Description ajh26483-sup-0001-Supinfo.docxWord 2007 document , 1.3 MB Appendix S1: Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. REFERENCES 1Thompson PA, Tam CS, O'Brien SM, et al. Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood. 2016; 127(3): 303- 309. 2Böttcher S, Ritgen M, Fischer K, et al. Minimal residual disease quantification is an independent predictor of progression-free and overall survival in chronic lymphocytic leukemia: a multivariate analysis from the randomized GCLLSG CLL8 trial. J Clin Oncol. 2012; 30(9): 980- 988. 3Pepper AGS, Zucchetto A, Norris K, et al. Combined analysis of IGHV mutations, telomere length and CD49d identifies long-term progression-free survivors in TP53 wild-type CLL treated with FCR-based therapies. Leukemia. 2022; 36(1): 271- 274. 4Fischer K, Bahlo J, Fink AM, et al. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood. 2016; 127(2): 208- 215. 5Caldeira D, Alves D, Costa J, Ferreira JJ, Pinto FJ. Ibrutinib increases the risk of hypertension and atrial fibrillation: systematic review and meta-analysis. PloS One. 2019; 14(2):e0211228. Citing Literature Volume97, Issue5May 2022Pages E168-E171 ReferencesRelatedInformation