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304 Efficacy of Ibrutinib, Rituximab and Mini-CHOP in Very Elderly Patients with Newly Diagnosed Diffuse Large B Cell Lymphoma: Primary Analysis of the Australasian Leukaemia & Lymphoma Group NHL29 Study

Program: Oral and Poster Abstracts
Type: Oral
Session: 626. Aggressive Lymphomas Prospective Therapeutic Trials: Challenging Populations
Hematology Disease Topics & Pathways:
Clinical Trials, Clinical Research
Saturday, December 11, 2021: 4:45 PM

Emma Verner, MBBS1,2*, Amanda Johnston, MBBS, FRACP, FRCPA2,3, Nalini Pati, MBBS, FRACP, FRCPA, DCH, MD, DNB4,5*, Eliza Hawkes, MD6,7, Hui-Peng Lee, MBChB, FRACP, FRCPA, BHB8*, Tara Cochrane, MBBS, FRCPA, FRACP9,10, Chan-Yoon Cheah11,12, Robin J Filshie, MBChB, PhD, FRACP, FRCPA13, Duncan Purtill14,15*, Hanlon Sia, MBBS, FRACP, FRCPA16*, Anoop Kumar Enjeti, MBBS, FRCPA, FRACP, PhD, MD, MRCP17,18, Christina Brown, MBBS PhD FRACP FRCPA2,19, Nicholas E. Murphy, FRCPA, MBBS, FRACP20,21, Jennifer Curnow, MBBS FRACP FRCPA PhD22,23*, Kenneth Lee, MBChB, FRCPA2,24*, Mannu Walia, Msc PhD25*, Belinda Butcher, BSci, MBiostat, PHD26,27* and Judith Trotman, FRACP2,28

1Department of Haematology, Concord Repatriation General Hospital, Concord, NSW, Australia
2University of Sydney, Sydney, NSW, Australia
3Westmead Hospital, Westmead, NSW, Australia
4ANU Medical School, Canberra, Australia
5The Canberra Hospital, Canberra, Australia
6Department of Medical Oncology and Haematology, Olivia Newton John Cancer Research and Wellness Centre, Heidelberg, AUS
7Eastern Health, Box Hill, VIC, Australia
8Flinders Medical Centre, Adelaide, Australia
9Griffiths University, Gold Coast, Australia
10Department of Haematology, Gold Coast University Hospital, Southport, Australia
11Department of Haematology, Sir Charles Gairdner Hospital, Nedlands, WA, Australia
12University of Western Australia, Crawley, WA, Australia
13Department of Hematology, St. Vincent's Hospital Melbourne, Melbourne, VIC, Australia
14University of Western Australia, Perth, Australia
15Department of Haematology, Fiona Stanley Hospital, Perth, Australia
16The Tweed Hospital, 4515, AUS
17University of Newcastle, Newcastle, Australia
18Calvary Mater Hospital, Waratah, AUS
19Institute of Haematology, Royal Prince Alfred Hospital, Sydney, Australia
20University of Tasmania, Hobart, Australia
21Royal Hobart Hospital, Hobart, Australia
22Department of Haematology, Westmead Hospital, Western Sydney Local Health District, Sydney, Australia
23Faculty of Health and Medicine, University of Sydney, Sydney, NSW, Australia
24Anatomical Pathology, NSW Health Pathology, Concord Repatriation General Hospital, Concord, Australia
25Australasian Leukaemia and Lymphoma Group, Richmond, Australia
26WriteSource Medical Pty Ltd, Lane Cove, Australia
27University of New South Wales, Sydney, Australia
28Department of Haematology, Concord Hospital, Concord, NSW, Australia

Introduction

R-mini-CHOP is an established standard of care in elderly patients with DLBCL, with a 2yr OS of 59% and PFS of 47% (Peyrade et al, Lancet Oncol 2011). The addition of ibrutinib to full dose R-CHOP in younger pts with DLBCL has efficacy, but significant toxicity limits the ability to complete therapy in pts ≥60 yrs (Younes et al, JCO 2019). We previously demonstrated the deliverability of ibrutinib with R-mini-CHOP in 80 pts ≥75yrs with DLBCL with a median average relative total dose of 97%; 77% of pts received 6 cycles of R-mini-CHOP despite SAEs in 62% (Verner et al, Haematol Oncol 2019). Here we present the primary efficacy endpoint and key secondary and exploratory endpoints.

Methods

This was a prospective, multicenter, single-arm, phase 2 study of patients aged ≥75yrs with newly diagnosed DLBCL. Pts received six 21-day cycles of ibrutinib 560mg/d and R-mini-CHOP (Rituximab 375mg/m2, cyclophosphamide 400mg/m2, doxorubicin 25mg/m2, vincristine 1mg on day 1 & prednisone 40mg/m2 or 100mg/d x 5) followed by an additional two 21-day cycles of rituximab + ibrutinib (or high dose methotrexate for CNS prophylaxis). The efficacy primary endpoint was 2yr OS. Sample size calculations were made using a one-sample two-sided approach to detect a 15% improvement on the fixed reference OS (59%) and PFS (47%) rates (Peyrade et al, Lancet Oncol 2011).

Results

Eighty pts were recruited from Nov 2015 to Dec 2018. One died prior to receiving treatment and is not included in the analysis. Median age was 82yrs (75-95); 51% female, 81% stage III/IV and 63% IPI 3-5: 47% had a CIRS-G score of ≥6 (range 0-17). On centralized immunohistochemistry (IHC), 57% (45/79) were non-Germinal Centre B cell-like (GCB) subtype; 43% (34/79) were GCB. At a data cut-off of 6 June 21, median follow-up was 29.5 months (m) (0.2 to 66.3).

Two-year OS was 68% (95% CI 55-77%), not differing significantly from the null hypothesis of 59% (p=0.10), (Figure 1A). Median OS was not reached (NR) (95% CI 34m to NR), and was longer in those with lower IPI (IPI 1-3: NR, IPI 4: 35m, IPI 5: 19m). Two-year PFS was 60% (95% CI 47-70%), significantly different from the reference 47% (p<0.03), (Figure 1B). Median PFS was NR (95% CI 20m to NR). Two-year DFS was 85% (95% CI 60-95%), median NR (95% CI 32m to NR). COO had no impact on either 2yr OS [median GCB NR (95% CI 29m to NR), median non-GCB NR (95% CI 24m to NR) p=0.99] or 2yr PFS [median GCB 39m (95% CI 17m to NR), median non-GCB NR (95% CI 19m to NR) p=0.97]. Cause of death in 28/79 pts (35%) was: 16 progressive lymphoma, 5 infection, 2 respiratory failure, 2 other malignancy, 1 cardiac arrest, 1 intra-abdominal hemorrhage, 1 gastric hemorrhage.

At least one adverse event (AE) occurred in 99% pts (78/79): 30% (24/79) grade 1-2, 64% (49/79) grade 3-4, and 6% (5/79) grade 5. Most common grade ≥3 AEs were lung infection (13%), other infections (11%), anemia (11%), febrile neutropenia (9%), thrombocytopenia (9%), and atrial fibrillation (8%). Serious AEs occurred in 67%: most commonly lung infection (11%), atrial fibrillation (9%), fever (9%), and other infection (9%). 12/14 pts with atrial fibrillation/flutter were new onset.

Ibrutinib was temporarily ceased in 62% of patients, and permanently ceased in 25%, mostly due to adverse events. As previously reported, the overall response rate on an intention to treat basis was 57/80 (71%) (Verner et al, ASH 2019). Response rates did not differ by cell of origin (COO) (ORR: non-GCB 76%, GCB 68% p=0.44).

When recorded, pt’s EORTC-QLQ-C30 global health status significantly improved between screening [n=78; mean (SD) 58(25)], end of treatment [n=57; 63(23)] and 18mo post-treatment [n=29; 74(19)] p=0.007. Significant reductions in fatigue, nausea and vomiting, pain, insomnia, appetite loss, constipation and diarrhea were also observed in respondents. There was no impact of CIRS-G score on disease response rate or risk of death.

Conclusion

The addition of ibrutinib to R-mini-CHOP was deliverable and improved 2-yr PFS compared to R-mini-CHOP alone. However, while there was a trend towards improvement in 2-yr OS, a target 15% increase was not achieved in this small sample size. Despite considerable and not unexpected toxicity in this elderly cohort, the QOL and functional improvements in survivors are also promising. These data support further study of the addition of ibrutinib to R-mini-CHOP in elderly patients with DLBCL.

Disclosures: Verner: Janssen-Cilag Pty Ltd: Research Funding. Hawkes: Merck KgA: Research Funding; Bristol Myers Squib/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Specialised Therapeutics: Consultancy; Antigene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees; Regeneron: Speakers Bureau; Merck Sharpe Dohme: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel and accommodation expenses, Research Funding, Speakers Bureau; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Lee: Roche: Honoraria; BeiGene: Membership on an entity's Board of Directors or advisory committees. Cheah: BMS: Consultancy, Research Funding; Abbvie: Research Funding; Janssen: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Ascentage Pharma: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Lilly: Consultancy, Honoraria; TG therapeutics: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: travel, Research Funding. Purtill: BMS Celgene: Honoraria; Gilead: Honoraria; Novartis: Honoraria. Enjeti: Astra Zeneca: Honoraria; Sanofi: Honoraria; AbbVie: Honoraria; Roche: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Curnow: Norgine: Consultancy, Honoraria; Mylan: Consultancy; Pfizer/BMS: Consultancy, Honoraria; Bayer: Consultancy, Research Funding. Butcher: WriteSource: Current Employment, Other: Medical writing for Pharma companies. Not pertinent to this abstract for which author is study Statisticiam. Trotman: JANSSEN: Research Funding; TAKEDA: Research Funding; BMS: Research Funding; PCYC: Research Funding; roche: Research Funding; beigene: Research Funding.

OffLabel Disclosure: Ibrutinib is not approved for use in DLBCL

*signifies non-member of ASH