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THE COMBINATION OF IBRUTINIB PLUS VENETOCLAX RESULTS IN A HIGH RATE OF MRD NEGATIVITY IN PREVIOUSLY UNTREATED CLL: THE RESULTS OF THE PLANNED INTERIM ANALYSIS OF THE PHASE III NCRI FLAIR TRIAL
Author(s): ,
Peter Hillmen
Affiliations:
St James's University Hospital,Leeds,Royaume-uni;St James's University Hospital,Leeds,Vereinigtes Königreich;St James's University Hospital,Leeds,Regno Unito;St James's University Hospital,Leeds,United Kingdom;St James's University Hospital,Leeds,Reino Unido;St James's University Hospital,Leeds,Verenigd Koninkrijk;St James's University Hospital,Leeds,Reino Unido;St James's University Hospital,Leed
,
Alexandra Pitchford
Affiliations:
Leeds Cancer Research UK Clinical Trials Unit,Leeds Institute of Clinical Trials Research,Leeds,Royaume-uni;Leeds Cancer Research UK Clinical Trials Unit,Leeds Institute of Clinical Trials Research,Leeds,Vereinigtes Königreich;Leeds Cancer Research UK Clinical Trials Unit,Leeds Institute of Clinical Trials Research,Leeds,Regno Unito;Leeds Cancer Research UK Clinical Trials Unit,Leeds Institute of
,
Adrian Bloor
Affiliations:
University of Manchester,Manchester,Royaume-uni;University of Manchester,Manchester,Vereinigtes Königreich;University of Manchester,Manchester,Regno Unito;University of Manchester,Manchester,United Kingdom;University of Manchester,Manchester,Reino Unido;University of Manchester,Manchester,Verenigd Koninkrijk;University of Manchester,Manchester,Reino Unido;University of Manchester,Manchester,Соедин
,
Andrew Pettitt
Affiliations:
Clatterbridge Cancer Centre NHS Foundation Trust,Liverpool,Royaume-uni;Clatterbridge Cancer Centre NHS Foundation Trust,Liverpool,Vereinigtes Königreich;Clatterbridge Cancer Centre NHS Foundation Trust,Liverpool,Regno Unito;Clatterbridge Cancer Centre NHS Foundation Trust,Liverpool,United Kingdom;Clatterbridge Cancer Centre NHS Foundation Trust,Liverpool,Reino Unido;Clatterbridge Cancer Centre NHS
,
Piers Patten
Affiliations:
King's College Hospital,London,Royaume-uni;King's College Hospital,London,Vereinigtes Königreich;King's College Hospital,London,Regno Unito;King's College Hospital,London,United Kingdom;King's College Hospital,London,Reino Unido;King's College Hospital,London,Verenigd Koninkrijk;King's College Hospital,London,Reino Unido;King's College Hospital,London,Соединённое Королевство;King's College Hospita
,
Francesco Forconi
Affiliations:
University of Southampton,Southampton,Royaume-uni;University of Southampton,Southampton,Vereinigtes Königreich;University of Southampton,Southampton,Regno Unito;University of Southampton,Southampton,United Kingdom;University of Southampton,Southampton,Reino Unido;University of Southampton,Southampton,Verenigd Koninkrijk;University of Southampton,Southampton,Reino Unido;University of Southampton,So
,
Anna Schuh
Affiliations:
Oxford University Hospital NHT Trust,Oxford,Royaume-uni;Oxford University Hospital NHT Trust,Oxford,Vereinigtes Königreich;Oxford University Hospital NHT Trust,Oxford,Regno Unito;Oxford University Hospital NHT Trust,Oxford,United Kingdom;Oxford University Hospital NHT Trust,Oxford,Reino Unido;Oxford University Hospital NHT Trust,Oxford,Verenigd Koninkrijk;Oxford University Hospital NHT Trust,Oxfor
,
Christopher Fox
Affiliations:
Nottingham University Hospitals NHS Trust,Nottingham,Royaume-uni;Nottingham University Hospitals NHS Trust,Nottingham,Vereinigtes Königreich;Nottingham University Hospitals NHS Trust,Nottingham,Regno Unito;Nottingham University Hospitals NHS Trust,Nottingham,United Kingdom;Nottingham University Hospitals NHS Trust,Nottingham,Reino Unido;Nottingham University Hospitals NHS Trust,Nottingham,Verenigd
,
Nagah Elmusharaf
Affiliations:
Wales Teaching Hospital,Cardiff,Royaume-uni;Wales Teaching Hospital,Cardiff,Vereinigtes Königreich;Wales Teaching Hospital,Cardiff,Regno Unito;Wales Teaching Hospital,Cardiff,United Kingdom;Wales Teaching Hospital,Cardiff,Reino Unido;Wales Teaching Hospital,Cardiff,Verenigd Koninkrijk;Wales Teaching Hospital,Cardiff,Reino Unido;Wales Teaching Hospital,Cardiff,Соединённое Королевство;Wales Teaching
,
Simona Gatto
Affiliations:
University Hospital of Wales,Cardiff,Royaume-uni;University Hospital of Wales,Cardiff,Vereinigtes Königreich;University Hospital of Wales,Cardiff,Regno Unito;University Hospital of Wales,Cardiff,United Kingdom;University Hospital of Wales,Cardiff,Reino Unido;University Hospital of Wales,Cardiff,Verenigd Koninkrijk;University Hospital of Wales,Cardiff,Reino Unido;University Hospital of Wales,Cardif
,
Ben Kennedy
Affiliations:
Leicester Royal Infirmary,Leicester,Royaume-uni;Leicester Royal Infirmary,Leicester,Vereinigtes Königreich;Leicester Royal Infirmary,Leicester,Regno Unito;Leicester Royal Infirmary,Leicester,United Kingdom;Leicester Royal Infirmary,Leicester,Reino Unido;Leicester Royal Infirmary,Leicester,Verenigd Koninkrijk;Leicester Royal Infirmary,Leicester,Reino Unido;Leicester Royal Infirmary,Leicester,Соедин
,
John Gribben
Affiliations:
St Bartholomew's Hospital,London,Royaume-uni;St Bartholomew's Hospital,London,Vereinigtes Königreich;St Bartholomew's Hospital,London,Regno Unito;St Bartholomew's Hospital,London,United Kingdom;St Bartholomew's Hospital,London,Reino Unido;St Bartholomew's Hospital,London,Verenigd Koninkrijk;St Bartholomew's Hospital,London,Reino Unido;St Bartholomew's Hospital,London,Соединённое Королевство;St Bar
,
Nicholas Pemberton
Affiliations:
Worcestershire Acute Hospitals NHS Trust,Worcester,Royaume-uni;Worcestershire Acute Hospitals NHS Trust,Worcester,Vereinigtes Königreich;Worcestershire Acute Hospitals NHS Trust,Worcester,Regno Unito;Worcestershire Acute Hospitals NHS Trust,Worcester,United Kingdom;Worcestershire Acute Hospitals NHS Trust,Worcester,Reino Unido;Worcestershire Acute Hospitals NHS Trust,Worcester,Verenigd Koninkrijk;
,
Oonagh Sheehy
Affiliations:
Belfast City Hospital,Belfast,Royaume-uni;Belfast City Hospital,Belfast,Vereinigtes Königreich;Belfast City Hospital,Belfast,Regno Unito;Belfast City Hospital,Belfast,United Kingdom;Belfast City Hospital,Belfast,Reino Unido;Belfast City Hospital,Belfast,Verenigd Koninkrijk;Belfast City Hospital,Belfast,Reino Unido;Belfast City Hospital,Belfast,Соединённое Королевство;Belfast City Hospital,Belfast,
,
Gavin Preston
Affiliations:
Aberdeen Royal Infirmary,Aberdeen,Royaume-uni;Aberdeen Royal Infirmary,Aberdeen,Vereinigtes Königreich;Aberdeen Royal Infirmary,Aberdeen,Regno Unito;Aberdeen Royal Infirmary,Aberdeen,United Kingdom;Aberdeen Royal Infirmary,Aberdeen,Reino Unido;Aberdeen Royal Infirmary,Aberdeen,Verenigd Koninkrijk;Aberdeen Royal Infirmary,Aberdeen,Reino Unido;Aberdeen Royal Infirmary,Aberdeen,Соединённое Королевств
,
Dena Howard
Affiliations:
Roche,Reading,Royaume-uni;Roche,Reading,Vereinigtes Königreich;Roche,Reading,Regno Unito;Roche,Reading,United Kingdom;Roche,Reading,Reino Unido;Roche,Reading,Verenigd Koninkrijk;Roche,Reading,Reino Unido;Roche,Reading,Соединённое Королевство;Roche,Reading,Storbritannien
,
Anna Hockaday
Affiliations:
Leeds Cancer Research UK Clinical Trials Unit,Leeds Institute of Clinical Trials Research,Leeds,Royaume-uni;Leeds Cancer Research UK Clinical Trials Unit,Leeds Institute of Clinical Trials Research,Leeds,Vereinigtes Königreich;Leeds Cancer Research UK Clinical Trials Unit,Leeds Institute of Clinical Trials Research,Leeds,Regno Unito;Leeds Cancer Research UK Clinical Trials Unit,Leeds Institute of
,
David Cairns
Affiliations:
Leeds Cancer Research UK Clinical Trials Unit,Leeds Institute of Clinical Trials Research,Leeds,Royaume-uni;Leeds Cancer Research UK Clinical Trials Unit,Leeds Institute of Clinical Trials Research,Leeds,Vereinigtes Königreich;Leeds Cancer Research UK Clinical Trials Unit,Leeds Institute of Clinical Trials Research,Leeds,Regno Unito;Leeds Cancer Research UK Clinical Trials Unit,Leeds Institute of
,
Sharon Jackson
Affiliations:
Leeds Cancer Research UK Clinical Trials Unit,Leeds Institute of Clinical Trials Research,Leeds,Royaume-uni;Leeds Cancer Research UK Clinical Trials Unit,Leeds Institute of Clinical Trials Research,Leeds,Vereinigtes Königreich;Leeds Cancer Research UK Clinical Trials Unit,Leeds Institute of Clinical Trials Research,Leeds,Regno Unito;Leeds Cancer Research UK Clinical Trials Unit,Leeds Institute of
,
Natasha Greatorex
Affiliations:
Leeds Cancer Research UK Clinical Trials Unit,Leeds Institute of Clinical Trials Research,Leeds,Royaume-uni;Leeds Cancer Research UK Clinical Trials Unit,Leeds Institute of Clinical Trials Research,Leeds,Vereinigtes Königreich;Leeds Cancer Research UK Clinical Trials Unit,Leeds Institute of Clinical Trials Research,Leeds,Regno Unito;Leeds Cancer Research UK Clinical Trials Unit,Leeds Institute of
,
Nichola Webster
Affiliations:
HMDS,Leeds Cancer Centre,Leeds,Royaume-uni;HMDS,Leeds Cancer Centre,Leeds,Vereinigtes Königreich;HMDS,Leeds Cancer Centre,Leeds,Regno Unito;HMDS,Leeds Cancer Centre,Leeds,United Kingdom;HMDS,Leeds Cancer Centre,Leeds,Reino Unido;HMDS,Leeds Cancer Centre,Leeds,Verenigd Koninkrijk;HMDS,Leeds Cancer Centre,Leeds,Reino Unido;HMDS,Leeds Cancer Centre,Leeds,Соединённое Королевство;HMDS,Leeds Cancer Cent
,
Surita Dalal
Affiliations:
HMDS,Leeds Cancer Centre,Leeds,Royaume-uni;HMDS,Leeds Cancer Centre,Leeds,Vereinigtes Königreich;HMDS,Leeds Cancer Centre,Leeds,Regno Unito;HMDS,Leeds Cancer Centre,Leeds,United Kingdom;HMDS,Leeds Cancer Centre,Leeds,Reino Unido;HMDS,Leeds Cancer Centre,Leeds,Verenigd Koninkrijk;HMDS,Leeds Cancer Centre,Leeds,Reino Unido;HMDS,Leeds Cancer Centre,Leeds,Соединённое Королевство;HMDS,Leeds Cancer Cent
,
Jane Shingles
Affiliations:
HMDS,Leeds Cancer Centre,Leeds,Royaume-uni;HMDS,Leeds Cancer Centre,Leeds,Vereinigtes Königreich;HMDS,Leeds Cancer Centre,Leeds,Regno Unito;HMDS,Leeds Cancer Centre,Leeds,United Kingdom;HMDS,Leeds Cancer Centre,Leeds,Reino Unido;HMDS,Leeds Cancer Centre,Leeds,Verenigd Koninkrijk;HMDS,Leeds Cancer Centre,Leeds,Reino Unido;HMDS,Leeds Cancer Centre,Leeds,Соединённое Королевство;HMDS,Leeds Cancer Cent
,
Kate Cwynarski
Affiliations:
University College London,London,Royaume-uni;University College London,London,Vereinigtes Königreich;University College London,London,Regno Unito;University College London,London,United Kingdom;University College London,London,Reino Unido;University College London,London,Verenigd Koninkrijk;University College London,London,Reino Unido;University College London,London,Соединённое Королевство;Univer
,
Shankara Paneesha
Affiliations:
Birmingham Heartlands Hospital,Birmingham,Royaume-uni;Birmingham Heartlands Hospital,Birmingham,Vereinigtes Königreich;Birmingham Heartlands Hospital,Birmingham,Regno Unito;Birmingham Heartlands Hospital,Birmingham,United Kingdom;Birmingham Heartlands Hospital,Birmingham,Reino Unido;Birmingham Heartlands Hospital,Birmingham,Verenigd Koninkrijk;Birmingham Heartlands Hospital,Birmingham,Reino Unido;
,
David Allsup
Affiliations:
Castle Hill Hospital,Hull,Royaume-uni;Castle Hill Hospital,Hull,Vereinigtes Königreich;Castle Hill Hospital,Hull,Regno Unito;Castle Hill Hospital,Hull,United Kingdom;Castle Hill Hospital,Hull,Reino Unido;Castle Hill Hospital,Hull,Verenigd Koninkrijk;Castle Hill Hospital,Hull,Reino Unido;Castle Hill Hospital,Hull,Соединённое Королевство;Castle Hill Hospital,Hull,Storbritannien
,
Andrew Rawstron
Affiliations:
HMDS,Leeds Cancer Centre,Leeds,Royaume-uni;HMDS,Leeds Cancer Centre,Leeds,Vereinigtes Königreich;HMDS,Leeds Cancer Centre,Leeds,Regno Unito;HMDS,Leeds Cancer Centre,Leeds,United Kingdom;HMDS,Leeds Cancer Centre,Leeds,Reino Unido;HMDS,Leeds Cancer Centre,Leeds,Verenigd Koninkrijk;HMDS,Leeds Cancer Centre,Leeds,Reino Unido;HMDS,Leeds Cancer Centre,Leeds,Соединённое Королевство;HMDS,Leeds Cancer Cent
Talha Munir
Affiliations:
UK NCRI CLL sub-group,Leeds,Royaume-uni;UK NCRI CLL sub-group,Leeds,Vereinigtes Königreich;UK NCRI CLL sub-group,Leeds,Regno Unito;UK NCRI CLL sub-group,Leeds,United Kingdom;UK NCRI CLL sub-group,Leeds,Reino Unido;UK NCRI CLL sub-group,Leeds,Verenigd Koninkrijk;UK NCRI CLL sub-group,Leeds,Reino Unido;UK NCRI CLL sub-group,Leeds,Соединённое Королевство;UK NCRI CLL sub-group,Leeds,Storbritannien
(Abstract release date: 05/12/22) EHA Library. Hillmen P. 06/12/22; 357009; S145
Prof. Peter Hillmen
Prof. Peter Hillmen
Contributions
Abstract
Presentation during EHA2022: All Oral presentations will be presented between Friday, June 10 and Sunday, June 12 and will be accessible for on-demand viewing from Monday, June 20 until Monday, August 15, 2022 on the Congress platform.

Abstract: S145

Type: Oral Presentation

Session title: CLL: Clinical

Background

Ibrutinib (I) and venetoclax (V) improve outcome in CLL. I rarely eradicates measurable residual disease (MRD), whereas V (alone or with anti-CD20) can eradicate MRD permitting time limited therapy. Small studies suggest synergy between I and V, as I+V results in MRD negativity in many patients (pts).   

Aims

The primary aim was to compare the MRD eradication rate between I and I+V. Key secondary aims were IWCLL overall (ORR), complete response (CR) and safety.

Methods
FLAIR (ISRCTN01844152), a phase III, randomised, controlled trial for previously untreated CLL requiring therapy by IWCLL criteria. Pts >75 yrs or with >20% 17p del were excluded. FLAIR was adapted in July 2017 to add two arms, I monotherapy and I+V. I was given at 420mg/day. For I+V, V was added after two months of I with dose escalation to 400mg/day over 5 weeks. The duration of therapy (DOT) was defined by MRD with treatment for up to 6 years. MRD was assessed centrally by flow cytometry, MRD negativity was defined as <1 CLL cell in 10,000 leucocytes (IWCLL criteria), was assessed in peripheral blood (PB) and bone marrow (BM) at 9 months post-randomisation, in PB at 12 months and then 6 monthly. When PB was MRD negative, this was repeated after 3 months and then in both PB & BM 3 months later. If PB & BM were negative the time to MRD negativity was calculated (treatment start to first MRD negative PB) and DOT was twice this. The earliest therapy could stop was 2 years post-randomisation. A formal interim analysis was performed when 50% pts in I and I+V arms had reached 2 yrs post-randomisation and a p-value of <0.005 was statistically significant.

Results

523 pts were randomised to I or I+V. We report the interim analysis in the first 274 pts (I [n=138] and I+V [n=136]) reaching 2 yrs post-randomisation from 83 UK Centres from 13/07/17 to 15/03/19. 72.3% male, median age 63 yrs (34.3% >65yo) and 40.9% Binet C. IGHV were available for 256 (93.4%) pts - 48.2% IGHV unmutated (≥98% homology to germline), 45.3% IGHV mutated and 9.1% Subset 2. Hierarchical FISH testing revealed 16.1% 11q del, 19% trisomy 12, 21.9% normal and 36.9% 13q del with 6.2% failed. The arms were well-balanced for all variables. For I+V arm, MRD negativity was achieved within 24 months in BM in 89/136 (65.4%) and PB in 97/136 (71.3%) compared to no pts for I (p<0.0001). MRD negativity for I+V in BM within 24 months was 51/64 (79.7%) for IGHV unmutated and 31/55 (56.4%) for IGHV mutated. At 9 months post-randomisation 49/136 (36%) I+V pts were MRD negative in BM and 56/136 (41.2%) negative in PB compared to 0/138 with I (p<0.0001).  ORR at 9 months in 120/136 (88.2%) I+V pts and 119/138 (86.2%) I pts (p=0.6157). At 9 months CR in 81/136 (59.6%) for I+V and 11/138 (8%) for I (p<0.0001). For I+V CR at any time was 93.4%. At 24 months, 54/136 (39.7%) stopped I+V due to meeting MRD stopping criteria.

SAEs were reported in 41.5% I+V and 38.2% I pts. Infectious SAEs 14.8% vs 19.9% and cardiac SAEs 11.9% vs 8.1% of pts for I+V & I respectively. Laboratory TLS was reported in 6/136 (4.4%) of I+V pts and none with I. There were no cases of clinical TLS. Most frequent any grade AEs within 12 months of randomisation differing between I+V & I were diarrhoea (52.6% I+V pts, 29.4% I), anaemia (28.9% vs 16.9%), leucopenia (36.3% vs 8.8%), thrombocytopenia (23.7% vs 14%). Leucopenia was the only grade ≥3 SAE reported in >10% of pts (27.4% I+V and 5.1% I). 

Conclusion

Ibrutinib plus venetoclax is an effective and well tolerated combination resulting in a high rate of MRD negativity in blood (71.9%) and marrow (65.4%) in the first 2 years of treatment.

Keyword(s): Bone Marrow, Chronic lymphocytic leukemia, MRD, Peripheral blood

Presentation during EHA2022: All Oral presentations will be presented between Friday, June 10 and Sunday, June 12 and will be accessible for on-demand viewing from Monday, June 20 until Monday, August 15, 2022 on the Congress platform.

Abstract: S145

Type: Oral Presentation

Session title: CLL: Clinical

Background

Ibrutinib (I) and venetoclax (V) improve outcome in CLL. I rarely eradicates measurable residual disease (MRD), whereas V (alone or with anti-CD20) can eradicate MRD permitting time limited therapy. Small studies suggest synergy between I and V, as I+V results in MRD negativity in many patients (pts).   

Aims

The primary aim was to compare the MRD eradication rate between I and I+V. Key secondary aims were IWCLL overall (ORR), complete response (CR) and safety.

Methods
FLAIR (ISRCTN01844152), a phase III, randomised, controlled trial for previously untreated CLL requiring therapy by IWCLL criteria. Pts >75 yrs or with >20% 17p del were excluded. FLAIR was adapted in July 2017 to add two arms, I monotherapy and I+V. I was given at 420mg/day. For I+V, V was added after two months of I with dose escalation to 400mg/day over 5 weeks. The duration of therapy (DOT) was defined by MRD with treatment for up to 6 years. MRD was assessed centrally by flow cytometry, MRD negativity was defined as <1 CLL cell in 10,000 leucocytes (IWCLL criteria), was assessed in peripheral blood (PB) and bone marrow (BM) at 9 months post-randomisation, in PB at 12 months and then 6 monthly. When PB was MRD negative, this was repeated after 3 months and then in both PB & BM 3 months later. If PB & BM were negative the time to MRD negativity was calculated (treatment start to first MRD negative PB) and DOT was twice this. The earliest therapy could stop was 2 years post-randomisation. A formal interim analysis was performed when 50% pts in I and I+V arms had reached 2 yrs post-randomisation and a p-value of <0.005 was statistically significant.

Results

523 pts were randomised to I or I+V. We report the interim analysis in the first 274 pts (I [n=138] and I+V [n=136]) reaching 2 yrs post-randomisation from 83 UK Centres from 13/07/17 to 15/03/19. 72.3% male, median age 63 yrs (34.3% >65yo) and 40.9% Binet C. IGHV were available for 256 (93.4%) pts - 48.2% IGHV unmutated (≥98% homology to germline), 45.3% IGHV mutated and 9.1% Subset 2. Hierarchical FISH testing revealed 16.1% 11q del, 19% trisomy 12, 21.9% normal and 36.9% 13q del with 6.2% failed. The arms were well-balanced for all variables. For I+V arm, MRD negativity was achieved within 24 months in BM in 89/136 (65.4%) and PB in 97/136 (71.3%) compared to no pts for I (p<0.0001). MRD negativity for I+V in BM within 24 months was 51/64 (79.7%) for IGHV unmutated and 31/55 (56.4%) for IGHV mutated. At 9 months post-randomisation 49/136 (36%) I+V pts were MRD negative in BM and 56/136 (41.2%) negative in PB compared to 0/138 with I (p<0.0001).  ORR at 9 months in 120/136 (88.2%) I+V pts and 119/138 (86.2%) I pts (p=0.6157). At 9 months CR in 81/136 (59.6%) for I+V and 11/138 (8%) for I (p<0.0001). For I+V CR at any time was 93.4%. At 24 months, 54/136 (39.7%) stopped I+V due to meeting MRD stopping criteria.

SAEs were reported in 41.5% I+V and 38.2% I pts. Infectious SAEs 14.8% vs 19.9% and cardiac SAEs 11.9% vs 8.1% of pts for I+V & I respectively. Laboratory TLS was reported in 6/136 (4.4%) of I+V pts and none with I. There were no cases of clinical TLS. Most frequent any grade AEs within 12 months of randomisation differing between I+V & I were diarrhoea (52.6% I+V pts, 29.4% I), anaemia (28.9% vs 16.9%), leucopenia (36.3% vs 8.8%), thrombocytopenia (23.7% vs 14%). Leucopenia was the only grade ≥3 SAE reported in >10% of pts (27.4% I+V and 5.1% I). 

Conclusion

Ibrutinib plus venetoclax is an effective and well tolerated combination resulting in a high rate of MRD negativity in blood (71.9%) and marrow (65.4%) in the first 2 years of treatment.

Keyword(s): Bone Marrow, Chronic lymphocytic leukemia, MRD, Peripheral blood

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