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4641 Lenalidomide Consolidation Improves Measurable Residual Disease (MRD) Rates and Progression Free Survival in Patients with Chronic Lymphocytic Leukemia Following Initial FCR Chemotherapy - Final Analysis of CLL6 Residuum Study of the Australian Leukaemia and Lymphoma Group (ALLG) and the French Innovative Leukemia Organization (FILO)

Program: Oral and Poster Abstracts
Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
clinical trials, Research, Lymphoid Leukemias, CLL, Clinical Research, Diseases, Therapies, therapy sequence, Lymphoid Malignancies, Minimal Residual Disease
Monday, December 11, 2023, 6:00 PM-8:00 PM

Therese Aurran-Schleinitz1*, Stephen P Mulligan, MBBS, PhD, FRACP, FRCPA2, Remi Letestu3*, Marie Christine Bene4*, Gavin Cull, MB, BS, FRACP, FRCPA5, Jean Pierre Vilque, MD6*, Constantine S. Tam, MD, MBBS7, Sophie De Guibert8*, Rosemary Anne Harrup9*, Bernard Drenou, MD10*, Andrew P Grigg, MBBS, MD, FRACP, FRCPA11*, Laurent Voillat12*, Belinda E Butcher, PhD13*, Caroline Dartigeas14*, Richard Eek, MBChB, MMed15*, Nicolas Daguindau16*, Cecily Forsyth, FRACP, FRCPA, MBBS17, Mourad Tiab, MD18*, Delaine Smith, BSc, RN19*, Jennifer Curnow, MBBS, FRACP, FRCPA, PhD20*, Veronique Leblond, MD21*, Stephen Robert Larsen, MBBS22, Florence Cymbalista, MD, PhD23* and David Gottlieb, MD, MBBS, FRACP, FRCPA24*

1Institut Paoli Calmettes, Marseille, France
2University of Sydney, Sydney, NSW, AUS
3APHP, Avicennes Hospital, Bobigny, FM, FRA
4Hopital Hotel Dieu & Hme, Nantes, France
5Sir Charles Gairdner Hospital Hematology Care Centre, Nedlands, WEA, AUS
6CHU Caen, Caen, FRA
7The Alfred Hospital and Monash University, Melbourne, VIC, Australia
8Centre Hospitalier Pontchaillou, Rennes, FRA
9Royal Hobart Hospital, University of Tasmania, Tasmania, Australia
10HôPital Emile Muller, Mulhouse Cedex 1, FRA
11Austin Hospital, Melbourne, VIC, AUS
12Ch William Morey, Chalon Sur Saone, Fr, FRA
13ALLG, Lane Cove, NSW, AUS
14CHU Bretonneau, Tours, FRA
15Department of Haematology, Border Medical Oncology, New South Wales, Australia, Wodonga, AUS
16Hematologie, Centre Hospitalier Annecy Genevois, Metz-Tessy, FRA
17Wyong Hospital, North Gosford, AUS
18Centre Hospitalier Departemental, La Roche Sur Yon Cedex 9, FRA
19Australasian Leukemia and Lymphoma Group, Melbourne, VIC, AUS
20Westmead Hospital, Sydney, AUS
21APHP, La pitié salpétriere, Paris, FRA
22Royal Prince Alfred Hospital, Camperdown, Australia
23Bobigny: Hématologie, CHU Avicennes, Bobigny, France
24Department of Haematology, Westmead Hospital, Sydney, AUS


Eradication of MRD after first line chemoimmunotherapy (CIT) correlates with longer progression-free survival (PFS) in chronic lymphocytic leukemia (CLL) patients. Lenalidomide (LEN) has antiproliferative and immunomodulatory effects in CLL and may improve response following CIT (Buhler et al 2016; Fink et al 2017). Here we report the final analysis of the phase III, randomized, CLL6 RESIDUUM trial, that aimed to determine whether LEN improves immunophenotypic (IP) complete response (CR) rates and extends remission duration in patients with CLL who have MRD following induction CIT.


The CLL6 trial was a joint trial of the ALLG and the FILO. CLL patients with CIRS score <6 requiring treatment according to iwCLL received 4 to 6 cycles of fludarabine, cyclophosphamide and rituximab (FCR). After completion of treatment, patients with clinical, radiological and/or flow cytometry evidence of MRD in blood (PB) or bone marrow (BM) were randomized 1:1 to receive 2 years of 10 mg daily LEN consolidation or observation (OBS). High sensitivity (HS) MRD were scheduled at month 3, 6 and every 6 months until month 24 then every 12 months until month 72 in PB and at screening and on months 12 and 24 in BM. The primary endpoint was time to clinical disease progression, or death, from randomization. The study planned to randomize 192 patients to detect a hazard ratio of 1.94, i.e., an increase in the % of patients remaining progression free at 4 years to 70% in the LEN arm compared with 50% in the OBS arm (two-sided log rank test at alpha = 0.05, no competing risks or loss to follow up, power = 0.86).


The study closed prematurely because of an acute lymphoblastic leukemia (ALL) warning (3 of 56 patients [5.4%]) in the CLLM1 trial (Fink et al., 2017; Fürstenau et al., 2021). Between May 2011 and January 2018, 143 patients were randomized (70 in Australia and 73 in France) to the LEN (n=71) or OBS (n=72) arms. Median age was 63 [range 41-78], and 60 [26-79] years in the LEN and OBS arms respectively, 113 patients were males. At randomization, 27 (38 %) and 23 (32%) patients were in CR, 9 (13%) and 10 (14%) in nPR, 35 (49%) and 39 (54%) in PR in LEN and OBS arms respectively. Forty-nine (69%) and 47 (65%) had PB and 56 (79%) and 58 (81%) had BM detectable MRD in LEN and OBS arm respectively. Median follow-up (FU) is 52.6 months (range 44.9-59.0; LEN 49.8 [41.9-57.1], OBS 55.59 [44.0-61.7]). Twenty-eight (39%) patients progressed in the LEN arm versus 40 (56%) in the OBS arm (χ² p=0.01), 8 died in each arm. Median PFS was 64.6 (95%CI 47.7-not reached [NR]) months in the LEN arm versus 42.4 (32.3-61.6) months in the OBS arm (p=0.039). Multivariate analysis did not identify any predictive factor of relapse. Median overall survival was not reached (NR) (77.58-NR) in the LEN arm and 107.7 (107.6-NR) months in the OBS arm. There were 118 adverse events (AE), 87 in the LEN and 31 in the OBS arms respectively, with more neutropenia (n=21 vs n=1), gastrointestinal (n=10 vs n=4), respiratory (n=9 vs n=0) nervous system (n=6 vs n=1) and musculoskeletal (n=4 vs n=1) in the LEN arm. Most of the excess of AEs in LEN arm occurred after the end of the treatment. Severe AEs were reported in 35 patients (24.5%), 24 in the LEN arm and 11 in OBS. Fifteen secondary malignancies occurred: 8 in the LEN arm; 7 in the OBS arm. Six were of hematological origin (2 Richter transformation in each arm, 1 marginal zone lymphoma in the OBS arm and 1 myelodysplastic syndrome in the LEN arm). No case of ALL occurred.

HS MRD analyses were performed in 71/73 patients in the French cohort. A follow-up was available in 65/71 with a median number of 7 time-points per patients (range 3-10). Different MRD kinetics were observed. While MRD rates in OBS arm increased in 33/34 patients, LEN consolidation led to long-lasting and transient deep IP CR in 4/31 and 9/31 patients respectively, MRD rate stabilization in 10/31 patients, and MRD increase in the remaining 6/31 patients.


The CLL6 RESIDUUM study demonstrated a significant benefit of consolidation therapy with lenalidomide in CLL patients with residual disease after FCR treatment. LEN resulted in a significantly longer PFS, with no unacceptable toxicity including ALL. Although FCR is no longer considered gold standard initial CLL therapy, eradicating residual disease can remain challenging with newer targeted agents. Patients with CLL MRD following initial therapy may experience prolongation in progression free survival from LEN consolidation.

Disclosures: Aurran-Schleinitz: Astrazeneca, Janssen: Other: congres inscription and travel. Mulligan: Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cull: Beigene, AstraZeneca, Glycomimetics: Research Funding. Tam: Roche: Honoraria; Novartis: Honoraria; LOXO: Honoraria; BeiGene: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. De Guibert: JANSSEN: Honoraria; Astra Zeneca: Honoraria; Beigene: Honoraria; ABBVIE: Honoraria. Harrup: F. Hoffmann-La Roche Ltd, Takeda: Current equity holder in publicly-traded company; F. Hoffmann-La Roche Ltd, Beigene: Research Funding; FibroGen: Research Funding. Drenou: Alexion Pharma France: Honoraria; Abbvie, Gilead, Janssen: Membership on an entity's Board of Directors or advisory committees. Dartigeas: Janssen, AbbVie, BeiGene, astrazeneca: Membership on an entity's Board of Directors or advisory committees, Other: travel grant. Forsyth: Roche: Honoraria. Cymbalista: Abbvie: Honoraria; AstraZeneca: Honoraria; Lilly: Honoraria.

OffLabel Disclosure: lenalidomide within approved randomized clinical trial

*signifies non-member of ASH