In previously untreated, medically fit, patients with chronic lymphocytic leukemia, research is focused on developing fixed-duration strategies to improve long-term outcomes whilst sparing patients from serious toxicities. The ICLL-07 trial evaluated a fixed-duration (15-month) immunochemotherapy approach with a 9 months obinutuzumab-ibrutinib (O+I) induction. Patients (n=10) in complete remission (CR) with low bone marrow (BM) measurable residual disease (MRD <0.01%) continued ibrutinib alone at 420 mg/day for 6 additional months (I arm). All other patients (n=115) received up to 4 cycles of fludarabine-cyclophosphamide-obinutuzumab consolidation together with ibrutinib (I-FCG arm). Primary analysis at month 16 showed that 62.2% (84/135) of all patients enrolled achieved CR with BM MRD <0.01% (Michallet AS, Lancet hematol 2019 ; Blood 2021). Peripheral blood (PB) MRD (low-level [i.e. detectable but <0.01%] or undetectable at a threshold of 10-4), in evaluable patients, was still 92.5% (74/80) at month 40 and 80.6% (50/62) at month 64. No difference in PB MRD status was apparent according to the IGHVlmutational status (Michallet AS, Blood advances 2023).

Here follow up with a median of 97 months (Inter quartile range [IQR] 93-102.5) is reported. Progression-free and overall survival rates are at 87 % and 93%, respectively.

At last follow up, 92/128 (72%) patients are alive in CR, 8 in PR, 1 in stable disease. Fourteen (11%) patients are progressing, 4 of them receiving treatment (rituximab venetoclax, n=3, or ibrutinib + venetoclax, n=1). Twelve patients died, including 2 from cardiac toxicity during treatment with O+I attributable to I (M6 and M7). The ten other deaths are distributed among 4 infections (3 bacterial pneumonias at M38, M55, M50 and 1 COVID 19 at M49), 1 histiocytic sarcoma (M47), 1 myelodysplasia (MDS; M56) and 1 acute myeloid leukemia (AML; M68). Three deaths were due to progression (n=1, M103) or transformation in Richter large B-cel lymphoma (n=1; M54) or Hodgkin lymphoma (n=1; M23). No second cancer developed in 88% of the patients (104/118). With a median time between treatment initiation and development of a second disease of 72 months (IQR 10.28-97.77), nine patients developed respectively prostate cancer (n=2), kidney cancer (n=1), Merkel cell carcinoma (n=1), choroidal melanoma (n=1), hepatocellular carcinoma (n=1), skin cancer (n=1), MDS (n=1) or AML (n=1).

In long-term infectious follow-up, no serious infections (grade 3-4) were observed in 84% (99/118) of the patients, while 10 (8%) developed a grade 3 infection (2 SARS-CoV2, 1 viral gastroenteritis, 2 respiratory syncytial virus, 3 bacterial pneumonias, 1 bronchitis, 1 shingles).

These long-term results show excellent survival rates (close to those of a healthy population in the same age range) in patients with first-line CLL regardless of IGHV mutation status, with no increased risk of infection or second cancer.

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2025
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