The duration of remission (DOR) is defined as the time from the date of first evaluation of the remission (cCR, uCR or PR) to the first documentation of progressive disease, relapsed disease or death. In case an assessment of progressive / relapsed disease or death does not exist, the DOR was censored at the time of the last disease assessment date. The DOR was calculated only for the patients with a remission that was assessed at 52 weeks.

The Progression Free Survival (PFS) is defined as the time from first dose administration until the occurrence of progressive disease, relapsed disease or death from any cause. Patients without an event at the time of the analyse were censored at his or her last disease assessment date. Patients with no post-Baseline assessment were censored at the day of the first dose administration.

The overall survival (OS) is defined as the time from first dose administration until death from any cause. Alive patients were censored at the most recent date they were known to be alive. Subjects with no assessment post-Baseline were censored at the day of the first dose administration.

During phase 1, patients received monalizumab, IV, at the dose of 2 mg/kg, as a single agent during 4 weeks and thereafter combined with ibrutinib 420 mg, orally, once daily, during 52 weeks.

In both parts of the trial, the first 4 administrations of monalizumab occured every 2 weeks. From the 5th administration monalizumab was administered every 4 weeks.

During phase 1, patients received monalizumab, IV, at the dose of 4 mg/kg, as a single agent during 4 weeks and thereafter combined with ibrutinib 420 mg, orally, once daily, during 52 weeks.

In both parts of the trial, the first 4 administrations of monalizumab occured every 2 weeks. From the 5th administration monalizumab was administered every 4 weeks.

During phase 2, patients received monalizumab, IV, at the dose recommended upon completion of phase 1 part, combined with ibrutinib 420 mg orally, once daily, from the first cycle and during 52 weeks.

In both parts of the trial, the first 4 administrations of monalizumab occured every 2 weeks. From the 5th administration monalizumab was administered every 4 weeks.

Total of all reporting groups

Eastern Cooperative Oncology Group performance status scale 0 Fully active, able to carry out all normal activity without restriction.

1. Restricted in physically strenuous activity but ambulatory and able to carry out light work.
2. Ambulatory and capable of all self-care but unable to carry out any work. Up and about more than 50% of waking hours.
3. Capable of only limited self-care, confined to bed or chair more than 50 % of waking hours.
4. Completely disabled. Cannot carry out any self-care. Totally confined to bed or chair.
5. Dead.

The RAI staging divides CLL into 5 stages:

stage 0, bone marrow and blood lymphocytosis only; stage I, lymphocytosis with enlarged nodes; stage II, lymphocytosis with enlarged spleen or liver or both; stage III, lymphocytosis with anemia; and stage IV:lymphocytosis with thrombocytopenia.

Stage 0 is low-risk, stages I and II are intermediate-risk, stages III and IV are high-risk.

Phase 1 (dose escalation) evaluating dose level 3 (4 mg/kg) of monalizumab alone during 4 weeks then in combination with ibrutinib during 52 weeks.

The rate of complete response (CR) was evaluated using the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) grading scale and confirmed by a bone marrow biopsy. Per International Workshop on Chronic Lymphocytic Leukemia (IWCLL), Complete Response (CR) is defined as lymphocytes <4x109/l, absence of lymphadenopathy, hepatomegaly and splenomegaly at CT scan, no constitutional symptoms, no cytopenia, normocellular bone marrow. Partial Response (PR) is a reduction > 50% in lymphocytes, lymphadenopathy, spleen or liver, no cytopenia. PD if appearance of any new lesion, or increase in lymphocytes > 50%, or occurrence of cytopenia attributable to CLL.

Efficacy population: 21 patients who received at least one dose of monalizumab. According to the protocol, patients who discontinued treatment due to disease progression before the end of 8 weeks were replaced. Of note,1 patient (grade 3 hemolytic anemia due to disease progression at W4) was replaced and was then excluded from efficacy population.

Measure of best overall response at any time during the study. cCR: confirmed complete response/remission; uCR: unconfirmed complete response / remission; PR: partial response/remission; SD: stable disease; PD: progressive disease.

Per International Workshop on Chronic Lymphocytic Leukemia (IWCLL), Complete Response (CR) is defined as lymphocytes <4x109/l, absence of lymphadenopathy, hepatomegaly and splenomegaly at CT scan, no constitutional symptoms, no cytopenia, normocellular bone marrow. Partial Response (PR) is a reduction > 50% in lymphocytes, lymphadenopathy, spleen or liver, no cytopenia. PD if appearance of any new lesion, or increase in lymphocytes > 50%, or occurrence of cytopenia attributable to CLL.

In order to have a confirmed CR (cCR), the CR must be confirmed by a scan and a bone marrow assessment assessed at least 2 months after the first occurrence of CR. Otherwise it would be an unconfirmed CR (uCR).

Efficacy population: 21 patients who received at least one dose of monalizumab. According to the protocol, patients who discontinued treatment due to disease progression before the end of 8 weeks were replaced. Of note,1 patient (grade 3 hemolytic anemia due to disease progression at W4) was replaced and was then excluded from efficacy population.

The duration of remission (DOR) is defined as the time from the date of first evaluation of the remission (cCR, uCR or PR) to the first documentation of progressive disease, relapsed disease or death. In case an assessment of progressive / relapsed disease or death does not exist, the DOR was censored at the time of the last disease assessment date. The DOR was calculated only for the patients with a remission that was assessed at 52 weeks.

21 patients evaluated for efficacy. 1 patient treated at 4 mg/kg was withdrawn due to grade 3 hemolytic anemia attribuated to disease progression at W4 and considered as not evaluable for efficacy. Due to the small size of the trial no subgroup analyses have been conducted.

The Progression Free Survival (PFS) is defined as the time from first dose administration until the occurrence of progressive disease, relapsed disease or death from any cause. Patients without an event at the time of the analyse were censored at his or her last disease assessment date. Patients with no post-Baseline assessment were censored at the day of the first dose administration.

All 22 enrolled patients were included in the ITT / Safety population

The overall survival (OS) is defined as the time from first dose administration until death from any cause. Alive patients were censored at the most recent date they were known to be alive. Subjects with no assessment post-Baseline were censored at the day of the first dose administration.

22 patients were included in the ITT / Safety population

During phase 1b and during phase 2a patients received monalizumab, IV, at the dose of 2 mg/kg, in combination with ibrutinib 420 mg, orally, once daily.

During phase 1b, patients receivde monalizumab, IV, at the dose of 4 mg/kg, in combination with ibrutinib 420 mg, orally, once daily.