Between November 2020 and November 2021, 26 patients were enrolled in the phase IB part of the LOC-R01 study within 10 centers of the LOC network. Thirteen patients were randomized in each of the treatment arms (Fig. 2). One patient in the ibrutinib arm (dose K + 1) was wrongly included as he presented with a major exclusion criterion (complete surgical resection). He did not receive the study treatment. Therefore, patients’ characteristics are described for the whole population (N = 26) whereas we report the secondary endpoints only for the patients who received at least one dose of treatment (N = 13 in the lenalidomide arm and N = 12 in the ibrutinib arm).

Main patient demographics and baseline clinical characteristics were well balanced between both arms, with some variations due to the small number of patients (Table 2). The median age was 52 years (32–60) and median KPS was 80 (40–100). Patients mostly presented with symptoms of motor/sensory deficit (34.6%) or cognitive impairment (30.8%).

All patients had cerebral MRI, showing contrast enhancement in all cases. In the lenalidomide arm, 23.1% and 69.2% of the patients had a unique or multiple lesions, respectively. In the ibrutinib arm, 53.8% and 46.2% of the patients had a unique or multiple lesions, respectively. Among the patients who had a lumbar puncture (84.6%) at inclusion, CSF infiltration by lymphoma cells was reported in 30% and 50% of the patients in the lenalidomide and ibrutinib arm, respectively. Among the patients who had an ophthalmologic examination (96.2%) at inclusion, ocular localization of the lymphoma was reported in 8.3% and 23.1% of the patients in the lenalidomide and ibrutinib arm, respectively. The diagnostic was made on a brain biopsy in 24/26 (92.3%) patients and CSF analysis or vitrectomy in 2/26 (7.7%) patients.

Eight and 11 patients completed the four cycles of R-MPV-based induction immunochemotherapy in the lenalidomide and ibrutinib arm, respectively (Fig. 2). Four patients (30.8%) discontinued lenalidomide early, because of toxicity (one post-cycle 2, one during cycle 2 and two during cycle 4, Fig. 2). Deaths were reported for 1 patient in the lenalidomide arm (progressive disease) and 1 patient in the ibrutinib arm (sepsis).

LOC-R01 phase IB flow chart. Lenalidomide dose K: 20 mg per day D1 to 14; Lenalidomide dose K-1: 15 mg per day D1 to 21; Ibrutinib dose K: 420 mg per day (D3 to 14 and D17 to 28); Ibrutinib dose K + 1: 560 mg per day (D3 to 14 and D17 to 28); DLT: dose-limiting toxicity; E: evaluable; NE: not evaluable; Disc: discontinued

At dose K (20 mg/D during 14 days, N = 7 patients), 2 patients experienced DLTs, including one grade 4 catheter-related infection lasting more than 7 days and one grade 3 increased alanine aminotransferase (ALT) levels lasting 16 days. These 2 DLTs required enrollment of a de-escalation cohort (dose K-1: 15 mg/D during 21 days, N = 6 patients). Of note, one patient was considered as not evaluable among the DLT period at dose K because he died from tumor progression only 2 days after treatment initiation. One of 6 patients treated at dose K-1 experienced a DLT, namely a grade 3 increased ALT lasting more than 14 days and leading to a postponement of cycle 2 by more than 7 days. Therefore, dose K-1 (lenalidomide 15 mg daily from D1 to D21) was the maximum tolerated dose and defined as the RP2D by the IDMC, in combination with R-MPV.

During the whole induction phase, the most frequently (N≥3 patients) reported TEAEs (all grade), across all dose levels, were hepatic cytolysis (N = 8, 61.5%), peripheral sensory neuropathy (N = 7, 53.8%), infections (N = 5, 38.5%), anemia (N = 5, 38.5%), constipation (N = 5, 38.5%), neutropenia (N = 4, 30.8%), maculopapular rash (N = 3, 23.1%), thromboembolic event (N = 3, 23.1%), dyspnea (N = 3, 23.1%) and fatigue (N = 3, 23.1%) (Table 3). Most patients (N = 10, 76.9%) experienced a grade 3 or higher TEAE. The most frequent grade 3 or 4 TEAEs related to lenalidomide in combination with R-MPV were hepatic cytolysis (N = 5, 38.5%), neutropenia (N = 3, 23.1%) and infections (N = 3, 23.1%). Of note, one patient had a grade 4 Lyell’s syndrome during cycle 2, most likely related to lenalidomide. She was transferred to an intensive dermatology unit for specialized care, and her Lyell’s syndrome gradually improved. The pharmacovigilance study concluded that the drugs to be preferentially incriminated were lenalidomide, followed by valaciclovir and atovaquone.

Treatment-related serious AEs were reported for 5 patients (38.5%), including infections (one bacteriemia of grade 2, one sepsis and one endocarditis of grade 3 and two catheter-related infections of grade 4), one grade 4 Lyell’s syndrome and one grade 2 thromboembolic event.

Dose delays (≥7 days) because of an AE occurred in 3 (42.9%) and 3 (50%) patients at dose K and K-1, respectively (Table 4). Besides, across all dose levels, 5 (38.5%) patients had a dose reduction of lenalidomide because of an AE, while 4 (30.8%) and 8 (61.5%) patients received less methotrexate and vincristine, respectively (Table 4).

At dose K (420 mg, N = 5 patients), 2 patients were not evaluable for the DLT since they received less than 80% of the planned ibrutinib dosage (39% and 54% respectively) because of a methotrexate-related hepatic cytolysis. No DLT was noted at dose K, which resulted in the enrollment of an escalation cohort (dose K + 1: 560 mg, N = 8 patients). Two patients were not evaluable for DLT at dose K + 1 (one patient had delirium and mistook the treatment (71% of the planned dose) and the other was the previously mentioned wrongly enrolled patient). One of 6 evaluable patients treated at dose K + 1 experienced a DLT, namely a grade 5 septic shock due to invasive pulmonary aspergillosis and pneumocystosis resulting in the patient’s death. The clinical course of this patient was very unfortunate. He was treated with high dose corticosteroids after he underwent the stereotactic biopsy. His tumor was placed in the hypothalamic-pituitary region responsible for a difficult-to-treat insipidus diabetes resulting in large natremia variations and a subsequent central pontine myelinolysis followed by comatose state. At the same time, he presented with a severe bronchopulmonary infection for which he was transferred to intensive care unit (ICU). Pneumocystosis and aspergillosis were identified, but the ICU physicians, together with the patient’s family decided to limit the healthcare and no specific treatment for pneumocystosis or aspergillosis was delivered. The patient had received one aerosolized pentamidine as pneumocystis prophylaxis.

Consequently, dose K + 1 (ibrutinib 560 mg daily from D3 to D14 and D17 to D28) was the maximum tolerated dose and defined as the RP2D by the IDMC, in combination with R-MPV.

During the whole induction phase, the most frequently reported TEAEs (all grade), across all dose levels, were infections (N = 6, 50%), peripheral sensory neuropathy (N = 6, 50%), hepatic cytolysis (N = 6, 50%), anemia (N = 5, 41.7%), diarrhea (N = 4, 33.3%), nausea (N = 4, 33.3%), thrombocytopenia (N = 4, 33.3%), fatigue (N = 3, 25%), neutropenia (N = 3, 25%), creatinine increased (N = 3, 25%) and headache (N = 3, 25%) (Table 3). Of note, only one patient experienced a grade 1 atrial fibrillation. Most patients (N = 9, 75%) experienced a grade 3 or higher TEAE. The most frequent grade ≥ 3 TEAEs related to ibrutinib in combination with R-MPV were hepatic cytolysis (N = 4, 33.3%), neutropenia (N = 3, 25%) and infections (N = 3, 25%), including one grade 5 septic shock previously described.

Treatment-related serious AEs were reported for 3 patients (25%), including infections (two sepsis and one urinary tract infection of grade 3 and one of grade 5), one grade 4 neutropenia and one grade 3 anemia.

Dose delays (≥7 days) because of an AE occurred in 1 (20%) and 3 (42.9%) patients at dose K and K + 1, respectively (Table 4). Besides, across all dose levels, 6 (50%) patients had a dose reduction of ibrutinib because of an AE, while 3 (25%) patients received less vincristine (Table 4).

In the lenalidomide arm (Fig. 3A), across all dose levels, ORR was 76.9% (10/13 patients), after 4 induction cycles, with 6/13 patients (46.1%) achieving CR/uCR and 4/13 patients (30.8%) achieving partial response (PR). Three patients were not evaluable for response. One patient died from tumor progression only 2 days after treatment initiation and two discontinued the treatment because of toxicity (Lyell’s syndrome and infection).

In the ibrutinib arm (Fig. 3B), after 4 induction cycles, across all dose levels, ORR was 83.3% (10/12 patients), with 3/12 patients (25%) achieving CR/uCR and 7/12 patients (58.3%) achieving PR. One patient had stable disease. One patient was non evaluable for response because he died from grade 5 septic shock during cycle 1.

Swimmer plots depicting patients’ responses to lenalidomide (A) or ibrutinib (B), in combination with R-MPV, over time. Lenalidomide dose K: 20 mg per day D1 to 14; Lenalidomide dose K-1: 15 mg per day D1 to 21; Ibrutinib dose K: 420 mg per day (D3 to 14 and D17 to 28); Ibrutinib dose K + 1: 560 mg per day (D3 to 14 and D17 to 28); CR: complete response; uCR: unconfirmed complete response; PR: partial response; SD: stable disease; PD: progressive disease; DLT: dose-limiting toxicity

After a median follow-up of 20.2 months (range: 13.5–28.3), the median PFS and OS were not reached in any of the treatment arms. In the lenalidomide arm, 18-month PFS and OS were 59% (95% CI 36% – 95%) and 85% (95% CI 67% – 100%), respectively. In the ibrutinib arm, 18-month PFS and OS were both 92% (95% CI 77% – 100%) (Figure S1).