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The CLL2-BIO trial
with bendamustine, 30 of 51 patients (59%) achieved a response according to IWCLL criteria, including 23 of 35 (66%) patients treated first-line and seven of 16 (44%) relapsed/refractory patients. Nineteen patients (37%) had stable disease and two patients (4%) had progressive dis- ease but proceeded with induction treatment on study. Eleven of the 21 patients with a del(17p)/TP53 mutation received debulking treatment: six achieved a response according to IWCLL criteria and the other five had stable disease. Nine of 15 patients who had previously been treated with bendamustine were re-exposed to ben- damustine in the trial and four of them (44%) responded to the debulking treatment.
Over time, the responses of the patients improved (Figure 2A). The best response achieved until 6 months after the final restaging was CR/CRi in four patients (6%), clinical CR/CRi without confirmatory CT scan and/or bone marrow biopsy in 28 patients (43%) and PR in 33 patients (51%). By the time of the data cut-off, 12 patients had stopped maintenance treatment: five due to a MRD- negative response, four with progressive disease, two due to adverse events and one patient died (Figure 2B).
At the time of the data cut-off (median observation time of 20 months) six patients (all in the relapsed/refractory cohort) had progressed and two had died. One of the deaths was due to sepsis with multi-organ failure after the sixth induction cycle in a 73-year old female patient who had received five prior therapies. The other death was caused by ischemic cerebral infarction in the second main- tenance cycle in an 73-year old male patient who had not received prior therapy and was initially hospitalized because of pneumonia, developed a tachyarrhythmia and in whom anticoagulant treatment was discontinued due to a fall and hemoptysis (see Online Supplementary Appendix, Table S3, page 7). The median progression-free and overall survival were not reached. The estimated 15- month progression-free survival rate was 94% (95% CI: 88-100%) for the entire cohort, being 97% (93-100%) among those treated first-line and 89% (76-100%) among the relapsed/refractory patients (Figure 3A). Estimated 15- month overall survival rates were 97% (95% CI: 93- 100%) for the entire cohort, 97% (93-100%) among patients treated first-line and 96% (89-100%) among the relapsed/refractory patients (Figure 3B).
By the time of data cut-off, a total of 959 adverse events had been reported in all 66 patients: 602 (63%) occurred in the treatment-naïve patients and 357 (37%) in the relapsed/refractory cohort (Online Supplementary Appendix, Table S4, page 7). In total, 158 adverse events (16%) occurred during the debulking treatment, 547 (57%) dur- ing induction and 254 (26%) in the maintenance/follow- up phase. According to investigator assessment, 600 (63%) were deemed related to the study treatment. The majority of the adverse events (742, 77%) resolved and 796 adverse events (83%) did not require an adjustment of the study drug. Most adverse events were mild (Common Toxicity Criteria [CTC] grade 1: n=468, 49%) or moderate (CTC grade 2: n=355, 37%), although 120 adverse events (13%) were severe/medically significant (CTC grade 3), 14 (1%) were considered life-threatening (CTC grade 4) and two had a fatal outcome. Both deaths and 97 of the 134 grade 3 or 4 adverse events (72%) were considered related to the study treatment. Eighty-seven of the 959 adverse events (9%) were reported as serious adverse events and 69 of them (79%) were considered treatment-related.
Table 2. Response at the end of induction (efficacy population).
Treatment-naïve (n=39)
39 (100%)
91-100% 61-94% 83-98%
Rel./refractory (n=26)
All patients (n=65)
Overall response rate, n (%) exact95%CI
21 (81%)
60 (92%)
Response, n (%)
CR ---
clinical CR/CRi*
PR
PR with lymphocytosis SD
PD
MRD in peripheral blood, n (%) negative (< 10-4)
intermediate (≥ 10-4 and < 10-2) positive (≥ 10-2)
missing
3 (12%)
17 (65%)
1 (4%)
- 3(12%) 3(5%) - 2(8%) 2(3%)
15 (38%) 24 (62%) -
18 (28%) 41 (63%) 1 (2%)
7 (18%) 9 (23%) 21 (54%) 2 (5%)
2 (8%) 3 (12%) 20 (77%) 1 (4%)
9 (14%) 12 (18%) 41 (63%) 3 (5%)
95% CI: 95% confidence interval; CR: complete remission; CRi: CR with incomplete recovery of bone marrow; MRD: minimal residual disease; PD: progressive disease; PR: partial response; SD: stable disease. *Clinical CR/CRi is a remission fulfilling all criteria of a CR/CRi according to International Workshop on Chronic Lymphocytic Leukemia criteria except a bone marrow examination and/or computed tomography/magnetic resonance imaging scan: the lympho- cyte count had to be normalized, patients had to be asymptomatic and have no evidence of lymphadenopathy and hepatosplenomegaly in clinical examination and ultrasound or other imaging.
During the two cycles of bendamustine debulking, 45 of 52 patients (87%) experienced adverse events of any grade (Table 3A), including 16 patients (31%) with grade 3 and three patients (6%) with grade 4 toxicities. Most common grade 1 or 2 toxicities were nausea (14 patients, 27%), rash/exanthema (8 patients, 15%) and fatigue (7 patients, 13%) and most common grade 3 or 4 toxicities were neu- tropenia (6 patients, 12%) and anemia (5 patients, 10%). Debulking did not lead to an increased rate of cytopenias or infections in the induction phase; 17% of patients with debulking had grade 3 or 4 hematologic toxicities and 8% experienced grade 3 or 4 infections in the induction phase compared to 50% and 21% among the 14 patients with- out prior debulking (Online Supplementary Appendix, Table S5, page 8). The rate of infusion-related reactions was 38%, including 4% grade 3 or 4 reactions among patients with prior debulking compared to 64% and 21%, respec- tively, among patients without debulking.
During the induction treatment with ofatumumab and ibrutinib, all 66 patients experienced adverse events (Table 3B), including 25 (38%) who had grade 3 events, eight (12%) who had grade 4 adverse events, and one patient (2%) who died of septic shock. The most common grade 1 or 2 toxicities were infusion-related reactions (24 patients, 36%), upper respiratory tract infections (20 patients, 30%), diarrhea (18 patients, 27%), muscle disorders (17 patients, 26%), fatigue (14 patients, 21%) and rash/exanthema (13 patients, 20%). The most common grade 3 or 4 toxicities were neutropenia (14 patients, 21%), infusion-related reac- tions (5 patients, 8%) and diarrhea (4 patients, 6%).
Cytopenias, including neutropenia and thrombocytope- nia, as well as epistaxis and hematoma occurred more often among the relapsed/refractory patients, while CTC grade 1 or 2 infections, mild gastrointestinal toxicities and skin/subcutaneous disorders, as well as hypertension were reported more often among the treatment-naïve patients.
Of note, four of 66 patients (6%) reported paresthesia or dysesthesia (all CTC grade 1 or 2) during the induction
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