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M. Fürstenau et al.
with bendamustine plus rituximab versus bendamustine plus rituximab only, the reported rate of undetectable MRD at 36 months was 26.3% in the ibrutinib, ben- damustine and rituximab arm and increased over time.56,57 Undetectable MRD status was associated with significant- ly improved PFS (3-year PFS rate: 88.6% for patients with undetectable MRD vs. 60.1% for patients with MRD ≥10-4). However, no termination of ibrutinib therapy was planned according to the study protocol, even when MRD was no longer detectable.
either nine cycles of ibrutinib plus obinutuzumab or three cycles of ibrutinib plus obinutuzumab and six cycles of ibrutinib only, depending on post-chemoimmunotherapy MRD status. Undetectable MRD at 1 year led to the dis- continuation of all therapy. All 28 patients who completed 12 months of treatment had undetectable MRD and stopped therapy per protocol: the CR rate was 86% at that time point. Michallet et al. evaluated a similar scheme in a larger study including previously untreated CLL patients with mutated or unmutated IGHV. Induction treatment consisted of 6 months of ibrutinib plus obinutuzumab fol- lowed by 3 months of ibrutinib.61 After this treatment, MRD was tested and patients with MRD-negative CR or CR with incomplete hematologic recovery (CRi) contin- ued treatment with ibrutinib for another 6 months while all other patients received an intensified regimen with four cycles of the quadruple combination (ibrutinib, fludara- bine, cyclophosphamide and obinutuzumab) and ibrutinib until month 16. With this approach, only 12% of the patients were in MRD-negative CR or CRi: after 9 months and could avoid intensive chemoimmunotherapy.
The dual PI3K inhibitor duvelisib was also evaluated in combination with fludarabine, cyclophosphamide and rit- uximab therapy. However, this regimen induced a slightly lower CR rate of 26% and a rate of undetectable MRD in bone marrow of 67%.62 Although the most frequent adverse events were hematologic toxicities, several immune-mediated toxicities, including transaminitis (grade 3: 34%), arthritis (9%), colitis (6%), pericarditis and pancreatitis (both 3%), were also reported.
A similar concept was tested with the PI3Kd inhibitor idelalisib in combination with bendamustine plus ritux- imab.58 While idelalisib together with bendamustine plus rituximab produced a significantly improved PFS com- pared with bendamustine plus rituximab only (median PFS 20.8 vs. 11.1 months), the triple combination was associated with an increased risk of severe infections, lim- iting its use in clinical practice.
Various phase II studies have evaluated the addition of kinase inhibitors to chemoimmunotherapy in young and fit, treatment-naïve CLL patients. Davids and colleagues reported an impressive rate of undetectable MRD in bone marrow of 78% and a CR rate of 36% after six cycles of fludarabine, cyclophosphamide and rituximab and 2 years of continuous ibrutinib.59 Another trial evaluated the MRD-guided use of frontline therapy with ibrutinib, flu- darabine, cyclophosphamide and obinutuzumab in patients with a favourable genetic risk profile (IGHV- mutated, no TP53 aberrations).60 After three courses of the quadruple combination, treatment was continued with
Figure 3. Proposed sequencing of therapy according to first-line treatment; approved options. CT: chemotherapy; CIT: chemoimmunotherapy; y: years; M: mutat- ed; UM: unmutated; R: rituximab; BTKi: Bruton tyrosine kinase inhibitor.
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