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P. Cramer et al.
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Treatment-naïve Relapsed/refractory All patients (n=40) (n=26) (n=66)
Maximumgrade 1/2 3 4 5 1/2 3 4 5 1/2 3 4 5
Skinandsubcutaneous 15(38%) 2(5%) 0 0 7(27%) 2(8%) 0 0 22(33%) 4(6%) 0 0 tissue disorders
Rash,exanthema 10(25%) 0 0 0 3(12%) 0 0 0 13(20%) 0 0 0 Dermatitis,eczema 2(5%) 1(3%) 0 0 1(4%) 0 0 0 3(5%) 1(2%) 0 0 Erythema 3(8%) 0 0 0 1(4%) 0 0 0 4(6%) 0 0 0
Vasculardisorders 9(23%) 1(3%) 0 0 8(31%) 1(4%) 0 0 17(26%) 2(3%) 0 0
Hematoma 2(5%) 0 0 0 6(23%) 0 0 0 8(12%) 0 0 0
Hypertension 4(10%) 1(3%) 0 0 0 0 0 0 4(6%) 1(2%) 0 0
*including bronchial carcinoma (grade 4 adverse event occurring in cycle 4 in a first-line patient), squamous cell carcinoma of the skin (2 cases in 2 relapsed/refractory patients), basal cell car- cinoma (1 case in a first-therapy naive patient),and seborrhoic keratosis (2 cases in 2 relapsed/refractory patients)
received bendamustine than in those who had not been given debulking treatment, and especially compared to the rate in patients in whom ibrutinib and ofatumumab were started concurrently in the above-mentioned phase Ib/II study.13 Although the majority of the patients experienced adverse events during the debulking treatment, including one third of patients with grade 3 or 4 toxicities, the administration of bendamustine did not seem to make patients more prone to cytopenias and infections in the induction phase and did not increase the risk of dose reductions and/or treatment interruptions. Due to low numbers of patients, it is difficult to draw a definite con- clusion on whether debulking therapy with bendamustine is beneficial for all patients or only for certain subgroups. Additional analyses including two other phase II trials with a similar design also evaluating bendamustine debulking, followed by obinutuzumab with either ibruti- nib or venetoclax (NCT02345863 and NCT02401503), are under way. First results suggest that the overall rate of adverse events and especially of cytopenias and infections are not increased, while infusion-related reactions seem to be less common in patients with prior debulking. The administration of single-agent ibrutinib over 2 to 3 months might serve as an alternative approach for debulking, as it effectively reduces the lymphadenopathy through a redis- tribution of the CLL cells to the blood.32
The inclusion of an all-comer population led to a quite heterogeneous group of patients. This might be seen as a limitation of the study but it can also be argued that it helps to transfer the results to routine clinical practice. The lack of CR confirmed by CT/MRI scan and bone marrow may also be criticized, but as the majority of patients con- tinue treatment in a maintenance phase, it is planned that the missing examinations will be performed later. These assessments were not mandatory per study protocol at a defined time point in order to avoid unnecessary and repetitive CT scans or bone marrow biopsies. Instead it was recommended to perform these examinations as soon as the best clinical response was achieved, which is con- sistent with the updated IWCLL guidelines.17 Figure 2A suggests that the depth of response increases over time and consequently also the rates of CR and MRD "negativ- ity". However, so far, only a few patients have achieved a deep, MRD-negative remission and have been able to stop maintenance treatment. The efficacy results in the current analysis are not superior to those achieved with ibrutinib monotherapy. The findings of six other clinical trials eval- uating a combination of ibrutinib with an anti-CD20 anti- body in patients with CLL have been published. Three
evaluated the combination of ibrutinib with rituximab (including 2 randomized studies with single-agent ibruti- nib as a comparator arm),5,6,12 two with obinutuzumab4,14 and one with ofatumumab.13 Cumulative evidence from these trials indicates that the addition of an antibody leads to faster and deeper remissions and one study showed that the achievement of a CR is associated with longer progression-free survival.33 However, the two randomized trials with ibrutinib with or without rituximab did not show (or have not yet shown) a difference in survival times.5,12 When comparing the results of this trial with those of the CLL2-BIG trial, which evaluated the same treatment regimen but with obinutuzumab instead of ofa- tumumab, the responses appear to be deeper, as the MRD "negativity" rate at the end of induction treatment was 48% compared to 14% in CLL2-BIO.34 The addition of an antibody to ibrutinib cannot be recommended in routine practice, but individual patients in whom a faster response or clearance of the lymphocytes from the peripheral blood is needed might benefit from a combination treatment. However, in such situations obinutuzumab should be favored over rituximab and ofatumumab based on the cur- rent data and because ofatumumab is available only in the USA but not in Europe anymore.
Further follow-up is necessary to determine whether bendamustine followed by ofatumumab and ibrutinib can produce deep, MRD negative remissions in a relevant pro- portion of patients and whether treatment can be stopped in this situation. For the regimen with bendamustine debulking followed by ibrutinib with obinutuzumab instead of ofatumumab it was already shown that patients, including those with high-risk cytogenetic abnor- malities, remain in remission for a clinically meaningful time after termination of treatment.35 Termination of ibru- tinib monotherapy would constitute a novel paradigm, as it overcomes the need for indefinite treatment, which is so far needed to maintain responses with the B-cell receptor signaling pathway inhibitors ibrutinib and idelalisib.7-9 Shortened treatment durations might reduce problems of patient compliance as well as treatment costs. It could also avoid resistance due to clonal evolution arising from a therapeutic pressure selecting small subclones with resist- ance mechanisms.9,36,37
Disclosures
PC reports research funding from AbbVie, Acerta, F. Hoffmann-LaRoche, Gilead, GlaxoSmithKline, Janssen-Cilag and Novartis, honoraria for scientific talks from AbbVie, F. Hoffmann-LaRoche and Janssen-Cilag and for advisory boards
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haematologica | 2021; 106(2)