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P. Cramer et al.
Table 3A. Adverse events during debulking with bendamustine reported in ≥5% of all patients: data are number of patients (%)
Maximumgrade
Patients with AE
Bloodandlymphatic system disorders
Anemia Neutropenias Thrombocytopenia
Treatment-naïve (n=36)
1/2 3 4 5
17 (47%) 13 (36%) 2 (6%) 0
2(6%) 4(11%) 1(3%) 0
0 3(8%) 1(3%) 0
Relapsed/refractory (n=16)
1/2 3 4 5
9 (56%) 3 (19%) 1 (6%) 0
1(6%) 1(6%) 1(6%) 0
1(6%) 1(6%) 0 0 0 0 1(6%) 0
All patients
(n=52)
1/2 3 4 5
26 (50%) 16 (31%) 3 (6%) 0
3(6%) 5(10%) 2(4%) 0
1(2%) 4(8%) 1(2%) 0 0 5(10%) 1(2%) 0
0 5(14%)
3 (8%) 1 (3%)
0 0
0 0
0 0
0 0
0 0
Nausea
Diarrhea
Constipation 2(6%)0001(6%)0003(6%)000
Earandlabyrinthdisorders 1(3%) 0
0 0
2(13%) 0
2(13%) 0
00
0 0
0 0
3 (6%) 1 (2%)
3(6%) 0
3(6%) 0
23 (44%) 2 (4%)
0 0
0 0
0 0
0 0
Vertigo
Gastrointestinal disorders
1(3%) 0
15 (42%) 1 (3%)
8(50%) 1(6%) 0 0
8(22%) 0 4(11%) 0
0 0 0 0
6(38%) 1(6%) 0 0 0 0 0 0
14(27%) 1(2%) 4(8%) 0
0 0 0 0
Abdominalpain 1(3%) 0 0 0 2(13%) 0 0 0
Generaldisordersand 9(25%) 1(3%) 0 0 5(31%) 0 0 0 administration site conditions
3(6%) 0 0 0
14(27%) 1(2%) 0 0
7(13%) 0 0 0 5(10%) 0 0 0 3(6%) 0 0 0
1(2%) 3(6%) 0 0
11(21%) 3(6%) 0 0
4(8%) 0 0 0 3(6%) 0 0 0
4(8%) 5(10%) 0 0
1(2%) 2(4%) 0 0
5(10%) 0 0 0
4(8%) 0 0 0
4(8%) 0 0 0
5(10%) 1(2%) 0 0
3(6%) 0 0 0
14(27%) 1(2%) 1(2%) 0
8(15%) 1(2%) 0 0
3(6%) 0 0 0
Fatigue Pyrexia Edema
3(8%) 0 0 0 4(25%) 0 0 0 4(11%) 0 0 0 1(6%) 0 0 0 2(6%) 0 0 0 1(6%) 0 0 0
Immunesystemdisorders 1(3%) 3(8%) 0 0 0 0 0 0
Renalandurinarydisorders 4(11%) 0 0 0 0 0 0 0
Acutekidneyinjury 4(11%) 0 0 0 0 0 0 0
Respiratory,thoracicand 3(8%) 1(3%) 0 0 2(13%) 0 0 0 mediastinal disorders
Cough 2(6%) 0 0 0 1(6%) 0 0 0
Skinandsubcutaneous 12(33%) 1(3%) 1(3%) 0 2(13%) 0 0 0 tissue disorders
Rash,exanthema 7(19%) 1(3%) 0 0 1(6%) 0 0 0
Infections and infestations
Upper repiratory tract inf. Oral herpes
Metabolism and nutrition disorders
Hyperuricemia
Nervous system disorders
Pruritus 3(8%) 0 0 0 0
months of induction therapy are comparable to those reported for ibrutinib as a single agent3,5,12,28,29 (although MRD negativity is seen infrequently) or combined with the antibodies rituximab5,11,12 or ofatumumab.13 Two ran- domized trials showed faster and deeper remissions with the addition of rituximab to ibrutinib, but this did not translate into progression-free or overall survival differ- ences.5,12 However, this might change with continued treatment and longer follow-up. Several trials showed that continued ibrutinib treatment is able to increase the rates of CR and MRD-negative remissions - responses also deepened in our study during the maintenance phase with continued ibrutinib and ofatumumab.
No unexpected or cumulative toxicities were seen with the combination of bendamustine, followed by ofatu- mumab and ibrutinib. The majority of adverse events were mild/moderate (CTC grade 1 or 2). The most com- mon CTC grade 3 or 4 adverse events were neutropenia and anemia during the debulking with bendamustine and neutropenia, infusion-related reactions and diarrhea dur- ing the induction with ofatumumab and ibrutinib. Except for two fatal adverse events, the toxicities were generally
0 0 0
550
7(19%) 3(8%) 0 0
2(6%) 0 0 0 2(6%) 0 0 0
4(11%) 4(11%) 0 0
1(3%) 2(6%) 0 0 3(8%) 0 0 0
4(25%) 0 0 0
2(13%) 0 0 0 1(6%) 0 0 0
0 1(6%) 0 0
0000 2(13%) 0 0 0
manageable: only six patients discontinued treatment pre- maturely due to toxicity and the mean dose intensity of both ibrutinib and ofatumumab in the induction phase was more than 90% of the planned dose. The rates of neu- tropenia, thrombocytopenia and infections in both cohorts compare favorably to those with chemoim- munotherapy and other targeted therapies (Online Supplementary Appendix, Table S6, page 9).3-5,12,14,21-31 The tox- icities seen in this trial are in accordance with those reported in a phase-Ib/II trial evaluating different adminis- tration sequences of ibrutinib and ofatumumab in 71 patients with relapsed CLL, small lymphocytic lym- phoma, prolymphocytic leukemia or Richter transforma- tion.13 Importantly, the high incidence of peripheral senso- ry neuropathy reported in that trial (31 of 71 patients, mostly CTC grade 1 or 2) was not confirmed in our study despite a longer period of observation.
The primary goal of the initial debulking with ben- damustine was to reduce the tumor load before initiation of treatment with ofatumumab and ibrutinib to improve treatment tolerability. As intended, the rate of infusion- related reactions was lower among patients who had
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