In relasped/refractory settings, PFS was significantly increased in the ibrutinib group compared with those receiving ofatumumab (see figure 1A) in RESONATE. The PFS at 6 months was 88% for ibrutinib vs 65% for ofatumumab. Of note, those with the poor prognosis 17p deletion had a 6 month PFS of 83% on ibrutinib, compared with 49% in the ofatumumab group. OS was also significantly increased in the ibrutinib group, despite a protocol amendment that allowed crossover from ofatumumab to ibrutinib in the setting of progressive disease. At 12 months, OS was 90% in the ibrutinib group, compared with 81% in the ofatumumab allocated group.r
43% of patients receiving ibrutinib achieved a partial remission (PR) compared with only 4% in the ofatumumab group. In addition, a further 20% of ibrutinib patients had a PR with lymphocytosis, giving an overall response rate of 63%.r Lymphocytosis in patients receiving ibrutinib is a well described phenomenon that does not represent progressive disease and does not affect patient prognosis.r In the RESONATE study, lymphocytosis resolved in 77% of patients during the follow up period.r
Longer term follow up of RESONATE (median 44 months) confirmed the superiority of ibrutinib over ofatumumab, with the median PFS still not reached for ibrutinib compared to 8.1 months for ofatumumab (see Figure 1). The ORR improved over the first 12 months of therapy, with an updated OFF of 91% coupled with a gradual reduction of partial responses with lymphocytoses (see Figure 2).
In a 3 year follow up of patients treated on the original Phase 1b/2 and extension studies of ibrutinib in CLL (PCYC-1102 and PCYC-1103), median PFS and OS were not reached. Amongst the treatment naïve patients (n=31), PFS was 96% and OS 97% at 30 months, whilst the relapsed/refractory CLL patients (n=101) had a PFS of 69% and OS of 79% at 30 months.r
Figure 1: Long term progression free survival in ibrutinib vs ofatumumab treated groups.
© Blood 2019
Figure 2: Long term response rates in ibrutinib vs ofatumumab treated groups.
© Blood 2019
The Resonate-2 trial, investigating the upfront use of ibrutinib in the elderly, found an overall survival rate at 24 months of 98% with ibrutinib versus 85% with chlorambucil.r The response rate was significantly higher in the ibrutinib group than in the chlorambucil group (86% vs. 35%). Among patients with anaemia at baseline, a significantly higher proportion of patients in the ibrutinib group than in the chlorambucil group had sustained improvement in the haemoglobin level (84% vs. 45%, P<0.001) with similar results shown for thrombocytopenia (77% improvement vs. 43%, P = 0.005).r
Longer term follow up of RESONATE-2, with a median follow up of 60 months continued to demonstrate the superiority of ibrutinib over chlorambucil, both in terms of 5 year PFS (70 vs 12%, p value not stated) and overall survival (83 vs 68%, p value not stated). The overall response rate was 92% for ibrutinib vs 37% for chlorambucil (p value not stated).r Median PFS is illustrated in figure 3.
Two further trials assessed response to ibrutinib in patients with del17p. Both studies showed response rates over 90% and progression free survival rates of over 60% however it should be noted that both studies were phase 2, single arm studies with no comparator.rr
The Alliance A041202 trial demonstrated superiority of ibrutinib and ibrutinib with rituximab compared to bendamustine and rituximab therapy in older untreated patients with CLL in terms of PFS at 2 years (87%, 88%, 74% respectively), with a significant difference seen only between the ibrutinib regimens and bendamustine. There was no significant difference seen in overall survival with a median follow up of 38 months.r
Finally the NCTN E1912 demonstrated the superiority of ibrutinib and rituximab over chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab in untreated CLL patients ≤ 70 years of age without 17p deletion both in terms of PFS and OS. At a median follow up of 33.6 months, interim analysis demonstrated estimate 3 year PFS of 89.4% for ibrutinib and rituximab vs 72.9% for chemoimmunotherapy (HR 0.35, P 0.001), and OS of 98.8% for ibrutinib and rituximab vs 91.5% for chemoimmunotherapy (HR 0.17, p 0.001).r
Figure 3: Progression free survival in RESONATE-2 long term follow up
© Leukemia 2019