ALESSANDRA TEDESCHI (MILAN)
IBRUTINIB TRIALS
Alessandra Tedeschi
Department of Hematology Niguarda Hospital Milano, Italy
In the last seven years the therapeutic options for chronic lymphocytic leukemia or small
lymphocytic lymphoma (CLL/SLL) have expanded after the approval of three new oral
inhibitors. Ibrutinib, the once-daily oral Bruton’s tyrosine kinase inhibitor is now approved in
the United States and Europe for the treatment of patients with treatment naive and relapsed
refractory disease. The approval of the drug was based on clinical trials providing there was
strong evidence about efficacy with a favourable toxic prophile. There is now a critical clinical
need to investigate also long-term efficacy and safety data, considering that ibrutinib is given
as a continuous therapy. The study with the longest follow-up presented to date, with a
follow-up of 7 years, is the PCYC-1102 study in which both treatment naive and pretreated
patients were enrolled.1,2,3 The study was an open-label, non randomized, multicenter phase
1b/2 enrolling 132 patients. With the extended follow-up, durable PFS and OS rates were
observed in the 31 untreated patients with a PFS and OS of 80 and 75% respectively. In the
heavily pretreated population, median prior therapies 4, the estimated 7 year rates of PFS
were 32% with an OS of 52%.3 This study clearly demonstrated that although ibrutinib is
effective in the heavily treated population the PFS depends on the previous number of
treatments. The long term follow-up also demonstrated that even in multiply relapsed
patients those without high risk genomic features experience a better outcome. Whereas
median PFS was reached at 26 and 51 months in del(17p), del(11q) patients respectively. The
RESONATE randomized, multicenter phase 3 study of R/R patients comparing ibrutinib to
Ofatumumab demonstrated that the BTK inhibitor is superior in terms of PFS and OS
compared to the anti Cd20 MoAb.4 With a median follow-up on study of 64 months (range:
0.3-72) in the ibrutinib arm median PFS remained significantly longer for patients randomized
to ibrutinib versus ofatumumab (44.1 vs 8.1 months P˂0.0001).5 In the Resonate trial ibrutinib
overcame the negative impact of both del(11q), reflected by a median PFS of 60.7 months,
and unmutated IGHV sttatus. Although in this trial even with the longer follow-up there was
no significant difference in PFS for ibrutinib-treated patients with or without del(17p) data
were conflicting when patients with TP53 mutation were pooled with those carrying the FISH
abnormality.
As regards treatment naive patients, up to now, one of the longest follow-ups is the one of
the RESONATE-2 phase III randomized study comparing single agent ibrutinib to chlorambucil
treatment in the elderly population.6,7 The PFS estimated at 5 years was 70% for the BTKi
versus 12%. Only 6% of patients showed a disease progression while on ibrutinib treatment.
The OS benefit with ibrutinib was maintained at 5 years follow-up although 57% of patients
crossed over from the chllorambucil arm to receive the BTKi as salvage treatment. Ibrutinib
benefit was also consistent in patients with high prognostic features (TP53 mutation, 11q
deletion, and/or unmutated IGHV).7