Download Ibrutinib for previously untreated and relapsed or refractory

Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with
TP53 aberrations: a phase 2, single-arm trial
Mohammed Z H Farooqui, Janet Valdez, Sabrina Martyr, Georg Aue, Nakhle Saba, Carsten U
Niemann, Sarah E M Herman, Xin Tian, Gerald Marti, Susan Soto, Thomas E Hughes, Jade Jones,
Andrew Lipsky, Stefania Pittaluga, Maryalice Stetler-Stevenson, Constance Yuan, Yuh Shan Lee,
Lone B Pedersen, Christian H Geisler, Katherine R Calvo, Diane C Arthur, Irina Maric, Richard Childs,
Neal S Young, Adrian Wiestner.
Lancet Oncol 2015; 16: 169–76
For patients with CLL, the major factor that limits response to Fludarabine-based therapy is the loss
of function of the tumour suppressor, p53. In CLL, loss of p53 occurs most commonly through
deletion of an allele on chromosome 17 (del17p), and in the majority of cases, this is accompanied
by mutation of the TP53 gene on the remaining allele. This renders the cells completely unable to
elicit their normal p53 signalling pathway in response to drugs like Fludarabine, and thus (in simple
terms) instead of cell death via apoptosis, cells with p53 loss survive. Although p53 loss at
presentation is around 10% in CLL, this frequency increases to around 40% in treated and refractory
patients. In terms of therapeutic outcome, unfortunately, patients whose CLL cells have lost p53 are
highly likely to be resistant to Fludarabine.
This is why there is so much current enthusiasm for therapeutic agents that act differently to
Fludarabine, and whose mechanism of action is independent of the p53 pathway. Two such drugs
which fall into this category are Idelalisib (a PI3 Kinase δ inhibitor) and Ibrutinib (a BTK inhibitor),
because they do not target cells via DNA damage but by targeting pathways in B-cell receptor
signalling. In particular, Ibrutinib has been very successful in clinical trials for CLL, leading to excellent
responses and long-term remissions even in patients that have been previously treated. This success
naturally led to the question of whether Ibrutinib would be also be successful in the group of CLL
patients who are chemo-resistant because of p53 loss.
The phase 2 study described in this Lancet Oncology paper by Farooqui and colleagues specifically
sets out to answer the question of whether Ibrutinib will retain its activity in patients who have CLL
with p53 loss. 47/51 of the patients recruited had del(17p) and the remaining 4/51 had a monoallelic
TP53 mutation (in the absence of del (17p)). 35 patients were previously untreated and 16 had
relapsed or refractory disease, but all patients required treatment.
Patients were treated with Ibrutinib and the response was assessed after 6 cycles of therapy at 24
weeks. 32/33 previously untreated patients responded, including partial response in 55% and partial
response with lymphocytosis (an on-target effect of Ibrutinib) in 42%. 80% of the patients with
relapsed/refractory disease had a response and 20% patients had stable disease. These data are
extremely encouraging.
One of the intriguing observations was the assessment of the clone size for cells with p53 loss, i.e.
the % of CLL cells with del(17p), and a comparison of this before and after (24 weeks) of treatment.
There was a decrease in 47% of patients, an increase in 47% and no change in 6% patients.
Interestingly the patients with an increase did not have progressive disease and all were continuing
on treatment at the time of data cut-off. This is in contrast to previously reported studies which
show that in patients with del(17p) that are treated with FCR, there is frequently an increase in the
% of del(17p) cells as a result of selection pressure and outgrowth of resistant cells following
chemotherapy.
Recent studies show that a small proportion of Ibrutinib-treated patients develop resistance that is
directly due to acquired mutations in BTK or PLCγ2 (Woyach JA, NEJM 2014), confirming (a) that BTK
is the target of Ibrutinib and (b) that BTK and associated downstream pathways must play a major
role in the survival of CLL cells). Although the reported number of such acquired mutations are small,
these have emerged relatively early in the clinical development of this agent, and although this
seems surprising for a slowly-proliferating disease like CLL, this highlights the key role of B-cell
receptor signalling during CLL pathogenesis and disease progression.
Interestingly, patients that became resistant due to acquired BTK mutations harboured del(17p) or
del(11q), and thus displayed the genomic instability that typically gives rise to a ‘mutator
phenotype’. We can hypothesise that this mutator phenotype gives rise to the BTK mutations that
drive the observed resistance, and longer-term studies are needed to determine the extent to which
p53 status plays a role in this acquired resistance. However, outcome data from the MD Anderson
group (O’Brien et al, ASCO, 2014) demonstrated that del(11q) and del(17p) are indicators of a poorer
response to Ibrutinib. While the mechanism of action of BCR-receptor targeting drugs may be p53independent, it seems that we still need to consider p53 status in Ibrutinib-treated patients, given
that the capacity of the cell to evolve to survive (e.g. acquiring BTK mutations) may be due to p53
loss.
The authors conclude that Ibrutinib is a safe and effective treatment for patients with p53 loss,
particularly compared with the poorer response of such patients to FCR. The median follow up for
this study was 24 months, and therefore longer follow up is required to extend the PFS and OS data,
(and compare to the current standard treatment, FCR), however the results from this clinical study
are very encouraging.