Therapeutic focus – The tide turns slowly in chronic lymphocytic leukaemia

It has been more than 30 years since the launch of the alkylating agent chlorambucil marked the first real breakthrough in drug treatment of chronic lymphocytic leukaemia, but progress since then has been slow and largely incremental.

However, the approval of Roche’s Rituxan three years ago might come to be seen as the turning of the tide. With several late-stage monoclonal antibodies that similarly target cell-surface markers on B-cells, a host of small-molecule tyrosine kinase inhibitors and several other approaches now in development, there are changes afoot (see tables below).

B-cells are a logical target given that in chronic lymphocytic leukaemia (CLL) these cells grow in abnormally high numbers and accumulate in the blood and bone marrow. Targeting B-cell surface markers – in Rituxan’s case CD20 – is thus a popular approach.

Today chemo-immunotherapy regimens, including Rituxan/fludarabine/chlorambucil and Rituxan/bendamustine, remain the standard of care for most CLL patients. However, chlorambucil monotherapy tends only to be used in older, frailer patients who tolerate it better than novel chemo agents.

Fludarabine, a purine analogue, had joined chlorambucil in the late 1980s for second-line CLL, and later took over as the preferred drug in younger patients. Rituxan plus fludarabine was the first regimen to improve survival. Bendamustine, an established anticancer, was approved in the US in 2008 for first-line use.

Anti-CD20 and other B-cell therapies

Beyond Rituxan one other anti-CD20 MAb has been launched for CLL, but this has struggled to make an impression; GlaxoSmithKline’s ofatumumab (Arzerra) is approved for double-refractory patients, and posted sales of just $95m in 2012, its second full year on the market.

But this has not deterred others, and at the Asco meeting Roche’s obinutuzumab showed highly impressive phase III data in elderly patients (Asco – GA101 and Arzerra shape up to Rituxan as biosimilars loom, June 6, 2013). Dr Kanti Rai, of the North Shore University Hospital, said this showed that “chlorambucil, which in the US we’ve virtually thrown out of the window as totally ineffective, might not be so if used in combination with an anti-CD20 MAb”.

The Roche MAb is now awaiting approval for CLL, and behind it several biological therapies are jostling for attention, targeting CD20 and other B-cell surface proteins like CD19. For instance, a phase II study of AstraZeneca’s MEDI-551 with bendamustine versus Rituxan plus bendamustine is due to read out in 2015. 

Small molecules also made a splash at Asco – in particular blockers of various parts of the complex B-cell receptor (BCR) signalling pathway, including inhibitors of phosphatidylinositol 3-kinase (PI3K), spleen tyrosine kinase and Bruton’s tyrosine kinase.

Phase III data have yet to be revealed for any of these, although Gilead at Asco boasted phase II results from a combination of idelalisib and Rituxan, and phase I trial of idelalisib alone. “There is no question that idelalisib is a very, very attractive drug. It did not take a genius to combine [it] with something else”, said Dr Rai, referring to the Rituxan study.

The molecule is Gilead’s entry into oncology, and the group is also studying idelalisib combined with GS-9973, its spleen tyrosine kinase inhibitor, in a phase II study due to end in 2015. Meanwhile, ibrutinib is the most advanced Bruton’s tyrosine kinase inhibitor and is central to Johnson & Johnson’s oncology strategy.

The other phase III asset in this category, Merck & Co’s cyclin-dependent kinase inhibitor dinaciclib, kept a low profile at Asco, but faces an important data readout in 2016 from a head-to-head trial versus Arzerra. Novartis/Astex’s similarly acting AT7519 should yield phase II data next year.

Less smooth

However, treating CLL by antagonising Bcl2, a protein that regulates apoptosis, seems to be proceeding less smoothly: Teva’s obatoclax is no longer in development for CLL, while navitoclax, a project that was subject to a deal between Roche and AbbVie, completed a phase II CLL trial last year but no longer appears in Roche’s R&D pipeline.

This leaves a few other approaches, the most advanced of which is Celgene’s multiple myeloma blockbuster Revlimid (lenalidomide), which could generate initial data this year from a phase III study in second-line CLL treatment. 

Perhaps the most cutting-edge approach of all is so-called chimaeric antigen receptor therapy (CART), involving the delivery of autologous T-cells modified to target CD19, which is expressed almost exclusively on B-cells. This project, coded CTL019, is being pursued by Novartis with the University of Pennsylvania, but, given the difficulties of manufacturing the cells consistently and the acute adverse events seen in some patients, work is likely to proceed cautiously.

Also in the highly speculative camp is Memgen’s ISF35, an immunotherapy involving an adenovirus vector that encodes a chimaeric CD154, a natural ligand for CD40; CD40 is also expressed on B-cells. The precise status of its phase I/II study is not clear.

But while some of the approaches have to be viewed speculatively, activity with the more advanced biologicals and small molecules suggests that significant headway is being made. “We really are making progress in the treatment of CLL – a fact which we were not able to acknowledge until as recently as 10-12 years ago,” says Dr Rai.

To contact the writer of this story email Jacob Plieth in London at[email protected]or follow@JacobEPVantageon Twitter