Good morning, we are changing gears to Waldenströms Macroglobulinemia which is a relatively infrequent disease.

Its incidence is about 10% of that of myeloma; it is a disease of the elderly.

In this particular study we investigated the activity of rituximab and ibrutinib in patients with macroglobulinemia.

We know that Waldenströms Macroglobulinemia is a low grade lymphoma characterised by the secretion of monoclonal IGM and also by lymphoplasmacytic neoplastic cells that infiltrate the bone marrow, the lymph nodes, the spleen and sometimes they have also extra-lymphatic invasion.

A few years ago it was described that a gene, MYD88, had a specific mutation and this was present in approximately 90% of patients with Waldenströms Macroglobulinemia.

Also we know that in these patients there is a constitutive activation on the NF-kappa B pathway via Bruton’s tyrosine kinase.

This led to the exploration of BTK inhibitors, the first one was ibrutinib, in the treatment of this disease.

Indeed, ibrutinib was administered in the context of two phase II studies and it showed responses up to 90% in patients with Waldenströms Macroglobulinemia.

This led to its approval in the United States and in Europe and this is the first drug actually approved for the treatment of this disease.

In this trial we wanted to investigate whether the addition of ibrutinib to rituximab may improve the results of these patients.

This is the design of the study.

We included 150 patients, some of them previously treated, but also later in the study we allowed newly diagnosed symptomatic patients to be included.

Regarding previously treated patients, they could have received rituximab but they should have not been resistant to rituximab and the last rituximab should have been given more than twelve months from study entry.

The patients were randomised on a 1:1 basis and they were stratified according to IPSS, to number of prior regimens and to ECOG status.

In both arms rituximab was given at the standard dose but at an extended fashion on weeks 1-4 and 17-20 because we and others have shown previously that this is more active in Waldenströms.

In arm B patients received oral placebo, in arm A patients received ibrutinib at a standard dose of 420mg once daily until evidence of disease progression.

This is the main finding of the study.

The primary endpoint was progression free survival and, as you can appreciate, with a median follow-up of 26.5 months there is a very significant improvement of PFS in favour of the combination of ibrutinib and rituximab.

The median PFS in the arm B with rituximab and placebo was 20.3 months whereas it has not been reached in the investigational arm with a hazard ratio of 0.2.

Even more significant was the observation that the combination of ibrutinib and rituximab was able to improve the outcomes of patients that had specific genotypes.

Previous experience with ibrutinib has shown that when we have patients with wild-type MYD88 or when we have patients with mutations at the CXCR4 gene the response to ibrutinib and the PFS is shorter as compared to patients without these features.

In this particular study we were able to show that the combination of ibrutinib and rituximab essentially abrogated these adverse events.

Furthermore, the safety profile of the combination was similar to that of rituximab with the exception of a few cases of hypertension and atrial fibrillation which are known side effects that occur in a minority of patients treated with ibrutinib.

We conclude that the combination of ibrutinib and rituximab improved progression free survival regardless of prognostic or genotypic factors.

There was a significantly higher response rate with ibrutinib and rituximab versus placebo and rituximab.

Furthermore, in 96% of the patients who presented with a haemoglobin less than 11 there was a significant improvement of the haemoglobin after treatment which is a very significant parameter for patients’ quality of life.

There was no IGM flare that we see with rituximab.

The discontinuation rate due to adverse events was low, around 5%.

We believe that this combination now could be considered as one of the standards of care for patients with both newly diagnosed or previously treated with Waldenströms Macroglobulinemia.

Thank you very much.