The first drug developed to specifically target a mutation involved in the pathogenesis of lymphoma, represents a ‘paradigm shift’ in the management of relapsed or refractory B-cell non-Hodgkin lymphomas.
Speaking after the CLL ARC Forum in Sydney recently, Professor John Seymour told the limbic tazemetostat was ‘not going to be a household name’ but was important for a small subset of patients.
Professor Seymour, director of cancer medicine at the Peter MacCallum Cancer Centre, was presenting a selection of highlights from the 14th International Conference of Malignant Lymphomas (ICML) held in Switzerland last month.
He said an interim report from a phase 2 study of tazemetostat, a selective EZH2 inhibitor, showed significant benefit in patients with follicular lymphoma and the EZH2 mutation compared to those with wild-type EZH2.
A partial response was noted in 85% of patients with mutated EZH2 compared to 20% in wild-type EZH2; the overall response rates were 92% and 26% respectively.
In diffuse large cell B-cell lymphoma (DLBCL), a partial response was evident in 29% of patients with the mutation and 7% without the mutation; overall response rates were 29% and 15% respectively.
Professor Seymour said there was evidence of pseudo-progression peaking at about eight weeks and dropping off by 16 weeks post-treatment.
“This is a phenomenon that is well recognised in immunotherapy studies, for example with PD-1 inhibitors, with an initial increase in the size and metabolic activity of the tumour that then diminishes. It is a transient flare not a true progression.”
The most common adverse events reported were nausea, thrombocytopenia, anaemia, cough, fatigue and diarrhoea.
Professor Seymour also highlighted an international study of patients with follicular lymphoma randomised to either involved field radiation therapy (IFRT) alone or IFRT and six cycles of CVP chemotherapy.
“The addition of systemic therapy increases the proportion of patients with durable disease control, and, potentially a cure.”
A protocol amendment, which added rituximab to the chemotherapy arm, resulted in additional benefit and a progression free survival of 88% at eight years, he said.
Professor Seymour said the risk of histologic transformation to a more aggressive disease was also reduced by the combined treatment.
Cellular immunotherapy using genetically modified autologous T cells was also singled out for its potential to transform the management of patients including those with DLBCL.
“This is the therapy I feel most likely to be durable and potent,” he said.
“While it is technically and practically the most complex and burdensome, if you have a group of patients ‘cured’, then that’s 20 to 40 years of benefit delivered from a one-off therapy.”
An interim analysis of the phase 2 trial of CD19-targeted therapy CTL019 reported a best overall response rate of 59% and complete response of 43% in the first 51 patients. Most responders (79%) remained relapse free at six months.
Adverse events included cytokine release syndrome, infections and cytopaenias.
Professor Seymour said it remains to be seen if the therapy can be delivered affordably and safely in the real world.
Abstract from other ICML presentations can be viewed here