A combination of new drugs brings hope for patients in the crosshairs of aggressive chronic lymphocytic leukemia

As a devotee of several BBC Radio 4 podcasts, I recently encountered this inspiring documentary about a potential new treatment for CLL (Chronic Lymphocytic Leukemia) and thought it was an excellent topic for a Eureka blog post, especially as the middle-aged son of a friend of mine was diagnosed with this illness last year.

First, some background. CLL is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell). This results in a build-up of lymphocytes in the bone marrow, lymph nodes, and blood leading ultimately to healthy blood cells being crowded out. Early on, the disease is typically asymptomatic, but later a variety of symptoms may emerge including the swelling of non-painful lymph nodes, tiredness, fever, or weight loss. Enlargement of the spleen and anemia may also occur. The disease typically worsens gradually.

In 2015, CLL affected about 904,000 people globally and resulted in 60,700 deaths. The disease most commonly occurs in people over the age of 50 and males are affected more often than females. In the US, five-year survival following diagnosis is approximately 83%. Overall, CLL accounts for less than 1% of deaths from cancer.

Those odds don’t sound too bad … unless of course you happen to be one of the few people suffering from CLL. One of the most difficult aspects of the illness, apart from the physical symptoms, is simply the uncertainty of the prognosis. Are you going to be one of the 17% that dies within five years of diagnosis? Or will you live longer? It’s a sword of Damocles that hangs heavily over the patients and their families and this came through very clearly in the interviews contained in the podcast.

The potential new treatment for CLL that is offering hope to patients is the combination of two targeted agents ibrutinib (Imbruvica) and venetoclax (Venclexta) that are already used to treat CLL.

At the American Society of Hematology conference last fall, the results of the Phase III CLARITY trial were reported by the clinical lead, Dr Peter Hillmen of the University of Leeds in the UK. Remarkably, of 36 patients who completed six months of combination treatment, all responded and 33% achieved the deepest measurable level of remission, with no detectable disease in the bone marrow. Importantly, the combination of the two drugs did not result in any obvious additional toxicity. Some of these patients were interviewed on the podcast mentioned at the start of this post.

On the basis of the CLARITY results, Dr. Hillmen is leading a randomized controlled phase III study—the FLAIR trial—to compare the ibrutinib-plus-venetoclax combination with both ibrutinib alone and a combined regimen of three chemotherapy drugs in patients with previously untreated CLL. This will take a few years to read-out, but the results will be eagerly awaited by CLL sufferers and their families.

Scientifically, the use of the combination of drugs with different therapeutic targets is notable as it may hint at the possibility of a polypharmacological approach to CLL in which the biological activities of ibrutinib and venetoclax (BTK inhibition and Bcl-2 blockade) are combined in a single molecule. Such approaches are of burgeoning interest (as highlighted in a previous Eureka post) and may offer even greater benefits to CLL patients