BTK Inhibition Saunters to the Front of the Line in CLL

Much of the progress within hematology-oncology throughout the past 30 years has been “incremental” — valuable of course, and leading to highly effective therapies in disorders such as diffuse large B-cell lymphoma and acute lymphoblastic leukemia. However, these are the days of “disruption,” and ambitious companies now seek to change the conventional paradigm, not tidy up the edges. 2016 was the year in which we saw Bruton tyrosine kinase (BTK) inhibitors stake a claim to disruption in the management of chronic lymphocytic leukemia (CLL).

The value of BTK inhibition in the setting of relapsed disease is well established. We have been stunned by the comparison against ofatumumab in the PCYC-1112 (RESONATE) trial¹  and the threat that p53 mutation status might soon become a laboratory request of historical interest for patients with CLL. However, what has been particularly striking in the last 12 months has been the experience of BTK inhibitors being used as first-line therapy in a direct challenge to chemoimmunotherapy.

Since the first description of the use of chlorambucil for CLL in 1961,²  chemotherapy has remained at the core of first-line therapy. The combination of fludarabine and cyclophosphamide is preferred for those patients who are best able to tolerate it, while bendamustine and chlorambucil are more appropriate for older people or those with comorbidities. A CD20-specific antibody such as rituximab is then added to this chemotherapy-backbone to produce regimens such as fludarabine, cyclophosphamide, and rituximab or bendamustine and rituximab. Ofatumumab or obinutuzumab are now starting to replace rituximab, most particularly in combination with chlorambucil.

Set against this solid progress, it has been remarkable to see how effective ibrutinib has now proven to be as first-line therapy for CLL. The PCYC-1115 (RESONATE-2) study included 269 patients with a median age of 73 years, and single oral treatment given at 420 mg each day reduced the risk of progression or death by 84 percent at a median follow-up of 18.⁴  months when considered in comparison to chlorambucil.³  The updates from the 2016 ASH Annual Meeting show that at median follow-up of 28.6 months, there was a 92 percent response rate, and only four of 135 patients on ibrutinib have discontinued treatment due to progressive disease.4 An encouraging feature was the increasing complete response rate, which had risen to 18 percent by this time. Five-year follow-up on the PCYC-1102 trial also shows a 29 percent complete response rate and an outstanding five-year estimated PFS rate of 92 percent.⁵ 

Of course there are many unanswered questions at this point. Chemotherapy offers a (relatively) “short sharp shock” of treatment following which patients can stop medication, typically for many years before further treatment is needed. Indeed the potential for R-FC to offer a functional “cure” for a subset of patients has been suggested. In contrast, BTK inhibitors seem to need continual daily therapy. Experience with imatinib has shown that patient compliance with even such effective daily therapy cannot be simply assumed.

After five years of clinical experience, the adverse effects of ibrutinib are now becoming clearer and include an incidence of 7 percent and 10 percent for major hemorrhage and atrial fibrillation, respectively, in RESONATE-2. Noteworthy here is the introduction of second-generation BTK inhibitors such as acalabrutinib (ACP-196) and ONO/GS-4059, which have themselves shown remarkable activity in the setting of relapsed CLL and are anticipated to exhibit a different adverse-effect profile.⁶  Additionally, it is not yet known how long-lasting the remissions induced by BTK inhibitors will prove to be. The management of patients who relapse following BTK-inhibition therapy is currently challenging. Venetoclax, itself a potentially disruptive agent,⁷  is demonstrating value in this setting, and perhaps even the most exciting opportunities for first-line therapy may ultimately arise from a sequential combination therapy of BTK inhibition prior to introduction of venetoclax. Nevertheless, given these challenges, should doctors reserve BTK inhibitors for the treatment of CLL relapse to “buy time” and extend the patient journey? Finally we should not neglect the issue of cost. As presaged with the chronic myeloid leukemia experience, if we can indeed turn CLL into a chronic disease requiring long-term daily therapy, the health-care cost burden could prove phenomenal.

In such situations of clinical equipoise we typically default to the need for comparative clinical trials, and studies such as FLAIR, which compares fludarabine, cyclophosphamide, and rituximab with BTK inhibition, will eventually provide a potentially definitive view.⁸  However, the natural history of CLL is indeed “chronic” and we can expect several years of uncertainty.

Doctors and patients are both moving rapidly to embrace a “post-chemotherapy” world within hematology-oncology, and 2016 represented a major step forward in the management of the most common subtype of leukemia.