A Potential Turning Point in Treatment of CLL

Nick Mulcahy

June 25, 2013

Clinical trial data showing high rates of response with the experimental targeted therapy ibrutinib (Pharmacyclics) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma have been published online in the New England Journal of Medicine.

When these results were presented at meetings recently, they generated considerable excitement among hematologists because of the promise shown for this agent, which is a first-in-class inhibitor of Bruton's tyrosine kinase (BTK), developed specifically for the treatment of B-cell cancers, including CLL.

Now, an accompanying editorial declares that "BTK inhibitors certainly represent an important step forward and a potential turning point in the treatment of CLL." The editorialists are Robin Foà, MD, and Anna Guarini, PhD, both from the Department of Hematology at Sapienza University, in Rome, Italy.

Another clinical trial, also published online June 19 in the New England Journal of Medicine, as reported by Medscape Medical News, shows promising results for ibrutinib in mantle cell lymphoma, which is likely to be another indication for the drug.

The editorialists say that the results from both these studies of ibrutinib are a "further advance in the ever-changing management of hematologic cancers." They note that treatment is shifting from chemotherapies to agents aimed at the "underlying biologic mechanisms of disease occurrence and progression."

Response Rate in Lymphocytic Patients

The trial of CLL or small lymphocytic lymphoma involved 85 patients, and the overall response rate to the novel oral therapy was 71%, report the investigators, led by John C. Byrd, MD, from the Ohio State University Comprehensive Cancer Center in Columbus.

The patients, 65% of whom had high-risk disease, had received a median of 4 previous therapies.

Among responders, 2 patients had complete responses and 58 had partial responses. At 26 months, the estimated progression-free survival rate was 75% and the rate of overall survival was 83%.

However, the editorialists note that the study, in which ibrutinib was used as monotherapy, "triggers a number of considerations" for clinicians. "Will ibrutinib alone be adequate for patients with more aggressive disease, such as those with 17p13.1 deletion and p53 disruption?" they ask.

In the study, some patients in high-risk genetic subgroups, including those with a 17p13.1 deletion, which is associated with the worst prognosis, were in fact responders. However, a high percentage of patients with disease progression during follow-up had a 17p13.1 deletion or a 11q22.3 deletion, another unfavorable prognostic marker, the editorialists point out.

The positive study results prompt another management question: Is aggressive treatment required for all patients with CLL? "The watch-and-wait policy has taught us that many patients with CLL can be cared for with a conservative approach and without intensive treatment," Drs. Foà and Guarini answer.

The relatively low toxicity associated with ibrutinib might help clinicians make these tough decisions, they suggest. Even though CLL "most often affects older patients" and quality of life is an important consideration, "oral compounds offer an appreciable advantage," they note, referring to the favorable toxicity profile.

Toxicity and Another Group of Responders

In addition to its effectiveness, ibrutinib has the appeal of not having toxic effects on normal T-cells, Dr. Byrd and colleagues explain. "This distinguishes it from most regimens used for CLL."

In their study, long-term therapy with ibrutinib was associated with "modest toxicity," and most adverse events were grade 1 or 2, they report. The findings include safety results from 2 treatment groups: ibrutinib 420 mg/day (n = 51) and ibrutinib 840 mg/day (n = 34).

The most common adverse events were diarrhea, fatigue, and upper respiratory tract infection. "Most adverse events resolved without the need for a suspension of treatment," the authors note.

The most common adverse events of grade 3 or higher were pneumonia (in 10 patients [12%]) and dehydration (in 5 patients [6%]). Two patients (4%) in the 420 mg group discontinued treatment because of adverse events, as did in 4 patients in the 840 mg group (12%).

Grade 3 or 4 hematologic toxic effects were "infrequent": 5 patients (6%) developed anemia, 13 (15%) developed neutropenia, and 5 (6%) developed thrombocytopenia.

Eight patients died within 30 days of receiving the last dose of ibrutinib: 3 from pneumonia, 1 from the systemic inflammatory response syndrome, 1 from sarcoma, and 3 from CLL progression.

The effectiveness of ibrutinib was seen in some other patients, but in a qualified way. Ten patients (20%) in the 420 mg group and 5 (15%) in the 840 mg group had a partial response with persistent lymphocytosis.

Dr. Byrd and colleagues point out that blood lymphocytosis was noted by day 7 in 78% of the patients, and peaked at a median of 4 weeks before slowly declining. In 50 of 63 patients (79%), the lymphocyte count eventually normalized or was reduced by 50% from the baseline level.

The editorialists point out that the some of the blood lymphocytosis was not what is typical in CLL.

"Treatment was associated with an initial lymphocytosis that was not due to disease progression but rather to the unique mechanism of action of the drug that induces a mobilization of leukemic B-cells from the bone marrow, lymph nodes, and spleen into the blood," Drs. Foà and Guarini write.

Study funding was provided by Pharmacyclics, the Leukemia and Lymphoma Society, the D. Warren Brown Foundation, Mr. and Mrs. Michael Thomas, the Harry Mangurian Foundation, and the National Cancer Institute. Some of the authors of both studies are employees of Pharmacyclics.

N Engl J Med. Published online June 19, 2013. Abstract, Editorial


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.