New molecular therapeutics are now paving the way for prolonging progression-free survival (PFS) and increasing overall survival (OS) for patients with chronic lymphocytic leukemia (CLL).

Although the cure rate for CLL has increased during recent years, the disease often recurs due to resistant cancer cells in the lymph nodes and bone marrow. However, novel therapies may soon be able to overcome this problem.

CLL is the most common form of leukemia in the United States, according to the Leukemia & Lymphoma Society. CLL tends to affect older adults and because of extended life expectancies, its prevalence is expected to increase in the coming years.  The total number of new cases of CLL in 2011 was estimated to be 14,570, and it was more common in men (8,520 cases) than in women (6,050 cases).1

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A study recently published in the New England Journal of Medicine found that the novel agent ibrutinib has demonstrated the potential to be a safe, effective, targeted treatment for CLL. The study suggests that patients with CLL may receive this agent for extended treatment with minimal hematologic toxic effects.2

“We are in a very exciting time for CLL when we are going to see therapies change. Chemotherapy will move to targeted therapies without chemotherapy, which is going to be the future of treatment for the disease. I think ibrutinib is one of the exciting new drugs, and there are many,” said John Byrd, MD, a CLL specialist and Director of the Division of Hematology at Ohio State University Comprehensive Cancer Center, Columbus, OH.

CLL is a cancer of B cells, and ibrutinib is the first drug designed to target Bruton’s tyrosine kinase, a protein essential for CLL cell survival and proliferation. Dr. Byrd said ibrutinib kills malignant B cells but has little effect on healthy T cells, unlike other CLL therapies. He and his colleagues conducted a study evaluating the safety, efficacy, and pharmacokinetics of ibrutinib on 85 patients who experienced a CLL relapse (median age 66 years); 51 patients received a 420 mg dose of ibrutinib and 34 patients received an 840 mg dose.

Ibrutinib produced an overall response rate (complete and partial) of 71%, and was associated with very good outcomes and high frequency of durable remissions even in patients with high-risk genetic lesions. At 16 months, the estimated PFS rate was 75% and the OS rate was 83%.2 Dr. Byrd said long-term use of this agent was associated with side effects such as diarrhea, fatigue, and upper respiratory tract infections, which usually resolved with no treatment delay. 

“Ibrutinib is the most active drug that has been tested to date, and it works independently of poor prognostic factors. So, it is an important advance,” Dr. Byrd told

He said the responses to ibrutinib appear to be independent of clinical risk factors as well as genetic risk factors that are present before treatment. The study showed that responses were similar in patients with advanced-stage disease and were not affected by the number of CLL therapies previously administered.

Younger Patients May Need Different Therapy than Older Patients

Age is not often considered when determining treatment for patients with CLL; however, a recent study published in the Journal of Clinical Oncology (JCO) suggests that older patients may not respond as well to the frequently used CLL therapies such as fludarabine.3

Investigators found that fludarabine improved PFS and OS in patients younger than age 70, but chlorambucil tended to produce higher OS rates in patients older than 70. Rituximab combined with fludarabine versus fludarabine alone improved PFS and OS in both younger and older patients. The study also showed that alemtuzumab consolidation therapy after chemotherapy or chemoimmunotherapy did not improve PFS or OS in either younger or older patients.3

“Age does matter when we talk about CLL,” said Dr. Byrd, who was a co-author on the JCO study. He said CLL most often strikes adults age 65 and older and the mean age at diagnosis is 72. Yet, most of the CLL clinical trial participants are in their early 60s. Dr. Byrd said this study suggests that chlorambucil is superior to fludarabine in older patients, and CD20 antibody therapies such as rituximab appear to be beneficial as front-line therapy for all patients with CLL.

Finding the Right Treatment Combination

A two-pronged approach combining ibrutinib and rituximab (Rituxin®) may produce a profound response with only minor side effects in patients with aggressive CLL, according to a recent phase 2 study.4 Researchers conducted a study of 40 high-risk patients with CLL who received oral doses of ibrutinib 420 mg throughout treatment, weekly infusions of rituximab (375 mg/m2) during weeks 1 through 4, and monthly rituximab infusions for the next 5 months.

At 6 months of follow-up, 33 (83%) of 40 patients had an overall response, 32 (80%) patients had a partial response, and one patient (3%) had a complete response.4 Previous studies that investigated ibrutinib have suggested that responses are lessened because of persistent lymphocytosis. In this current study, lymphocytosis peaked earlier and the duration was shorter than with ibrutinib alone.

The treatment was well-tolerated and many of the patients reported improved overall health and quality of life after three cycles of treatment. Although the findings are promising, researchers say the follow-up is short and larger studies are needed. “For high-risk patients given this combination we found patients go into remission faster. So, there may be an advantage compared to single-agent ibrutinib, where it takes significantly longer. Whether that affects progression-free survival is unclear,” said study investigator Jan Berger, MD, PhD, an associate professor in the Department of Leukemia at the University of Texas M.D. Anderson Cancer Center, Houston, TX.

Combating the CLL Reserves

Currently, researchers at Dartmouth-Hitchcock’s Norris Cotton Cancer Center in Lebanon, NH are studying the mechanism in CLL cancer cells that cause the resistance to treatment in certain patients. They combined gossypol with navitoclax in an attempt to overcome resistance to the BCL2 inhibitor ABT-737.5

CLL cells in the lymph nodes increase levels of a protein known as BCL-X. Gossypol appears to inhibit BCL-X and this allows navitoclax to work more effectively to kill the cancer cells. Researchers tested the combination of the two agents on CLL cells ex vivo.5

“I would say there is tremendous optimism,” said Alan Eastman, PhD, senior researcher on the study and Professor of Pharmacology and Toxicology at the Geisel School of Medicine at Dartmouth College.

Dr. Eastman said both agents have been given to patients with CLL during recent years but never in combination. Now, he thinks this may be one of the most promising combination approaches to date. “I am excited about the future. We have some good drugs in the clinic and combinations in the pipeline that will further increase survival,” he said in an interview with

Although current chemotherapy combinations have improved cure rates, side effects can often be severe. A significant number of CLL deaths are due to treatment-related secondary cancers. There is now hope that will soon change with these new treatment approaches. “Discussions with patients with CLL are now different because we can discuss CLL disease biology and the role of B-cell receptor signaling in CLL,” Dr. Berger said.


1. Leukemia & Lymphoma Society. Leukemia and Lymphoma Facts 2012 Booklet.

2. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013 Jul 4;369(1):32-42.

3. Woyach JA, Ruppert AS, Rai K, et al. Impact of age on outcomes after initial therapy with chemotherapy and different chemoimmunotherapy regimens in patients with chronic lymphocytic leukemia: results of sequential cancer and leukemia group B studies. J Clin Oncol. 2013 Feb 1;31(4):440-7.

4. Berger JA, Keating MJ, Wierda WJ, et al. The Btk Inhibitor Ibrutinib (PCI-32765) in Combination with Rituximab Is Well Tolerated and Displays Profound Activity in High-Risk Chronic Lymphocytic Leukemia (CLL) Patients (Abstract 187). Presented at the American Society of Hematology 2012 Annual Meeting, Atlanta, GA, Dec 8-11, 2012.

5. Soderquist R, Bates DJP, Danilov AV, Eastman A. Gossypol overcomes stroma-mediated resistance to the BCL2 inhibitor ABT-737 in chronic lymphocytic leukemia cells ex vivo. Leukemia. 2013, May 3; DOI: 10.1038/leu.2013.13.