Chronic lymphocytic leukemia (CLL) is mainly a disease of the elderly, and the lack of a standard regimen for elderly patients has been a major challenge. The myelosuppressive regimens used to treat younger patients are not well tolerated by the elderly. However, some newer approaches currently under investigation and on the horizon appear to be promising. In particular, small-molecule inhibitors have had encouraging results in early clinical trials.
“The whole CLL community is excited about the newer strategies,” said William G. Wierda, MD, PhD, The University of Texas MD Anderson Cancer Center, Houston. Dr. Wierda discussed real-world management of challenges in older patients with CLL at the recent NCCN 7th Annual Congress on Hematologic Malignancies.1
Median age at diagnosis of CLL is 72 years, yet the median age in most clinical trials is in the early 60s, Dr. Wierda said. “The evolution of treatments [for CLL] has been based on studies of younger patients who can tolerate myelosuppressive agents.”
Current treatments for previously untreated CLL include chemoimmunotherapy, alemtuzumab (Campath), and bendamustine (Treanda). A regimen pioneered at MD Anderson Cancer Center, FCR (fludarabine, cyclophosphamide, rituximab [Rituxan]), is preferred for younger patients but is used very cautiously with reduced chemotherapy doses in high-risk elderly patients, Dr. Wierda said. Unfavorable prognostic factors associated with high-risk CLL include advanced age, increased beta2-microglobulin, 11q- and 17p- deletions by fluorescence in situ hybridization (FISH), unmutated VH status, and leukemia expression of CD38 or ZAP-70.
“FCR is for elderly patients at high risk. I use it if I think the CLL will kill them. When I start FCR in elderly patients, I reduce the dose of fludarabine and cyclophosphamide from the get-go and anticipate myelosuppression and dose reductions in order to get six cycles of treatment,” he told listeners. Even with FCR, Dr. Wierda said, survival is shorter in older patients, for whom median progression-free survival is about 3 years, compared with more than 6 years in younger patients.
Other Current Options
Rituximab monotherapy is a reasonable option in elderly patients. “It does not compromise response to subsequent chemotherapy if needed,” he stated.
Lenalidomide (Revlimid) is active and well tolerated as front-line therapy and salvage therapy in elderly CLL patients. Myelosuppression is the dose-limiting toxicity. “I think patients need at least 5 mg/d of lenalidomide to achieve a response, so I try to get them to at least that daily continuous dose, and I may use growth factor support,” he continued.
Moving forward, the combination of rituximab plus lenalidomide is being studied in elderly CLL patients for first-line therapy, and thus far, results are encouraging. “If a patient is doing well on lenalidomide, continue therapy,” he recommended. “If you stop, they are likely to lose their response.”
Experience thus far suggests that elderly patients do not do well on fludarabine vs chlorambucil (Leukeran), and that alemtuzumab does not improve survival, irrespective of age. Rituximab-containing regimens improve outcomes over fludarabine alone, regardless of age.
“I would argue that there is no standard regimen for elderly patients. Lenalidomide is an option, and FCR is an option for aggressive disease,” Dr. Wierda suggested.
Bendamustine has activity as monotherapy in CLL, but Dr. Wierda was not enthusiastic about this option. “In my opinion, bendamustine is better in combination with rituximab, but it is not clear whether [the combination] is better tolerated than any other chemoimmunotherapy regimen. Further study is needed to characterize tolerability in the elderly,” he commented.
Novel Small-molecule Inhibitors
“It is an interesting and exciting time for CLL. The newer agents [ie, Bruton’s tyrosine kinase, PI3K, and Bcl-2 inhibitors] are entering clinical trials and will change the face of CLL. We may be moving away from chemotherapy for these patients,” Dr.Wierda stated.
Bruton’s tyrosine kinase inhibitor interferes with intracellular signaling downstream of the B-cell receptor and causes B-cell leukemia to undergo apoptosis. Ibrutinib (formerly PCT-32765), an oral Bruton’s tyrosine kinase inhibitor, is now in clinical trials. Studies thus far show a high frequency of durable response in treatment-naive patients over age 65, he said. The drug is well tolerated with no significant myelosuppression, making it particularly suitable for elderly patients. The most frequent adverse events have been grade 1 or 2 diarrhea and nausea.2
“Ibrutinib affects interaction between CLL cells and the microenvironment. With this drug, we see early redistribution of leukemia cells, and efflux of leukemia cells results in reduction of lymph node size,” he said. “Because of this phenomenon, the criteria for response to this drug have been modified to include the lymph node response and not to consider a transient increase in leukemia count as disease progression. We have seen responses with ibrutinib in all high-risk categories, including advanced age and 17p deletion, and the response improves over time. This drug is impressive, and there is much excitement about it. Refer patients to clinical trials,” he advised.
CAL-101 (now called GS1101) is another new oral small-molecule inhibitor that selectively acts on PI3K. The drug is active as monotherapy and in combination therapy for CLL.3 It is being studied as front-line therapy in combination with rituximab in previously untreated elderly patients with CLL.
ABT-199, another oral small-molecule inhibitor, is selectively targeted to Bcl-2. It is being studied in phase I trials. In the first cohort of patients, the drug achieved rapid reduction of CLL burden, with normalization of lymphocyte count at 6 weeks in 79% of patients, as well as reduction in nodal size. The only toxicity to emerge thus far requiring dose reduction was tumor lysis syndrome.4 This trial is continuing to enroll patients.
“ABT-199 is active in high-risk patients, including those with 17p deletions and those who are fludarabine-refractory,” Dr. Wierda noted. ■
Disclosure: Dr. Wierda reported no potential conflicts of interest.
1. Wierda W: Challenges in managing elderly patients with CLL. NCCN 7th Annual Congress: Hematologic Malignancies. Presented September 14-15, 2012.
2. O’Brien S, Furman R, Coutre S, et al: The Bruton’s tyrosine kinase inhibitor ibrutinib is highly active and tolerable in relapsed or refractory (R/R) and treatment naïve (TN) CLL patients: Updated results of a phase Ib/II study. European Hematology Association 2012. Abstract 542. Presented June 14-17, 2012.
3. Sharman J, de Vos S, Leonard JP, et al: A phase I study of the selective phosphatidylinositol 3-kinase delta (PI3K) inhibitor, CAL-101 (GS-1101) in combination with rituximab and/or bendamustine in patients with relapsed CLL. Blood 118(21):1787, Abstract 642, 2011.
4. Roberts A, Davids M, Mahadevan D, et al: Selective inhibition of BCL-2 is active against CLL: First clinical experience with the BH3-mimetic ABT-199. European Hematology Association 2012. Abstract 546. Presented June 14-17, 2012.