Sequencing Therapy in Chronic Lymphocytic Leukemia

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Although the indications to initiate treatment for chronic lymphocytic leukemia (CLL) have not changed, determining the optimal first-line treatment and sequence of therapies once treatment has begun remain challenges for providers. At the National Comprehensive Cancer Network® (NCCN®) 12th Annual Congress: Hematologic Malignancies™, William G. Wierda, MD, PhD, summarized first- and second-line treatment options for CLL, with an emphasis on patient characteristics and goals.1

“We need to pay more attention to the goals of treatment, which are going to be different depending on the patient population we’re discussing,” said Dr. Wierda, of The University of Texas MD Anderson Cancer Center.

First-Line Ibrutinib: Durable Control

As Dr. Wierda reported, with the exception of allogeneic stem cell transplantation, treatments for CLL are generally not curative, so the goal of first-line therapy is to use the most effective treatment to achieve the longest duration of response. In the first-line setting, he explained, the two treatment approaches are deep remission vs durable control.

These responses are durable, but they’re also partial. Patients need to stay on these agents continuously to maintain that response.
— William G. Wierda, MD, PhD

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According to Dr. Wierda, approximately 75% of people diagnosed with CLL are older than age 65 and/or are physically unfit. The majority of these patients do not need treatment when first diagnosed, he said, but because of their age and the increased number of comorbidities, they experience more toxicities than do younger patients in any line of therapy.

In a randomized, multicenter, open-label phase III study comparing the safety and efficacy of ibrutinib (Imbruvica) vs chlorambucil (Leukeran) in treatment-naive patients at least 65 years old, ibrutinib, a small-molecule inhibitor of Bruton’s tyrosine kinase (BTK), demonstrated prolonged progression-free and overall survival over chlorambucil chemotherapy.2 Patients randomized to receive ibrutinib had an 88% reduction in the risk of disease progression or death. Subgroup analyses showed a progression-free survival benefit across all subgroups, patients with del(11q) mutation had a 99% reduction in the risk of disease progression or death with ibrutinib compared with chemotherapy. Moreover, complete response rates continue to improve over time, increasing from 7% at 12 months to 15% at 24 months to 18% with a median follow-up of 29 months.

“These responses are durable, but the majority are partial remissions,” said Dr. Wierda. “Patients need to stay on these agents continuously to maintain their response.”

Although uncommon in the front-line setting, for the 5% of CLL patients presenting with del(17p) or TP53 mutations, ibrutinib is the best treatment option, Dr. Wierda added.

First-Line Chemoimmunotherapy: Deeper Remission

The combination of a CD20 monoclonal antibody with chemotherapy has also demonstrated improved outcomes in the front-line setting for both physically fit patients and for those with coexisting conditions. According to Dr. Wierda, chemoimmunotherapy-based regimens can achieve deeper remission and give patients a treatment-free interval for varying periods depending on the regimen and how deep the remission is.

In the CLL11 trial, 781 patients with previously untreated CLL and coexisting conditions were randomized to receive either chlorambucil, obinutuzumab (Gazyva) plus chlorambucil or rituximab (Rituxan) plus chlorambucil.3 Treatment with obinutuzumab/chlorambucil or rituximab/chlorambucil showed increased response rates and prolonged progression-free survival (26.7 months and 16.3 months, respectively) as compared with chlorambucil monotherapy (11.1 months; P < .001).

“In this population of older, unfit patients, obinutuzumab was superior to rituximab when each was combined with chlorambucil,” Dr. Wierda reported. “The obinutuzumab combination resulted in improved progression-free survival and higher rates of complete response and molecular response.”

Update on CLL Treatment

  • In the first-line setting of CLL, two treatment approaches achieve the longest duration of response: (1) continuous treatment with ibrutinib to maintain disease control; and (2) chemoimmunotherapy for deeper remission, with a treatment-free interval.
  • In the relapsed/refractory setting, the goal is long-term disease control. A variety of options for patients helps providers to sequence through them.

For patients with mutated IGHV gene, treatment with fludarabine, cyclophosphamide, and rituximab (FCR) was shown to yield long-term disease-free survival.4 Progression-free survival was 53.9% for IGHV-mutated patients and 8.7% for patients with unmutated IGHV at 10 years’ follow-up. Moreover, patients with IGHV mutation who achieved minimal residual disease negativity posttreatment, and progression-free survival was 79.8% at 12.8 years. According to the investigators, accurate identification of mutation status is essential, given the availability of less toxic alternatives such as ibrutinib.

Finally, a study comparing FCR vs bendamustine and rituximab showed improvements in median progression-free survival with FCR but no difference in overall survival.5 When patients were stratified by age, however, a progression-free survival difference was most pronounced for those younger than age 65 in favor of FCR.

“Younger, fitter patients benefited the most from the FCR regimen, but bendamustine and rituximab was associated with less toxic effects, particularly in patients over age 65. FCR is probably the best chemoimmunotherapy option in patients under 65, because it gets the deepest remissions, but bendamustine and rituximab is a reasonable option for older patients,” said Dr. Wierda.

Therapeutic Sequencing for Relapsed CLL

In terms of relapsed CLL, previous treatment, cytogenetic abnormalities by fluorescence in situ hybridization and TP53 mutation status are the major considerations, said Dr. Wierda, but outcomes can be nearly as impressive as in the front-line setting. Analysis based on the PCYC-1102 trial and PCYC-1103 extension study of single-agent ibrutinib demonstrated progression-free survival of 43% in 5 years in those with relapsed or refractory disease, and overall survival has not been reached.6 Although patients with del(17p) mutations still remain at high risk (median progression-free survival, 26 months), Dr. -Wierda called the outcomes “remarkable” for a relapsed population.

“Treatment of relapsed patients without del(17p) with ibrutinib for first salvage therapy is nearly as effective as when used in the front-line setting,” he observed.

For patients with del(17p) mutations, venetoclax (Venclexta), a BCL-2 selective inhibitor, has been approved in the relapsed/refractory setting. Early data showed a median progression-free survival of 27.2 months in this population, and median overall survival has not been reached.7 As Dr. Wierda reported, patients in this study were evaluated for minimal residual disease as well, with 30% (48 of 158) of those tested demonstrating blood -minimal residual disease negativity by flow cytometry.

Venetoclax monotherapy also demonstrated efficacy in a trial of patients whose disease was refractory to ibrutinib or idelalisib (Zydelig).8 With an overall response rate of approximately 70%, venetoclax has clearly demonstrated activity in the management of CLL, with some durability, Dr. Wierda reported.

Cost Considerations

Andrew D. Zelenetz, MD, PhD, Medical Director of Quality Informatics at Memorial Sloan Kettering Cancer Center, highlighted the impressive performance of ibrutinib as a second-line therapy, which nearly equals the outcomes in the first-line setting. “Given these results,” said Dr. Zelenetz, “maybe it makes more sense, medically and economically, for a patient who tolerates chemoimmunotherapy to receive that as first-line therapy and then use ibrutinib afterward.”

“It definitely does,” said Dr. Wierda. “We have to consider what the options are and what we’re trying to achieve. There’s a cost associated with the kinase inhibitors because they are a continuous treatment, and there’s a benefit to having a treatment-free interval with chemoimmunotherapy, but I think both are reasonable options.”

“Ultimately, I think we’re moving toward achieving the same thing with a small-molecule inhibitor like venetoclax as with chemotherapy,” Dr. Wierda continued. “We can have a discussion about defined treatment period with a small-molecule inhibitor, perhaps used in combination, followed by a treatment-free interval, and then, hopefully, re-treat patients with expectations of good responses.” ■

DISCLOSURE: Drs. Wierda and Zelenetz reported no conflicts of interest.


1. Wierda WG: How to sequence therapy in chronic lymphocytic leukemia. 2017 NCCN Hematologic Malignancies Congress. Presented October 7, 2017.

2. Barr P, Robak T, Owen CJ, et al: Updated efficacy and safety from the phase 3 RESONATE-2 study: Ibrutinib as first-line treatment option in patients 65 years and older with chronic lymphocytic leukemia/small lymphocytic leukemia. 2016 ASH Annual Meeting. Abstract 234. Presented December 3, 2016. 

3. Goede V, Fischer K, Busch R, et al: Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med 370:1101-1110, 2014.

4. Thompson PA, Tam CS, O’Brien SM, et al: Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood 127:303-309, 2016.

5. Eichhorst B, Fink AM, Bahlo J, et al: First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): An international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol 17:928-942, 2016.

6. O’Brien SM, Furman RF, Coutre SE, et al: Five-year experience with single-agent ibrutinib in patients with previously untreated and relapsed/refractory chronic lymphocytic leukemia/small lymphocytic leukemia. 2016 ASH Annual Meeting. Abstract 233. Presented December 3, 2016.

7. Stilgenbauer S, Chyla B, Eichhorst B, et al: Venetoclax in relapsed/refractory chronic lymphocytic leukemia with 17p deletion: Outcome and minimal residual disease from the full population of the pivotal M13-982 trial. 2017 European Hematology Association Congress. Abstract S771. Presented June 25, 2017.

8. Jones JA, Wierda WG, Choi MY, et al: Venetoclax activity in CLL patients who have relapsed after or are refractory to ibrutinib or idelalisib. 2016 ASCO Annual Meeting. Abstract 7519. Presented June 6, 2016.