Looking Ahead in Treating Chronic Lymphocytic Leukemia

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John C. Byrd, MD

There is no advantage to treating CLL before symptoms develop, irrespective of genomic features.

—John C. Byrd, MD

It’s the dawn of a new era in the treatment of chronic lymphocytic leukemia (CLL), largely due to the development of agents targeting the BCR signaling pathway, according to John C. Byrd, MD, of The Ohio State University Comprehensive Cancer Center, Columbus. At the 19th Annual Conference of the National Comprehensive Cancer Network (NCCN) in Hollywood, Florida, Dr. Byrd presented new standards of care, and looked to the future, in the treatment of CLL.

Key Considerations

Among the adult leukemias, CLL is the most prevalent, is generally diagnosed early, is associated with the longest life span, and is a disease of the elderly—“factors that are important, as we think of new therapies,” he noted.

Treatment is initiated only when patients become symptomatic. “There is no advantage to treating CLL before symptoms develop, irrespective of genomic features,” he emphasized.

“The biggest disaster I see is the patient with stage 0 to 1 disease who was started on treatment based on a lymphocyte count changing, in the absence of symptoms, and he experiences treatment-related toxicity,” Dr. Byrd said. “You treat the disease in the setting of symptoms.”

Treatment choice is differentiated by age or functional status and by genomic features. New to the NCCN Guidelines is an emphasis on considering del(17p), which indicates patients who are predicted to have worse outcomes and who require different management strategies. “Rather than treat low-risk patients with less chemoimmunotherapy, if you treat any group, this is the one,” he said.

Symptomatic Patients

The value of adding rituximab (Rituxan) to fludarabine/cyclophosphamide (FC) was solidly established by the updated, 6-year analysis of the German CLL Study, where the addition of rituximab to FC (FCR) significantly improved response rates, progression-free survival, and overall survival.1 Most genetic subgroups (except for del 17p) benefited from FCR and patients negative for minimal residual disease or disease in the nodes had a very long remission from chemoimmunotherapy—out to 10 years, he noted.

Less evidence-based, but commonly used in practice, is bendamustine (Treanda) plus rituximab in young patients. However, the CLL10 study found this doublet to be inferior to FCR, though easier to administer.2

“For a chance at cure, it’s worth considering FCR. This is one area where the field is changing,” he said.

Summarizing his treatment paradigm, Dr. Byrd said that fludarabine/rituximab may be preferred for low-risk patients, with cyclophosphamide added for patients with del(11q). Patients with del(17p) can receive FCR or high-dose methylprednisolone plus rituximab, or be enrolled in a clinical trial. Elderly patients should not receive fludarabine, as it carries no benefit over chlorambucil (Leukeran). These patients can be treated with bendamustine/rituximab (which is more toxic but feasible). Early data suggest chlorambucil/rituximab is also a good treatment option here.

New Standard of Care

The NCCN Guidelines have added a new standard-of-care regimen, obinutuzumab (Gazyva) plus chlorambucil. Obinutuzumab is a humanized monoclonal antibody targeting CD20, with novel properties as compared to rituximab. In the German CLL11 study, chlorambucil plus obinutuzumab was superior to chlorambucil plus rituximab in multiple endpoints.3 Progression was reduced by 81% (P < .001), and vs chlorambucil alone, mortality was reduced by 59% (P = .002).

Obinutuzumab/chlorambucil is indicated as first-line treatment in CLL patients (1) without del(11q) or del(17p), both those < 70 years old (with or without comorbidities) and those ≥ 70, (2) with del(17p) (any age), and (3) with del(11q) if ≥ 70 or younger with comorbidities.

“Importantly, for the first time in the elderly, infirm population, we see a survival advantage [over monotherapy]. The additional cost is probably justified by more than 1 year additional progression-free survival. For the elderly, this is a better drug, and we should incorporate it,” he maintained.

Novel Agents for Relapsed Disease

Even with relapsed disease, only the presence of symptoms should dictate treatment, and patients with unfavorable risk factors should be evaluated for transplant, Dr. Byrd said.

With the approval of ibrutinib (Imbruvica), the traditional second-line therapies have largely become irrelevant. Response to ibrutinib has been independent of all features except IgVH mutation status, he said, and while del(17p) and del(11q) patients “do drop off,” relapsed/refractory patients lacking these mutations have a progression-free survival time that is similar to what is seen in treatment-naive patients. With additional follow-up, very few patients have shown disease progression, he noted.

Several ongoing studies are evaluating ibrutinib in combination with ofatumumab, rituximab, and bendamustine/rituximab, and clinicians are encouraged to enroll patients on trials that are still accruing, including ECOG 1912 and Alliance 041202.

Noting that resistance to ibrutinib has been “rumored,” he countered that of 267 patients treated at Ohio State University, 201 are still on treatment at a median follow-up of 16 months. “We have patients who are out close to 4 years. There were 42 who went off treatment for reasons other than progressive disease, and only 24 have [had progression] on drug,” he noted.

“If a relapsed/refractory patient does not respond to ibrutinib, the patient probably has something else going on and should be biopsied,” he suggested. Most patients who relapse typically do so between years 1 and 2, and they should be retreated.

Excitement is also building over idelalisib, an inhibitor of PI3K-delta, which both targets the BCR signaling pathway and inhibits B-cell signaling in CLL. In combination with rituximab, ofatumumab, or bendamustine, response rates have been higher than seen with single-agent idelalisib, and a pivotal study of the idelalisib/rituximab combination may lead to the drug’s approval.4

This study evaluated this regimen in 220 relapsed patients with diminished renal function, previous therapy-induced myelosuppression, or major coexisting illness. Median progression-free survival was 5.5 months with rituximab only and was not reached in the idelalisib group—a 50% reduction in risk (P < .001). Response rates were increased 30-fold (P < .001) and mortality was reduced 72% (P = .02).

Complementary Agents?

“Clearly, idelalisib in relapsed disease is more active than rituximab. As monotherapy, it is probably not as good as ibrutinib, but the study populations were not the same. I believe these drugs are complementary,” Dr. Byrd commented.

Phase II and III studies of idelalisib in combination with bendamustine, ofatumumab, and rituximab are in progress in untreated CLL and in relapsed/refractory disease. Other PI3K inhibitors (eg, IPI-145) are also in late-stage development, as are other experimental BCR-signaling agents and second-generation Bruton’s tyrosine kinase inhibitors. The hope is that these novel agents will be effective, even in the presence of newly defined mutations related to resistant disease. ■

Disclosure: Dr. Byrd reported no potential conflicts of interest.


1. Fischer K, Bahlo J, Fin A-M, et al: Extended followup of the CLL8 protocol, a randomized phase III trial of the German CLL Study Group comparing fludarabine and cyclophosphamide to FC plus rituximab for previously untreated patients with chronic lymphocytic leukemia. 2012 American Society of Hematology Annual Meeting. Abstract 435. Presented December 10, 2012.

2. Eichhorst B, Fink A-M, Busch R, et al: Chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab in previously untreated and physically fit patients with advanced chronic lymphocytic leukemia. 2013 American Society of Hematology Annual Meeting. Abstract 526. Presented December 9, 2013.

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. Furman RR, Sharman JP, Coutre SE, et al: Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 370:997-1007, 2014.