New Upfront Treatment Algorithm Emerges for Chronic Lymphocytic Leukemia

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The B-cell receptor inhibitors are changing the landscape of CLL.
— Susan M. O’Brien, MD

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According to Susan M. O’Brien, MD, an expert in the treatment of chronic lymphocytic leukemia (CLL), novel agents and new data on patient subsets have led to a new upfront treatment algorithm for this malignancy.

Speaking at the 2016 Pan Pacific Lymphoma Conference in Koloa, Hawaii, Dr. O’Brien described the new treatment landscape.1 Dr. O’Brien is Professor of Medicine at the University of California, Irvine, in Orange, and Medical Director for the Sue and Ralph Stern Center for Cancer Clinical Trials and Research.

Until recently, the algorithm for the upfront treatment of CLL fell into three categories, as originally defined by the German CLL Study Group: (1) the “go go” group, who are generally fit patients, without comorbidities and with a normal life expectancy, and who may achieve long-lasting remission with intensive therapy; (2) the “slow go” group, who are less fit, have some comorbidities, and may achieve disease control with milder therapy, including the new oral agents; and (3) the “no go” group, who are not fit and have many comorbidities, for whom palliative care is most suited.

First-line regimens have typically been fludarabine/cyclophosphamide/rituximab (Rituxan) or bendamustine/rituximab for the “go go” group and bendamustine/rituximab or a chlorambucil (Leukeran)-based regimen for the “slow go” group. Choices were based on the ability to tolerate chemoimmunotherapy, but the emergence of nonchemoimmunotherapy treatment options has led to the proposal of a new algorithm, she said.

Three main patient populations and treatment strategies constitute her new algorithm: Group 1 consists of older patients with comorbidities who are not fit and who are good candidates for ibrutinib (Imbruvica); group 2 includes younger patients with IGVH mutations, who can achieve long remissions with fludarabine, cyclophosphamide, and rituximab; and group 3 comprises fit patients lacking IGVH mutations, who should be enrolled on clinical trials or treated with ibrutinib, according to Dr. O’Brien.

She indicated the newer agents have proven to be superior to chlorambucil in a number of clinical trials.

Ibrutinib in Older, Unfit Patients

“The B-cell receptor inhibitors are changing the landscape of CLL,” Dr. O’Brien said. These include two new agents that target B-cell receptor–­associated kinases—the Bruton’s tyrosine kinase inhibitor ibrutinib and the selective PI3 kinase inhibitor idelalisib (Zydelig)—and others in preclinical and clinical development.

In the longest follow-up yet for single-agent ibrutinib, high response rates have been observed “across the board,” including in patients ≥ 65 years who were treatment-naive (85%) and those with relapsed or refractory disease (94%). With each follow-up, the complete response rate appears to be increasing in the previously untreated cohort (now at 26%), “though it’s still the minority of patients who achieve a complete response,” she noted.2

At 45 months’ follow-up in a study of 94 ibrutinib-treated patients, progression-free survival at 30 months was 96% in treatment-naive patients and 76% in relapsed/refractory patients.2 By cytogenetic subgroup, the median progression-free survival in patients with del(17p) was 32.4 months, “which is phenomenal for these patients,” she commented. “The previous best front-line data for this group showed a progression-free survival of 12 months.”

In the RESONATE trial, which compared ibrutinib to ofatumumab ­(Arzerra), median progression-free survival was not reached with ibrutinib but was 8 months with ofatumumab, representing a 78% risk reduction (P < .0001).3

The trade-off with ibrutinib is mostly mild, generally self-limited diarrhea and bleeding, usually ecchymoses. Atrial fibrillation is seen in 7% to 8% of patients, mostly older individuals with comorbidities. This percentage could rise as the treatment population ages, she suggested.

Idelalisib and Venetoclax

Idelalisib, which potently and selectively inhibits PI3 kinase delta and results in “dramatic” reductions in lymphadenopathy, is also an option but not in the upfront setting. In the pivotal trial, median progression-free survival was not reached with idelalisib plus rituximab but was 5.5 months with rituximab alone—an 85% reduction in risk (P < .0001).4 Despite a very high (81%) nodal response rate, lymphocytosis seems to resolve more slowly with idelalisib than with ibrutinib; therefore, this drug is combined with rituximab, she explained.

In the upfront setting, idelalisib/rituximab yielded a 97% response rate overall, a 100% response rate in patients with del(17p) and/or TP53 mutations, and a 3-year progression-free survival rate of 83% in a study led by Dr. O’Brien.5 However, because greater toxicity has been observed in less heavily pretreated patients, idelalisib will not be developed for upfront use.

Recommended Treatment of CLL

  • A new treatment algorithm is emerging for the upfront treatment of chronic lymphocytic leukemia.
  • Group 1 are older, unfit patients with comorbidities, who are good candidates for ibrutinib.
  • Group 2 are younger patients with IGVH mutations, who can achieve long remissions with fludarabine/cyclophosphamide/rituximab.
  • Group 3 are fit patients who lack IGVH mutations, who should be enrolled on clinical trials or treated with ibrutinib.

The main toxicities are elevated transaminases and pneumonitis, which occur early on, and colitis, which typically develops later in the treatment course and primarily in treatment-naive patients—presumably because there is less T-cell depletion in this population. Patients who develop disabling diarrhea can often be rechallenged without further problems, she added.

Also recently approved for patients with del(17p)—though also not in the first-line setting—is venetoclax (Venclexta), a potent and selective Bcl-2 inhibitor. In the pivotal trial of this drug in relapsed disease, the overall response rate was 79%; responses were also seen in high-risk patients. Complete remissions occurred in 20% of patients, and the 15-month progression-free survival estimate was 69%.6 Venetoclax should be slowly dose-escalated to avoid tumor lysis.

While complete responses are uncommonly seen with B-cell receptor inhibitors, they can be achieved with this Bcl-2 inhibitor, and some patients become [minimal residual disease] negative. “[Minimal residual disease]-negative complete responses in a relapsed/refractory population with a single agent are previously unheard of,” Dr. O’Brien commented, “and it appears the [minimal residual disease]-negative rate increases when venetoclax is combined with an antibody.”

Young, Fit Patients

Fludarabine/cyclophosphamide/rituximab and bendamustine/rituximab are the recommended regimens in young, fit patients. Whether ibrutinib will ultimately prove more effective is an important question, she said.

Regarding the choice between fludarabine/cyclophosphamide/rituximab and bendamustine/rituximab, she noted that fludarabine/cyclophosphamide/rituximab is associated with longer remissions (by at least 1 year) but can produce more neutropenia and infections than bendamustine/rituximab (though these studies did not mandate prophylactic growth factors). “That’s why these two camps still exist,” she said. “Using [bendamustine/rituximab] is easier.”

Two Intergroup trials are evaluating the benefit of ibrutinib vs these two standard regimens. One is a three-arm comparison of bendamustine/rituximab, ibrutinib/rituximab, and ibrutinib alone. The other is comparing fludarabine/cyclophosphamide/rituximab vs ibrutinib/rituximab.

Meanwhile, for fludarabine/cyclophosphamide/rituximab, long-term follow-up of the pivotal FCR300 study from The University of Texas MD Anderson Cancer Center has revealed a plateau in progression-free survival, with about 40% of patients progression-free at 14 years.7 “It would be nice if we could figure out which patients are on that curve,” Dr. O’Brien said. “We assume they must have been [minimal residual disease]-negative at the end of treatment, but there was very little [minimal residual disease] data in that study,” she said.

Data from a subsequent cohort have shown that [minimal residual disease] negativity after a response to fludarabine/cyclophosphamide/rituximab is the most important determinant of progression-free and overall survival. Among responders to fludarabine/cyclophosphamide/rituximab who were [minimal residual disease]-negative, there was only 1 progression and no deaths after 4 years, Strati et al reported.8 According to Dr. O’Brien, these patients may be “cured” of CLL.

Importance of Mutation Status

Unfortunately, minimal residual disease–negative status cannot be determined before treatment. Therefore, it cannot help select patients for treatment with fludarabine/cyclophosphamide/rituximab. What can help, however, is the presence of IGVH mutation, she said, and, especially, the presence of trisomy 12, which was also shown in the Strati study. Patients with IGVH-mutated disease had a 2.7-fold higher chance of being minimal residual ­disease–negative.8

In the long-term follow-up of the FCR300 study, “the plateau is seen in patients with the IGVH mutation,” she noted. “About 60% of the patients with the mutation who were minimal residual disease–negative at the end of treatment were progression-free out to 14 years.”

New Algorithm

Dr. O’Brien said that based on these data, she stratifies patients for treatment differently from the traditional algorithm. “Group 1 would be older, unfit patients with comorbidities. We are not worried about 20-year remissions; we just want to minimize toxicity. Ibrutinib is a very good choice here,” she said.

“Group 2 are younger, IGVH mutation–positive patients. I have lengthy conversations with these patients about fludarabine/cyclophosphamide/rituximab vs ibrutinib, and they often opt for the three-drug regimen. They want shorter therapies with the potential for long-term benefit,” she said, adding that for bendamustine/rituximab, no data show a plateau in the progression-free survival curve.

“Group 3 are fit, IGVH mutation-negative patients. They will not achieve 10- to 15-year remissions with [fludarabine/cyclophosphamide/rituximab], so you can give them ibrutinib,” she said. It remains unknown, however, whether ibrutinib “will produce the same tail on the curve as we know exists for [fludarabine/cyclophosphamide/rituximab],” she cautioned.

When you are faced with a younger patient, [mutation testing] determines therapy. It’s an important distinction for practicing physicians to understand?
— Andrew D. Zelenetz, MD

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Andrew D. Zelenetz, MD, Professor of Medicine at Weill Cornell Medical College, New York, commented that because IGVH-mutated patients do so well on fludarabine/cyclophosphamide/rituximab, mutation testing is required. “It’s not just prognostic now,” he emphasized. “When you are faced with a younger patient, it determines therapy. It’s an important distinction for practicing physicians to understand.” ■

Disclosure: Dr. O’Brien is a consultant for Amgen, Celgene, GSK, and Janssen and has received research support from Acerta, TG Therapeutics, Regeneron, Gilead, Pharma­cyclics, and ProNAI.


1. O’Brien SM: How do we sequence the best treatment options for patients with CLL based on age and prognostic features? 2016 Pan Pacific Lymphoma Conference. Presented July 22, 2016.

2. Coutre S, Furman R, Flinn I, et al: Long-term treatment with single-agent ibrutinib 420 mg leads to durable responses including complete responses in CLL. 2015 AACR Annual Meeting. Abstract CT132. Presented April 19, 2015.

3. Byrd JC, Brown JR, O’Brien S, et al: Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med 371:213-223, 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.

5. O’Brien SM, Lamanna N, Kipps TJ, et al: A phase 2 study of idelalisib plus rituximab in treatment-naive older patients with chronic lymphocytic leukemia. Blood 26:2686-2694, 2015.

6. Roberts AW, Davids MS, Pagel JM, et al: Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med 374:311-322, 2016.

7. 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.

8. Strati P, Keating MJ, O’Brien SM, et al: Eradication of bone marrow minimal residual disease may prompt early treatment discontinuation in CLL. Blood 123:3727-3732, 2014.