Integration of Novel CLL Agents Into Frontline Setting Continues to Evolve

Jeffrey Jones, MD, presented evidence supporting the integration of obinutuzumab, ibrutinib, ofatumumab, and idelalisib into the frontline setting for patients with chronic lymphocytic leukemia.

Jeffrey A. Jones, MD, MPH

In a little over a year, four new therapeutic options have been approved for use in the treatment of patients with chronic lymphocytic leukemia (CLL): obinutuzumab, ibrutinib, ofatumumab, and idelalisib. In a discussion at the 2015 International Congress on Hematologic Malignancies, Jeffrey Jones, MD, discussed the evidence supporting the integration of these treatments into the frontline CLL setting.

Currently, the anti—CD-20 agents obinutuzumab (Gazyva) and ofatumumab (Arzerra) are approved for use in the frontline CLL setting, while the BTK inhibitor ibrutinib (Imbruvica) and the PI3K-delta inhibitor idelalisib (Zydelig) are approved for resistant/relapsed CLL.

Before discussing these novel agents, Jones, who is Section Chief for CLL/HCL at The Ohio State University Comprehensive Cancer Center, noted that even in the targeted era, chemotherapy may still have a role in upfront CLL therapy. He specifically addressed the role of the FCR (fludarabine, cyclophosphamide, rituximab) chemoimmunotherapy regimen.

“There is a subset of younger, fitter patients with favorable genetic risk features who may enjoy prolonged survival after FCR—failure-free survival, treatment-free survival,” said Jones.

However, Jones noted that FCR has a substantial amount of toxicity. “Many of the physicians in the community practices around us in Columbus have discontinued giving FCR because it is a bit challenging for many of the patients.”

Jones said that one of the most common alternatives to FCR in frontline CLL is BR (bendamustine and rituximab). BR has been shown to have a much better toxicity profile than FCR in this setting; however, FCR bests BR in key efficacy outcomes, including complete response (CR) and progression-free survival (PFS).

Neither regimen, however, is effective in patients with a deletion of chromosome 17p, and it is in this population where the novel CLL agents are emerging as an important option in the frontline CLL setting.

“On the basis of data that are available, with much more to come, it’s already appearing that the B-cell receptor targeted agents represent a significant advance for the group of patients at highest risk of treatment failure after chemoimmunotherapy—that is patients with deletion 17p CLL.”

Jones discussed data from a small trial of ibrutinib in 31 previously untreated patients with high-risk CLL/SLL who were aged ≥65 years.1 Patients received 420 mg/daily of ibrutinib in 28-day cycles.

At a median follow-up of 22.1, months overall response rate (ORR) was 71% (n = 22; 95% CI, 52.0-85.8), including 4 CRs, one nodular partial response, and 17 partial responses (PRs).

“Progression-free survival at nearly 3 years of follow-up is largely a straight line. We talk about ‘survival curves,’ but it’s hard to call this one a curve. So for many of the patients who receive ibrutinib in the frontline, we’ll expect long progression-free survival,” said Jones.

Idelalisib has also shown promise in frontline CLL. An abstract presented at the 2013 ASCO Annual Meeting included results for frontline idelalisib plus rituximab in patients with CLL/SLL aged ≥65 years.2 Patients received 150 mg twice daily of idelalisib continuously for 48 weeks plus 375 mg/m2 of rituximab weekly for the first 8 weeks. Patients who did not progress could continue idelalisib on an extension study after 48 weeks.

In the overall population, ORR was 97%, including a 100% ORR in patients with 17p deletion or TP53 mutations (n = 9). The 100% ORR included 3 CRs and 6 PRs. PFS at 2 years’ follow-up was 93%, including in patients with deletion 17p and TP53 mutations.

These early results with frontline ibrutinib and idelalisib “suggest that the biology is feasible and we look forward to larger trials coming that will help us sort out exactly which group of high-risk patients most benefits from ibrutinib, idelalisib, or a combination with an anti-CD20 monoclonal antibody,” said Jones.

Specifically regarding the efficacy of the anti-CD20 monoclonal antibodies in the first-line setting, Jones first discussed the phase III CLL11 trial,3 which was the basis for the FDA’s approval of obinutuzumab in combination with chlorambucil as a first-line treatment for patients with CLL.

In the three-arm study, patients were randomized in a 1:2:2 ratio to receive six cycles every 28 days of chlorambucil (n = 118), chlorambucil plus obinutuzumab (n = 238), or chlorambucil plus rituximab (n = 233). The median age of these patients was 73 years. An additional 192 patients were enrolled for a second stage of the study to allow for the direct comparison of the obinutuzumab and rituximab combinations.

In stage 1 of the study, obinutuzumab plus chlorambucil reduced the risk of progression by 81% compared with chlorambucil alone (27.2 vs 11.2 months; HR = 0.19; 95% CI, 0.14-0.27; P <.0001). In stage 2 of the study, obinutuzumab plus chlorambucil led to a median PFS of 26.7 months compared with 14.9 months with rituximab and chlorambucil (HR = 0.42; 95% CI, 0.33-0.54; P <.0001).

For the anti-CD20 drug ofatumumab, Jones discussed the phase III COMPLEMENT 1 trial,4 which was the basis for the FDA’s approval of frontline ofatumumab plus chlorambucil for patients with CLL who are considered inappropriate for treatment with the chemotherapy fludarabine.

Patients were enrolled in a 1:1 ratio to receive ofatumumab plus chlorambucil (n = 221) or chlorambucil alone (n = 226). The median age of patients was 69 years with 82% ≥65 years.

PFS was 22.4 months with ofatumumab plus chlorambucil compared with 13.1 months for chlorambucil alone (HR = 0.57; 95% CI, 0.45-0.73 19.0-25.2; P < .001). ORR was 82% versus 69% with a complete response rate of 12% versus 1%, for ofatumumab plus chlorambucil compared with chlorambucil alone, respectively.

The approvals of the obinutuzumab and ofatumumab combinations for frontline treatment of CLL “represent an advance over single-agent alkylator therapy for older patients with CLL,” Jones said.

Looking ahead with novel agents in the first-line CLL setting, Jones said, “Two very important trials are ongoing in the Unites States that will help us sort out the role of ibrutinib in the frontline.”

The first is the phase III ECOG E1912 trial, which is randomizing patients with CLL in a 2:1 ratio to FCR or the combination of ibrutinib plus rituximab (NCT02048813). Enrolled patients are younger (aged ≤70 years), fit, and lack 17p deletions. PFS is the primary endpoint of the trial.

The second notable ongoing study is the randomized phase III A041202 trial, which is examining ibrutinib with or without rituximab versus BR in treatment-naïve patients with CLL who are aged ≥65 (NCT01886872). Patients who progress on BR are allowed to cross over to ibrutinib. PFS is the primary endpoint of the study.

Both of these trials are “very important going forward to understanding the roll of B-cell-receptor—targeting agents in the frontline,” said Jones.


  1. O'Brien S, Furman RR, Coutre SE, et al. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet Oncol. 2014;15(1):48-58.
  2. O'Brien SM, Lamanna N, Kipps TJ, et al. A phase II study of the selective phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor idelalisib (GS-1101) in combination with rituximab (R) in treatment-naive patients (pts) ≥65 years with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). J Clin Oncol 31, 2013 (suppl; abstr 7005).
  3. Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014;370(12):1101-1110.
  4. Hillmen P, Robak T, Janssens A, et al. Ofatumumab + chlorambucil versus chlorambucil alone in patients with untreated chronic lymphocytic leukemia (CLL): results of the phase III study complement 1 (OMB110911). 2013 ASH Annual meeting; New Orleans, LA. Abstract 528.


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