In this issue of Blood, Byrd et al present data from a randomized phase 2 study in which 78 previously untreated patients with chronic lymphocytic leukemia (CLL) received 8 cycles of either 1000 mg (the current standard dose) or 2000 mg of the anti-CD20 monoclonal antibody (mAb) obinutuzumab.1  The authors report a higher overall response rate with higher doses of obinutuzumab (67% vs 49%), but there was no significant difference in progression-free survival (PFS) between groups.

Obinutuzumab (GA101) is a novel type 2 humanized anti-CD20 mAb that was glycoengineered to reduce attachment of fucose residues to the crystallizable fragment (Fc) portion of the mAb. This enhances the affinity of the antibody for binding to Fcγ receptors of the IIIA subgroup (FcγRIIIA or CD16a) on effector cells, thus improving antibody-dependent cell-mediated cytotoxicity (ADCC). Being a type 2 antibody, obinutuzumab mostly relies on ADCC and direct cytotoxic effects. In contrast, type 1 antibodies (rituximab and ofatumumab) display stronger complement-dependent cytotoxicity, less ADCC, and minimal direct cytotoxicity.

Over the past 2 decades, anti-CD20 mAbs have become a cornerstone of therapies for patients with B-cell malignancies, including CLL. As a single agent, rituximab was initially perceived as a relatively inactive agent in CLL, with response rates ranging between 5% and 14%. The characteristic low CD20 expression, which distinguishes CLL from other mature B-cell malignancies, presumably contributes to these relatively low response rates. However, more dose-dense2  or higher-dose regimens3  increased the response rates to single-agent rituximab and invigorated the interest in treating CLL patients with CD20 mAbs. The most established use of anti-CD20 mAbs in CLL is as a partner in chemoimmunotherapy (CIT) regimens combined with conventional agents. In these combinations, anti-CD20 mAbs improved PFS and overall survival when added to fludarabine and cyclophosphamide,4,5  bendamustine,6  or chlorambucil.7,8  Furthermore, single-agent anti-CD20 mAbs are commonly used (especially in the United States) in CLL patients who are unfit for chemotherapy-based regimens because of advanced age and/or poor performance status.

The data presented by Byrd et al1  demonstrate that obinutuzumab as a single agent can induce complete remissions in 5% of CLL patients treated with standard-dose and in 20% of patients treated with higher-dose obinutuzumab, an indicator of the high efficacy of obinutuzumab, which was highlighted in the pivotal trial.7  On the basis of these data, one could speculate that obinutuzumab, currently approved for use in combination with chlorambucil for untreated CLL patients who are unfit to undergo CIT, will increasingly be used as a single agent. The data clearly corroborate that obinutuzumab has high single-agent activity, but they do not definitively answer what dose is optimal or whether obinutuzumab is best used alone or in combination. Cross-trial comparisons have many limitations, but the 18-month PFS with standard-dose obinutuzumab (59%) reported in the article by Byrd et al appears shorter than what was reported for obinutuzumab plus chlorambucil (∼80% at 18 months),3  and the authors argue that this may favor the use of higher-dose obinutuzumab in which the PFS at 18 months was more similar to that in the data for the chlorambucil combination. However, at later time points, the PFS curves of the 2 obinutuzumab dose regimens merged (see Figure 2 in the article by Byrd et al that begins on page 79), and there was no significant PFS benefit that favored the higher-dose obinutuzumab or that would change current dosing practice. These data indicate that higher-dose obinutuzumab has only limited advantage; it achieves deeper remissions which, after finishing the 6 months of treatment, do not translate into any major PFS benefit when compared with standard-dose obinutuzumab. Accordingly, current trials use standard dosing of obinutuzumab and favor obinutuzumab maintenance strategies over the higher-dose obinutuzumab used in combination trials (see table).

Table:

Ongoing clinical trials with obinutuzumab

ClinicalTrials.gov identifierTitlePhaseObinutuzumabCombination drugPrimary end point
NCT02292225 Duvelisib With Obinutuzumab in Patients With CLL/SLL Previously Treated With a BTKi (SYNCHRONY) 1B C1: 100 mg D1, 900 mg D2, 1000 mg D8 and D15, C2-6: 1000 mg D1 Duvelisib (IPI-145) dose escalation Safety, tolerability, and DLT 
NCT02537613 A Study of Ibrutinib + Obinutuzumab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia 1B C1: 100 mg D1, 900 mg D2, 1000 mg D8 and D15; C2-6: 1000 mg D1; arm B: same as above, but start at C2 Ibrutinib 420 mg daily starting at C2 (arm A), or ibrutinib 420 mg daily starting at C1 (arms B and C) Safety, tolerability, and DLT 
NCT02315768 Ibrutinib in Combination With GA101 (Obinutuzumab) in Previously Untreated Chronic Lymphocytic Leukemia (CLL) Patients 1B/2 C1: 100 mg D1, 900 mg D2, 1000 mg D8 and D15; C2-6: 1000 mg D1 Ibrutinib 420 mg by mouth daily for up to 6 cycles Phase 1B: safety, tolerability, and DLT, phase 2: ORR 
NCT02427451 Bcl-2 Inhibitor GDC-0199 in Combination With Obinutuzumab and Ibrutinib in Treating Patients With Relapsed, Refractory, or Previously Untreated Chronic Lymphocytic Leukemia 1B/2 C1: 100 mg D1, 900 mg D2, 1000 mg D8 and D15; C2-6: 1000 mg D1 Starting at C2: ibrutinib 420 mg daily; starting at C3: GDC-0199 by mouth daily for up to 14 courses Phase 1B: safety, tolerability, and DLT; phase 2: ORR, MRD negative CR rate 
NCT02345863 Sequential Regimen of Bendamustin [B] Followed by GA101 and Ibrutinib [I] in CLL Patients C1: 100 mg D1, 900 mg D2, 1000 mg D8 and D15; C2-6: 1000 mg D1; maintenance dose every 3 months Bendamustine 70 mg/m2 for 2 cycles; C2-6: ibrutinib 420 mg daily ORR 
NCT02320383 CLLR3: FC + GA101 and B + GA101 in Relapsed or Refractory CLL Followed by GA101 Maintenance for Responding Patients C1: 100 mg D1, 900 mg D2, 1000 mg D8 and D15; C2-6: 1000 mg D1; maintenance dose every 3 months C1: fludarabine 25 mg/m2 D3-5 and D2-4 in C2-6; C1: cyclophosphamide 250 mg/m2 D3-5 and D2-4 in C2-6 ORR 
NCT02071225 A Study Evaluating the Efficacy of Obinutuzumab and Bendamustine Treatment in Patients With Refractory or Relapsed Chronic Lymphocytic Leukemia C1: 100 mg D1, 900 mg D2, 1000 mg D8 and D15; C2-6: 1000 mg D1 C1: bendamustine 70 mg/m2 D2-3; C2-6: 70 mg/m2 D1-2 ORR 
NCT01980875 Idelalisib + obinutuzumab vs chlorambucil + obinutuzumab in untreated CLL 1000 mg IV for a total of 8 doses over 21 weeks Idelalisib 150 mg by mouth twice daily; chlorambucil 2 mg every other week for a total of 12 doses PFS 
NCT02475681 Study of Obinutuzumab + Chlorambucil, ACP-196 + Obinutuzumab, and ACP-196 in Subjects With Previously Untreated CLL C1: 100 mg D1, 900 mg D2, 1000 mg D8 and D15; C2-6: 1000 mg D1 C1-6: chlorambucil D1 and D15; starting on C1: ACP-196 D1 until progression or toxicity PFS 
NCT02242942 A Study to Compare the Efficacy and Safety of Obinutuzumab + GDC-0199 Versus Obinutuzumab + Chlorambucil in Patients With Chronic Lymphocytic Leukemia C1: 100 mg D1, 900 mg D2, 1000 mg D8 and D15; C2-6: 1000 mg D1 C1-12: chlorambucil 0.5 mg/kg D1 and D15; C1-2: GDC-0199 dose-increase from 20 to 400 mg daily; C3-12: 400 mg daily PFS 
ClinicalTrials.gov identifierTitlePhaseObinutuzumabCombination drugPrimary end point
NCT02292225 Duvelisib With Obinutuzumab in Patients With CLL/SLL Previously Treated With a BTKi (SYNCHRONY) 1B C1: 100 mg D1, 900 mg D2, 1000 mg D8 and D15, C2-6: 1000 mg D1 Duvelisib (IPI-145) dose escalation Safety, tolerability, and DLT 
NCT02537613 A Study of Ibrutinib + Obinutuzumab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia 1B C1: 100 mg D1, 900 mg D2, 1000 mg D8 and D15; C2-6: 1000 mg D1; arm B: same as above, but start at C2 Ibrutinib 420 mg daily starting at C2 (arm A), or ibrutinib 420 mg daily starting at C1 (arms B and C) Safety, tolerability, and DLT 
NCT02315768 Ibrutinib in Combination With GA101 (Obinutuzumab) in Previously Untreated Chronic Lymphocytic Leukemia (CLL) Patients 1B/2 C1: 100 mg D1, 900 mg D2, 1000 mg D8 and D15; C2-6: 1000 mg D1 Ibrutinib 420 mg by mouth daily for up to 6 cycles Phase 1B: safety, tolerability, and DLT, phase 2: ORR 
NCT02427451 Bcl-2 Inhibitor GDC-0199 in Combination With Obinutuzumab and Ibrutinib in Treating Patients With Relapsed, Refractory, or Previously Untreated Chronic Lymphocytic Leukemia 1B/2 C1: 100 mg D1, 900 mg D2, 1000 mg D8 and D15; C2-6: 1000 mg D1 Starting at C2: ibrutinib 420 mg daily; starting at C3: GDC-0199 by mouth daily for up to 14 courses Phase 1B: safety, tolerability, and DLT; phase 2: ORR, MRD negative CR rate 
NCT02345863 Sequential Regimen of Bendamustin [B] Followed by GA101 and Ibrutinib [I] in CLL Patients C1: 100 mg D1, 900 mg D2, 1000 mg D8 and D15; C2-6: 1000 mg D1; maintenance dose every 3 months Bendamustine 70 mg/m2 for 2 cycles; C2-6: ibrutinib 420 mg daily ORR 
NCT02320383 CLLR3: FC + GA101 and B + GA101 in Relapsed or Refractory CLL Followed by GA101 Maintenance for Responding Patients C1: 100 mg D1, 900 mg D2, 1000 mg D8 and D15; C2-6: 1000 mg D1; maintenance dose every 3 months C1: fludarabine 25 mg/m2 D3-5 and D2-4 in C2-6; C1: cyclophosphamide 250 mg/m2 D3-5 and D2-4 in C2-6 ORR 
NCT02071225 A Study Evaluating the Efficacy of Obinutuzumab and Bendamustine Treatment in Patients With Refractory or Relapsed Chronic Lymphocytic Leukemia C1: 100 mg D1, 900 mg D2, 1000 mg D8 and D15; C2-6: 1000 mg D1 C1: bendamustine 70 mg/m2 D2-3; C2-6: 70 mg/m2 D1-2 ORR 
NCT01980875 Idelalisib + obinutuzumab vs chlorambucil + obinutuzumab in untreated CLL 1000 mg IV for a total of 8 doses over 21 weeks Idelalisib 150 mg by mouth twice daily; chlorambucil 2 mg every other week for a total of 12 doses PFS 
NCT02475681 Study of Obinutuzumab + Chlorambucil, ACP-196 + Obinutuzumab, and ACP-196 in Subjects With Previously Untreated CLL C1: 100 mg D1, 900 mg D2, 1000 mg D8 and D15; C2-6: 1000 mg D1 C1-6: chlorambucil D1 and D15; starting on C1: ACP-196 D1 until progression or toxicity PFS 
NCT02242942 A Study to Compare the Efficacy and Safety of Obinutuzumab + GDC-0199 Versus Obinutuzumab + Chlorambucil in Patients With Chronic Lymphocytic Leukemia C1: 100 mg D1, 900 mg D2, 1000 mg D8 and D15; C2-6: 1000 mg D1 C1-12: chlorambucil 0.5 mg/kg D1 and D15; C1-2: GDC-0199 dose-increase from 20 to 400 mg daily; C3-12: 400 mg daily PFS 

C, cycle; CR, complete response; D, day; DLT, dose-limiting toxicity; IV, intravenous; MRD, minimal residual disease; ORR, overall response rate.

The most obvious combination partners for obinutuzumab are the standard CIT regimen (fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab) in which rituximab is replaced by obinutuzumab to achieve more complete and/or durable responses. We also need to take into account that the use of CIT in CLL patients, especially in patients with high-risk disease, is declining because of superb data and broader availability of kinase inhibitors targeting B-cell receptor signaling (ie, the Bruton’s tyrosine kinase inhibitor ibrutinib,9  the phosphatidylinositol 3-kinase delta inhibitor idelalisib,10  and the B-cell lymphoma 2 antagonist GDC-0199). These agents are changing the current landscape of CLL therapy; the high number of obinutuzumab trials in combination with novel agents (see table) reflects this ongoing major change in clinical practice. With the addition of these new effective agents, including obinutuzumab, to our therapeutic armamentarium, long-term disease control can be achieved in more and more CLL patients, even those with high-risk features. Conversely, the high costs of long-term treatment with these agents to maintain remissions will increase the burden on our health care systems and our patients. Combination treatment strategies to eradicate CLL, allowing for treatment discontinuation, would therefore be desirable, and clinical trial efforts with this goal are currently ongoing (eg, NCT02401503).

In summary, the study by Byrd et al1  highlights the high activity of obinutuzumab as a single agent in patients with CLL and corroborates earlier trial experience showing that there is a dose response with anti-CD20 mAbs in CLL.2,3  Thus, despite the limitations of the trial by Byrd et al, which does not provide a robust rationale for use of higher-dose obinutuzumab in the short-term because of the lack of any major PFS benefit, we should not discard the possibility of a revival of higher-dose obinutuzumab in the future, for example in combination strategies in which achievement of deep remissions is the goal.

Conflict-of-interest disclosure: J.A.B. received research funding from Pharmacyclics and Gilead.

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