Ibrutinib EU Indications Expanded in CLL and Waldenstrom Macroglobulinemia

The European Commission has expanded the approval of ibrutinib to include use in combination with obinutuzumab for adult patients with previously untreated chronic lymphocytic leukemia, and also in combination with rituximab for the treatment of adult patients with Waldenström macroglobulinemia.

Alessandra Tedeschi MD

The European Commission has expanded the approval of ibrutinib (Imbruvica) to include use in combination with obinutuzumab (Gazyvaro, EU; Gazyva, US) for adult patients with previously untreated chronic lymphocytic leukemia (CLL), and also in combination with rituximab (Rituxan) for the treatment of adult patients with Waldenström macroglobulinemia (WM).1

The expanded indications stem from a positive recommendation from the European Medicines Agency’s Committee for Medicinal Products for Human Use in June 2018.

“The data supporting both the CLL and WM approvals show significant improvements in progression-free survival with the use of ibrutinib-based therapy versus the standard of care study comparators respectively,” Alessandra Tedeschi, MD, medical director, Department of Hematology, Niguarda Hospital, Milan, Italy, stated in a press release. “These approvals therefore provide healthcare professionals with new chemotherapy-free options for patients with these complex blood cancers.”

The approval for the expanded indication in CLL is based on results of the phase III iLLUMINATE (PCYC1130) study, which showed that the combination led to a 77% reduction in the risk of progression or death versus chlorambucil plus obinutuzumab in patients with patients with CLL or small lymphocytic lymphoma.2,3 At a median follow-up of 31.3 months, the median progression-free survival (PFS) was not reached (95% CI, 33.6—not estimable) compared with 19 months (95% CI, 15.1-22.1) for chlorambucil and obinutuzumab (HR, 0.23; 95% CI, 0.15-0.37; P <.0001).

The international, open-label, randomized, phase III iLLUMINATE trial randomized 229 patients 1:1 to receive 420 mg of continuous ibrutinib daily plus 1000 mg of obinutuzumab split on days 1 and 2, and on days 8 and 15 of cycle 1, and day 1 of the subsequent 28-day cycles for 6 cycles; or 0.5 mg/kg of chlorambucil on days 1 and 15 of each 28-day cycle for 6 cycles plus the obinutuzumab regimen.

The primary endpoint was PFS as assessed by an Independent Review Committee (IRC); secondary endpoints were PFS in a high-risk patient population—those with 17p deletion [del(17p)]/TP53 mutations, 11q deletion [del(11q)], and/or unmutated IGHV disease—rate of undetectable minimal residual disease (uMRD), overall response rate (ORR), overall survival (OS), infusion-related reactions (IRRs), and safety. Patients who progressed on chlorambucil/obinutuzumab, determined by IRC, were permitted to cross over to second-line therapy with single-agent ibrutinib.

To be eligible for enrollment, treatment-naïve patients were ≥65 or <65 years of age with a Cumulative Illness Rating Scale (CIRS) score >6, creatinine clearance (CrCI) <70 mL/min, and/or del(17p) or TP53 mutation. The median age was 71 years (range, 40-87) and 65% of patients had high-risk genomic features. Fifty-two percent of patients overall had either Rai III or IV disease, while bulky disease was in 27% of ibrutinib-treated patients and 38% of patients who received chlorambucil therapy.

In the ibrutinib cohort, 62% of patients had unmutated IGHV disease, 12% had del(11q), and 16% had del(17p) and/or TP53 mutations. In the chlorambucil/obinutuzumab arm, 53% of patients had unmutated IGHV disease, 19% had del(11q), and 20% had del(17p) and/or TP53-mutant disease. Thirty-three percent of patients in the ibrutinib cohort had a CIRS score >6 versus 31% of those treated with chemoimmunotherapy; 23% in the ibrutinib arm had CrCI <60 mL/min compared with 33% of those who received chlorambucil.

Moreover, patients with high-risk disease—which includes those with 17p deletion/TP53 mutation, 11q deletion, or unmutated IGHV—who were treated with the ibrutinib combination experienced an 85% reduction in the risk of progression or death (HR, 0.15; 95% CI, 0.09-0.27). The IRC-evaluated overall response rate (ORR) was 89% in ibrutinib/obinutuzumab arm versus 73% in the chlorambucil/obinutuzumab arm.

OS had not yet been reached in either arm (HR, 0.92; 95% CI, 0.48-1.72; P = .81). Forty-six patients (40%) on the chlorambucil arm have crossed over to treatment with ibrutinib monotherapy, Moreno added.

Ibrutinib/obinutuzumab also led to an improvement in ORR and complete response (CR) or CR with incomplete bone marrow recovery (CRi) rate when assessed by IRC and investigator assessment. In the IRC assessment, the ORR and CR/CRi rates were 88% and 19% with ibrutinib/obinutuzumab versus 73% and 8% with chlorambucil/obinutuzumab, respectively. The ORR and CR/CRi rates via investigator assessment were 91% and 41% versus 81% and 16%, respectively.

In the high-risk population, the IRC-assessed ORR rates with ibrutinib/obinutuzumab and chlorambucil/obinutuzumab were 90% and 68%, respectively; the CR/Cri rates were 14% and 4%.

The combination of ibrutinib and obinutuzumab for the first-line treatment of patients with CLL or small lymphocytic lymphoma, also based on the iLLUMINATE data, was approved by the FDA in January 2019.

For the recommendation in the WM indication, the approval was based on data from the phase III iNNOVATE (PCYC-1127) trial, which showed that the combination had an estimated 30-month PFS rate, which was assessed by an IRC, of 79% compared with 41% for those who received rituximab/placebo in patients with previously untreated and relapsed/refractory WM, at a median follow-up of 30.4 months.4,5

The double-blind, placebo-controlled, parallel assignment, randomized phase III iNNOVATE trial included 150 relapsed/refractory or treatment-naïve patients with confirmed symptomatic Waldenström macroglobulinemia. Patients were enrolled at 45 sites in 9 countries between July 2014 and January 2016.

The median patient age was 69 and 33% were aged ≥75 years. Forty-five percent of patients had not received prior therapy. Thirty-eight percent were considered high risk per the International Prognostic Scoring System for Waldenström Macroglobulinemia, and 79% of patients had extramedullary disease at baseline. Among 136 patients with available baseline mutational data, 85% had MYD88L265P mutations and 36% had CXCR4WHIM mutations.

The median number of prior therapies in patients with relapsed disease was 2 (range, 1-6), and 85% had prior rituximab. Patients who had prior rituximab had to have achieved at least a minimal response to their last rituximab-based treatment.

Patients received IV rituximab at 375 mg/m2 once weekly for 4 straight weeks, followed by another 4-week rituximab course after a 3-month interval. Ibrutinib, at 420 mg, or placebo were taken once daily continuously. PFS was the primary endpoint, with secondary endpoints including ORR, hematological improvement measured by hemoglobin, time-to-next treatment, OS, and safety.

The PFS benefit with the combination was observed across key subgroups, including previously untreated patients (HR, 0.34; 95% CI, 0.12-0.95), relapsed patients (HR, 0.17; 95% CI, 0.08-0.36), MYD88L265P/CXCR4-mutation wild-type (WT; HR, 0.17; 95% CI, 0.06-0.49), MYD88L265P/CXCR4WHIM (HR, 0.24; 95% CI, 0.09-0.66), and MYD88WT/CXCR4-mutation WT (HR, 0.21; 95% CI, 0.04-1.08).

The 24-month PFS rate in treatment-naive patients was 84% in the experimental arm versus 59% in the control arm. In relapsed patients, the 30-month PFS rates were 80% vs 22%, respectively.

In the overall population, the ORR was 92% with the ibrutinib combination versus 47% with rituximab alone (P <.0001). The major response rate (at least a partial response) was 72% versus 32%, respectively (P <.0001).

Three-fourths of patients in the combination arm remained on treatment at the data cutoff. Sustained increases in hemoglobin level occurred in 73% of the ibrutinib/rituximab group versus 41% of the rituximab-alone arm (P <.0001). The median time to next treatment was not reached for the ibrutinib arm versus 18 months for the control arm (HR, 0.096; P <.0001).

The OS rate at 30 months was 94% versus 92%, in the combination versus control arms, respectively. Dimopoulos noted that 30 patients in the control arm crossed over to receive single-agent ibrutinib.

The FDA approved this combination as a treatment option across all lines of therapy for patients with WM in August 2018.

“With five European Commission approvals in 5 years, this latest [European Commission] decision further extends the potential reach and impact ibrutinib can have for patients,” said Craig Tendler, MD, vice president, Clinical Development and Global Medical Affairs, Oncology, Janssen Research & Development, LLC. “We remain committed to a comprehensive clinical development program for ibrutinib, including exploring its use in other combinations, to address the needs of more and more patients with B-cell malignancies.”


  1. Janssen Announces European Commission Approval of Imbruvica (ibrutinib) for Expanded Use in Two Indications. Janssen. Published August 13, 2019. https://yhoo.it/2yUYabx. Accessed August 13, 2019.
  2. Moreno C, Greil R, Demirkan F, et al. Ibrutinib + obinutuzumab versus chlorambucil + obinutuzumab as first-line treatment in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL): results from phase 3 iLLUMINATE. Presented at: 2018 ASH Annual Meeting; December 1 to 4, 2018; San Diego, California. Abstract 691.
  3. Moreno C, Greil R, Demirkan F, et al. Ibrutinib plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicenter, randomized, open-label, phase 3 trial [published online ahead of print, December 3, 2018]. Lancet Oncol. doi: 10.1016/S1470-2045(18)30788-5.
  4. Dimopoulos MA, Tedeschi A, Trotman J, et al. Randomized phase 3 trial of ibrutinib/rituximab vs placebo/rituximab in Waldenström's macroglobulinemia. J Clin Oncol. 2018;36 (suppl; abstr 8003).
  5. Dimopoulos MA, Tedeschi A, Trotman J, et al. Phase 3 trial of ibrutinib plus rituximab in Waldenström’s macroglobulinemia [published online June 1, 2018). N Engl J Med. doi: 10.1056/NEJMoa1802917.