Ibrutinib Promising as Initial Therapy for Elderly Patients With CLL in Phase IB/II Trial


Key Points

  • Objective response was achieved in 71% of patients.
  • Three grade 3 infections, one case of grade 3 neutropenia, and one case of grade 4 thrombocytopenia were observed.

Chemoimmunotherapy has produced improved response and survival in young patients with chronic lymphocytic leukemia (CLL), but its use in elderly patients has been limited by myelosuppression and infection. In a phase IB/II study reported in The Lancet Oncology, O’Brien et al assessed the use of the Bruton's tyrosine kinase inhibitor ibrutinib (Imbruvica) in previously untreated patients aged ≥ 65 years with CLL. Treatment was associated with a high response rate and low rates of severe infection and myelosuppression.

Study Details

In the study, 31 previously untreated patients from U.S. sites were enrolled between May 2010 and December 2012 and were treated with 28-day cycles of once daily ibrutinib at 420 mg or 840 mg; the 840-mg dose was discontinued because comparable activity of the two doses had been demonstrated.

Patients had a median age of 71 years (range, 65–84 years; 23 ≥ 70 years), 61% were male, 94% had CLL and 6% had small lymphocytic lymphoma, 26% had Rai stage I disease and 35% had Rai stage IV, and 74% had Eastern Cooperative Oncology group performance status of 0. Nineteen percent of patients had bulky nodes; 55% had del(13q14) interphase cytogenetics; 3%, 35%, and 39% had neutropenia, anemia, and thrombocytopenia; 26% had β2 microglobulin > 3 mg/L; 29% had lactate dehydrogenase ≥ 350 U/L; and 45% had methylated Zap-70.

A total of 27 patients received ibrutinib at 420 mg, and four received ibrutinib at 840 mg. Median treatment duration was 21.0 months.


After median follow-up of 22.1 months, objective response had occurred in 22 patients (71%), including complete response in 4 patients (13%), nodular partial response in 1 (3%), and partial response in 17 (55%); an additional 4 patients (13%) had partial response with lymphocytosis, and 3 (10%) had stable disease. The mean time to response was 2.7 months (median, 1.9 months).

Progression occurred in only one patient, with del(17p13.1), who achieved response at 3.7 months and developed Richter’s transformation at 9.6 months. The patient was treated with oxaliplatin, fludarabine, cytarabine, and rituximab (Rituxan) after stopping ibrutinib and died of progressive disease 113 days after stopping ibrutinib; this patient was the only patient to die on the study. Overall, 26 patients (84%) continued ibrutinib treatment in a long-term extension study.


The most common adverse events of any grade were diarrhea (68%), nausea (48%), fatigue (32%), hypertension (29%), and peripheral edema (29%). Grade 3 toxicity consisted of diarrhea (13%), hypertension (6%), and neutropenia, fatigue, dizziness, urinary tract infection, headache, and back pain (one patient, 3% each). Grade 4 adverse events consisted of thrombocytopenia in one patient (3%). Three patients (10%) had grade 3 infections and no infections of higher grade were observed.

Two patients (6%) discontinued treatment due to adverse events (grade 3 fatigue and grade 2 viral infection) and 29% had treatment interrupted due to grade 3 or higher toxicity. Two patients withdrew consent, one to start a new treatment because of insufficient improvement. Nine (29%) of 31 patients had treatment interrupted due to grade 3 or greater toxicity.

The investigators concluded, “The safety and activity of ibrutinib in elderly, previously untreated patients with symptomatic chronic lymphocytic leukaemia, or small lymphocytic lymphoma is encouraging, and merits further investigation in phase [III] trials.”

Susan O’Brien, MD, of The University of Texas MD Anderson Cancer Center, is the corresponding author for The Lancet Oncology article.

The study was supported by Pharmacyclics, Leukemia and Lymphoma Society, D. Warren Brown Foundation, Mr. and Mrs. Michael Thomas, and Harry Mangurian Foundation. For full disclosures of the study authors, visit

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