Ibrutinib has a favorable therapeutic index, which may facilitate its use in combination with other agents for the treatment of CLL. However, the durable remissions obtained thus far suggest that many patients may be treated successfully with monotherapy.
—John C. Byrd, MD, and colleagues
Durable remissions are uncommon with current treatments for relapsed chronic lymphocytic leukemia (CLL). Bruton’s tyrosine kinase is an essential component of B cell–receptor signaling that mediates interactions with the tumor microenvironment and promotes survival and proliferation of CLL cells. Ibrutinib is a first-in-class oral covalent inhibitor of Bruton’s tyrosine kinase designed for treatment of B-cell cancers. As reported in The New England Journal of Medicine, John C. Byrd, MD, of Ohio State University, and colleagues found that ibrutinib treatment produced high rates of durable responses in patients with relapsed or refractory CLL or small lymphocytic lymphoma.1
In a phase Ib/II multicenter study, 85 patients with relapsed or refractory CLL (n = 82) or small lymphocytic lymphoma received oral ibrutinib once daily at 420 mg (n = 51) or 840 mg (n = 34) continuously until disease progression or unacceptable toxicity. Patients had a median age of 66 years, 76% were male, the median number of prior therapies was 4, and the median time since last treatment was 3 months (range, 1–98 months). The most common prior treatments were rituximab (Rituxan, 98%), nucleoside analogs (95%), and alkylators (89%).
Most patients (65%) had high-risk disease (Rai stage III or IV) and unmutated immunoglobulin variable-region heavy-chain genes (81%). Bulky nodes of ≥ 5 mm and ≥ 10 mm in diameter were present in 52% and 15% of patients, respectively. Interphase cytogenetic abnormalities consisted of 17p13.1 deletion in 33% and 11q22.3 deletion in 36%.
High Response Rate and Survival
Response occurred in 36 (71%) of 51 patients in the 420-mg group (2 complete responses and 34 partial responses) and 24 (71%) of 34 in the 840-mg group (24 partial responses). In addition, 10 patients (20%) in the 420-mg group and 5 (15%) in the 840-mg group had a partial response with persistent lymphocytosis. Response was independent of clinical and genomic risk factors present before treatment, including advanced-stage disease, number of previous therapies, and the 17p13.1 deletion.
At 26 months, the estimated progression-free survival rate was 75% and the overall survival rate was 83%. Among patients with 17p13.1deletion, estimated 26-month progression-free survival was 57% and overall survival was 70%.
At a median follow-up of 20.9 months (range, 0.7–26.7 months), 64% of patients were still receiving treatment. Reasons for treatment discontinuation included disease progression in 13% of patients, patient or investigator decision in 15% (with 5 of these 13 patients subsequently undergoing stem cell transplantation), and adverse events in 7 patients (8%), including 3 with pneumonia, 2 with sepsis, 1 with staphylococcal bacteremia without signs of sepsis, and 1 with gastrointestinal hemorrhage.
Disease progression occurred in 11 patients (13%) during follow-up, with 7 having progression by biologic transformation. The median time from diagnosis to transformation was 98 months (range, 24–143 months). Among these 11 patients, 10 had a 17p13.1 or 11q22.3 deletion and 1 had no high-risk cytogenetic abnormalities.
Rising blood lymphocytosis was observed by day 7 in 78% of the patients, peaked at a median of 4 weeks, and then slowly declined. In 50 (79%) of 63 evaluated patients, the lymphocyte count normalized or was reduced by 50% from the baseline level. Increasing lymphocytosis developed in similar proportions of patients with unmutated vs mutated immunoglobulin variable-region heavy-chain genes (77% vs 83%), although lymphocyte counts normalized more rapidly (median, 6.4 vs 14.8 months) and more frequently (in 85% vs 50%) in those with unmutated immunoglobulin genes. Increasing lymphocytosis was associated with notable reductions in lymph node and spleen size and frequent improvement in cytopenias.
Favorable Toxicity Profile
Toxic effects were predominantly grade 1 or 2. The most common adverse events of any grade were diarrhea (49%), upper respiratory tract infection (33%), fatigue (32%), and cough (31%). The most common grade 3 or 4 nonhematologic adverse events were pyrexia, hypertension, and sinusitis, each occurring in 5% of patients. Grade 3 or 4 hematologic toxic effects consisted of neutropenia in 15% of patients, anemia in 6%, and thrombocytopenia in 6%. Neutropenia did not require treatment discontinuation and was managed with growth factor treatment in 5 of 13 patients. Bleeding events of grade 3 or higher occurred in 4 patients. A total of 8 patients died within 30 days after receiving the last dose of ibrutinib, 3 due to pneumonia, 1 from systemic inflammatory response, 1 from sarcoma, and 3 from CLL progression.
The authors concluded, “Ibrutinib was associated with a high frequency of durable remissions in patients with relapsed or refractory CLL and small lymphocytic lymphoma, including patients with high-risk genetic lesions.”
They further noted, “Ibrutinib has a favorable therapeutic index, which may facilitate its use in combination with other agents for the treatment of CLL. However, the durable remissions obtained thus far suggest that many patients may be treated successfully with monotherapy. Randomized clinical trials of ibrutinib in patients with CLL or small lymphocytic lymphoma are ongoing.” ■
Disclosure: The study was supported Pharmacyclics, Janssen, and others. For full disclosures of the study authors, visit www.nejm.org.
1. Byrd JC, Furman RR, Coutre SE, et al: Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med 369:32-42, 2013.