The combination of ibrutinib and rituximab is a promising treatment option for patients with relapsed or refractory blood cancers, according to results of two studies presented at the 56th ASH Annual Meeting.
“Ibrutinib as a single agent is well known to cause a redistribution lymphocytosis during the first months of therapy, due to mobilization of [abnormal] cells from the tissue sites into the peripheral blood,” said Ekaterina Kim, MS, from the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston. Dr. Kim and other investigators targeted this transient lymphocytosis with the anti-CD20 monoclonal antibody rituximab, with the hopes of improving ibrutinib efficacy in relapsed/refractory lymphoma or leukemia.
“For patients who need this drug, it is a lifesaver,” said Mitchell Smith, MD, PhD, in his discussion of ibrutinib during the Special Education Session on Newly Approved Drugs. “At this point, a lot of patients with CLL and MCL are in remission from their previous therapy and ibrutinib is in our back pocket, waiting for that patient to need therapy.”
Ibrutinib + Rituximab in Relapsed/Refractory MCL
In a single-center, phase 2 trial of 50 relapsed or refractory mantle cell lymphoma (MCL) patients, the ibrutinib + rituximab combination was found to be efficacious and well tolerated. At an oral abstract presentation, Michael Wang, MD, from the Department of Lymphoma/Myeloma at The University of Texas MD Anderson Cancer Center presented data from 46 evaluable patients after a median follow-up of 11 months.
Patients enrolled in the study had an overall response rate (ORR) of 88 percent, including a complete response rate (CR) of 40 per, adding to data for single-agent ibrutinib in relapsed/refractory MCL previously reported by Dr. Wang and colleagues (68% ORR; 21% CR). The median duration of response and progression-free survival (PFS) have yet to be reached.
The study also identified the Ki-67 protein, a known marker of cell proliferation, as a potential predictor of response. All 34 patients with lower levels of baseline Ki-67 (<50%) responded to combination treatment, including 56 percent experiencing CR and 44 percent experiencing partial response (PR). In contrast, the subgroup of 12 patients with higher baseline Ki-67 (≥50%) exhibited an ORR of 50 percent, including 8 percent with CR and 42 percent with PR.
Grade 1 hematologic adverse events included anemia (30%) and thrombocytopenia (25%). The most common (>15%) treatment-related, non-hematologic adverse events included fatigue, diarrhea, myalgia, and dyspnea. There were no deaths due to treatment.
Combination Therapy in CLL
The ibrutinib + rituximab combination may also benefit patients with relapsed chronic lymphocytic leukemia (CLL), according to preliminary findings from a multi-center, randomized, phase Ib/II trial presented in a poster session by Ms. Kim.
Ibrutinib has shown high single-agent efficacy in CLL, and response rates are improved when combined with rituximab. “However, the added benefit of combination therapy versus single-agent ibrutinib has not previously been tested side-by-side,” said Ms. Kim.
After four months of follow-up, the combination therapy group experienced a more rapid decrease in absolute lymphocyte count, compared with the ibrutinib single-agent arm. Further analyses of biomarker response and PFS are ongoing.
“The addition of rituximab in the combination therapy arm substantially shortened [the] initial, ibrutinib-induced lymphocytosis – presumably due to rituximab promoting a faster clearance of leukemic B cells from the peripheral blood,” Ms. Kim told ASH Clinical News. “A key question for the coming years will be whether achieving earlier responses and higher response rates with ibrutinib combination therapy, for example with ibrutinib plus rituximab, translates into higher durability of responses.”
So, how does ibrutinib fit into the current treatment landscape for CLL? “At first glance, we might think, ‘This is a pill, this is easy – we should give it to everyone,’” said Dr. Smith. “However, many patients with low-grade CLL are going to survive for 10 to 20 years. The issue is: do we want patients to be on a pill for the rest of their lives with all of these concerns that we don’t fully understand?”
Quality of life and patient preference will play a large role in treatment decision, he added. “I will feel better in five years, when I know that we have not seen any big surprises with long-term therapy. We need to weigh the risks and benefits of a short, six-month intensive chemotherapy treatment – and a long time off treatment – against the unknown toxicities with long-term ibrutinib treatment.”
- Wang M, Hagemeister F, Westin JR, et al. “Ibrutinib and rituximab are an efficacious and safe combination in relapsed mantle cell lymphoma: preliminary results from a phase II clinical trial.” Abstract #627. Presented at the American Society of Hematology Annual Meeting, December 8, 2014.
- Kim E, Werner L, Keating MJ, et al. “Addition of rituximab abrogates ibrutinib-induced lymphocytosis and promotes more rapid decrease in absolute lymphocyte counts in patients with relapsed chronic lymphocytic leukemia.” Abstract #1998. Presented at the American Society of Hematology Annual Meeting, December 8, 2014.