Treatment of mantle cell lymphoma continues to evolve, both in the front-line and relapsed settings. Key advances include better use of established agents, such as the incorporation of high-dose cytarabine into initial induction regimens and application of rituximab (Rituxan) consolidation/maintenance following response to initial therapy. More excitement has been generated by new, and now not so new, targeted agents with demonstrated activity in the relapsed setting. They are quickly being moved into earlier lines of therapy in combination with, or replacing, standard cytotoxic immunochemotherapy.
New Targeted Agents
For patients with previously treated mantle cell lymphoma, there are now four approved drugs, including bortezomib (Velcade), lenalidomide (Revlimid), and ibrutinib (Imbruvica) in the United States and ibrutinib and temsirolimus (Torisel) in Europe. The proteasome inhibitor bortezomib was approved almost a decade ago as treatment for relapsed or refractory mantle cell lymphoma based on the single-arm phase II PINNACLE trial, demonstrating an overall response rate of 33%, median time to progression of 6 months, and median duration of response of 9 months.
The immune-modulatory agent lenalidomide was approved for treatment of bortezomib-exposed mantle cell lymphoma patients based on the single-arm phase II EMERGE trial, with a response rate of 28%, median time to progression of 4 months, but median duration of response of 17 months.
The mTOR inhibitor temsirolimus was approved in Europe based on the randomized three-arm phase III trial of temsirolimus at two different doses vs investigator’s choice of single-agent chemotherapy. In that study, temsirolimus was administered weekly at 175 mg for 3 weeks, then weekly at either 25 mg or 75 mg. In the 175/75 cohort, the response rate was 22%, median progression-free survival was 5 months, and median duration of response was 5 months.
Most recently, the Bruton tyrosine kinase inhibitor ibrutinib has been approved for relapsed/refractory mantle cell lymphoma based on a single-arm phase Ib/II trial, with a response rate of 67%, median progression-free survival of 14 months, and median duration of response of 18 months. These trial outcomes cannot be directly compared given differences in patient populations, including age and number and types of prior therapy, but certainly the sense is that the ibrutinib response rates and duration were superior to those of the other agents.
Phase III Study of Ibrutinib vs Temsirolimus
As summarized in this issue of The ASCO Post, Dreyling and colleagues recently reported the first phase III randomized trial comparing any of these approved single agents in relapsed or refractory mantle cell lymphoma—in this case, the two approved in Europe, ibrutinib and temsirolimus.1 The study enrolled patients with mantle cell lymphoma who had received at least one prior rituximab-chemotherapy regimen (median number of prior regimens was two). Notable strengths of the study include the phase III design and the international cooperation and rapid accrual (280 patients in < 1 year), making this a contemporary trial. The median age of 68 years suggests a “real-world” patient cohort, although all had an Eastern Cooperative Oncology Group performance status of 0 or 1. Central review of pathology was another vital component.
The response rate was 72% with ibrutinib vs 40% with temsirolimus. For the primary endpoint, median progression-free survival was 14.6 vs 6.2 months. Median duration of response was not yet reached for ibrutinib; response of ≥ 18 months occurred in 58% of ibrutinib responders vs 20% of temsirolimus responders. An important component of this study was acquisition of patient-reported outcomes on the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) scale, demonstrating faster and more marked improvement with ibrutinib treatment. Thus, the improved outcomes with ibrutinib, assessed as response rate, progression-free survival, and duration of response, also improve quality of life.
Key Implications
These data clearly support the already generally accepted concept of ibrutinib as the better choice for therapy in patients with previously treated mantle cell lymphoma. Although not surprising, the results of this trial are important, since phase III trials do not always confirm early-phase data in terms of efficacy or toxicity. It is comforting that in this study the response, progression-free survival, and duration of response outcomes in the ibrutinib group closely match the phase Ib/II data, and no new safety signals were observed. Further, the FACT-Lym data are new. We should also not ignore the temsirolimus data, since a 40% response rate in a rigorously designed and executed phase III trial represents significant activity in 139 patients (only 54 patients were treated with this temsirolimus dose in the trial leading to approval in this setting). This implicates PI3K/AKT/mTOR as useful targets in mantle cell lymphoma, as new agents affecting this pathway reach the clinic.
There are other bits of informative data in this report. Importantly, patients with mantle cell lymphoma or chronic lymphocytic leukemia (CLL) who came off or “failed” ibrutinib in early studies have very poor outcomes, with survival measured in months and concerns for aggressive disease such as Richter’s transformation in CLL and blastoid mantle cell lymphoma. Whether this was due to the heavy pretreatment in patients in those studies or some biologic selection for aggressive clones has not been clear. Supplementary data (Figure 3) in the Dreyling et al report demonstrate encouraging second progression-free survival (ie, time from the start of therapy to progression after the next therapy) in the ibrutinib group, which exceeded that observed in the temsirolimus group. This finding suggests that ibrutinib “failure” does not necessarily confer dismal prognosis in this perhaps less heavily pretreated population. In addition, subgroup analysis, though with small numbers, suggests that patients with blastoid mantle cell lymphoma remain an unmet need, having poor outcomes even with ibrutinib. Note that presumably they were blastoid at diagnosis, as we have disappointingly few data on serial biopsies of mantle cell lymphoma; such data will become very important to collect as patients cycle through different targeted therapies.
Ibrutinib is a marvelous addition to mantle cell lymphoma treatment options. There remains room for improvement, however, as mantle cell lymphoma in one of three patients does not respond to ibrutinib, and with median follow-up of 20 months fewer than 50% of patients remain on ibrutinib therapy. We await additional data on combination regimens in the relapsed as well as front-line settings. ■
Disclosure: Dr. Smith has received research support from Abbvie and is on the advisory boards of Celgene, Genentech, and Seattle Genetics.
Reference
1. Dreyling M, Jurczak W, Jerkeman M, et al: Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: An international, randomised, open-label, phase 3 study. Lancet. December 4, 2015 (early release online).
Dr. Smith is Director, Lymphoid Malignancy Program, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
