Simon Rule, MD, PhD
Despite advancements in treatment strategies for mantle cell lymphoma (MCL), patients experience diminishing responses from sequential lines of therapy as their disease progresses, sharpening the focus on developing new agents and combinations.1
In the realm of targeted therapies, researchers are continuing to explore novel agents that inhibit activity of Bruton tyrosine kinase (BTK), BCL-2, and phosphoinositide 3-kinase (PI3K).2
Emerging therapies also include immunotherapeutic regimens using immune checkpoint inhibitors and T-cell– based adoptive immunotherapy.3
According to David Tucker, MD, and Simon Rule, MD, “In addition to improvements in immunochemotherapy, a succession of new molecular targets and corresponding drugs has revolutionized MCL therapy. The best way to sequence and combine these agents with existing regimens and how to overcome the problem of drug resistance represent new challenges in this rapidly developing field.”4
The potential synergy of these new agents with other treatment strategies, including immunotherapeutic and targeted approaches, is currently being investigated in various clinical trials, with the hope of identifying combinations that will lead to longer responses and improvements in duration of response (DOR) for patients with MCL.
Ibrutinib (Imbruvica) is a potent orally bioavailable inhibitor of BTK that binds irreversibly to the cysteine residue (C481) at the phosphorylation site of BTK, leading to irreversible inactivation and disruption of the signaling pathway from the B-cell receptor (BCR) to the nucleus.4
The BCR signaling pathway plays a crucial role in cell division, differentiation, homing, and survival.5
In 2013, the FDA approved ibrutinib as monotherapy for patients with MCL who have received at least 1 prior therapy. The efficacy and safety of single-agent ibrutinib demonstrated in the relapsed or refractory (R/R) setting has led to considerable interest in sequencing and combination regimens with other agents.4
The combination of ibrutinib and rituximab (Rituxan) was evaluated in a phase II singlecenter open-label trial of 50 patients with R/R MCL.6
Preliminary trial results show this combination to be well tolerated and highly effective in patients with Ki-67 ˂50% who achieved an objective response rate (ORR) of 100% and a complete remission (CR) rate of 54%. However, response was substantially reduced in patients with Ki-67 ˃50% who had an ORR of 50% and a CR rate of 8%. Atrial fibrillation (AF) was noted in 6 patients (12%) and was the only grade 3 adverse event (AE) occurring in more than 10%. Two grade 4 AEs were also reported (1 each of diarrhea and neutropenia).
Previous studies have demonstrated that ibrutinib monotherapy and combination therapy with lenalidomide (Revlimid) plus rituximab have high activity in MCL.7,8
Based on these results, the combination of ibrutinib, lenalidomide, and rituximab was explored in the phase II open-label PHILEMON trial of patients with R/R MCL.9
A total of 50 patients were enrolled and received induction therapy with rituximab, ibrutinib, and lenalidomide for up to 12 cycles. Patients who had a CR, partial response (PR), or stable disease entered a maintenance phase, with treatment consisting of ibrutinib and rituximab only. After a median follow-up of 17.8 months, the ORR was 76% and the CR rate was 56%. The most common grade ≥3 AEs included neutropenia (38%), infection (22%), and cutaneous toxicity (14%).
Palbociclib (Ibrance) is an oral, specific CDK4/6 inhibitor that has demonstrated cytotoxicity against the mutated BTKC481S protein.10
Prolonged early G1 cell-cycle arrest induced by palbociclib can overcome ibrutinib resistance in primary human samples and MCL cell lines with wild-type BTK.11
Adding palbociclib to ibrutinib could help deepen the response seen with ibrutinib through dual CDK 4/6 and BTK inhibition in MCL.
Martin and colleagues12
conducted a phase I dose-escalation study to evaluate the safety and preliminary activity of palbociclib plus ibrutinib in patients with previously treated MCL. Phase I data suggest that this is an active combination in patients with MCL. Twelve of 18 patients (67%) responded to treatment and 8 (44%) achieved CR. After a median follow-up of 14 months, the rate of progression-free survival (PFS) at 1 year was 61%; only 1 patient had disease progression. Grade 3 cutaneous toxicity was observed at the highest dosage (ibrutinib 560 mg/palbociclib 125 mg); otherwise, grade 1/2 myelosuppression was the most common AE.