Chemotherapy-free induction in MCL: ready for prime time?

In this issue of Blood, Ruan et al report on the 5-year follow-up of a multicenter phase 2 study in patients with previously untreated mantle cell lymphoma (MCL) who received the nonchemotherapy combination regimen of rituximab and lenalidomide as induction and maintenance therapy.¹ 

Initial treatment of MCL represents a unique challenge to physicians, given that there is no standard first-line therapy. Despite improvements in survival with current treatment approaches, MCL remains incurable. Treatment selection for an individual considers patient factors such as age and comorbidities and lymphoma features, including extent of disease burden and disease biology. The most commonly used induction approach includes chemoimmunotherapy often followed by consolidation with autologous stem cell transplantation and/or rituximab maintenance, which has shown the greatest impact on the duration of remission. These intensive approaches are associated with treatment-related toxicities that render them intolerable in patients with impaired organ function, poor performance status, or advanced age in a disease in which median age at diagnosis is 65 years. Establishing first-line regimens that prolong disease remission while minimizing unacceptable toxicities remains a priority, especially in those patients not considered candidates for aggressive treatment or those with high-risk disease features who have inferior outcomes despite aggressive treatment. Ruan et al designed this phase 2 study of lenalidomide and rituximab (LR) as an alternative regimen to that of standard chemoimmunotherapy in patients with untreated MCL.

Ruan et al²  previously reported interim results of their multicenter phase 2 trial in untreated MCL with LR induction followed by LR maintenance. The study enrolled 38 patients across 4 sites. At a median follow-up of 30 months, the LR combination had a 92% overall response rate (ORR) and 64% complete response (CR) rate in 36 evaluable patients. Median progression-free survival (PFS) was not reached; 2-year PFS was 85% and 2-year overall survival (OS) was 97%. Responses were independent of high-risk disease features, including MCL International Prognostic Index and Ki-67 proliferation index. These results were impressive in the context of median PFS reported with standard chemoimmunotherapy regimens in a comparable patient population,^3,4  which provided a rationale for further development of nontraditional induction regimens. However, the durability of the regimen remained uncertain.

In the article by Ruan et al in this issue, the authors provide longer-term data on the LR combination. With a median follow-up of 64 months, LR continued to be well tolerated, and reported adverse events occurred with less frequency and severity in the maintenance phase than previously reported with induction. Median PFS was not reached. Three-year PFS was estimated at 80.3% and 5-year PFS was estimated at 63.9%; 3-year OS was 89.5% and 5-year OS was 77.4%. Although this combination treatment was not prospectively studied, the authors were able to show that it produced minimal residual disease negative state in a subset of patients achieving CR.

Several novel targeted therapies have proven highly effective in relapsed/refractory MCL, leading to US Food and Drug Administration (FDA) approval, including the oral Bruton’s tyrosine kinase inhibitors ibrutinib⁵  and acalabrutinib,⁶  the proteasome inhibitor bortezomib,⁷  and the oral immunomodulatory agent lenalidomide.^8,9  Lenalidomide received FDA approval based on studies demonstrating activity in this patient population, with the largest study having an ORR of 35%⁸  when used as single-agent therapy, which increased to 57% when used in combination with rituximab.⁹ 

The efficacy and safety of these therapies in relapsed MCL have resulted in prioritizing the incorporation of these agents into initial therapy regimens, including both induction and maintenance strategies. Although several clinical trials are investigating these agents in combination with standard chemoimmunotherapies (NCT02427620, NCT02427620, NCT01415752, NCT01776840, NCT01972840, and EudraCT Number 2012-002542-20), Ruan et al present long-term follow-up data on the first nonchemotherapy based induction and maintenance regimen for MCL. Although only 38 patients were treated, the 5-year PFS of the regimen was notable when considering that of some of the more intensive chemotherapy regimens,¹⁰  which raises the possibility that aggressive chemotherapy may not be the optimal approach in all patients, despite their ability to tolerate such therapy. An ongoing phase 2 trial of LR in combination with ibrutinib (NCT03232307) may further improve on this regimen’s efficacy and durability, but the expense to toxicity remains to be seen. Ultimately, a randomized study and a larger number of patients treated will be required before universally adapting an entirely chemotherapy-free approach to MCL in the first-line setting. However, in a disease that is incurable with standard therapies, the success of these regimens should not rely on their ability to achieve superior efficacy to chemotherapy but instead should rely on their ability to provide an alternative effective therapy that is well tolerated in the vast majority of patients.