Acalabrutinib with lenalidomide and rituximab for R/R aggressive B-cell non-Hodgkin lymphoma

Rituximab plus chemoimmunotherapy has improved outcomes for patients with CD20⁺ aggressive B-cell non-Hodgkin lymphoma (NHL), including diffuse large B-cell lymphoma (DLBCL); however, a significant portion of patients relapse. While chimeric antigen receptor T-cell therapy has demonstrated efficacy in patients with relapsed/refractory (R/R) DLBCL, alternative strategies are being explored due to the potential financial burden of this treatment.¹ The combination of Bruton's tyrosine kinase inhibitors with lenalidomide and rituximab could be an effective regimen for patients with R/R aggressive B-cell NHL.¹

Park et al.¹ recently published results from a phase II trial (NCT04094142) assessing the safety and efficacy of acalabrutinib, a Bruton's tyrosine kinase inhibitor, in combination with lenalidomide and rituximab (R2A regimen) in patients with R/R B-cell NHL in Nature Communications. Below, we summarize the key findings.

Study design and patient population¹

• This was an open-label, single-arm phase II trial.
• Patients received 375 mg/m² rituximab intravenously on Day 1, 20 mg lenalidomide orally once daily on Days 1–21, and 100 mg acalabrutinib orally twice daily on Days 1–28, repeated every 4 weeks for up to 6 cycles.
  • Patients with a response could receive acalabrutinib monotherapy as maintenance therapy for up to one year.
• The primary endpoint was the objective response rate (ORR).

Key findings¹

Patient characteristics

• In total, 66 patients received treatment, most of whom had DLBCL (Table 1).
• The median age was 67.5 years (range, 20–87).

Table 1. Pathological diagnosis of patients treated with R2A regimen*

Pathological diagnosis, %	Patients (n = 66)
DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; GCB, germinal center B-cell type; non-GCB, non-germinal center B-cell type; NOS, not otherwise specified; PCNSL, primary central nervous system lymphoma; PMBCL, primary mediastinal B-cell lymphoma; R2A, acalabrutinib with lenalidomide and rituximab. *Adapted from Park, et al.1
DLBCL, non-GCB	71.2
DLBCL, GCB	16.7
DLBCL, NOS	4.5
PCNSL	3.0
PMBCL	3.0
FL	1.5

Efficacy

• The ORR and complete remission rate were 54.5% and 31.8%, respectively (Figure 1).
  • The ORR and complete remission rate were not significantly different between patients with non-germinal center B-cell type DLBCL and germinal center B-cell type DLBCL (p = 0.179 and p = 0.310, respectively; Figure 1).
• The median duration of response was 12.9 months and median progression-free survival was 4.4 months.
• The 1-year progression-free survival and overall survival rates were 33.1% and 67.5%, respectively.
• In total, seven patients had MYD88 mutations, and the median progression-free survival among these patients was 4.5 months.

DLBCL, diffuse large B-cell lymphoma; GCB, germinal center B-cell; NOS, not otherwise specified; R2A, acalabrutinib with lenalidomide and rituximab.
*Data from Park et al.¹ 

Safety

• In total, 39 patients experienced adverse events, most commonly neutropenia (n = 21), skin rash (n = 17), thrombocytopenia (n = 6), and pruritus (n = 6).

Key learnings
The R2A regimen was well tolerated and showed high efficacy in patients with R/R aggressive B-cell NHL. In addition, exploratory analysis showed that patients with MYD88 mutations responded well to the R2A regimen.