Lenalidomide Response in Relapsed/Refractory Aggressive Non-Hodgkin’s Lymphoma Is Related to Tumor Burden and Time from Rituximab Treatment.
Authors: Wiernik Peter H. , Lossos Izidore S. , Tuscano Joseph M. , Justice Glen , Vose Julie M. , Cole Craig E. , McBride Kyle , Wride Kenton , Pietronigro Dennis , Takeshita Kenichi , Ervin-Haynes Annette , Zeldis Jerome B. , Habermann Thomas M. 
Published: April 2020

Abstract
Background: Lenalidomide (Revlimid®) has been reported to show activity in non-Hodgkin’s Lymphoma (NHL). However, prognostic factors predicting an individual patient’s response were unavailable.
Aim: To investigate prognostic factors for lenalidomide response in patients with relapsed/refractory aggressive NHL.
Methods: Patients with relapsed/refractory aggressive NHL with measurable disease ≥2 cm after at least 1 prior treatment regimen were eligible. Patients received 25 mg lenalidomide orally once daily on Days 1-21 every 28 days and continued therapy for 52 weeks as tolerated or until disease progression. Response and progression were evaluated using the IWLRC methodology. Univariate analyses using Fisher’s exact test and multivariate analyses using logistic regression were conducted to investigate associations of prognostic variables with response.
Results: Forty-nine patients received lenalidomide oral monotherapy. The median age was 65 (23-86) and 24 were female. Histology was diffuse large B-cell lymphoma (n=26), follicular center lymphoma grade 3 (n=5), mantle cell lymphoma (n=15) and transformed (n=3). Median time from diagnosis was 2.7 (0.4-32) years and median number of prior treatment regimens was 4 (1-8). Forty-five (92%) of the patients had received prior rituximab and 63% were rituximab-refractory. Seventeen patients (35%) exhibited an objective response (2 complete responses, 4 complete responses unconfirmed and 11 partial responses). Response to lenalidomide was the same for patients who were refractory to rituximab (30%) and those who were not (31%). Three of 4 patients who were rituximab naive responded. Multivariate analysis including IPI, ECOG PS, stage, LDH, # of extranodal sites, age, sex, # of prior regimens and time from diagnosis identified only time since last rituximab and tumor burden as correlated with response. Response to lenalidomide was associated with low tumor burden (52% for &lt;50 cm2v 0% for ≥50 cm2, P=0.033, odds ratio=10.9) and longer time from rituximab to lenalidomide treatment (52% for ≥ 230 days v 6% for &lt;230 days, P=0.031, odds ratio=6.6). Rituximab depletes normal host B-cells and the kinetics for their loss and recovery are consistent with the timing of lenalidomide activity following rituximab. This may be a basis for this effect. However other tumor/host biological factors may also play a role. Patients with favorable values for both prognostic factors (N=24) had a 67% response rate [RR] compared to a 4% RR for patients with unfavorable values (N=25; P&lt; 0.001) and a progression free survival (ongoing) of 7.5 months v 1.9 months. Although absolute lymphocyte count was not selected as a prognostic indicator of response in the multivariate setting, a trend was evident in the univariate analysis (42% for &gt; 0.6 × 109/L v 9% for ≤0.6 × 109/L, P=0.071).
Conclusion: Tumor burden and host immune competence may determine the response of relapsed/refractory aggressive NHL to lenalidomide monotherapy.