Salvage Treatment with Lenalidomide and Dexamethasone In Patients with Relapsed Refractory Mantle Cell Lymphoma: Clinical Results and Modifications of Angiogenic Biomarkers

Previous in vivo and in vitro studies have highlighted the activity of Lenalidomide (Len) in patients with relapsed or refractory mantle cell lymphoma (MCL), achieving a 53% overall response rate (ORR), which included 20% complete responses (CR) (Habermann et al. Br J Haematol. 2009) and the possible synergistic anti-proliferative effect of Dexamethasone (Dex).

On this basis we performed a prospective, multicenter, phase II study, to evaluate safety and efficacy of Len Dex combination for adult patients with MCL.

Patients had to have ≥1 prior treatment regimen, and were either not eligible for, or had relapsed after, more intensive treatments including stem cell transplantation (SCT). During the induction phase (month 1 to 3), patients received Len 25 mg/day on days 1 to 21 and Dex 40 mg/day on days 1, 8, 15, 22 of a 28-day cycle (Len Dex). Enoxaparin 4000 U/day was administered as anti-thrombotic prophylaxis. Patients who achieved a partial response (PR) or stable disease (SD) at the end of the induction phase continued to the consolidation phase, which consisted of treatment with Len Dex until disease progression or unacceptable toxicity, for a maximum of 12 months. Patients with a CR at the end of the induction phase, or those who achieved a CR during consolidation, received an additional 3 courses of Len Dex. The primary objective was to evaluate the ORR and CRR. Response data were correlated with the modification of angiogenic biomarkers by analyzing immunohistochemistry macrophage infiltration and the bone marrow (BM) microvessel counts, and by measuring plasma levels of VEGF, bFGF and HGF before and after therapy.

Between July 2008 and July 2009, 33 patients were enrolled on this study. Patients' median age is 68 years (range 51–80); 30 have the classic histology while 3 patients have the blastoid variant; 10 patients previously received two lines of therapy, 10 patients had three lines and 13 patients had >3 prior lines (median 3; range 1–7). Twelve patients previously underwent an autologous SCT and 8 received prior therapy with Bortezomib. The number of patients who responded to induction phase was: OR= 22 (67%) including 5 CR (15%), SD= 1 (3%), no response (NR) or progression (PD)= 10 (30%); OR in patients previously treated with Bortezomib or an autologous SCT was 50% each. At present, 13 patients completed the therapeutic program, 15 discontinued therapy prematurely (14 NR or PD, 1 poor compliance) and 5 remain on therapy. The final response status at the end of the therapeutic program is: OR= 18 patients (55%) including 8 CR (24%), NR/PD= 15 (45%). After a median follow-up of 6 months (range 3–13 months) from the end of therapy, none of the CR patients had subsequent progression while 2 PR patients had progression 7 and 10 months after the end of therapy. The macrophage counts increased significantly in the BM after the first three months of therapy (P < 0.01; r²=0,8927). This was parallel to a significant increase in the microvessel counts (P < 0.05, r²= 0,1547). The within-group comparisons showed that both counts were always significantly correlated (P < 0.001). Regarding angiogenic plasma biomarkers, preliminary data of bFGF, VEGF and HGF concentrations showed a trend, albeit not significant, to decrease after the first three cycles of therapy. Most common Grade 3–4 adverse events were hematologic and included neutropenia (48%), thrombocytopenia (18%) and anemia (6%). Other events included 4 patients (12%) with Grade 3–4 neutropenic fever and 3 patients (9%) with Grade 3 bacterial pneumonia. Grade 3–4 hypotension and dyspnea developed in 1 and 3 patients respectively; no patient developed thrombo-embolic or neuropathic complications.

Results from this study confirm the high therapeutic activity of Len in association with Dex in patients with relapsed and refractory MCL with a favourable safety profile. The significant increase of the macrophage infiltration in the BM seems to be a possible immunomodulatory effect of Len. Perhaps, the increase in microvessel counts may be induced by the activated macrophages and be an example of “indirect angiogenesis”. On the other hand, angiogenic plasma biomarkers tend to be lower, suggesting only a limited effect of Len on the neovascularization.

Off Label Use: Lenalidomide in Mantle Cell Lymphoma. Vitolo:Celgene: Membership on an entity's Board of Directors or advisory committees.