Efficacy and Safety of Thalidomide In Mantle Cell Lymphoma: Results of the French ATU Program.

Abstract 1794

Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy that represents approximately 8% of lymphoma cases. Up-front treatment with intensive chemotherapy and autologous stem cell transplantation (ASCT) for younger patients has demonstrated improvement in prognosis and outcome but virtually all patients experience relapse. Thalidomide is an antiangiogenic and immunomodulatory drug whose mechanism of action is unclear. Promising results were reported but only on small series, with a limited median follow up.

Thalidomide in France is currently not approved in this indication, but its use is allowed by French authorities (AFSSAPS) after reviewing unique patient medical chart, mainly indication (relapsed/refractory MCL) and absence of appropriate alternative treatment. There is no other inclusion or exclusion criteria based on past medical history or biological findings. Authorization has to be confirmed every 3 months, based on efficacy and safety data. Patient informed consent was required prior to inclusion.

Overall, 58 patients (pts) with available data were included in this program between 06/2001 and 09/2009. There were 38 males and 20 females. At time of diagnosis, median age was 62.8 years (range 39.2–77.9); 89.5% of pts had PS £ 1; 89.7% presented with stage IV, including 78.9% with documented bone marrow involvement, 61.4% with leukemic phase and 28% with gastro-intestinal involvement.

Before Thalidomide, pts received a median of 2 lines of chemotherapy (range 1–5), including ASCT for 39. All but 6 received prior Rituximab. Median time between diagnosis and start of Thalidomide was 41.8 months (range 3.5–196.8) and 2.1 months between last line of chemotherapy and Thalidomide (range 0–126.8). At time of inclusion, median age was 66.8 years (43.9-82.7); 86.2% of pts presented with stage IV and 18 (31%) with PS > 1.

Thalidomide was administrated alone in 19 patients (32.7%), associated with Rituximab (n=19; 32.7%), Bortezomib (n=5; 8.6%), or both (n=9; 15.5%), or with others treatments (n=8; 13.8%). Initial dosage was 200 mg/d for 24 patients or less (100 or 50 mg/d) for 33 patients (unknown for 1 pt), according to physician decision.

Grade 1–2 adverse events included fatigue, constipation and neuropathy as previously described with Thalidomide. Three pts experienced grade 3 neuropathy. There were 6 events related to thromboembolism (deep-vein thrombosis: n=5; stroke: n=1). Hematological toxicity consisted in 4 pts with grade 3 neutropenia, including 2 with febrile neutropenia. A patient experienced severe hepatitis but link with thalidomide was doubtful. Overall, 7.3% of pts experienced grade 3–4 adverse events. Finally, 13 pts discontinued Thalidomide because of toxicity, including 6 who received Rituximab and Bortezomib.

The overall response rate (CR + PR) was 50%, with 12 pts (20.7%) who achieved a CR and 17 pts (29.3%) a PR, 17 pts (29.3%) had stable disease and 12 (20.7%) progressive disease. Median time to response was 3 months (range 1–8). Median follow-up was 41.3 months. For the entire cohort, 1-y TTF and OS rates were 29.3% (95% CI: 17.4–41.3) and 61.9% (95% CI: 49.0–74.8) respectively; 2-y TTF and OS rates were 10.9% (95% CI: 2.2–19.6) and 49.6% (95% CI: 36.0–63.2) respectively.

In univariate analysis, factors predictive for better OS were male sex (p=0.037), stage < 4 (p=0.043), PS 0–1 (p<0.001), time since last treatment > 6 months (p=0.004) and addition of Rituximab (p=0.013). Addition of Bortezomib was not predictive for OS.

LDH, leukocytes count at time of inclusion and Thalidomide dosage (200 mg/d) were only predictive for better TTF (respectively p=0.014; 0.008 and 0.041).

In multivariate analysis, male sex (p=0.002), stage <4 (p=0.025), PS 0–1 (p<0.001) and time since last chemotherapy > 6 months (p=0.010) showed prognostic relevance for OS.

In conclusion, in this cohort of unselected patients, efficacy of Thalidomide compare favorably with currently approved drugs for relapsed MCL such as Bortezomib (ORR : 33%, median duration of response : 9.2 months) or Temsirolimus (ORR : 22%, median PFS : 4.8 months), with less toxicity. This efficacy is comparable with others Imids such as Lenalidomide with a trend to less toxicity and a better side effect profile, justifying its use with Rituximab for relapsed MCL as well as in a maintenance schedule.