Analysis of Second Primary Malignancies in Lenalidomide-Treated Patients with IPSS Low- or Int-1-Risk Myelodysplastic Syndromes

Lenalidomide (LEN) is approved in the US for the treatment of RBC transfusion-dependent patients with IPSS Low- or Int-1-risk myelodysplastic syndromes (MDS) with del(5q), with or without other cytogenetic abnormalities. In a phase 3 trial, treatment with LEN 5 mg and 10 mg resulted in RBC transfusion independence (TI) for ≥ 26 weeks in 43% and 56% of such patients, cytogenetic response in 25% and 50%, and a significant improvement of health-related quality of life (p <.05 for both 5 mg and 10 mg). Achievement of RBC-TI ≥ 8 weeks was associated with a significantly reduced risk of AML progression and death (p <.05 for both) (Fenaux P et al. Blood 2011;doi: 10.1182/blood-2011-01-330126). In newly diagnosed multiple myeloma patients, results of phase 3 trials showed a numerical imbalance in the occurrence of second primary malignancies (SPMs) between patients treated with LEN (in combination with melphalan or immediately after high-dose melphalan therapy and stem cell transplantation) and control cohorts. SPMs were analyzed in clinical trials of LEN across indications, including MDS. Methods: This was a single arm analysis of SPM data retrieved from RBC transfusion-dependent patients with IPSS Low- or Int-1-risk MDS with or without del(5q) who received LEN as monotherapy in 5 studies (MDS-001, -002, -003, -004, and -007). The cutoff date was February 28, 2011. SPMs were defined using MedDRA (Medical Dictionary for Regulatory Activities) categories of invasive SPMs (hematologic malignancies and solid tumors) and non-melanoma skin cancers (NMSC). Acute myeloid leukemia (AML) is considered part of the natural history of disease progression in MDS. Although further follow-up is needed, results of a phase 3 study showed no obvious evidence for an increased risk of AML progression in LEN-treated RBC transfusion-dependent patients with IPSS Low- or Int-1-risk MDS and del(5q) (Fenaux P et al. Blood 2011;doi: 10.1182/blood-2011-01-330126). AML was not included in the present analysis. The overall number of SPMs (invasive malignancies and NMSC), and the number and incidence rate (IR) of all invasive SPMs were evaluated, with IR defined as the number of new events per 100 person-years (pys). The IR of invasive SPMs was compared with the IR of new events of invasive cancer as reported from the SEER (Surveillance, Epidemiology, and End Results) cancer registry (2.1/100 pys for persons aged ≥ 65 years) (Howalder N et al. National Cancer Institute, 2011). Results: The combined population of all 5 studies comprised 557 LEN-treated patients. The median age was 71 years (range 27–95 years) and 72% of patients were aged ≥ 65 years. 88 patients (15.8%) had a prior history of cancer including malignant melanoma, meningioma, breast cancer, lung cancer, squamous cell carcinoma, and basal cell carcinoma. A total of 28 patients (5.0%) developed ≥ 1 SPM, including 17 (3.1%) with an invasive SPM and 12 (2.2%) with NMSC; 1 patient had both an invasive malignancy and a NMSC. Two of the 17 patients with invasive SPMs had a B-cell malignancy and 15 had solid tumors of heterogeneous type. Of the 28 patients with SPMs in total, 5 patients had a prior history of cancer. The IR of invasive SPMs was 2.60/100 pys (95% confidence interval 1.56–4.07), which is consistent with the IR reported in the SEER database among patients in this age group (2.1/100 pys for persons aged ≥ 65 years). The median time to onset of SPMs was 13.5 months (range 0.3–48.6 months). Conclusion: There was no clear evidence to associate LEN treatment with an increased risk of developing SPMs in patients with Low- or Int-1-risk MDS with or without del(5q). The IR of invasive SPMs among these LEN-treated patients is what would be expected from population-based estimates of invasive cancer incidence among persons in this age group. The collection of data on SPMs in LEN-treated patients including post-marketing information is ongoing.

Giagounidis:Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. List:Celgene Corporation: Consultancy, Honoraria, Research Funding. Fenaux:Merck: Honoraria; Johnson & Johnson: Honoraria; Amgen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Cephalon: Honoraria; Novartis: Honoraria. Benettaib:Celgene Corporation: Employment, Equity Ownership. Brown:Celgene Corporation: Employment, Equity Ownership. Zhong:Celgene Corporation: Employment, Equity Ownership. Brandenburg:Celgene Corporation: Employment, Equity Ownership. Mufti:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.