This article reviews lenalidomide in the setting of myelodysplastic syndromes (MDS). Lenalidomide, a thalidomide analog, is an immunomodulatory medication that is used in the lower-risk and intermediate-risk MDS settings and a specific genetic mutation (deletion in the long arm of chromosome 5, abbreviated as del(5q). Thalidomide is no longer used to treat MDS due to its side effects.
The mutation of del(5q) is important as it likely deletes genes that are important for erythropoiesis (production of red blood cells) and cell cycle regulation. Genes that are near this del(5q) region include those that affect platelet production. Furthermore, the entity of 5q-syndrome (which is different than solely harboring the deletion of 5q) is characterized by low red blood cells and platelets, typically in older women. Depending if other genes are deleted with the 5q, other clinical characteristics can manifest.
The mechanism of action of lenalidomide is not completely understood at this time. However, as lenalidomide reduces the copies of del(5q) clones, normal cells can repopulate the bone marrow and produce normal, healthy stem cells. In addition to reducing the absolute number of abnormalities, it can upregulate genes to increase red blood cell production and certain white blood cell subtypes to help fight viral and bacterial infections.
Prior to lenalidomide, MDS patients with anemia were treated with red blood cell transfusion and red blood cell growth factors. The first clinical trial using lenalidomide was MDS-001 – revealing a 56% hematological overall response rate. Response rate was significantly higher in those with del(5q) compared to those without the del(5q) mutation – 83% vs 53%. Subsequent trials confirmed the superior response in those patients with del(5q). The MDS-003 trial found 67% achieved red blood cell transfusion independence. Red blood cell transfusion independence was achieved in a median of 4.6 weeks and lasted for a median duration of 2.2 years. Suppression of the bone marrow was the most significant side effect of lenalidomide. Quality of life was improved in both the short and long term settings in the MDS-004 trial. Data on cost-effectiveness of lenalidomide is unknown at this time.
There was an initial concern that patients treated with lenalidomide had an increased risk of acute myeloid leukemia (AML) progression, but studies have shown this not to be true. In fact, those patients with lower-risk MDS based on international prognostic scoring system (IPSS) and achieve a hematologic (red blood cell transfusion independence) and cytogenetic (elimination of del(5q) mutation) have better overall survival and decreased risk of AML progression.
In higher-risk MDS settings per IPSS, response rate to lenalidomide is much lower compared to the lower-risk MDS. A single study demonstrated that higher doses of lenalidomide may be useful in settings of higher-risk del(5q) MDS. Additionally, lenalidomide has been used in the non-del(5q) settings. Overall response rate is 43%, with only 23% of patients becoming red blood cell transfusion independent and lasting 41 weeks of duration – significantly decreased compared to the del(5q) positive patients.
Currently, there are no clinical or molecular factors that consistently predict the response to lenalidomide in patients with or without del(5q). With new mutations being discovered and readily detectable using next-generation sequencing, future clinical trials will be able to better examine the significance of specific mutations. Resistance to lenalidomide has also been seen, which is still poorly understood and thought to be associated with gaining of additional mutations.
The current landscape of MDS treatment involves combination therapy. Initial studies show promising data of combination red blood cell growth factors and lenalidomide. Confirmatory Phase III study is underway now. A study combining platelet growth factors and lenalidomide preliminarily demonstrated decreased thrombocytopenic events. Multiple studies have been performed to examine the combination of hypomethylating agent azacitidine and lenalidomide. The verdict is still out whether regarding the best regimen – concurrent vs sequential and maintenance therapy. Data suggest that this combination is well tolerated and can lead to increase better and faster overall response rate. The greatest limitation is the neutropenia and thrombocytopenia.
In conclusion, the only US FDA approved indication for lenalidomide is IPSS lower-risk MDS patients with
del(5q) and symptomatic transfusion-dependent anemia. The dose is typically 10mg daily for 21 days of a 28 days cycle; responders should be continued on treatment indefinitely. Myelosuppression (depressed blood counts) is the most common side effect; thus, blood count checks are required frequently in the beginning. Risk for blood clots are low and prophylactic anticoagulation is not recommended. Lenalidomide can be used in those patients who are purely anemic and do not harbor the del(5q) mutation. Lenalidomide is generally not recommended in higher-risk MDS patients outside of clinical trials. Combinations of lenalidomide and other agents are currently being studied in clinical trials.