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Lenalidomide reduced transfusion burden in myelodysplastic syndrome
In pivotal phase-2 study results, 45% of patients had no cytogenic trace of MDS.
Results from a pivotal phase-2 trial of lenalidomide in patients with the del(5q) subtype of myelodysplastic syndrome showed that the drug helped 76% of patients go without transfusion. Furthermore, 45% of patients in the study had no cytogenic trace of MDS.
After two years of follow-up, patients continue to respond well to the treatment, according to the study, which was conducted by a national consortium of researchers.
“These new, landmark data demonstrate that [lenalidomide,] in some cases, eliminates all signs of the cancer’s genetic cause, an abnormality on the chromosome 5,” said lead researcher Alan List, MD, professor of oncology and medicine and chief of the division of hematologic malignancies at H. Lee Moffitt Cancer Center and Research Institute in Tampa, Fla. “It can reduce or even eliminate the need for transfusions in many patients with MDS, and after two years, these responses have continued to hold. It is very rewarding to see patients treated with [lenalidomide], living three or four years transfusion free and living with a better quality of life.”
Study design
Researchers enrolled 148 patients, who initially received 10 mg of daily lenalidomide (Revlimid, Celgene) for 21 days of a 28-day cycle. The treatment schedule was amended to a 10 mg daily dose of lenalidomide because of the short interval between treatment initiation and response in a pilot study, researchers wrote.
Of the 148 patients, 112 had a reduced need for transfusions (76%; 95% CI, 68-82) and 99 patients (67%; 95% CI, 59-74) no longer needed transfusions, regardless of their karyotype complexity. Researchers observed a rapid, 4.6-week median response to lenalidomide. The response was also durable, as the median duration of transfusion independence had not been reached after a median 104-week follow-up. The maximum hemoglobin concentration reached a median of 13.4 g/dL, with a corresponding median rise of 5.4 g/dL, as compared with the baseline nadir value before transfusion. Among the 85 patients who could be evaluated, 62 had cytogenetic improvement, and 38 of the 62 had a complete cytogenetic remission. There was complete resolution of cytologic abnormalities in 38 of 106 patients whose serial bone marrow samples could be evaluated, according to the study.
Transfusion burden
Patients with myelodysplastic syndrome who are transfusion-dependent tend to have a lower survival, even those who are classified as low-risk, because of complications stemming from iron loading, cardiac failure and progression to acute myeloid leukemia.
“These observations suggest that sustained improvement in erythropoiesis might improve the outcome of the disease,” researchers wrote in The New England Journal of Medicine.
The study also confirmed that lenalidomide suppresses the chromosome 5q-deletion clone. After 24 weeks of therapy, 73% of patients had a cytogenetic response and 45% of patients were in complete cytogenetic remission.
Additionally, bone marrow morphologic features returned to normal in 36% of patients who could be evaluated, researchers wrote. Among most patients with an excess of bone marrow myeloblasts or ringed sideroblasts, the number of these cells returned to normal.
Researchers also found no significant differences in the frequency of transfusions or cytogenetic responses among patients with different degrees of karyotype complexity, or among patients with an isolated 5q deletion, either with or without the classical 5q- syndrome.
“Among patients with myelodysplastic syndrome and a 5q deletion, the presence of one or more additional chromosomal abnormalities was associated with an aggressive clinical course and considerably poorer overall survival, as compared with patients with the 5q deletion,” researchers wrote.
The most common treatment- related adverse events were neutropenia and thrombocytopenia. Grade-3 or -4 neutropenia (fewer than 1,000 polymorphonuclear neutrophils/mm3) and thrombocytopenia (fewer than 50,000 platelets/mm3) were reported in 54.7% and 43.9% of patients, respectively.
Grade-4 neutropenia (fewer than 500 polymorphonuclear neutrophils/mm3) was more common among patients receiving continuous daily dosing than among those receiving 21-day dosing (44.1% vs. 17.4%, P<.001), whereas grade-4 thrombocytopenia (fewer than 10,000 platelets/mm3) was less common among those receiving continuous daily dosing than among those receiving 21-day dosing (6.9% vs. 15.2%, P=.05), researchers wrote.
Severe myelosuppression generally occurred early in the course of treatment, with 62% of grade-3 or -4 hematologic adverse events occurring within the initial eight weeks of treatment. Neutropenia was accompanied by fever in only 4.1% of patients, according to the study. Most other adverse events were of low or moderate severity, and included pruritus, rash, diarrhea and fatigue.
The trial was sponsored by Celgene.
Editor’s note: This study demonstrated that lenalidomide, an immunomodulating derivative of thalidomide with a markedly different toxicity profile, was capable of generating major hematologic and cytogenetic responses in a high proportion of patients with the del(5q) subtype of MDS. This group of patients accounts for approximately 10% of those with MDS. The drug was relatively well tolerated although myelosuppression was a common and potentially serious side effect, which required careful monitoring and management. Given the substantial beneficial impact of lenalidomide against the abnormal clone in this disorder, its use holds promise for causing important positive alteration of the natural history of this disease. Biologic studies are ongoing attempting to delineate the mechanism(s) underlying these dramatic and relatively selective effects for this disease subtype. A separate recently completed clinical trial is currently undergoing analysis to define the role of this drug for treating lower risk patients with non-del(5q) subtypes of MDS. – Peter Greenberg, MD
For more information:
- List A, Dewald G, Bennett J, et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med. 2006;355:1456-1465.