Thalidomide Analog Reduces Transfusion Needs in MDS Patients

TAMPA, Fla., Oct. 5 -- Patients with severe refractory anemia caused by myelodysplastic syndrome (MDS) with a 5q31 deletion could reduce or halt transfusion dependency after treatment with Revlimid (lenalidomide), investigators have found.

Some patients with MDS have genetic deletions in the long arm of chromosome 5 (5q), and a subset at 5q31, resulting in severe hypoplastic anemia, normal or elevated platelet counts, atypical marrow megakaryocytes with less than 5% myeloblasts in the bone marrow, and a relatively indolent clinical course.

In an uncontrolled open label trial, three-fourths of patients with MDS with the 5q31 deletion needed fewer red-cell transfusions after six months of Revlimid therapy, and two-thirds of patients became transfusion free, reported Alan List, M.D., of the University of South Florida H. Lee Moffitt Center and Research Institute here, and colleagues in the Myelodysplastic Syndrome 003 Study.

The investigators also saw cytogenetic improvements or remissions in some patients, and a complete resolution of cytogenetic abnormalities in about a third of patients with evaluable serial bone marrow samples, the investigators reported in the Oct. 5 issue of the New England Journal of Medicine.

In a preliminary study published in NEJM in 2005, Dr. List and colleagues had shown that Revlimid has hematologic activity in patients with low-risk myelodysplastic syndromes who have no response to erythropoietin, or who are not likely to benefit from conventional therapies.

In the current study, they evaluated the effect of Revlimid, an analog of Thalomid (thalidomide), in 148 MDS patients with the 5q31 deletion.

The patients all had a confirmed histologic diagnosis of primary MDS according to French-American-British (FAB) criteria, a chromosome 5q31 deletion that was either isolated or accompanied by additional cytogenetic abnormalities, low or intermediate-1 disease risk, according to the International Prognostic Scoring System, and transfusion-dependent anemia, defined as anemia requiring a transfusion of at least two units of red cells within the eight weeks before enrollment.

The patients in the trial initially took Revlimid in one 5 mg capsules twice daily for 21 days during a 28-day cycle. The protocol was subsequently changed to 10 mg daily, based on data from the pilot study.

If patients developed adverse effects of grade 3 or greater the treatment was interrupted, after the side effects had resolved the treatment was resumed at a dose of 5 mg/day or every other day, according to tolerance.

The investigators obtained complete blood counts weekly during the first eight weeks and every two weeks after that, and performed bone marrow aspiration, biopsy, and cytogenetic examination after 24 weeks of treatment.

The primary end point was the proportion of patients who no longer needed transfusions. The authors defined transfusion independence as a period of at least 56 consecutive days during which no transfusions were given and the hemoglobin concentration rose by at least 1 g/dL.

The secondary end points were duration of transfusion independence, the frequency of minor erythroid, cytogenetic, and pathological responses, and safety. Analysis was by intention to treat.

They found that 112 of the 148 patients (76%, 95% confidence interval, 68%-82%) had a reduced need for transfusions, and 99 of the 112 (67%, 95% CI, 59%-74%) became transfusion independent, regardless of the complexity of individual patients karyotype.

The median time to a drug response was 4.6 weeks (range, 1 to 49), and the median duration of transfusion independence had not been reached after a median of 104 weeks follow-up.

The median maximum hemoglobin concentration was 13.4 (range, 9.2 to 18.6) g/dL, with a corresponding median rise of 5.4 (range, 1.1 to 11.4) g/dL compared with the pre-transfusion baseline nadir.

Among the 85 patients evaluable, 62 had cytogenetic improvement, and 38 of these patients had a complete cytogenetic remission (defined as the absence of cells in metaphase containing any abnormal clone).

In addition, among the 106 patients with evaluable serial bone marrow samples, 38 had complete resolution of cytologic abnormalities.

The most common treatment-associated adverse events --and the most common reasons for dose adjustment -- were neutropenia and thrombocytopenia. Grade 3 or 4 neutropenia (fewer than 1000 polymorphonuclear neutrophils/ml³ occurred in 54.7%.

Thrombocytopenia (fewer than 50,000 platelets/ml³) occurred in 43.9%. Grade 4 neutropenia (fewer than 500 polymorphonuclear neutrophils/ml³) occurred in 44.1% of patients who received the daily dose, compared with 17.4% of patients on the 21-day dosing cycle (P<0.001).

In contrast, grade 4 thrombocytopenia (fewer than 10,000 platelets per cubic millimeter) was less common among those receiving continuous daily dosing than among those receiving 21-day dosing (6.9% vs. 15.2%, respectively P=0.05).

Among the 11 patients who died while receiving treatment or within 30 days after the last dose of Revlimid, three of the deaths attributed to neutropenic infection were judged to be possibly treatment-related by the treating physician. The remaining deaths were not thought to be treatment related.

The estimated median survival (based on a median follow-up from the diagnosis of MDS of 3.8 years) was 7.6 years for patients with an isolated 5q deletion, and 5.6 years for patients with one or more year cytogenetic abnormalities. This difference was not statistically significant (P=0.064).

"Among patients who have the myelodysplastic syndrome with a 5q deletion, the presence of one or more additional chromosomal abnormalities is associated with an aggressive clinical course and considerably poorer overall survival, as compared with the 5q deletion [alone]," the authors wrote.

"Our finding that survival was similar among patients with additional chromosomal abnormalities and patients with an isolated 5q deletion suggests that lenalidomide may extend survival in higher-risk patients with the myelodysplastic syndrome."

Five of the authors are employees of Revlimid maker Celgene and have equity positions in the company. Other co-authors have received consulting fees and/or grant support from the company.