Immunomodulatory Drugs in the Treatment of Myelodysplastic Syndromes

Myelodysplastic syndrome (MDS) constitutes a group of malignant hematopoietic stem cell disorders characterized by ineffective hematopoiesis, and a risk of progression to acute myeloid leukemia (AML). In low-risk MDS, the main cause of cytopenia is increased apoptosis of hemopoietic progenitors. Signs and symptoms of low-risk MDS relate to hematopoietic failure. The anemia of MDS is often severe, leading to regular transfusion need, iron overload, and reduced quality of life [Italian Cooperative Study Group 1998]

The recent reclassification by the World Health Organization (WHO) allows distinction between pure refractory anemia (RA) and refractory anemia with ringed sideroblasts (RARS) and RA / RARS with multi-lineage dysplasia. Moreover, it transfers patients with an isolated deletion of 5q and <5 Prozent blasts, into a separate category, the 5q- syndrome. This definition has proven extremely valuable, since the genetic defect(s) of low-risk MDS patients with del 5q may constitute a target for biological therapy.

The International Prognostic Scoring System (IPSS) is currently the best available tool for estimating the prognosis of untreated patients with MDS [Bouscary D 2005]. Patients with IPSS Low or INT-1 are usually defined as "low-risk" MDS, and subject to therapy aiming to relieve anemia or cytopenia. Recent epidemiological data indicate that the presence of a transfusion need is associated with a poorer prognosis, irrespective of other risk factors [Greenberg P 1997].

Treatment with erythropoietin as monotherapy may induce erythoid responses in around 25 Prozent of patients with low-risk MDS, and the addition of G-CSF may double this response rate [Hellstrom-Lindberg E 1998] [Hellstrom-Lindberg E 1993]. Epo +/- addition of G-CSF is considered a first line treatment for patients with MDS and anemia, provided they show pre-treatment variables predicting for a response to tretment [Hellstrom-Lindberg E 2005]. The median duration of a response to Epo + G-CSF is around 2 years and this should be used a comparison, when evaluating the effect of new treatments for the anemia of MDS. It is generally considered that the response rate to Epo in patients with 5q- syndrome is lower than average, probably due to high endogenous S-Epo levels in this MDS group.

Several phase II studies have shown that treatment with anti-thymoglobulin (ATG) may be effective in subsets of patients with low-risk MDS. Responders to this treatment are mainly younger, with WHO RA or RCMD, normal cytogenetics, short history of transfusion dependency and HLA DR15 phenotype, while the finding od del5q is infrequent [List A 2005]. Thalidomide may also induce erythroid responses in a small proportion of low-risk MDS, also in patients refractory to Epo, but has generally problematic side effects, which limits its use [Malcovati L 2005].

Lenalidomide, one of the new immunomodulating oral drugs (IMIDS) is a thalidomide structural analogue, and was initially evaluated in a phase II study of 43 transfusion-dependant patients with low-risk MDS. Unexpectedly 56 Prozent of the patients reached transfusion independency, and the majority of these normalized their hemoglobin levels. Furthermore, the response rate in patients with a deletion of 5q was 83 Prozent, with 8/11 patients showing a complete cytogenetic response to treatment [Saunthararajah Y 2002]. Lenalidomide is at present investigated in a series of follow-up studies to establish its role in MDS. Two large phase II studies, MDS-002 for patients with non-5q- low-risk MDS, and MDS-003 for patients with 5q- low-risk MDS have been completed although final report is pending. The vast majority of the included patients had failed, or become refractory to erythropoietin. In the MDS-002 study, 27 Prozent of patients reached transfusion independence, with a median duration of response of 43 weeks. In the MDS-003 study 66 Prozent of patients reached transfusion independence, and the median duration of responses has not been reached.

Lenalidomide is not without side effects. In the completed study where the starting dose was 10 mg daily, or 10 mg 21/28 days, the incidence of grade III-IV thrombocytopenia and neutropenia was around 50 Prozent, and in particular grade IV neutropenia was associated with several episodes of severe and in some cases lethal infections. In the ongoing MDS-004 study, patients with del5q low-risk MDS are therefore randomized to placebo, 5 mg daily and 10 mg 21/28 days, to further evaluate the toxicity profile and the dose - efficacy relation.

To conclude, lenalidomide is a remarkably effective drug for a biologically relatively well defined subset of MDS patients, and will most likely play an important role in the future management of MDS [WHO 2001].