Introduction
Myelodysplastic syndromes (MDS) with chromosomal deletion of 5q [del(5q) MDS] are heterogeneous diseases [
3,
5]. Apart from the 5q- syndrome [
7,
16], patients with del(5q) MDS may present with one additional chromosomal abnormality, with multiple additional chromosomal abnormalities leading to a complex karyotype, or with an increase of bone marrow and/or peripheral blasts irrespective of chromosomal complexity. These distinct disease subgroups have dramatically different prognostic features [
3,
5,
6,
12].
Lenalidomide is a thalidomide analog with a distinct clinical profile that has demonstrated erythroid responses leading to RBC transfusion independence, particularly in del(5q) MDS [
10,
11] and in some patients with Low or Int-1 MDS lacking the del(5q) chromosomal abnormality [
14]. Although the exact mechanism of action has not been defined, lenalidomide is known to have multiple biological activities including anti-angiogenesis, immunomodulation, anti-cytokine, and direct toxic effects on malignant bone marrow cells [
1,
4].
We experienced unexpected effects of lenalidomide in del(5q) MDS patients that are suggestive of the mode of action in this patient subgroup and may have implications for future use of the substance in this patient population. To our knowledge, these types of responses to lenalidomide have not been previously described.
Study design
Between November 2003 and May 2006, 43 patients with del(5q) MDS with or without additional chromosomal abnormalities were treated with lenalidomide at St. Johannes Hospital, Medizinsche Klinik II, Duisburg, Germany. As of December 27, 2005, lenalidomide has been approved for clinical use in the United States, but not in Europe. These patients received lenalidomide as participants of clinical trials or through an expanded access program. Of the cases reported in this paper, only one patient took part in a lenalidomide clinical trial, and that patient was a non-responder. Patients were informed of inclusion of their information in the present report and consent was given.
Discussion
Clinical trials of lenalidomide have demonstrated cytogenetic and erythroid responses in patients with del(5q) MDS [
10,
11] that have not been achieved with other non-cytotoxic agents [
8]. The activity of lenalidomide in patients with complex karyotypes including del(5q) represents a major advance, as those patients have an ominous prognosis and are expected to transform rapidly to acute myeloid leukemia [
6]. Patient 1, who had Int-2 MDS with del(5q) and a complex karyotype, is of special interest because repetitive karyotyping showed the number of affected metaphases to be gradually reduced during lenalidomide treatment. Patient 2, who also had del(5q) with a complex karyotype, experienced both complete cytogenetic response and normalization of hemoglobin. Two other patients with complex cytogenetic abnormalities are being treated at our institution, but the duration of treatment is too short for final evaluation.
Whereas cytogenetic remission with lenalidomide treatment correlates closely with erythroid response [
10], complete suppression of the malignant clone was not required for transfusion independence in four of the five cases (patients 1, 3, 4, and 5) reported here. Hematologic remissions occurred in three patients despite treatment interruption and persistence of the del(5q) karyotype (patients 3, 4, and 5). Patient 5 had a late effect and reached transfusion independence after discontinuation of lenalidomide. The long-term hematologic responses seen with patient 3/4 patients may be an exception, as another patient at our department had worsening of anemia 3 months after stopping lenalidomide after a short period of administration (5 weeks).
Two other patients at our institution had interrupted lenalidomide treatment after prolonged intake (at months 24 and 13, respectively) in complete hematologic and cytogenetic remission for reasons other than an adverse event. Both patients remain in complete hematologic remission, ongoing for more than 6 and 21 months. Thus, altogether six out of 43 patients at our site have interrupted lenalidomide treatment for non-toxicity reasons. Five experienced an ongoing erythroid response and one patient relapsed after 3 months.
Although all of the patients reported here have achieved transfusion independence, lenalidomide treatment does not uniformly lead to transfusion independence in del(5q) MDS. Of note, the lenalidomide MDS 003 study in del(5q) MDS patients shows that recurrence of the cytogenetic aberration or cytogenetic evolution is not an uncommon feature in this patient population during lenalidomide treatment: New chromosomal abnormalities occurred in 24 out of 119 patients, and no single type was seen in more than one patient [
10]. Interestingly, chromosome 7 abnormalities occurred in only one patient, in contrast with the higher incidence in the MDS 001 study [
11].
List et al. suggested that lenalidomide may act by suppression of the del(5q) clone [
11]. All but one patient in our series reported here had reduction of affected metaphases, which supports this hypothesis. However, this may not be a result of an immediate cytotoxic effect, as evidenced by the slow decrease in malignant metaphases as seen with patient 1. The other responding patients, particularly patient 5, showed a slow erythroid response more consistent with a sustained effect on the bone marrow microenvironment. Effective bone marrow modulation might, in some instances, lead to (partial) suppression of del(5q) clones. However, even if clonal suppression did not occur, normal hematopoiesis may be sufficiently strengthened to support a partial erythroid response in some patients.
Examples of such erythroid response without alteration of the underlying cytogenetic abnormality have occurred in studies with other immunomodulating drugs like antithymocyte globulin and cyclosporine A [
15], differentiation-inducing agents like all-
trans-retinoic acid [
8], and with cytokine treatment like darbepoietin [
13]. Thus, among individual patients within the del(5q) MDS subset, lenalidomide may affect the del(5q) clone and the bone marrow microenvironment to different degrees to result in hematopoietic normalization. Further study is needed to better understand the relationship between erythroid response and cytogenetic remission with lenalidomide treatment.
In conclusion, although the above case reports obviously represent only selected cases out of a larger number of lenalidomide treated del(5q) MDS patients, these unusual and unexpected cytogenetic and erythroid responses suggest that some patients with complex karyotypes including del(5q) or who discontinue therapy may still benefit from lenalidomide treatment.