Treatment with mycophenolate mofetil followed by recombinant human erythropoietin in patients with low-risk myelodysplastic syndromes resistant to erythropoietin treatment

Anemia is present in most patients with low-risk MDS (LR-MDS).1 Supportive treatment with transfusions was the final outcome of most of them, and transfusion-dependency is a prognostic factor for poor survival.2 A number of studies have demonstrated that, overall, one third of LR-MDS responded to growth factor treatment. A score system was developed3 which, according to transfusion requirements and serum erythropoietin levels, identifies cases with high or low probability of response.3,4 One important aspect is that the response to growth factors is not maintained, with a median duration of 24 months. However, only 20% of patients had a response which lasted more than four years.5

One important aspect, frequently forgotten, is that many LR-MDS are elderly handicapped patients. In fact, the number of patients lost during treatments was as high as 20% in studies using Epo+/−G-CSF-G, which only required subcutaneous injections.3,4

Immunological disturbances have been proposed to be among the mechanisms involved in MDS pathogenesis. As in aplastic anemias, in MDS abnormal SMD stem cells trigger an immunological cellular response which in turn attacks abnormal stem cells causing more damage to the remaining stem cells. This finding is probably the physiological basis for anti-lymphocytic gammaglobulin +/−cyclosporine responses.6 In MDS patients with trisomy 8, an expansion of a number of CD8 T-lymphocyte repertoires have been demonstrated, suggesting their involvement in the pathogenesis of MDS. In patients with refractory anemia, HLA-DR 15 and trisomy 8, the rate of response was 70%.7,8 However, the immunosuppressive treatment is not well tolerated and requires hospital admission.9

The purpose of this work was to rescue LR-MDS patients who had lost their response to Epo, or to treat patients with low probability of response to Epo using the Scandinavian Score.3 A therapeutical approach using sequentially immunosuppresion and growth factors was investigated. Mycophenolate mofetil and prednisone were used as immunosuppression because mycophenolate mofetil is given orally and is very well tolerated.10

The trial scheme (www.clinicaltrials.gov. Identifier: ML20559) used mycophenolate mofetil (Cell Cept) 1 g twice a day orally and oral prednisone 0.5 mg/Kg/d tapering prednisone to 10 mg/d. Mycophenolate mofetil and prednisone 10 mg were maintained to the end of the study. Response was evaluated at 12 weeks. In patients without major erythroid response, subcutaneous 30,000 U/week of recombinant human erythropoietin beta (Neorecormon) was added during six weeks. This was increased to 60,000 U/week in case of no major response following the IWG criteria.11

A total of 10 patients were treated (Table 1), including 8 cases that had received erythroid stimulating agents and had lost their response and 2 with high levels of serum erythropoietin. Seven of them were under transfusions. In one case the treatment was stopped because of pneumonia at two weeks. In 5 out of the 9 remaining cases, a response was observed; in 3 this was a major response (in one case under transfusions at the end of the study Hb was 96 g/L without transfusions, in one case with initial Hb of 81 g/L, Hb was 109 g/L after treatment, and in a case under transfusion final Hb was 97 g/L without transfusions). A minor response was seen in 2 patients (in one case the amount of transfusions was reduced from 6 units/month to 2 units, and in one case without transfusions Hb increased from 85 g/L to 101 g/L). Treatment was well-tolerated; 3 cases showed grade 1–2 diarrhea, in one case with diabetes mellitus an increase in diabetes treatment was required, and one case was admitted to hospital due to pneumonia.

In spite of the low number of cases included, this treatment with oral immunosuppresion followed by addition of growth factors, as antiapoptotic agents, obtained a good rate of response. It is worth remembering that the cases included were patients with few alternative treatments. This approach is easy to manage and well-tolerated, and does not require hospital admission.

Table 1.Clinical characteristics and response to immunosuppression and growth factors treatment.

In summary, using the scheme of oral immunosuppresion and growth factors, in 3 out of the 9 LR-MDS patients transfusions were no longer required. Obviously, larger studies should be carried out to confirm and validate this scheme of treatment. Immunosuppression and growth factors could be an alternative to new drugs that have appeared recently.