MDS is a disease of older patients, and the course is frequently protracted, often leading to conservative management.  The development of scoring systems such as the IPSS (or WPSS) has been useful in guiding physicians and patients, and the approval by the FDA of several compounds for the treatment of subgroups of patients with MDS has brightened the outlook.  

By IPSS criteria the patient under discussion is scored as follows:  0.5 for myeloblasts, 0 for cytopenias, and 0.5 or 1.0 for his karyotype (dependent upon whether we consider the loss of the Y chromosome in 11 of 20 cells as age related or as clonal) for a total score of 1 or 1.5, i.e. risk group intermediate 1 (median life expectancy 5 years) or 2 (median life expectancy 1.5-2 years)¹.  Based on the results of a decision analysis by Cutler et al., this places the patient in the grey zone between conservative management and transplantation².  

Transfusion with packed red blood cells only was selected by 35% of respondents to our Clinical Challenge, but is not expected to have a favorable impact on the disease course.  The use of lenalidomide was recommended by 15% of respondents.  In transfusion dependent patients without del (5q), lenalidomide resulted in transfusion independence in 26% of patients for a median duration of 10 months; no significant improvements in karyotypes were observed³ (and the drug is currently not approved for this indication).

The response rates with DNA methyltransferase inhibitors have been in the range of 30% to 60% in patients with “advanced” MDS, and recent data suggest that survival is prolonged⁴.  Half of respondents recommended this therapy.  Conceivably, results are further improved with incorporation of etanercept (to neutralize TNFα mediated signals) into the regimen.

Currently the only strategy with the potential of curing the disease is hematopoietic cell transplantation (HCT).  In view of the patient’s young age and the karyotype, HCT from an HLA-identical related or unrelated donor should be considered as recommended by 70% of respondents.  We prefer related donors, but results with unrelated donors are comparable (except for a higher incidence of GVHD)⁵.  The ideal conditioning regimen has yet to be determined.  In patients with elevated myeloblast counts, higher dose regimens may be associated with a lower probability of relapse, but only retrospective analyses are available; a randomized study has been initiated.  Similarly, there are no prospective data as to the benefit of pre-HCT debulking therapy.  Studies are under way to determine whether DNA methyltransferase inhibitors given before HCT may lead to a reduced relapse incidence without increasing toxicity.

Of the respondents recommending HCT, almost 80% favored a reduced intensity preparative regimen.  It should be noted that  many of the so-called “myeloablative” regimens have been modified and early (regimen-related) mortality may not differ from that seen with “non-myeloablative” regimens.  In Seattle, patients up to 60 years of age who do not have clinically significant comorbid conditions are usually treated with the “myeloablative” regimens currently in use (e.g., targeted BU+FLU; targeted BU+CY; Melphalan +FLU and others).  The probability of survival in remission should be about 50%⁶. 

Importantly, this case again illustrates that prospective trials are needed to define optimal treatment approaches.