Improving the prognostic evaluation of patients with lower risk myelodysplastic syndromes

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With great interest we read the recent paper by Garcia-Manero et al.1 who proposed a new prognostic score for patients with lower risk myelodysplastic syndromes (MDS). We agree that it is important to identify within the group of patients with low-risk and int-1-risk MDS (according to International Prognostic Scoring System (IPSS)2) those who actually have an inferior prognosis and, thus, should receive early treatment. This necessity has become of particular importance during the recent years due to the availability of new drugs and the improved tolerability of the current transplantation protocols.

We applied the new score to 475 patients from the Düsseldorf MDS Registry who received best supportive care. The score successfully separated a very-low-risk group with a median survival of 80 months (n=164 and 35%), whereas no significant difference (35 vs 30 months) was observed between Garcia-Manero's intermediate and high-risk groups (n=257 (54%) and n=54 (11%), respectively). Relatively few patients received a high-risk score. The risk of evolution to acute myeloid leukemia (AML) within 3 years did not differ significantly between the proposed subgroups (13, 25 and 24%, respectively) (Figures 1a and b). In comparison, survival in the two IPSS subgroups was 70 and 31 months, respectively.

Figure 1
figure1

(a) Kaplan–Meier survival estimates based on 475 patients from the Düsseldorf MDS Registry. All patients belonged to the low- or int-I-risk groups according to International Prognostic Scoring System (IPSS) and were re-stratified according to the newly proposed score by Garcia-Manero et al. (b) Kaplan–Meier estimates of the risk of acute myeloid leukemia (AML) transformation based on 475 patients from the Düsseldorf MDS Registry. All patients belonged to the low- or int-I-risk groups according to IPSS and were re-stratified according to the newly proposed score by Garcia-Manero et al.

In contrast, another recently proposed scoring system, the WHO classification-based prognostic scoring system (WPSS),3 was capable of separating the low-risk and int-1-risk patients from the Düsseldorf MDS Registry into four risk groups that differed significantly regarding survival as well as leukemic transformation (4, 11, 23 and 37%, respectively, at 3 years) (Figures 2a and b).

Figure 2
figure2

(a) Kaplan–Meier survival estimates based on 475 patients from the Düsseldorf MDS Registry. All patients belonged to the low- or int-I-risk groups according to International Prognostic Scoring System (IPSS) and were re-stratified according to the WPSS. (b) Kaplan–Meier estimates of the risk of acute myeloid leukemia (AML) transformation based on 475 patients from the Düsseldorf MDS Registry. All patients belonged to the low- or int-I-risk groups according to IPSS and were re-stratified according to the WPSS.

To identify confounding factors in Garcia-Manero's new score and the reasons for its inferior performance in our patient cohort, we looked at the variables included. An improvement of the new score, when compared to the IPSS, is the inclusion of hemoglobin and platelets only, as the absolute neutrophil count is not an independent prognostic parameter. The new cut-off value of 4% bone marrow blasts is interesting but should be further evaluated. In patients from our registry we could not find a significant influence on survival. This might be due to the small number of patients (12%) concerned.

The largest discrepancy that we noted, when re-analyzing Garcia-Manero's score in the Düsseldorf MDS Registry, relates to the importance attached to platelet count, especially when compared to the importance of karyotype. In a multivariate analysis in the patients from our registry including WHO type, medullary blast count and cytogenetic risk groups according to IPSS, lactate dehydrogenase (LDH) and transfusion dependency, with or without age, platelet count did not remain an independent prognostic parameter. We have the impression that the patient population analyzed by Garcia-Manero et al., had an inferior-risk profile when compared to patients from the Düsseldorf Registry. According to IPSS, we have 39% low- and 61% int-1-risk patients, compared to 29% low- and 71% int-1-risk patients at the MD Anderson Cancer Center. Our patients had a platelet count of less than 100 × 109/l in 34% of the cases, in contrast to 52% at MD Anderson. Only 16% of our patients had a platelet count <50 × 109/l, qualifying for the top score of 2 points in Garcia-Manero's scoring system. Although, like MD Anderson, we are a tertiary referral center for MDS patients, our registry also includes patients diagnosed at our hematological cytology laboratory but treated somewhere else. Another difference between the two registries may relate to the fact that the initial evaluation of MDS patients at the MD Anderson Cancer Center is not at the time of the first diagnosis but at the time of referral, which is usually later during the course of the disease. This could at least partly explain the higher frequency of thrombocytopenic patients.

There is increasing evidence that, in comparison with medullary blast count, the importance of cytogenetics is underestimated in the IPSS.4 This is not taken into account in the proposed score, which treats unfavorable cytogenetics like a blast count 4%, comparable to the IPSS and WPSS. The inferior influence of karyotype on survival when compared with platelet count or age, found by Garcia-Manero et al., may be attributable to an oversimplification of karyotype risk groups. When we, for example, calculated the risk of AML evolution, unfavorable cytogenetics as defined by Garcia-Manero had no significant impact in contrast to cytogenetic risk groups according to IPSS. The latter are widely accepted. Recent analyses confirmed and refined these groups.5 The analysis by Haase and co-workers revealed a large number of rare chromosomal anomalies that carry a relatively good risk. These favorable-risk karyotypes, associated with a median survival of 3 years or more, are lumped together with intermediate-risk karyotypes (median survival about 1–2 years) and poor-risk karyotypes (median survival less than 1 year) by Garcia-Manero et al. Although we agree that it is desirable to make a scoring system as simple as possible, we believe that special attention must be paid to the karyotype. This is the most important variable in MDS prognostication as, in contrast to other parameters, it shows prognostic impact not only in untreated patients with de novo MDS, like the IPSS, but also in those treated with intensive chemotherapy or allogeneic stem cell transplantation, as well as in patients with therapy-related secondary MDS.

The main difference between the new score and the IPSS is the inclusion of age as a risk factor. Thus, the score especially separates older MDS patients. In our cohort, the median age was 55 years in the low risk, 68 years in the intermediate and 70 years in the high-risk group. In our opinion, this is not particularly useful in clinical practice because the decision to start early treatment is better informed by an assessment of the biology of the patient's bone marrow disease. The median age in the four WPSS risk groups on the other hand was 65, 67, 65 and 64 years (P=NS), respectively.

Identification of prognostic factors is more difficult for lower risk than for higher risk MDS because a large proportion of lower risk patients die without ever experiencing transformation to AML. It is difficult to develop a scoring system that is capable of reflecting the various causes of death in low-risk patients.

Due to the fact that MDS is a disease of the elderly several patients might die of causes unrelated to MDS. These patients are very likely selected by scoring systems including patient related variables like age, performance status and comorbidities. It would be conceivable to develop a score including only patient-related without disease-related variables to evaluate the general suitability of a patient for intensive treatment approaches. Usually the treating physician will be able to estimate the therapeutic risk-benefit ratio without such a scoring system, but it might be valuable within clinical trials.

Regarding patients who die from MDS related cytopenia but never develop AML, the degree of transfusion dependency and the related problem of transfusional iron overload are among the most interesting ‘new’ prognostic factors.3 Despite pointing out that a considerable proportion of MDS patients belong to that group, transfusion dependency is not validated by Garcia-Manero et al., and ferritin level is calculated in univariate analysis only, due to a large number of missing data, which is currently a problem within many MDS registries. In the next few years, the collection of data on these risk factors will likely improve MDS prognostication, although it remains to be seen if patients with high transfusion frequency benefit most from early intensive interventions, from therapies mainly targeting hematologic improvement (that is, growth factors, immunmodulatory drugs or inhibitors of histone deacetylase) or from consequent iron chelation.

Life threatening MDS-related complications include bleeding and infection, but severe thrombocytopenia (<30 × 109/l) and neutropenia (<0.5 × 109/l) are relatively rare in the lower risk groups. In our registry, patients with severe thrombocytopenia and neutropenia account for only 10 and 6%, respectively, of patients belonging to the IPSS low- and int-I-risk groups. Still, these patients are likely to benefit from early therapeutic intervention.

Concerning patients whose lower risk MDS undergoes leukemic transformation, existing scoring systems are suboptimal for this endpoint because they usually represent a compromise, trying to reflect both AML transformation and overall survival or consider survival only. Few variables have a clear impact on AML evolution, mainly medullary blast count and cytogenetics. Some other disease-related variables like β2-microglobuline, LDH, bone marrow fibrosis and the presence of small numbers of circulating blast cells might be useful for improving the accuracy of predicting early disease progression. Serum LDH levels, not included in Garcia-Manero's score, can separate two different prognostic subgroups within each IPSS risk category, including the low-risk (107 vs 63 months) and the int-I-risk group (66 vs 36 months).6 Elevated LDH is also an important predictor of AML evolution. Recently, we demonstrated that the presence of small numbers of blast cells (1%) in the peripheral blood significantly predicts inferior survival (P<0,00005) and increased risk of AML evolution (P=0,003) in patients with an otherwise lower risk MDS subtype (RA, RARS, 5q-, RCMD and RCMD-RS). This risk factor was independent of IPSS and LDH.7 A very recent analysis showed a more aggressive course of disease in patients with marrow fibrosis.8 This prognostic feature was independent of IPSS score and disease classification.

We agree with Garcia-Manero et al., that it is important to identify among patients with lower risk MDS those who are proper candidates for early therapeutic intervention. However, patient-related factors like age, performance status and comorbidities, despite strongly influencing survival, are not particularly useful to select patients for treatment approaches that go beyond best supportive care. In our opinion, this goal can only be achieved by adding appropriate disease-related variables to the IPSS and by improving the consideration of refined cytogenetic risk groups. Garcia-Manero and colleagues took a step in that direction by including β2-microglobulin and ferritin in their univariate analysis. These and other variables, for example, the degree of bone marrow dysplasia, transfusion dependency, marrow fibrosis, presence of peripheral blast cells and LDH, must be further evaluated in multivariate analyses. For the time being, the WPSS represents a suitable scoring system to identify MDS patients with a very long survival and a very low risk of AML evolution.

References

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Correspondence to A Kuendgen.

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Kuendgen, A., Gattermann, N. & Germing, U. Improving the prognostic evaluation of patients with lower risk myelodysplastic syndromes. Leukemia 23, 182–184 (2009) doi:10.1038/leu.2008.153

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