MDS with Ph chromosomes are very rare, with only a few cases reported to date. The vast majority of cases died or develop leukemia within a year [11–16]. In addition, the presence of Ph chromosomes may predict progression of the disease to leukemia. Fukunaga et al. reported a 76-year-old male with a karyotype of 46, XY, del (5q), add(16) (q13) at initial diagnosis of MDS, who progressed to AML 18 months later, when the Ph chromosome was also detected [29]. Katsuno et al. reported a 39-year-old man who was initially diagnosed with MDS without Ph chromosomes, but three months later progressed to acute non-lymphocytic leukemia and Ph chromosomes were detected [30]. These results indicate that Ph chromosomes promote malignant progression of MDS. However, these conclusions are based on a small number of case reports, which require further verification in clinical cohort studies. To the best of our knowledge, this is the first cohort study on the clinical characteristics and outcomes of patients with Ph chromosomal MDS.
In our study, there were no significant differences in age, sex, disease type and morphological changes between the groups of MDS patients with and without the Ph chromosome abnormality. However, the WBC count of MDS patients with the Ph chromosome patients was higher than that of MDS patients without the Ph chromosome. There were no significant differences in hemoglobin and platelet counts between the two groups. We suggest that the higher WBC counts in MDS patients with Ph chromosomes may be due to increased tyrosine kinase activity, which promotes myeloid cell dysplasia.
It is also worth noting, the proportion of primitive cells in BM and the IPSS-R score of MDS patients with Ph chromosomes was higher than that in MDS patients without Ph chromosomes, with the differences close to the level of statistical significance. Although our study on this topic was conducted in the largest cohort so far, only 17 MDS patients with Ph chromosomes were included. Therefore, we speculate that a statistically significant difference may be identified in further studies with more patients. Indeed, previous studies have confirmed that the BM blast percentage is one of the most important independent risk factors for progression to leukemia and death in patients with MDS [26]. Our data indicate that MDS patients with Ph chromosomes have a higher potential to progress to leukemia at the onset of the disease and a poorer prognosis than MDS patients with Ph chromosomes. These results also support previous findings that the presence of Ph chromosomes in MDS patients implies a transition to leukemia and poor prognosis [11–16].
Due to the reported influence of karyotype complexity on the prognosis of MDS patients [26–28], we performed further subgroup analyses. We observed that the percentage of blast cells in the BM and the number of patients diagnosed with RAEB-2 in were higher in MDS patients with isolated Ph chromosomes than in MDS patients with normal chromosomes. These results suggest that MDS patients with isolated Ph chromosomes have a higher risk of progressing to leukemia than MDS patients without chromosomal aberrations. However, we did not obtain similar results in MDS patients with Ph chromosomes with additional abnormalities. In a careful review of the included cases, we found that some of the included patients with Ph chromosomes with additional abnormalities had only 5q- abnormalities in addition to the Ph chromosome. Previous studies have confirmed that 5q- anomalies can delay the malignant progression of MDS [31–34]. Therefore, we hypothesize that the 5q- abnormality overrides the apparent ability of the Ph chromosome to promote disease progress, thus leading to the differences in the results of patients with Ph chromosomes with additional abnormalities compared with patients with isolated Ph chromosomes. In addition, we found that patients with Ph chromosomes with additional abnormalities were mainly concentrated in the extremely high-risk group according to IPSS-R scores. The number of patients in the low-risk group of patients with isolated Ph chromosomes was significantly higher than that of patients with chromosomal abnormalities without Ph.
In our cohort, we observed that the OS and LFS of MDS patients with Ph chromosomes were significantly shorter than MDS patients without Ph chromosomes. These findings suggested that MDS patients with Ph chromosomes have a high-risk of conversion to leukemia and a poor prognosis, which is consistent with previous reports [11–16]. For a more accurate prognosis, we analyzed the outcomes of the isolated Ph chromosome group and the additional chromosome abnormal group compared those of the MDS patients with Ph chromosomes patients. The OS of patients in the isolated Ph group was significantly shorter than that of those in the normal chromosome group, but significantly longer than that of patients in the Ph with additional abnormalities group. Furthermore, although the difference in the OS of the isolated Ph group compared to that of the chromosomal abnormalities without Ph group was not statistically significant, we observed that patients with chromosomal abnormalities without Ph had a better survival advantage than patients with isolated Ph. Patients in the Ph with additional abnormalities group had significantly shorter OS than those in the other three groups. The LFS of patients in the isolated Ph group was significantly shorter than that of those in the normal chromosome group and chromosomal abnormalities without Ph group. There was no significant difference in the LFS of the isolated Ph group and the Ph with additional abnormalities group. The LFS of patients in the Ph with additional abnormalities group was also significantly shorter than that of those in the normal chromosome group and chromosomal abnormalities without Ph group. These data suggest a poor prognosis for patients with isolated Ph chromosomal abnormalities and those with Ph with additional abnormalities, especially those with Ph with additional abnormalities. It is noteworthy that in the analysis of patient characteristics, we found that patients with isolated Ph abnormalities had lower IPSS-R scores than those with chromosomal abnormalities without Ph chromosomes. According to this result patients with chromosomal abnormalities without Ph chromosomes should theoretically have a worse prognosis than those with isolated Ph chromosomes, but we found the opposite in our survival analysis. Therefore, we conclude that Ph chromosome aberration may be an important predictor of poor prognosis in MDS patients, and if it can be included in IPSS-R, it will be a supplement to the current scoring criteria. Of course, this requires further verification in a larger sample study.
Our analysis suggests that elevated WBC count and the presence of the Ph chromosome are risk factors for OS in MDS patients, and BM blast percentage and the presence of the Ph chromosome are risk factors for LFS in MDS. Furthermore, we identified the presence of the Ph chromosome as an independent risk factor for OS and LFS in MDS. These data provide further evidence that Ph chromosomes may be predictors of poor prognosis in MDS. In accordance with previous studies, we found that prognostic risk factors of MDS include BM blast percentage, peripheral blood cytopenia, and BM cytogenetic abnormalities, while high WBC count is not [26, 35]. Our analysis of the included cases revealed that patients with high WBC count were mainly in the MDS patients with Ph chromosome aberration group. A study by Hasford et al. in 2060 patients treated with imatinib demonstrated that elevated WBC count was a prognostic risk factor for CML [36]. In a study of 610 cases of acute lymphoblastic leukemia with the Ph chromosome, Arico et al. found that leukocyte elevation was an independent risk factor for prognosis [37]. Based on results combined with our own studies data, we hypothesize that the mechanism underlying the influence of the Ph chromosome in MDS patients may have similarities with that in ALL and CML, and high WBC may also be a prognostic risk factor for Ph-positive MDS. However, this is conjecture that requires confirmation in further studies.
In conclusion, we showed that MDS patients with Ph chromosome have a poorer prognosis and are more likely to convert to leukemia than patients with MDS without Ph chromosomes, especially in patients with Ph chromosomes with additional abnormalities. In terms of baseline characteristics, patients with Ph chromosomes had higher WBC, but there were no significant differences in age, sex, disease characteristics, and morphological changes compared with patients without Ph chromosomes. In addition, Ph chromosomes may be important prognostic predictors. If inclusion of it can be included in the IPSS-R in future, which will may be a supplement to the current scoring criteria.