Favorable prognostic phenotype in myelodysplastic syndrome with der(1;7)(q10;p10)

Abstract Unbalanced translocation der(1;7)(q10;p10) is a characteristic chromosomal abnormality in myelodysplastic syndrome (MDS). The current study revealed that among 13 MDS patients with der(1;7)(q10;p10), seven cases with no apparent dysplasia also had low numbers of myeloblasts in the bone marrow and a 3‐year survival rate of 86%; in contrast, the remaining six cases had a 3‐year survival rate of 0% (P = .003). It was therefore suggested that MDS patients with der(1;7)(q10;p10) are classified into a distinct group with a favorable prognosis and another distinct group with a very poor prognosis.


Methods
All patients were diagnosed and classified according to the 2017 World Health Organization (WHO) revised definitions [5]. The evaluation of dysplasia of hematopoietic cells was confirmed by two independent morphologists who were unaware of the survival outcomes. Dysplasia was evaluated according to a grading system for the diagnostic accuracy of MDS [6]. At least 100 erythroid precursors, 100 neutrophils and precursors, and 25 megakaryocytes were observed in a bone marrow smear to determine dysplasia. The thresholds for dysplasia are ≥10% in each affected cell lineage. To determine the percentage of myeloblasts in the bone marrow, we identified 500 nucleated cells in the smear. The following parameters were retrospectively analyzed: age, sex, diagnosis, date of diagnosis, cytogenetics, peripheral blood parameters at diagnosis, history of therapy, presence or absence of LT, status at last follow-up, and date and cause of death.

Statistical analysis
The clinical data of der(1;7) patients were divided into patients with apparent dysplasia (dysplasia group) and without apparent dysplasia (no-dysplasia group  Table 1 shows the characteristics of the 13 patients (all male) with der(1;7) MDS, at the diagnosis, classified by the presence or absence of dysplasia in the bone marrow. The median age of seven cases (54%) without apparent dysplasia in at least one hematopoietic lineage was 72 years, which did not differ from that of the six cases with dysplasia (73 years; P = .8). The median percentage of myeloblasts in the nodysplasia and dysplasia groups was 1.4% (range, 0.4-2.2%) and 6.1% (range, 2.0-15.4%; P = .005), respectively. The number of neutrophils in the no-dysplasia group (median, 2.1 × 10 9 /L; P = .07) tended to be higher than that in the dysplasia group (median, 1.5 × 10 9 /L). The hemoglobin concentrations and platelet counts of the groups were not significantly different. These findings affected the difference in IPSS-R classification composition (P = 0.02).

Clinical outcomes
The no-dysplasia group showed significantly better 3-year OS than the dysplasia group (86% vs 0%, P = .003; Figure 1A); the median survival time of the two groups was 44 and 17 months, respectively. The LT rates of the no-dysplasia and dysplasia groups were 29% and 17%, respectively, which were not significantly different (P = 1.0; Figure 1B).
The main causes of death in the no-dysplasia group were infection (n = 2) and LT (n = 2), all six patients in the dysplasia group died of infection.

DISCUSSION
This study showed that MDS with der(1;7) was clearly divided into a favorable prognosis group (n = 7, 54%) with no apparent dysplasia and low numbers of myeloblasts in the bone marrow, and a poor prognosis group (n = 6, 46%) with dysplasia and increased myeloblasts in the bone marrow. In our study, 54% (7/13) of the cases were classified as myelodysplastic syndrome unclassified (MDS-U), according to the WHO classification; all cases in the no-dysplasia group were classified as MDS-U. Approximately half of MDS cases with der(1;7) were reportedly classified as MDS-U, which is consistent with our study [2]. The concordance of the evaluation of dysplasia by two independent morphologists in this study also supports the credibility of our study. In There was also a significant difference between the low-risk (very low or low or intermediate; n = 9, 69%) and high-risk (high or very high; n = 4, 31%) groups, classified according to IPSS-R, which showed 3- year survival rates of 67% and 0%, respectively (P = .003). The mechanism by which the presence or absence of dysplasia affected the prognosis and was correlated with the number of myeloblasts is unknown. A plausible hypothesis is that there may be differences in the gene mutation profiles between the two groups affected by dysplasia, the myeloblast count, and the prognosis. In a previous report [9], 845 (89.5%) of 944 patients with MDS had at least one gene mutation, and most gene mutations resulted in elevated myeloblast counts and a poor prognosis. Another report [10] showed that in MDS patients with der(1;7), those with TP53 mutations had a favorable prognosis. Furthermore, in patients with MDS or acute myeloid leukemia, TP53 mutation was reported to be associated with a better response rate to DNA methylation inhibitors in comparison to its absence (100% vs 41%, P < .001) [11]. In our study, DNA methylation inhibitors were used in three of seven patients in the no-dysplasia group and four of six in the dysplasia group; the survival times of these groups were 43-62 months and 8-25 months, respectively (P = .018), which may suggest that der(1;7) MDS patients with no dysplasia possess the TP53 mutation, which leads to a survival benefit. However, this requires validation, since a gene mutation analysis was beyond the scope of this study.
In the current study, the dysplasia group had more deaths from infectious diseases and early deaths due to infectious diseases than the no-dysplasia group; this difference affected the prognosis. This suggested that the natural and adaptive immune functions may be reduced in the dysplasia group. This is supported by the fact that all patients in the dysplasia group had dysgranulopoiesis. Neutrophil dysfunction is reportedly observed in all MDS patients with apparent dysgranulopoiesis, and such patients are more likely to develop infections [12]. If immunocompromise associated with neutrophil dysfunction is found to be responsible for the poor prognosis in MDS patients with der(1;7) with dysplasia, it may lead to the development of specific targeted therapies. However, because blood samples were not available in this study, the neutrophil function was not analyzed.
In our study, there was no correlation between the presence or absence of dysplasia and LT. The cause is unknown; however, five of six der(1;7) patients with dysplasia may have escaped LT because of premature death from infection at 8-34 months (median 17.5 months) after the diagnosis.
One major limitation of this study was the small study population.
The further accumulation of cases is necessary to validate the findings.
A second limitation is the lack of iron staining on bone marrow aspirate smears, although previous reports showed no patients with MDS with der(1;7) with ringed sideroblasts [3,4].
In conclusion, we showed that MDS patients with der(1;7) may be divided into favorable and poor prognosis groups based on the presence of dysplasia and the myeloblast count. Large-scale prospective studies and a comprehensive gene analysis are warranted to confirm the results, considering the importance of identifying MDS patients with der(1;7) who should avoid highly toxic treatments, such as allogeneic hematopoietic stem cell transplantation.

AUTHOR CONTRIBUTIONS
A. Takami

CONFLICT OF INTEREST
The authors declare no conflict of interest in association with the present study.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.