| Objective:To elucidate the incidence and risk factors for clonal evolution in aplastic anemia (AA) patients.Methods:We used the Cumulative incidence curves to estimate the probability of evolution to paroxysmal nocturnal haemoglobinuria (PNH) or myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) in 802 hospitalized AA patients from January,1991 through December,2007. The Cox proportional hazards model was used to assess the risk factors for evolution to MDS/AML or PNH.Results:①A total of 802 patients met the eligibility criteria including 174 very severe AA (VSAA,21.7%),335 severe AA (SAA,41.8%) and 293 non-severe AA (NSAA, 36.5%)。Median follow-up period for all patients is 71 months and the median age was 23.0 years. The overall survival at 5 years after diagnosis was 77.2%. Thirty-eight patients (38/802,4.7%) were considered to have evolved to a new hematologic disorder. The cumulative incidence of clonal evolution was estimated as 3.7%(95 percent confidence interval,2.6%—5.3%) and the incidence of MDS/AML was 1.7%(1.0%—3.0%), PNH 2.1%(1.3%-3.4%) at 5 years.②We found 19 patients evolved to MDS/AML between 12 and 240 months (median,33 months) following initial AA diagnosis. Median age at diagnosis of AA was 37 years (9-59 years). The median evolution time of patients treated with rhuG-CSF more than 300 days was 20.5 months (12-37 months) compared with 88 months (29-240 months) for patients with 0-100 days rhuG-CSF therapy (P=0.001). Cytogenetic analysis of bone marrow at the time of diagnosis of MDS revealed monosomy 7 (11 patients), trisomy 8 (1 patient),20q-(1 patient) and normal karyotype (5 patient), while at initial diagnosis they all had a normal karyotype. The prognosis was very poor and 12/19(63.2%) died at the median follow-up time of 13 months (2-95 months) after evolution.③By multivariate analysis, age (P=.007, RR=1.043), severity of disease (P=.001), and the number of days rhuG-CSF therapy (P=.000, RR=1.005) are associated with translation to MDS/AML. The RR for VSAA is 6-7 times higher than that for SAA and NSAA (P=.001), but the last two do not differ significantly (P=.743). Age and the number of days rhuG-CSF therapy were analyzed as a continuous variable and each year or day increases the risk of evolution by about 4.3% or 0.5%, respectively. RR for patients who received rhuG-CSF longer than 300 days was 21 times higher than that for patients who did not receive rhuG-CSF (P< 0.001, RR=21.919), but there was no statistical difference between 0 day and 1-89 days or 90-300 days of rhuG-CSF therapy (P>.10).④In addition, there are 9 patients developing clonal abnormalities without the morphologic features of MDS. Trisomy 8 (3 patients) and monosomy y (2patients) and add 13 (2 patient) were noted in these patients. All of them responsed to IST and were alive at a median follow up 114 months (51-210 months).⑤Twenty-one patients developed to overt PNH, and 2 of them combined with MDS. Median age was 25 years (11-43 years) and the median time of evolution was 24 months (6-216 month).17/21(81%) patients are alive at 92 months (29-313 moths) after dianosis of AA or 52 months after evolution. By univariate analysis, transformation to PNH was not statistically significantly associated with death (P=0.216).⑥As for evolving to PNH, white blood cell count at initial diagnosis is the only significant risk factor (P=.007, RR=1.453). It was worth mentioning that Hemoglobin, Reticulocyte count, with or without PNH clone at initial diagnosis, treatment and response to IST were all not linked with evolving to PNH.⑦PNH clone was monitored sequentially in 237 patients and transient or instable PNH clone were detected in 26.2%patients compared with persistent PNH clone in 14.8%patients including 4.2% developed to overt PNH.Conclusions:①Patients with older age, VSAA and long-term rhuG-CSF therapy are at higher risk for evolving to MDS/AML.②long-time administration of rhuG-CSF should be avoided and it is necessary to monitor morphology and cytogenetics in AA with long-term rhuG-CSF. Furthermore, normalizing hematopoiesis of AA may represent a viable approach to prevent clone evolutions, especially to MDS/AML.③The appearance of abnormal clone does not necessarily mean the subsequent expansion of those clones. Transformation to PNH for subpopulations of AA patients may be natural evolution and PNH clone should be detected serially after therapy. Objective To explore the clonal evolution of monosomy 7 in patients with aplastic anemia (AA) and the clinical implications of small monosomy 7 clones at initial diagnosis.Methods We retrospectively detected-7 clones by interphase-fluorescence in situ hybridization (FISH) in 81 AA patients with normal karyotype at initial diagnosis. We also performed serial analyses of -7 clones in 46 AA treated with immunosuppressive therapy (IST) and more than 6 months of recombinant human granulocyte colony-stimulating factor (rhuG-CSF).Results We disclosed 5.4%—7.6% monosomy 7 cells in 11 (13.6%) of 81 patients at initial diagnosis of AA, the survival and response rate to IST of the 11 patients did not differ significantly from that of the other 70 patients (P=.481,.865); Monosomy 7 cells disappeared after IST in all of 11 patients including 5 received long-term rhuG-CSF administration, and none of them evolved to myelodysplastic syndromes/acute myeloid leukemia (MDS/AML) at a median follow-up of 44 months. Serial assessments of-7 clones were performed in 46 patients, none of them detected-7 clones 3-6 months after IST, but we detected-7 in 5 patients 12-15 months after IST, at a median follow up time of 48 months, FISH identified 6 patients with-7 clones while the conventional cytogenetic analysis (CCA) recognized in 5. Moreover, the time when-7 was first evident by FISH was 3-18 months earlier than that by CCA. All of the 6 patients evolved to MDS/AML with -7 and four of them were retrospectively analysed -7 at initial diagnosis of AA, but none of them waspositive.Conclusions Monosomy 7 existed in a part of AA onset, but the preexisting -7 cells seemed neither associated with fatality nor evolving to MDS/AML. rhuG-CSF might facilitate the expansion of -7 clones; thus it should be necessary to monitor -7 in AA, especially received long-term rhuG-CSF administration. |
PDF Full Text Request