t-MDS Patients Research Articles

Altered neural activation pattern during teeth clenching in temporomandibular disorders.

The aim was to explore the neural activations during teeth clenching in TMDs patients pre- and post-treatment. Thirty TMDs patients and 20 controls underwent clinical evaluations and functional magnetic resonance imaging with a teeth clenching task. Eleven patients received repeat evaluation and imaging after wearing a stabilization splint for 3months. During teeth clench, the TMDs patients showed decreased positive activity in the left precentral gyrus, right and left inferior temporal gyrus, and left cerebellum and increased negative activations in the right medial prefrontal cortex (P<0.05 after AlphaSim correction). The 11 TMDs patients after treatment showed a return to normal neural activity in these areas. No brain areas in TMDs patients showed differences in activation after treatment compared with the controls, except for an increase in activation in the right cerebellum in the 11 TMDs patients (P<0.05 after AlphaSim correction). Decreased activations in cerebral areas associated with motor and cognitive functions in TMDs patients during teeth clenching were observed. Normalized activations of these areas happened in patients after routine treatment. These findings may facilitate the understanding of TMDs pathogenesis and the therapeutic mechanisms of the stabilization splint.

Clinical Features and Prognostic Assessment in 233 Patients with Therapy-Related Myelodysplastic Syndromes: The IPSS-R Is a Powerful Predictor of Outcome

▪BackgroundTherapy-related Myelodysplastic Syndromes (t-MDS) are those MDS occurring after cytotoxic and/or radiation therapy administered for a prior neoplastic or non-neoplastic disorder. Their prognosis is generally very poor. The commonly used risk prognostic models for MDS (IPSS and IPSS-R) are not validated in this entity as they were developed after the exclusion of therapy-related cases (Greenberg et al. Blood 1997; Greenberg et al. Blood 2012).AimsThe main aims of this study are: a) to report clinical findings and overall survival on 233 patients with t-MDS, and to compare them with a large series of de novo cases; b) to test if IPSS-R is applicable to t-MDS patients.Patients and methodsThe study is based on the Spanish Registry for MDS, a retrospective database that includes more than 10000 cases. The investigators were asked to fill in a questionnaire regarding prior disease (PD) and prior therapy in those cases reported to be t-MDS. Herein are described the clinical features and overall survival of the first 233 cases with the required information, and compared with patients with de novo MDS from a single center series (n=725). Log Rank test was applied to asses IPSS-R in t-MDS group.ResultsThe 233 reported patients were diagnosed between January 1993 and February 2014. The series includes 104 women (44,6%) and 129 men (55,4%). One hundred and two patients (43.9%) had a primary hematologic malignancy, 119 (51%) had a solid tumor, and 12 (5.1%) received cytotoxic therapy for autoimmune disorders. Ninety eight patients (42.6%) received only chemotherapy (CT), 45 (19.6%) received only radiotherapy (RT), 44 (19.1%) received combined modality treatment (CMT), and 43 (18.6%) received an autologous stem cell transplantation (ASCT). The median time of latency between PD and diagnosis in t-MDS group was 4.56 years (range: 0.03-29.63) in patients previously treated with CT or CMT, significantly lower than the observed after RT (8.54; range 0.83-23.02) or ASCT (8.64; range 2.87-28.32) groups (p=0.023 and p<0.0001, respectively). Median age, hemoglobin concentration, platelet count and absolute neutrophil count at diagnosis were significantly lower in t-MDS compared with de novo MDS, while bone marrow blast cell count was significantly higher. A higher proportion of high risk karyotypes (intermediate, poor and very poor categories of R-IPSS for cytogenetics) in t-MDS than in de novo MDS was observed (45.5% versus 25.6% respectively, p<0.0001). Within t-MDS cases, those patients who had received CT, CMT or ASCT also presented a higher proportion of high risk karyotypes compared with t-MDS after RT (52.1 vs 24.1% respectively, p=0.006). There was a significantly shorter median overall survival in patients treated with CT/CMT or ASCT in comparison with de novo patients or t-MDS patients treated with RT (14.88 versus 25.06 versus 47.18 months, respectively (log rank test < 0, 0001). In contrast, no difference between de novo and t-MDS after RT was found (median survival 53.6 months vs. 47.17 months, respectively, n.s). These findings are in concordance with previously published data (Nardi et al, JCO 2012) suggesting that some t-MDS after RT may not be truly t-MDS, but just coincidental. The IPSS-R prognostic score could separate t-MDS patients into five risk groups in terms of overall survival, with a median survival of 76.68 months, 38.73 months, 16.59 months, 13.3 months and 6.37 months, respectively (p<0.0001; Figure 1). A shorter overall survival for each category was found in t-MDS in comparison with de novo MDS, reaching statistical significance in the intermediate and high risk category and showing a trend towards significance in the very low and low risk categories (Figure 2).ConclusionsIn conclusion, our data supports the notion that t-MDS may contain entities with heterogeneous prognosis due to a diverse biological basis. The capacity of the IPSS-R for separating good prognostic from bad prognostic cases shown in this study could be very useful in the clinical setting in order to offer risk-adapted treatments to patients, although the development of a specific prognostic score for these entities would be needed. [Display omitted] [Display omitted] <![if !vml]><![endif]> [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The Role of Ribosomal Protein Deficiency in T-MDS Pathogenesis

Therapy-related myelodysplastic syndrome (t-MDS) is a lethal complication of cytotoxic cancer treatment and a leading cause of non-relapse mortality among patients undergoing autologous hematopoietic cell transplantation (aHCT) for lymphoma. The molecular abnormalities leading to t-MDS, however, are poorly understood. We are studying a prospective, longitudinal cohort of patients undergoing aHCT for lymphoma at our center with serial sample collection and banking. Using this approach we have identified impaired hematopoietic function and altered gene expression in CD34+ progenitor cells from pre-aHCT samples from patients who later developed t-MDS (cases) as compared to patients who did not develop t-MDS (controls) (Cancer Cell 2011, 20:591). These results indicate that genetic programs associated with t-MDS are perturbed long before disease onset. The alterations seen include down-regulation of genes related to ribosome biogenesis and translation, highlighting the potential contribution of altered ribosome function to disease development. Interestingly, a group of inherited ribosomal disorders including Diamond-Blackfan Anemia (DBA), called ribosomopathies, are characterized by cytopenias and a propensity for MDS development, features that closely resemble those of t-MDS patients. We evaluated the expression level of 79 ribosomal genes and a selected group of ribosome associated genes in cases and controls by multiplex Q-RT-PCR. Expression of DBA associated genes RPL10, RPL11, and RPL27 was significantly reduced in cases compared to controls. Each of these genes is reported to be associated with DBA. In addition, expression of p53, p21, c-Myc, and hdm2 were significantly upregulated in t-MDS cases. Altered expression of RPL11 is hypothesized to contribute to hematopoietic dysfunction by modulating the p53 ubiquitin ligase, HDM2, and activating p53-dependent apoptosis. We therefore characterized the effect of reduced RPL11 expression on hematopoietic function and determined the role of p53 activation in mediating the effects of RPL11 knockdown. We generated lentiviral vectors expressing shRNAs against RPL11 to reduce its expression in hematopoietic cell lines and CD34+ stem cell populations. Cells were cultured for 48 to 96 hours post-transduction followed by apoptosis analysis using Annexin-V staining, and proliferation by dye dilution assays. We confirmed >90% knockdown of RPL11 in shRNA expressing cells (MOLM13) by Q-RT-PCR and Western blot analysis. RPL11 knockdown resulted in 5-fold increase in apoptosis (Figure 1a) and 2-fold inhibition of proliferation of MOLM13 hematopoietic cells that express wild type p53, but did not affect survival and proliferation of p53 mutated HL60 cells. This suggests that cellular responses to RPL11 deficiency may depend at least in part on intact p53 signaling. This was confirmed in experiments showing that concomitant shRNA mediated knockdown of p53 and RPL11 (Figure 1a) resulted in a 2-fold reduction of apoptosis compared to RPL11 knockdown alone. Furthermore, RPL11 knockdown in CD34+ stem/progenitor cells resulted in 40% increase in apoptosis, 30% inhibition of proliferation and 90% decrease in colony forming cell (CFC) frequency in methylcellulose progenitor assays. We measured protein translation by measuring the intensity of an alkyne analog of puromycin (OPP) integrated into newly translated proteins, ligation to an azide dye, and flow cytometry analysis. We observed a 5-fold drop in global protein translation with RPL11 knockdown using the Click-iT Plus Alexa Fluor Protein Synthesis Assay (Figure 1b). Our results suggest that ribosomal abnormalities occur early in the course of t-MDS development and may lead to enhanced cell death and impaired proliferation. These results support a potential role of aberrant RPL11 expression in altered cell survival, proliferation, and differentiation, which may contribute to hematopoietic dysfunction seen early in the course of t-MDS development. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

1096 - Treatment of Primary and Therapy-Related Myelodysplastic Syndrome with 5-Azacytidine – Comparative Results from a Single Centre

ABSTRACT Introduction Therapy-related Myelodysplastic Syndrome (tMDS) is a late and rare complication of chemotherapy, especially that with alkylating agents or topoisomerase II inhibitors., They are often associated with unfavourable karyotypes, lower remission rates and shorter survival. PURPOSE: Retrospective analysis of clinical, analytical and cytogenetic features of patients diagnosed with primary (pMDS) and tMDS treated with 5-Azacytidine (AZA) between 2005 and 2011 in our Institute. Methods Data was obtained from patient notes and analysed with SPSS. Results 48 MDS patients treated with AZA were identified. 43 patients had pMDS, 57% male, median age of 67 years. The IPSS was Intermediate 2 in 42.9% and high in 40.5%; cytogenetics were normal in 33%, complex in 16.7%. A median of 7 courses (range 1-23) of AZA were administered, 52.4% as 2nd line therapy. Response assessment revealed 14.3% complete responses, 31% partial responses and 16.7% stable disease; best responses were reached after a median of 4 courses (range 2-6). Progression to secondary AML occurred in 38%; the mean survival was 25 months. Five patients had tMDS: 60% male, median age of 62 years. Previous chemotherapy included alkylating agents in 100% and topoisomerase II inhibitors in 80%. The median time to MDS development was 12 years. The IPPS risk was high in 80%; all with complex cytogenetics. A median of 6 courses of AZA were administered, 60% as 1st line therapy, with partial response in 40% (4 courses until response) and failure in 60%; 40% developed sAML and the mean survival was 12 months. DISCUSSION: Despite the small cohort size, our results were similar to those described in literature. Even with AZA treatment, tMDS patients had a worse clinical outcome, with shorter mean survival, compared to pMDS. Conclusion tMDS is a rare complication of chemotherapy with a very poor outcome. Careful review and individualization of chemotherapeutic regimens may help reduce its incidence. Disclosure All authors have declared no conflicts of interest.

Azacitidine for Treatment of Therapy Related Myelodysplastic Syndrome

Abstract 1712 Background:Therapy related MDS (t-MDS) is a rising challenge, it accounts for about 10%-15% of MDS cases. Outcome of t-MDS is generally poor. Azacitidine is currently standard of care for higher risk MDS based on AZA-001 randomized clinical trial demonstrating survival advantage. Efficacy of azacitidine in t-MDS is not well studied. We investigated the outcome of t-MDS patients treated with azacitidine at the Moffitt Cancer Center (MCC). Methods:This was a retrospective review of t-MDS cases treated at Moffitt Cancer Center (MCC) with azacitidine. Patients were identified through MCC MDS database and individual charts were reviewed. The primary objective was overall survival (OS) from time of azacitidine starting date. Patients were included if at least received one cycle of azacitidine. Disease status was defined by both the French American British (FAB) and the World Health Organization (WHO) classification systems, and risk was scored by the International Prognostic Scoring System (IPSS), and MD Anderson Scoring System (MDAS). Response to azacitidine was defined per the International Working Group (IWG 2006) criteria. All analyses were conducted using SPSS version 15.0. (SPSS Inc, Chicago, IL). Descriptive statistics were used for baseline characteristics and responses. Kaplan-Meier estimates were used to calculate overall survival (OS). Results:Between July 2004 and April 2010, 76 patients with t-MDS/AML were treated with azacitidine. The median duration of follow up was 58 months. The median age was 64.5 years (36–84). Majority of patients were Caucasians race 87% (n=66) and 55% (n=42) were male gender. The underlying malignancy was hematological malignancy in 38 patients (50%), solid tumor in 34 patients (45%), and 4 patients (5%) had both. Prior treatment for primary malignancy included chemotherapy in 44 patients (58%), chemoradiation in 23 patients (30%), and 9 patients (12%) received radiation therapy only. Fourteen patients received prior autologous SCT.According to WHO classification 2.6% (2) were Refractory anemia (RA), 3.9% (3) Refractory anemia with ring sideroblasts (RARS), 30.3% (23) refractory anemia with multilineage cytopenia (RCMD), 28.9% (22) refractory anemia with excess blasts I (RAEB-I), 25% (19) refractory anemia with excess blasts II (RAEB-II), 1.3% (1) CMML, 6.6% (5) AML, and 1.3 % (1) unknown. The IPSS risk was low in 1.3% (1), intermediate-1 (int-1) 19.7% (15), int-2 57.9% (44), high risk 17.1% (13) and unknown 3.9% (3). Based on MDAS the risk groups were 1.3% (1) low, 7.9% (6) int-1, 26.3% (20) int-2, 63.2% (48) high risk, and 1.3% (1) unknown. The cytogenetic risk groups were in 13.2% (10) good, 10.5% (8) intermediate, 72.4% (55) poor, and 1.3% (1) unknown.The median number of azacitidine cycles was 4 (Range 1–18). The response rates (IWG 2006 criteria) were 11.8% (9) CR, 2.6% (2) marrow CR, 10.5% (8) PR, 18.4% (14) HI, 14.5% (11) Stable disease (SD), 21.1 % (16) progressive disease (PD), and 17.1% (13) unknown. The overall response rate (CR+mCR+PR+HI) was 43.4 % (33). Among all patients 34.2% (26) had HI-E, 23.7% (18) had HI-N, and 32.9% (25) HI-P.The median OS was 14.9 months (95%CI 12.2–17.7) from start of azacitidine treatment. Twenty patients underwent allogeneic stem cell transplant (allo SCT). The median OS survival for patients who underwent allo SCT was 22.2 months compared to 13.6 months for those who did not. (p-value 0.015, log rank test). The median OS for patients who achieved SD or better best response with azacitidine therapy was 17.2 months compared to 8.3 months for patients with PD (p-value 0.014). Conclusion:Azacitidine is active in t-MDS; response rates are comparable to de novo MDS patients. Overall survival for t-MDS treated with azacitidine is slightly inferior to de novo MDS treated on AZA-001 study in general but similar to those with poor karyotype on the same study. Disclosures:Komrokji:Celgene: Honoraria, Research Funding, Speakers Bureau. Lancet:Celgene: Research Funding. List:Celgene: Consultancy.

Relationship of differential gene expression profiles in CD34+ myelodysplastic syndrome marrow cells to disease subtype and progression

AbstractMicroarray analysis with 40 000 cDNA gene chip arrays determined differential gene expression profiles (GEPs) in CD34+ marrow cells from myelodysplastic syndrome (MDS) patients compared with healthy persons. Using focused bioinformatics analyses, we found 1175 genes significantly differentially expressed by MDS versus normal, requiring a minimum of 39 genes to separately classify these patients. Major GEP differences were demonstrated between healthy and MDS patients and between several MDS subgroups: (1) those whose disease remained stable and those who subsequently transformed (tMDS) to acute myeloid leukemia; (2) between del(5q) and other MDS patients. A 6-gene “poor risk” signature was defined, which was associated with acute myeloid leukemia transformation and provided additive prognostic information for International Prognostic Scoring System Intermediate-1 patients. Overexpression of genes generating ribosomal proteins and for other signaling pathways was demonstrated in the tMDS patients. Comparison of del(5q) with the remaining MDS patients showed 1924 differentially expressed genes, with underexpression of 1014 genes, 11 of which were within the 5q31-32 commonly deleted region. These data demonstrated (1) GEPs distinguishing MDS patients from healthy and between those with differing clinical outcomes (tMDS vs those whose disease remained stable) and cytogenetics [eg, del(5q)]; and (2) molecular criteria refining prognostic categorization and associated biologic processes in MDS.

Temporomandibular Disorder in Mosul City.

Aims: To describe the subjectively perceived symptoms and frequency of the objective signs of the mandibular dysfunction and their severity by using Helkimo index ,age distribution and their relation to sex. Materials and methods: This study includes 450 TMDs patients, who admitted to TMJ clinic at college of dentistry in Mosul City, Helkimo index was used to assess the symptoms and signs of the TMDs and their severity. Results: It was found that TMDs most frequently affected the age group 21– 30 years. TMJ sounds (Clicking and Crepitation) were found as the most frequent symptoms (71.5%) followed by difficulty in opening (29.3%). No sex difference in relation to TMJ sounds was found p>0.05. Impaired TMJ function was the most prevalent sign (82.6%). No sex difference in relation to ITF was found p>0.05. Concerning the distribution of the patients according to Ai (Anamenstic dysfunction index). It was found that 51patients (11.3%) were symptoms free (Ai0), 169 patients (37.5%) reported mild symptoms (AiI) and 230 patients (51.1%) complained from severe symptoms (AiII). No significant sex difference in relation to Ai was found p>0.05. Regarding the distribution of the patients in relation to Di (Clinical dysfunction index).This study reveals that 7 patients (1.5%) were sign free (Di0), 114 patients (25.3%) with mild signs (DiI), 172 patients (38.2%) with moderate signs (DiII)and 157 patients (34.8%) with severe signs (DiIII). No significant sex difference in relation to clinical dysfunction index (Di) p>0.05 was found in this study. Conclusions: The age 21–30 years consider the high risk age group. The TMJ sounds were the most frequent symptoms. Severe symptoms (Ai II) and signs (DiIII) represents high percentages (51.1%) and (34.4%) respectively in a patients with TMDs in Mosul City.

Rapid Telomere Loss in Hematopoietic Cells Associated with Development of t-MDS after Autologous Transplantation for Lymphoma.

Therapy-related MDS (t-MDS) is a lethal complication of autologous hematopoietic cell transplantation (HCT) for Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). Although t-MDS is known to result from damage to hematopoietic stem cells (HSC) from genotoxic cancer treatment, the sequential cellular and molecular changes leading to its development are not known. To better understand t-MDS pathogenesis we are conducting a prospective study of a cohort of patients undergoing autologous HCT for HL and NHL. Patients are followed longitudinally from pre-HCT to 5 yrs post-HCT, with serial collection of marrow and blood samples. We investigated whether development of t-MDS after HCT was associated with altered telomere dynamics in hematopoietic cells. Telomeres are non-coding sequences at ends of chromosomes. Telomere shortening may be associated with genetic instability and myeloid leukemogenesis, and could predispose to t-MDS after HCT. Telomere length was measured in peripheral blood (PB) samples from 8 patients from the cohort who developed t-MDS after HCT and 24 matched controls who did not develop t-MDS (3 controls per case: matched for primary diagnosis, age at HCT, race and length of follow-up). Samples were analyzed pre-HCT and at d100, 6 months, 1 yr and then annually post-HCT till development of t-MDS. PB cells were mixed with equal numbers of 1301 cells, as internal controls, and hybridized with a telomere PNA-FITC probe. Relative telomere length (RTL) values (ratio of telomere signal of PB sample and control 1301 cells) were determined by flow cytometry (FlowFISH). RTL values of lymphoid and myeloid cells, identified by scatter properties, were separately analyzed. The median PBSC CD34+ count (106/kg) for cases was 4.9 (2.6–17.4) and controls was 5.2 (2.1–33.5). Differences in RTL were seen at several time points in t-MDS cases and controls for total cell, lymphoid and myeloid cells, but were most marked in the myeloid cells. Patients developing t-MDS showed reduced RTL pre-HCT (myeloid RTL: cases=18.2±4.8, controls=27.2±2.8); an increase in RTL at d 100 (myeloid RTL for cases=31.4±4.6, controls=19.6±2.5, p=0.04); and progressive reduction in RTL subsequently (myeloid RTL at 3 years: cases= 9.7±4.1, controls=22.0±2.2). An increase in RTL from pre-BMT to d 100 was seen in t-MDS patients (+16.0) but not in controls (−8.2) (p=0.004). A fixed effect growth curve model fitted to the data from d100 to 3 years to examine the rate of change in RTLs over time revealed a sharp decline in RTL for cases (β per 100 days = −1.93 for myeloid cells), but no change in RTL over time for controls (β = 0.07) (p = 0.02). In summary, we observed severely altered telomere dynamics in hematopoietic cells from patients who develop t-MDS post-HCT, with an initial increase in telomere length followed by a very sharp rate of telomere attrition till development of t-MDS. The initial increase in telomere length may reflect a need for increased recruitment of fresh HSC, with longer telomeres, to achieve hematopoietic recovery post-HCT. Subsequent rapid attrition of telomere length may reflect increased hematopoietic cell proliferation associated with ineffective hematopoiesis characteristic of MDS or represent altered telomere regulation in damaged HSC. Altered telomere regulation and reduced telomere length may contribute to leukemic transformation of HSC in t-MDS.

A Comparative Analysis of Outcomes in Primary Myelodysplastic Syndrome (MDS) and Therapy-Related MDS Reveals Two Subgroups with Differing Risk Profiles: Implications for the Application of a Prognostic Classification.

Myelodysplastic syndrome is a heterogenous clonal disorder stemming from an insult at the progenitor cell level. The development of an International Prognostic Scoring System (IPSS) based on bone marrow blast percentage, degree of cytopenia and karyotype has allowed the widespread application of the IPSS to guide therapy in patients with MDS. To date, there are no reports distinguishing primary MDS from therapy related MDS (t-MDS) in terms of outcomes within a treatment algorithm. We performed a comparative analysis of patients with primary MDS and t-MDS, to ascertain whether both groups have similar risk profiles and outcomes within a defined treatment protocol. Between 1995 and 2005, 95 patients were diagnosed with MDS at our centre with an average follow-up of 6 years. In total, 50 patients presented in a de novo setting of which 41 received intensive therapy and 9 patients received non-intensive treatment. Of the 45 patients diagnosed with t-MDS, 25 received intensive treatment and 20 patients were managed non-intensively. Therapeutic decisions were based on ECOG performance status and cytogenetic risk group. Demographic analysis of primary and t-MDS patients showed no significant differences when comparing age, sex, degree of presentation cytopenia, or median IPSS score (IPSS 2.0 for primary MDS and 1.5 for t-MDS, p=0.4). In the primary MDS group, 32 patients had an IPSS of ≥1.5 (INT-2/high risk MDS) compared to 27 patients in the t-MDS group. There were 18 patients with primary MDS and 18 patients with t-MDS in the INT-1/low risk category (IPSS ≤1.0). Cytogenetic analysis of primary MDS and t-MDS patients showed a greater frequency of complex karyotypes and chromosome 7 abnormalities in t-MDS patients. A normal karyotype was commoner in the primary group (19:6 patients respectively). The median overall survival (OS) was 25 months for primary MDS patients and 16 months for the t-MDS group (p=0.1). On multivariate analysis, WBC and blast percentage were independent predictors of OS in primary MDS patients (p<0.001, p=0.02). Using a WBC cut-off of 4.0, the median survival was 46 months if WBC <4.0 and 11 months if WBC ≥ 4.0 (p=0.003). IPSS score was not a significant prognostic parameter for this group. In t-MDS patients, Hb, platelets and IPSS score were all independent predictors of OS (p=0.05, p=0.04, p=0.009). WBC was not significant. This group had a median survival of 21 months if IPSS ≤1.0 and 10 months if IPSS >1.0, p=0.02). Remission rates were higher in primary MDS (86%) compared to t-MDS patients (68%) within the intensively treated arm (81% versus 39% for whole group, respectively). However, this did not translate into a better relapse free survival for primary MDS patients (p=0.9). Univariate analysis using binary logistic regression did not identify any factors that predicted response in the primary group. Age was a significant predictive factor for likelihood of response in the t-MDS group (p=0.008). These findings suggest that prognostic systems may need to be refined in MDS for patients presenting with de novo or therapy related disease. Adjustment for performance status may additionally contribute to risk based therapeutic protocols. According to our results, primary MDS may be more chemosensitive than t-MDS but if responses are obtained in t-MDS patients, they are maintained at a similar rate to primary MDS.

Therapy-related myelodysplasia and/or acute myeloid leukaemia after autologous haematopoietic progenitor cell transplantation in a prospective single centre cohort of 221 patients.

To evaluate the incidence and the predictive signs of therapy-related myelodysplasia and/or acute myeloid leukaemia (tMDS/tAML), we undertook a prospective study over a 4-year period of 221 patients who underwent autologous haematopoietic progenitor cell transplantation. Only seven patients (3.1%) were identified to have tMDS/tAML. Peripheral cytopenia was the first sign; diagnosis could be achieved by cytological analysis of bone marrow smears using World Health Organization criteria. All patients presented with bi- or trilineage dysplasia. Haematopoietic reconstitution was significantly delayed in patients progressing to tMDS/tAML compared with the control group. Typical cytogenetic abnormalities were observed in five of seven patients. The mean time interval between transplantation and cytological diagnosis, or detection of cytogenetic abnormalities, was 20.0 months and 31.2 months respectively. Pantelomeric fluorescence analysis using quantitative fluorescence in situ hybridization enabled us to make two major observations: (i) the fluorescence intensity in metaphases of all autografted patients was weak, and highly variable between tMDS patients; (ii) a drastic reduction of the telomere fluorescence intensity was observed in two patients who rapidly evolved to acute leukaemia. In conclusion, early detection of tMDS/tAML could be achieved by close follow-up of the bone marrow repopulation, and confirmed by cytological bone marrow examination and cytogenetic study. Our results address the implication of several factors, such as the initial telomeric status, and the effect of cytogenetic abnormalities and clonal expansion on bone marrow repopulation.