Risk Of AML Transformation Research Articles

Understanding What Matters to Myelodysplastic Syndrome Patients - a Study of Preferences for Treatments with Hypomethylating Agents

Introduction/Background: Hypomethylating agents (HMAs) are the standard of care for the treatment of myelodysplastic syndrome (MDS). Understanding how patients with MDS perceive and value different HMA characteristics provides critical treatment selection insight for healthcare providers. Objectives: To understand HMA preferences for United States (US) and Canadian patients with MDS. Given HMAs’ treatments’ similar efficacy and safety profiles, we also investigated how HMA administration burden can play a role in patients’ preferences when all other factors are equal. Materials and Methods: We used the discrete-choice experiment (DCE) method to conduct a preference study in collaboration with patient organizations in the US and Canada (i.e., MDS Foundation, the Aplastic Anemia and MDS International Foundation, and the Aplastic Anemia and Myelodysplasia Association of Canada). The study was comprised of two Phases: (1) a qualitative Phase (i.e., DCE survey design) and (2) a quantitative Phase (i.e., DCE survey implementation). In Phase 1, literature review, interviews with clinician, patient and caregiver, and input from the patient organizations informed the DCE survey design. Qualitative interviews were analyzed through content analysis. In Phase 2, survey participants answered a series of DCE choice tasks to indicate their preference between different hypothetical HMA profiles that varied in characteristics (i.e., attributes). Respondents were also asked to indicate their preferences by choosing between HMA profiles mirroring real-life options, all associated with the same risk of AML transformation and level of fatigue but differing in mode of and frequency administration: IV HMAs requiring 5 days or 7 days of treatment session each month, SC HMA with 5 sessions each month, oral HMA and no treatment. Survey results were analyzed using random parameter logit models. The relative importance of attributes (RAI) was calculated, which is the contribution (expressed in percentages) of each attributes relative to all attributes in patient preferences. A larger RAI percentage score shows that the attribute has a larger effect on how the respondents make their decisions. All patient respondents were recruited through the patient organizations’ networks. Results: 16 Phase 1 respondents completed the interview and 184 Phase 2 respondents (including 158 patients and 26 caregivers serving as patient proxies) completed the DCE survey. Interview respondents in Phase 1 valued efficacy attributes (i.e., risk of AML transformation and fatigue) and expressed the treatment burdens associated with injectable treatments (such as injection site reaction, stressful experience of damaged veins, burden of travelling to clinic, etc.). The Phase 2 survey participants had a mean age of 67.2 years old and 88% were from the US. About one-third of the survey participants did not know their MDS risk, 35% were low risk and 31% were high risk. Most (56%) participants were currently receiving treatment, while 24% had received treatment but discontinued and the remaining 20% had not received treatment. The attributes’ importance rankings (via RAI) were risk of AML transformation (40%), fatigue level (33%), number of visits (12%), mode of administration (6%), visit duration (5%), and administration frequency (4%). When HMA treatments were assumed to be associated with the same risk of AML and level of fatigue but to differ in terms of mode and frequency administration, 77% of respondents were predicted to switch to an oral pill if available to them. When considering real-life profiles, 77% and 88% of participants considered the oral option to be the best choice and no treatment to be the worst one, respectively. Conclusion: MDS patients demonstrated strong preferences for HMA with lesser treatment burden (i.e., oral pill) when such agents are with similar treatment efficacy and safety profiles. Understanding patients’ treatment preferences can facilitate shared decision making towards optimal management of MDS.

Del5q with One Additional Cytogenetic Abnormality Other Than Del20q Identifies a Higher Risk Population of MDS Patients

Background: According to the IPSS-R cytogenetic risk classification for myelodysplastic syndrome (MDS), patients with isolated deletion 5q (del5q), isolated deletion 20q (del20q), and del5q with an additional cytogenetic abnormality are classified as having good cytogenetics, similar to those with a normal karyotype. However the international database study, on which the IPSS-R cytogenetic risk classification is based, has its limitations in the small number of patients with del5q plus one additional cytogenetic abnormality (n=46). We sought to further define the prognostic significance of del5q with one additional cytogenetic abnormality in an evaluation of 86 patients. Methods: We performed a retrospective analysis of 857 MDS patients with a karyotype of isolated del20q (n=160) or any karyotype involving del5q seen at a single tertiary cancer center between 1987-2021. Patients with del5q (n=697) were divided into 3 cohorts: isolated del5q (n=147), del5q with concomitant del20q (del5q+del20q, n=8), and del5q with a non-del20q cytogenetic abnormality (del5q+1, n=78). The remainder of del5q patients with complex karyotypes were excluded. Patient characteristics, laboratory values, and bone marrow data, including blast percentage and cytogenetics, were reviewed. Median OS was estimated using the Kaplan-Meier method and two-tailed log-rank test. Results: The median age of patients was 70 years, with the majority being male (58%). Patients were more likely to present with lower risk disease (IPSS low to int-1, 78% of patients). The median follow-up was 2 years. Patients with del5q+1 had an inferior survival when compared to patients with isolated del5q (median OS 1.78 years vs. 3.87 years, p=0.0047). Del5q+1 patients also had a higher risk of AML transformation (26% vs. 16%, p=0.098, table I) with a shorter median time to AML transformation (1.07 years vs. 3.46 years, p<0.0001, figure 1). A multivariate analysis of the combined del5q and del5q+1 cohort was performed, which evaluated age >60, percent blasts in the bone marrow, IPSS score, and cytogenetics. The only statistically significant prognostic factors for OS with a p-value <0.01 were age>60 (HR: 3.67 (2.24-6.0), p<0.0001 ) and cytogenetics (HR for del5q+1: 1.96 (1.3-2.9), p=0.001). The only prognostic factor for time to AML transformation with a p-value <0.01 was cytogenetic classification (HR for del5q+1: 5.2 (2.0-13.2), p=0.0006). Patients with del20q had an OS between that of del5q (2.63 years vs. 3.87 years, p=0.14) and del5q+1 (2.63 years vs. 1.78 years, p=0.18). Del20q patients were less likely to transform to AML when compared to del5q+1 patients (11% vs. 26%, p=0.0035) with a trend towards longer time to AML transformation (2.1 years vs. 1.07 years, p=0.09). There were no statistically significant differences in AML transformation between the del5q and del20q cohorts (20% vs. 11%, p=0.1; median time to AML transformation: 3.46 years vs. 2.1 years, p=0.1). The evaluation of OS and risk of AML transformation in patients with del5q and a contaminant del20q was limited due to low patient numbers (n=8, 1.1%). The median follow-up for these patients was 2.67 years, and none of the patients transformed to AML during this time. Two patients (25%) expired from the non-disease related causes of presumably underlying heart failure and massive pulmonary embolism following surgery. Interestingly, both deceased patients had >10% bone marrow blasts and were IPSS intermediate risk. The median OS for these 8 patients was not reached. However, the median follow-up time of 2.67 years may suggest their OS is better than those with del5q+1 (median OS ≥2.67 years vs. 1.78 years). Conclusion: Contrary to the suggested IPSS-R cytogenetic risk stratification scheme, this analysis demonstrates a significant difference in terms of OS and risk of AML transformation when patients with isolated del5q or isolated del20q were compared to patients with del5q+1. Patients with del5q+1 had inferior median OS and a shorter time to AML transformation, suggesting more aggressive management may be warranted in this population. Though rare, patients with del5q+del20q may have better clinical outcomes than those with del5q+1, warranting further investigation into this group of patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Patient Preferences for Benefits, Risks, and Administration Route of Hypomethylating Agents in Myelodysplastic Syndromes.

Therapy with infused or injected hypomethylating agents (HMAs) may lead to higher treatment administration burden (ie, local reaction, visit frequency and duration) vs. oral HMAs. OBJECTIVES: To reveal preferences of US and Canadian patients with myelodysplastic syndromes (MDS) for HMAs' benefits, risks, and administration burden through an online discrete-choice experiment (DCE). Choice of DCE attributes and survey development were informed by literature review and interviews with clinicians, MDS patients, and caregivers serving as patient proxies, and patient advocacy groups (PAGs) representatives, including from AAMAC, AAMDS, and MDSF. DCE choice tasks were analyzed using random parameter logit models. Survey patients were recruited by the PAGs via their networks. To understand key preference drivers and how much patients were willing to trade between attributes, we calculated each attribute's relative attribute importance (RAI) and marginal rates of substitution. One hundred eighty-four respondents (including 158 patients; mean age, 67.2 years; male, 50.5%; White, 50.5%; US residents, 88%) completed the survey. MDS risk was low (34.8%), high (30.9%), or unknown (34.2%). RAI (in decreasing order) was as follows: risk of AML (40%), fatigue level (33%), number of visits (12%), mode of administration (6%), visit duration (5%), and administration frequency (4%). Assuming the same risk of AML transformation or level of fatigue, most respondents (76.6%) were predicted to switch to an oral pill if it were available to them. Given equivalent effectiveness across HMAs, patients' preferences for HMA administration method should be considered in treatment decision-making to minimize burden and facilitate adherence.

The Monosomal Karyotype Is an Independent Predictor of Poor Survival and Risk of AML Transformation in Patients with Myelodysplastic Syndrome

The revised international prognostic scoring system (IPSS-R) improved cytogenetic prognostic classification in comparison with IPSS classification in patients with myelodysplastic syndromes (Greenberg P et al. Blood 2012, Schanz J et al. JCO 2011). Monosomal karyotype (MK) defined as the presence of at least two autosomal monosomies or one monosomy associated with structural abnormalities has been investigated in MDS patients with contradictory results regarding its independent prognostic significance (Patnaik M et al. Leukemia 2011, Gangat N et al. AJH 2013, Valcarcel D et al. JCO 2013).The aim of this study was to investigate the prognostic significance of MK in relation to IPSS-R and the presence of complex karyotype (CK).The study was conducted in 391 patients with primary MDS treated at three hematology departments in Serbia. The median age was 65 years, from 15 to 89 years. There was a predominance of male patients who made 60% (235) of patients. 229 (58 %) patients died. 87 patients (22 %) transformed to AML. The sixty eight % of patients were transfusion dependent. Disease modifying treatment was applied in 48 (12.3%) of patients (AML like chemotherapy in 37 patients, low dose ara-c in 11 patients, stem cell transplantation in five patients, and in one patient azacitidine). The rest of the patients received supportive treatment.Karyotypes were classified according to the International System for Cytogenetic Nomenclature Criteria. The inclusion of patients was based on criteria used in IPSS-R classification (a white blood cell count ≤12x109/l, an absolute neutrophil count ≤8x109/l, peripheral blood blasts ≤19%, and bone marrow blasts ≤30%).The distribution of patients according to FAB classification was as follows: 129 (32.99%) RA, 47 (12.02%) RARS, 143 (36.57%) RAEB, 48 (12.27%) RAEB-T, and 22 (5.6%) non proliferative CMML. The classification according to WHO 2008 classification was as follows: RCUD 29 (7.43%), RARS 39 (9.97%), RCMD 90 (23.01%), RAEB1 78 (19.95%), RAEB2 65 (16.62%), AML/RAEB-T 48 (5.27%), 5q- 11 (2.81%), MDS-u 7 (1.8%), CMML 1 15 (3.83%), CMML 2 7 (1.8%).IPSS-R distribution was: very low risk 38 (9.71%), low risk 108 (27.6%), intermediate risk 86 (21.99%), high risk 83 (21.23%), very high risk 74 (18.9%). Two patients could not be classified because of lack of all data.Median number of metaphases was 15, from 2 to 30. The abnormal karyotype was found in 166 (42.45%) patients.CK defined as the presence of at least three cytogenetic aberrancies was present in 32 patients (8.18%) with median survival of 5 months. CK shown prognostic significance regarding the overall survival (OS) (p = 0.00001) as well as time to AML transformation (p = 0.00014).MK was detected in 34 patients (8.69%). The patients with MK had significantly shorter OS in comparison with patients without MK (median survival 5 months versus 34 months, p < 0.00001, Figure 1) as well as a shorter time to AML transformation (p = 0.00006, Figure 2). If we included only the patients who have MDS according to 2008 WHO classification MK shown prognostic significance for OS (p = 0.00121) as well as for time to AML progression (p = 0.00010). The presence of MK defines the group of patients with shorter OS in high risk and very high risk IPSS-R prognostic groups (p=0.008, Figure 3). In multivariate analysis, MK shown to be independent predictor of poor survival together with age, haemoglobin concentration, platelet count and bone marrow blast cells (p<0.001, HR 2.97, 95% CI 1.91-4,66) as well as for the risk of AML transformation with bone marrow blasts and platelet count (p<0.001, HR 3.44, 95% CI 1.79-6.61).In 29 patients MK was associated with CK. However, in five patients (16% of MK + patients) with monosomy and an additional aberration who do not fulfil the criteria for CK the OS seems to be very short (median survival 3.5 months). The significance in OS between this small group of patients and other patients excluding the patients with CK was not significant (p=0.09). Yet, only in one case of MK cytogenetic aberrations were defined as high risk according to IPPS-R cytogenetic classification.In conclusion, MK has an independent prognostic significance for survival and risk of AML transformation in MDS patients particularly in high and very high risk IPSS-groups. In majority of patients with MK there is an association with complex karyotype. Yet, there are a few patients with MK who do not have CK and seems to have unfavourable prognosis. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Comparison of DNA Methyltransferase Inhibitors in Patients with Myelodysplastic Syndrome

The aim of this retrospective study was to compare the response rates (RR), overall survival (OS), time–to–acute myeloid leukemia–transformation (TTAMLT), hematologic toxicity and transfusion requirement of azacitidine and decitabine in patients with Myelodysplastic Syndrome Refractory Anemia with Excess Blasts (MDS RAEB) types 1 and 2. A total of 51 patients (35 male, 16 female, median age (years): 67) diagnosed with MDS RAEB-1 and RAEB-2 treated with azacitidine (n=31) or decitabine (n=20) in three Turkish institutes were evaluated . Response to treatment was classified according to International Working Group response criterias. Competing risk analysis was used to compare TTAMLT. There was no significant difference between the two groups in terms of age, gender, performance score, diagnosis, etiology, treatment cycles, bone marrow cellularity and blast percentage. Most patients received at least 4 cycles of azacitidine or decitabine. Patients who received azacitidine or decitabine had comparable response rates (58.1% vs 66.7%, respectively, p= 0.55). There was no difference in terms of red blood cell and platelet transfusion requirement and febrile neutropenia episodes (p= 0.46, p= 0.27, p= 0.19, respectively). Median follow–up was 31 months for azacitidine and 20 months for decitabine. Median OS was 18.4 months for azacitidine and 13.4 months for decitabine (p= 0.16). Only predictor of OS was at least 4-cycle treatment with any DNA methyltransferase inhibitors. 1–year risk of AML transformation was comparable across the groups (26% vs 33%, p= 0.55). In conclusion, both azacitidine and decitabine have similar efficacy and toxicity profiles in the treatment of MDS RAEB-1 and RAEB-2. Until a head–to–head comparison in prospective, randomized studies are conducted, the current source of available data will derive from meta–analyses that consist of the indirect comparison of treatment arms, or retrospective analyses with inevitable biases. DisclosuresNo relevant conflicts of interest to declare.

Time Changes In Predictive Power Of MDS Prognostic Scores – Effects On Revised Scores Such As The IPSS-R, Impact Of Age

▪ IntroductionNew, refined prognostic scoring systems have been established for MDS. Most scores assess prognosis at time of diagnosis assuming stable prediction over time. Earlier studies have shown moderate loss of prognostic power over time in scores using clinical parameters whereas cytogenetic scores maintained prognostic power, scores including comorbidity had shown gain of prognostic power (Pfeilstöcker et al, 2012).The aim of this multicenter retrospective study was to assess the relative stability of the newly developed scoring systems over time, to compare and explain observed time-related losses of prognostic power, and to discuss their clinical implications. MethodsThis study is based on 7212 untreated (no disease modifying treatment) MDS patients from multiple institutional databases of the IWG-PM, which generated the IPSS-R (Greenberg et al, 2012). Patient characteristics were well comparable with other populations: median age 71 years, male gender 60 %, median overall survival 3.8 years (range 3.7-4.0), median time to AML transformation not reached with 25% of patients transforming to AML after 6.8 years. Patients were diagnosed and classified by FAB and WHO; cytogenetics were classified by original IPSS subtypes and by the recently refined proposal integrated into the IPSS-R (Schanz et al, 2012). The following scores were analysed for their stability over time: IPSS, IPSS-R, WPSS variants, cytogenetic scores, age, performance status and other differentiating features of the IPSS-R. Time variations were described by the Cox-zph-test, and by applying Dxy, a measure of concordance, for censored data at separate observation periods. ResultsIn line with previous observations, loss of prognostic power occurred over time after diagnosis in all scoring systems. While for the entire population the risk between adjacent IPSS-R risk categories differs by ∼80%, for patients observed at least 1 year the increase is ∼66%, and for those observed 4 years it is only ∼25%. The IPSS-R and particularly its age-including version (the IPSS-RA) retained the highest prognostic values compared to all other scoring systems at all time points. Dxy for IPSS-R: at diagnosis 0.43, 1 year 0.35, 2 years 0.27, 4 years 0.14. Including age, as in the IPSS-RA, was associated with less loss of prognostic power over time: Dxy at diagnosis 0.46, 1 year 0.38, 2 years 0.31, 4 years 0.22. For the IPSS and WPSS (available for the latter in only 33% cases), these values were: 0.37, 0.30, 0.22, 0.11 and 0.44, 0.36, 0.29, 0.18 respectively.Considering risk categories, the risk remained fairly constant over time for the lower risk categories in every analyzed scoring system, while the risks in the higher risk categories were especially high in the second half of the first year after diagnosis, diminishing thereafter, thus reducing the prognostic value of these categories over time. To determine whether statistical weights optimized for each time period would alter these results, time-specific weights were applied, which did not demonstrate substantially different prognostic values from the basic model analysis. Particularly good retention of prognostic power was found in the lower risk categories over time. The lesser retention of prognostic power in the higher risk categories appeared related to loss of a larger portion of these patients over time due to their deaths or being censored by their beginning treatment. For the IPSS-R intermediate risk category patients, the prognosis for survival approached the “high” category ∼3 years after diagnosis, while it remained intermediate regarding their risk of AML transformation. ConclusionsThese data demonstrate that a degree of attrition of prognostic value occurred over time from diagnosis for all of the assessed MDS prognostic scoring systems. The IPSS-R, particularly the age-inclusive IPSS-RA, best retained such prognostic capability over time for the untreated patients analyzed. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Prognostic Impact of Monosomy 7 as a Single Anomaly In Primary MDS – Reclassification From Poor to Intermediate Prognosis

AbstractAbstract 1861 Introduction:Total or partial Monosomy 7 (-7/del(7q)) is one of the most frequent cytogenetic abnormalities in MDS, occurring in about 11% of abnormal cases in patients (pts) with primary MDS. The cytogenetic module of the IPSS defines any abnormality of chromosome 7 as unfavourable and classifies them, combined with complex abnormalities, into the poor risk cytogenetic subgroup. However, in previous publications from other groups, the prognosis of isolated -7/del(7q) was described as intermediate. The aim of the present study was to re-analyze the prognostic impact of -7/del(7q) as a single anomaly based on a large, international MDS database which was previously presented at the 2009 ASH-meeting (Schanz et al. abstract #2772). Materials and Method:Patients with -7/del(7q), derived from the international MDS database were examined. The large international data collection contains 2901 patients with MDS, originating from the German-Austrian (GA)-, the International MDS Risk Analysis Workshop (IMRAW)- and the Spanish Cytogenetic Working group (GCECGH) and the International Cytogenetics Working Group of the MDS Foundation (ICWG). Inclusion criteria for the study were defined as follows: Primary MDS, age >=16, and bone marrow blasts <=30%. Regarding therapy, patients with primary MDS who received supportive care, short courses of oral chemotherapy or hemopoietic growth factors were included. Univariate and multivariate analysis were performed for overall survival (OS) and risk of AML-transformation (AML-t). In multivariate analysis, site, age, gender, bone marrow blast count, date of first diagnosis and number of peripheral cytopenias were defined as co-variables. Results:In total, 60 patients (2.1% of all pts/4.4% of abnormal cases) with an isolated -7/del(7q) were detected. The median age of these pts was 66.1 years, which is significantly lower compared to pts without monosomy 7 (70.0 years; p<0.01; t-test, 2-sided). Regarding peripheral blood count, the mean hemoglobin in -7/del(7q) pts (9.2 g/dl) as well as ANC (1.7*103/ul) did not differ significantly as compared to pts without -7/del(7q) whereas the platelet count in pts with -7/del(7q) was significantly lower (82*103/ul vs. 125*103/ul; p<0.01). The median overall survival in -7/del(7q) pts was 16.0 (95% CI 14.0–21.4) months and the Hazard ratio (HR; as compared to a normal karyotype with a median survival of 47.4 (44.0-53.4) months as the reference category) was 1.6 (1.1-2.3; <0.01). Regarding the risk of AML-transformation, the median time to AML was 42.2 (14.4-not reached) months and the HR 1.7 (0.9-3.2; p<0.01). In comparison, this differed significantly from the median survival- (p<0.0001) and time to AML-transformation (p=0.027) for complex abnormalities, which are included with -7/del(7q) in the poor risk IPSS cytogenetic subgroup and were 5.7 (4.7-6.8) and 8.2 (6.4-14.0) months, respectively. The HR for complex abnormalities was 4.3 (3.4-5.4; p<0.01) for OS and 5.2 (3.8-7.5; p<0.01) for AML-transformation. Conclusions:The re-analysis of -7/del(7q), based on the largest MDS patient cohort yet published, confirms that the prognostic impact of an isolated total or partial monosomy 7 for overall survival as well as the risk of AML-transformation is intermediate, rather than poor. This finding is anticipated to be considered in the upcoming revision of the IPSS.Acknowledgments: The authors like to thank the MDS-Foundation for its support. Disclosures:Valent:Novartis: Research Funding; Bristol-Myers Squibb: Research Funding. Bennett:Johnson & Johnson: Consultancy.

Unrelated Clones In Myelodysplastic Syndromes and Acute Myeloid Leukemia - Characterization and Prognostic Relevance

AbstractAbstract 4022▪ Introduction:The occurrence of cytogenetically-unrelated clones is a rare but recognized event in haematological malignancies that may appear at either presentation or in further progression of disease. As yet, little is known about the composition and prognostic relevance of unrelated clones in MDS and AML. The aim of this retrospective study was to analyze cases of unrelated clones in a large, multicentric and international study to further characterize their clinical relevance in myeloid disorders. Patients/Methods:A total of 95 patients with unrelated clones and their corresponding clinical data were collected from 10 different databases: MLL (n=30), German-Austrian-Swiss (16), Athens (11), City of Hope (10), Bobigny (6), Lund (5), Tokyo (5), Spanish (4), IMRAW (3), and Dortmund (2). 77 pts. (81.1%) had a diagnosis of primary MDS, 5 (5.3%) t-MDS, 9 (9.5%) de novo AML, and 4 (4.2%) AML following MDS. Abnormalities detected FISH only were excluded. Unrelated clones were defined as two abnormal clones that were not evolvable from each other. Overall survival and the risk of AML transformation was calculated. For comparison MDS cases without unrelated clones were included from the international MDS database, including 2901 pts. with primary MDS. Result:Two unrelated clones were seen in 80 pts. (84%), three in 14 (15%) and five in 1 patient (1%). The majority of cases showed one aberration per clone (84.5%). The most frequent single aberration was +8 (43.2%), followed by del(5q) (28.4%). Other anomalies were -7/del(7q) (14.7%), -Y (12.6%), del(20q) (9.5%), +21 (7.4%), i(17q) (5.3%) and del(9q) (5.3%). Complex aberrations were identified in 3/95 cases (3.2%) only. Patients with unrelated clones showed an overrepresentation of +8 (p<0.0001), -Y (p=0.031) and i(17q) (p=0.013) in comparison to patients without unrelated clones. A combination of del(5q) and +8 was observed in 13/95 (13.7%) cases. Other recurrent combinations were: -7/+8 (n=2; 2.1%), -Y/del(5q) (n=2; 2.1%) and del(5q)/20q- (n=2; 2.1%). Translocations occurred only in single cases. The median survival of all patients with unrelated clones was 26.5 months, a finding consistent with an intermediate prognosis. Patients with a +8 clone and a clone with any other aberration showed a median survival of 21.0 months. Combinations of del(5q)/+8 (median 45.8 months) as compared to isolated del(5q) showed no significant difference in survival and in comparison to cases with +8 plus a clone with any other aberration, led to a significantly better survival (p=0.004). Summary:Our data presents the largest series of MDS/AML patients showing unrelated clones published to date. While the most frequent combination del(5q)/+8 is associated with a favourable outcome, all other combinations have to be assigned to the intermediate risk group until further distinct combinations can be evaluated. Further data will be presented in detail. Disclosures:Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Slovak:PerkinElmer: Employment. Ohyashiki:Nippon Shinyaku Co., Ltd.: Research Funding. Giagounidis:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bennett:Johnson & Johnson: Consultancy.

Survival, Prognostic Factors, and Rates of Leukemic Transformation in a Multicenter Study of 303 Untreated Patients with MDS and Del(5q).

Abstract 945In 2001, the WHO defined the category MDS with del(5q) due to unique cytogenetic, morphologic, hematologic, clinical, prognostic and therapeutic features. The survival of these patients, as well as patients with refractory cytopenia with unilineage dysplasia (RCUD) and refractory anemia with ring sideroblasts is favorable in comparison to other MDS types. Data on disease progression to a more advanced MDS category or to acute leukemia (AML) are sparse and have not been examined in detail. In order to address this issue we collated data of all patients with MDS and del(5q) characterized by low or intermediate-1 IPSS risk score that had been included into various collaborating MDS registries. Patients were followed from diagnosis and data on cell counts, transfusion dependency, and MDS progression were documented. No patients received treatment other than best supportive care. The status of 62 patients was censored at the time of the initiation of Lenalidomide therapy. AML progression was defined as >20% marrow blasts. Estimates of survival probability were calculated with the Kaplan-Meier method. The cumulative incidence of progression to AML was calculated both with the Kaplan-Meier method and with the competing risk method where “death without progression to AML” is considered as competing event, not as censoring. For both events the cumulative incidences are estimated simultaneously. This method has the advantage that it takes into account that there is a difference between end of follow-up and death. Depending on the number of competing events, the curves are lower than those calculated with the Kaplan-Meier estimator.We identified 303 patients, median age at diagnosis 65 years (28-91), 71% were females. Median follow up time was 3 years. Median survival was 71.5 months. Patients with del(5q) as a sole chromosomal aberration had a median survival of 73 months as compared to 19.3 months in patients with more than 1 additional aberrations. Patients who had red cell transfusion need at diagnosis had a median survival of 39 months vs. 97 months in transfusion independent patients (p=0.00005). Transfusion need at diagnosis was the most important parameter for survival. Patients in the WPSS very low risk group had a median survival of 107 months, as compared to 73 and 56 months in the low and intermediate risk group and 37 months in the high risk group.44 of the 303 patients (15%) progressed to AML (>20% marrow blasts). The cumulative AML progression rate calculated with the Kaplan-Meier method was 7% at 2 years and 18.2% at 5 years. The cumulative risk of AML progression calculated with the competing risk method was 6.6% at 2 years and 15.1% at 5 years. Factors associated with the risk of AML transformation were intermediate-I IPSS risk and high risk WPSS score, marrow blast count >5%, and red-cell transfusion need at diagnosis. Survival and progression rates did not differ among the participating centers.In conclusion, survival of patients with MDS and del(5q) is high and is comparable to patients with RCUD and RARS, but is associated with a risk of AML-transformation similar to RCMD without del(5q). Further cytogenetic and molecular studies are warranted in order to identify patients at greater risk of progression. Disclosures:Germing:Novartis, Celgene: Honoraria, Research Funding. Lauseker:Celgene: Research Funding. Hildebrandt:Celgene: Research Funding. Symeonidis:Celgene: Research Funding. Cermak:Celgene: Research Funding. Pfeilstöcker:Celgene: Research Funding. Nösslinger:Celgene: Research Funding. Sekeres:Celgene: Research Funding. Maciejewski:Celgene: Research Funding. Haase:Celgene: Research Funding. Schanz:Celgene: Research Funding. Seymour:Celgene: Research Funding. Weide:Celgene: Research Funding. Lübbert:Celgene: Research Funding. Platzbecker:Celgene: Research Funding. Valent:Celgene: Research Funding. Götze:Celgene: Research Funding. Stauder:Celgene: Research Funding. Blum:Celgene: Research Funding. Kreuzer:Celgene: Research Funding. Schlenk:Celgene: Research Funding. Aul:Celgene: Research Funding. Kündgen:Celgene: Research Funding. Hasford:Celgene: Research Funding. Giagounidis:Celgene: Research Funding.

High Frequency of AML1 Mutations in Patients with Chronic Myelomonocytic Leukemia.

Transcription factor AML1 is essential for normal hematopoiesis. AML1 mutations have been described in myelodysplastic syndrome (MDS), especially in therapy-related MDS but were rarely examined in patients with chronic myelomonocytic leukemia (CMML). We sought to determine the frequency of AML1 mutations in CMML and to assess their role in the progression of CMML to AML. Mutation analysis of AML1 was performed on bone marrow samples from 63 patients with CMML by direct sequencing of all RT-PCR products amplified with 3 overlapping primer pairs which cover the coding sequences of AML1 gene from exon 3 through exon 8. AML1 mutations were detected in 24 of 63 patients (38%) at initial diagnosis, 16 patients had mutations located in Runt homology domain (RHD) (exons 3–5), and 8 had mutations located in the C-terminal region (exons 6–8). One patient had 2 missense mutations in RHD and another one had 2 frameshift mutations in RHD. Taken together, the patterns of 26 mutations consisted of 7 missense mutations, 5 nonsense mutations, 2 silent mutations and 12 frameshift mutations. Ten of 24 patients (41.7%) with mutations progressed to AML compared to 13 of 39 patients (33.3%) without mutations, no difference was observed in the risk of AML transformation between the two groups (P=0.593). Of the 23 patients who progressed to AML, 17 also had bone marrow samples available at AML transformation for mutation analysis. AML1 mutations were detected in 8 of 17 patients at both diagnosis of CMML and AML transformation, all exhibited identical patterns at both phases, with no loss or gain of mutations during AML progression. There were no differences in age, sex, blood counts, percentage of blasts in bone marrow or peripheral blood, subtype of CMML (1 or 2), and cytogenetic risk group between patients with AML1 mutations and those without mutations. Time to AML transformation and overall survival of patients with AML1 mutations did not differ from those without AML1 mutations. Our study showed that AML1 mutations were frequently detected in CMML, with 70% located in RHD. All mutant clones remained identical at initial diagnosis and AML transformation, suggesting that AML1 mutations play an important role in the leukemogenesis in this subset of patients with CMML.

Understanding the Myelodysplastic Syndromes

The myelodysplastic syndrome (MDS) remains challenging to the clinician in terms of diagnosis and management. The diagnosis is essentially one of exclusion in first ruling out other disorders that can also cause peripheral blood/bone marrow cell dysplasia and cytopenias. The distinguishing biological characteristic of MDS is that it is a clonal disorder of the marrow with impaired differentiation. Recent studies implicate extensive apoptosis as the explanation of the paradoxical observation of marrow hyperplasia but peripheral blood cytopenia. Neutropenia and/or neutrophil dysfunction account for the primary clinical manifestation of MDS in terms of an increased risk for infection, which is the leading cause of death in MDS. The clonal nature of MDS places it also at continual risk for transformation to acute leukemia. Predicting overall survival as well as the risk of AML transformation has been improved by the recent development of a scoring system (International Prognostic Scoring System) that incorporates three laboratory variables: percent of marrow blasts, degree of cytopenias, and presence of chromosomal abnormalities. Based on these variables, four prognostic subgroups can be delineated ranging from low risk with a median survival of 5.7 years, to high risk with a median survival of 0.4 years. Management of MDS can now be based on the patient's respective prognostic subgrouping, with low-risk patients being considered for hematopoietic growth factor singly or in combination if at the point of red cell transfusion dependence and/or neutropenia with recurrent infections, while high-risk patients should be offered AML-induction therapy or novel agents such as topotecan. One must individualize further in patients in the remaining intermediate groups, I and II, in choosing the most appropriate therapy. Future advances upon understanding the molecular details of the MDS clone should ultimately improve the care of patients with MDS.