Primary MDS Research Articles

Azacitidine Is Effective in Patients with Myelodysplastic Syndrome Managed in Community-Based Practice: Preliminary Data From the Spanish Azacitidine Compassionate Use Registry.

Abstract 4836 BackgroundAzacitidine (AZA), a hypomethylating agent recently approved in Europe for the treatment of MDS, prolongs the median survival time in patients enrolled in clinical trials (Fenaux et al 2009). Decisions regarding treatment are based on performance status, age, patient preference and concomitant illnesses. NCCN-recommended treatment approaches vary according to International Prognostic Scoring System (IPSS) classification. AZA was available in Spain under compassionate use before its regulatory approval in May 2009. Material and MethodsWe present the preliminary analysis of the clinical results of the data from a longitudinal, multicenter Spanish patient registry, which retrospectively collected data from community-based hematology clinics on the disease course and management of patients with MDS treated with AZA in a compassionate use setting, in whom the dosing schedule administered was documented. AZA dosing was applied to the patients in different regimens in 28-day cycles. As of August 1, 2009, data from 147 patients with MDS diagnosed according to WHO criteria had been collected. ResultsMedian age was 71 years and 66% were men. Most of the patients had primary MDS (129 patients; 88%). The most prevalent ECOG performance status was 0-1 (125 patients; 85%). An IPSS risk classification of low/intermediate-1 was documented in 80 patients (55%). An initial AZA dose of 75 mg/m2 was used in 124 patients (84%). Most of the patients (57%) received a 7-day regimen (either with or without a weekend rest). A 5-day regimen was used in 50 patients (31%). AZA was administered mostly subcutaneously (122 patients, 84%). The mean number of cycles administered was 6 (range 2-29). The overall treatment response was 60% (International Working Group 2006 criteria): 18% complete response, 16% complete bone marrow response, 7% partial response, 23% hematological response. Stable disease was documented in an additional 17% of the patients, who did not achieve a response. AZA was generally well tolerated. Grade 3/4 adverse events documented in these patients, regardless of their relationship to the active treatment, were neutropenia (42%), thrombocytopenia (31%), anemia (22%), febrile neutropenia (10%), rash (1%), vomiting or nausea (1%), septic shock (1%), injection site reaction (1%), and constitutional symptoms (1%) ConclusionThese preliminary data do not differ from those previously obtained from clinical trials (Silverman et al 2006, Fenaux et al 2009). These results demonstrate that in a community-based setting, patients with MDS respond to AZA treatment. In line with previous clinical trials, we expect this could point to a better prognosis for MDS patients in Spain, with prolonged survival and a better quality of life. DisclosuresNo relevant conflicts of interest to declare.

Applicability of a New Prognostic Scoring System in Myelodysplastic Syndromes. MDS Study Group of Hematology.

Abstract 4838 BackgroundMyelodysplastic Syndromes (MDS) are so heterogeneous, that new prognostic scoring systems are being continuously developed to help choose the best treatment strategy. The International Prognostic Scoring System (IPSS) excludes secondary MDS, prior therapy and Chronic Myelomonocytic Leukemia (CMML) with leucocytosis. Recently, a new risk model has been published by Kantarjian et al. (Cancer 2008; 113; 6; 1351) that is applicable to all MDS patients. AimsTo validate this new risk model in our MDS population. MethodsWe analyzed 253 patients reported from 15 centers in our country from Jan 2007 through Jun 2009. We took into account age, performance status (PS), hemoglobin, platelets, leucocytes, bone marrow blasts, karyotype, and transfusion requirements. The new model divided patients into 4 prognostic groups: Low Risk (LR): 0-4; Intermediate-1 (I-1): 5-6; Intermediate-2 (I-2): 7-8; and High Risk (HR): ≥9. We assessed the prognostic impact of this New Risk Model and compared results to IPSS. Mortality Rate and AML progression risk were analyzed. Results164 patients were evaluable, mean age 69 (R 21-92), primary MDS: 144, and secondary MDS: 20. Risk Group assessment for the new score: LR (34%), I-1 (31%), I-2 (18%), and HR (17%). The mean Follow-up was 22 months; Resultsare shown in table and graphic. [Display omitted] ConclusionEven though our sample is not considerably big, and follow-up is short, we confirmed 4 categories with different prognosis and found a close correlation with Mortality Rate. This New Scoring System allowed us to identify Low Risk IPSS patients with different outcomes, highlighted the importance of adding new prognostic factors like age and performance status, refined the cut-offs of thrombocytopenia and anemia, and recognized the adverse impact of prior transfusions needs. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Azacitidine Is Effective in Patients with Intermediate-2 / High IPSS Risk Myelodysplastic Syndrome Managed in Community Based Practice: Preliminary Data From the Spanish Azacitidine Compassionate Use Registry.

Abstract 4835 BackgroundMyelodysplastic syndrome (MDS) is comprised of a group of heterogeneous hematological disorders. Although the decision regarding treatment of a patient with MDS is based on performance status, age, patient preference and concomitant illnesses, NCCN-recommended treatment approaches vary according to IPSS risk score. Azacitidine (AZA) is a hypomethylating agent recently approved in Europe for the treatment of MDS. AZA was available in Spain under compassionate use before its regulatory approval and marketing authorization from the Spanish Medicines Agency in May 2009.Material and MethodsWe present the preliminary analysis of the clinical data from a longitudinal, multicenter Spanish patient registry. Data on the disease course and management of patients with MDS treated with AZA under compassionate use conditions were retrospectively collected from community-based hematology clinics. As of August 1, 2009, 65 patients with intermediate-2 / high IPSS-risk MDS diagnosed according to WHO criteria had been included. ResultsAt baseline the median age was 69 years, the male/female ratio was 60/40, and the majority of patients had primary MDS (56 patients; 88%) and an ECOG performance status of 0-1 (43 patients; 67%). The most frequent initial dose of AZA applied was 75 mg/m2 (53 patients, 83%), and the most common dosing schedules were as follows: days 1-7 (82%), and days 1-5 and 8-9 (5%) in a 28-day cycle. AZA was administered mostly subcutaneously (56 patients, 89%). The mean number of cycles administered was 6 (range 2-29). The overall treatment response was 59% (International Working Group 2006 criteria): 16% complete response, 13% complete bone marrow response, 13% partial response and 18% hematological response. In addition, 23% achieved stable disease. AZA was generally well tolerated. The grade 3/4 adverse events documented in these patients, regardless of their relationship to active treatment, were neutropenia (37%), thrombocytopenia (26%), anemia (17%), febrile neutropenia (8%), rash (2%), vomiting or nausea (2%), and constitutional symptoms (2%). ConclusionThese preliminary data do not differ from those previously obtained from clinical trials (Silverman et al 2006, Fenaux et al 2009). Our results demonstrate that in a community-based setting, patients with intermediate-2 / high-risk MDS respond to treatment with AZA. In line with previous clinical trials, we expect this could point to a better prognosis for MDS patients in Spain, with prolonged survival and a better quality of life. DisclosuresNo relevant conflicts of interest to declare.

Azacitidine Is Effective in Patients with Low / Intermediate-1 Risk Myelodysplastic Syndrome Managed in Community Based Practice: Preliminary Data From the Spanish Compassionate Use Registry.

Abstract 3801Poster Board III-737 BackgroundMyelodysplastic syndrome (MDS) is comprised of a group of heterogeneous hematological disorders. Although the decision regarding treatment of a patient with MDS is based on performance status, age, patient preference and concomitant illnesses, NCCN-recommended treatment approaches vary according to IPSS risk score. Azacitidine (AZA) is a hypomethylating agent recently approved in Europe for the treatment of MDS. AZA was available in Spain under compassionate use before its regulatory approval and marketing authorization from the Spanish Medicines Agency in May 2009. Material and MethodsWe present the preliminary analysis of the clinical data from a longitudinal, multicenter Spanish patient registry. Data on the disease course and management of patients with MDS treated with AZA under compassionate use conditions were retrospectively collected from community-based hematology clinics. As of August 1, 2009, data from 90 patients MDS diagnosed according to WHO criteria had been collected with low / intermediate-1 International Prognostic Scoring System (IPSS) risk score. ResultsAt baseline, the median age was 70 years, the male/female ratio was 69/31, and the majority of patients had primary MDS (80 patients; 90%) and an ECOG performance status of 0-1 (62 patients; 69%). The most frequent initial dose of AZA administered was 75 mg/m2 (77 patients, 86%). Almost all patients followed one of the following three schedules: days 1-7 (31%), days 1-5 and 8-9 (29%) or days 1-5 (37%) in a 28-day cycle. AZA was administered mostly subcutaneously (71 patients, 79%). The mean number of cycles administered was 7 (range 2-25). The overall treatment response was 61% (International Working Group 2006 criteria): 21% complete response, 11% complete bone marrow response, 3% partial response, 27% hematological response. In addition, 12% had stable disease. AZA was generally well tolerated. Grade 3/4 adverse events documented in these patients, regardless of their relationship to the active treatment, were neutropenia (48%), thrombocytopenia (36%), anemia (26%), febrile neutropenia (12%), rash (3%), injection site reaction (2%), asthenia (1%), septic shock (1%), constitutional symptoms (1%), and hypotension (1%). ConclusionThese preliminary results demonstrate that, in a community-based setting, patients with low / intermediate-1 IPSS risk MDS respond to treatment with AZA, with an acceptable safety profile. More data derived from this registry and from the clinical trials are awaited. Disclosures:No relevant conflicts of interest to declare.

Secondary Myelodysplastic Syndrome.(sMDS) Presentation and Evolution.

Abstract 4850 BackgroundThe Secondary Myelodysplastic Syndrome (sMDS) represents a severe complication in the treatment of cancer. They are associated to the use of alkylating agents, radiation and immunosuppressive therapy. Their prognosis is unfavorable. Conventional chemotherapy is mainly palliative whereas allogenic bone marrow transplantation allows the cure of a small percentage of cases. Aims: To characterize and to describe the clinical presentation, therapeutic conduct and evolution in sMDS. This results where compared with those of primary MDS (pMDS) in patients enrolled into the observational study of Sociedad Argentina de Hematología from January 2007 to June 2009 MethodsThere were analyzed 253 patients with diagnosis of MDS. sMDS correspond to 12.2 % (31/253)of the total, mean age 71 years old (r 23-84), relation M: F of 1:2.8 (being 1:2.2 in pMDS). Previous pathologies were: solid tumors in 17 patients (54%); 6 prostate Ca, 5 breast Ca, 4 GI Ca, 1 thyroid Ca, 1 bladder Ca, 1 pharynx Ca. Hematology malignancies were found in 7 patients: 2 Non Hodgkin Lymphoma, 2 Hodgkin Lymphoma, 1 Myeloma Multiple, 1 Chronic Myelomonocyticleukemia, 1p aplastic anemia. Six patients (23%) received immunosuppressive treatment for kidney transplantation, Wegener disease and glomerulonephritis. 85% of the patients received previous chemotherapy and/or radiotherapy. Result: There were analyzed 217 karyotypes (85.7%), 25 in the sMDS group and 189 in the pMDS, abnormal karyotypes in 14/25 (56%) vs 55/189 (29%) (p=0.006), complex karyotypes (unfavorable): 6/25 (24%) vs 8/189 (7%) (P=0.002). Twenty eight patients requiered treatment 28/31 (90.3%) vs 167/222 (75.2%) (p=0.09), transfusional therapy 23/31 (77.55%) vs 93/222 (42%) (p=0.001). Hypomethylating agents were used in 22,5% in sMDS vs 21,1% in pMDS and Erythropoyetin in 45,2% vs 48,6%. With a median follow up of 136 days (r:4-650), 8/31 progressed to AML (25.8%) vs 28/222 (13%) (p=0.005). Fourteen patients (45%) were death vs 47/222 (20.6%) (p=0.005); 17/31 (54.8%) of patients were alive in the sMDS group and 153/189 (80%) in the pSMD group (p= 0.005). Summary and ConclusionssMDS constituted 12.2% of the total of MDS that were reported. This entity has in our experience presence of unfavorable karyotype in more than the 50% of the cases, greater transfusion request, greater evolution to acute myeloid leukemia with high mortality and greater mortality than pMDS. This results confirm the bad prognosis of sMDS. DisclosuresNo relevant conflicts of interest to declare.

Dysregulation of TGF-Beta Stimulated Smad Signaling Is Seen in Myelodysplasia and Points to the Potential Therapeutic Efficacy of TGF-Beta Receptor I Kinase Inhibition in Low Grade Disease.

Abstract 737Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis that leads to peripheral cytopenias. TGF-beta is a hematopoietic inhibitory cytokine that has been indirectly linked to the pathogenesis of some subsets of MDS and acute leukemias. We have shown (Blood, 112(8):3434; 2008) that smad2, a component of the TGF-beta signaling pathway, is constitutively activated and upregulated in MDS progenitors. Since there is conflicting data about upregulation of TGF-beta levels in MDS, we next sought to determine the molecular basis of TGF-beta receptor-I (TBRI) overactivation and subsequent smad2 phosphorylation / activation in this disease. We observed that smad-7, a negative regulator of TBRI kinase, is markedly down regulated in a meta-analysis of gene expression studies from 89 MDS bone marrow derived CD34+ cells when compared to 61 normal controls (Adjusted P<0.001, Benjamini Hochberg). Smad-7 protein was also found to be significantly decreased in MDS BM progenitors (n=14) when compared to anemic controls (n=18) when examined immunohistochemically in a bone marrow tissue microarray (P=0.04, T test). siRNA mediated knockdown of smad-7 levels led to increased TGF mediated gene transcription over baseline, that could be effectively inhibited by a TBRI (ALK5 kinase) inhibitor. TBRI kinase inhibition effectively abrogated TGF-beta mediated activation of smad-2 in hematopoietic cells. Most importantly, treatment with the TBRI inhibitor increased erythroid and myeloid colony formation from primary MDS bone marrow specimens in a concentration-dependent fashion. Furthermore, the hematopoietic potentiating effect of the TBRI kinase inhibition was validated in a TGF-overexpressing transgenic mouse model. This mouse constitutively expresses TGF-beta through an albumin promoter, develops progressive anemia and dysplasia and thus serves as a novel model of human bone marrow failure. Treatment with the TBRI inhibitor by oral lavage at 100 mg/kg/d for two weeks led to significant increases in hematocrit when compared to placebo (Mean increase in hematocrit=48%, P value=0.01, T test). Taken together, these studies demonstrate an important role for reduction in smad-7 in contributing to ineffective hematopoiesis in MDS by activating TGF-beta signaling in hematopoietic cells. These studies also illustrate the promising therapeutic potential of TBRI inhibitors in this disease. Disclosures:No relevant conflicts of interest to declare.

Epidemiological data from the registry of patients with myelodysplastic syndrome in a single hospital center of Romania

We present the first Romanian study on the epidemiological characteristics of MDS, based on the data existing in Fundeni Clinical Institute, Hematological Department, Bucharest. The files at diagnosis of the adult patients with primary MDS admitted during the period 1982–2005, recorded in the registration forms provided by the MDS Foundation (USA), represented the primary database. This study indicates an increase in the number of new MDS cases over the period of time investigated. Also, a 10 years lower median age of the patients, a noticeable proportion of young patients and a low proportion of patients ≥81years have been found, which situates our findings in the middle between the Eastern and Western epidemiological reported data on MDS.

P122 Treatment of CMML by azacytidine (AZA): a preliminary report on 23 patients (pts)

well characterized. AVIDA is a longitudinal, multicenter patient registry designed to prospectively collect data from community-based hematology clinics on the natural history and management of patients with MDS and other hematologic disorders, including acute myeloid leukemia, who are treated with azacitidine. We investigated the transfusion independence of patients enrolled in this ongoing registry. Methods: Baseline demographics, disease characteristics, and historical (6 months prior to AVIDA) transfusion requirements were obtained at enrolment. Transfusion requirements and onset of RBC and platelet transfusion independence were recorded. Transfusion independence was defined as no transfusions for at least 56 days. The first day of the 56-day period with no transfusions was noted as the time at which patients first achieved transfusion independence. Results: As of October 8, 2008, 237 (164 males, 73 females) have been enrolled. At baseline, the majority of patients had primary MDS (203 patients; 86%), an Eastern Cooperative Oncology Group performance status of 0 or 1 (184 patients; 78%), and an International Prognostic Scoring System (IPSS) risk classification of Low/Intermediate-1 (151 patients; 64%); 61 (26%) had an Intermediate-2/high IPSS risk and 25 (11%) had unknown IPSS risk. Median time from first MDS diagnosis until azacitidine treatment was 3 months (range, 0 to 148). A total of 923 cycles of azacitidine have been administered; median number of 3 cycles (range, 1−16). The most common dose and schedule was 75mg/m2 (84%) at 5 days on treatment (51%). Transfusion data are available for 139 patients who have received at least 56 days of azacitidine treatment. Forty-two of 78 patients (54%) with a history of RBC transfusion achieved RBC transfusion independence; 36/42 (86%) first achieved RBC transfusion independence during the first 2 cycles. Eleven of 17 patients (65%) with a history of platelet transfusion achieved platelet transfusion independence; 10/11 (91%) first achieved platelet transfusion independence during the first 2 cycles. Azacitidine was generally well tolerated; the most common adverse events were anemia (19%), thrombocytopenia (14%), nausea (13%), constipation (12%), fatigue (11%), and neutropenia (11%). Conclusions: In the community-based setting, patients with MDS can achieve transfusion independence within the first 2 cycles of azacitidine therapy at a rate comparable to that reported in a clinical trial (Aza-001). Full benefit of achieving transfusion independence on quality of life and clinical outcomes will be elucidated as more patients are enrolled. P122 Treatment of CMML by azacytidine (AZA): a preliminary report on 23 patients (pts)

Molecular Cytogenetic Studies of Complex Karyotypes in Myelodysplastic Syndromes (MDS): Conventional Cytogenetics, FISH and Multiplex FISH (mFISH/mBAND)

Karyotype represents one of the most valuable prognostic markers for MDS patients with profound impact on differential diagnosis and therapeutic decisions despite of the fact that it is a heterogenous patient population with diverse pathogenesis and clinical course. In approximately 10–20% of MDS patients complex chromosomal aberrations (CCA; three or more numerical/structural cytogenetic aberrations) are present at diagnosis and this finding is associated with the treatment resistance and poor outcome. Precise identifications of chromosomal regions involved in CCA could help in detection of cryptic, recurrent, prognostically relevant aberrations and in identification of candidate genes involved in leukemogenesis and progression of the disease. In this study we used various modifications of molecular cytogenetic techniques to specify CCA more precisely and to determine exact localization and frequency of chromosomal breakpoints. During the last seven years we examined bone marrow samples of 630 adults with MDS and in 81 of them (12,9%) complex karyotypes were found (in 73 patients at diagnosis and in 8 cases during the disease progression). Out of 73 patients with CCA at diagnosis were 43 males and 30 females, age range 22 to 82 years (median 65,5 years). Primary MDS was diagnosed in 63 (86.3%) of them, in 10 cases therapy related MDS was ascertained. Diagnoses according to the WHO classifications: MDS NS 3x, RA 2x, RA/RCMD 6x, RCMD 5x, RAEB I 20x, RAEB II 20x, MDS-AML 16x and RARS 1x. 63 patients died, 10 patients are still alive (four of them after stem cell transplatation). Chromosomal aberrations found by G-banding were verified by FISH with appropriate locus specific probes (Abbott-Vysis, Des Plaines, Illinois, USA), and by multiplex FISH (mFISH/mBAND) with the “XCyte” probe kits (MetaSystems, Altlussheim, Germany).Deletion of 5q31 region was proved in 63 patients (86.3%). In 29 cases mFISH analyses showed that parts of deleted No. 5 were translocated into other chromosomes. The most recurrent chromosomal partners of No. 5 in unbalanced translocations were Nos. 17 (9x), 12 (5x), 7 (5x), 2 (4x) and 3 (4x). Monosomy of No. 5 was confirmed in one case only, thus it was proved that monosomy 5 is not separated diagnostic unit in CCA. Except No. 5 the most frequently involved in CCA were chromosomes 7 (36x), 3 (33x), 12 (31x), 17 (31x) and 11 (23x). Presence of CCA at diagnosis was connected with poor response to the therapy and with short overall survival. For survival analysis patients were classified into three groups according to the molecular cytogenetic findings:del(5)(q31) and additional CCA – 33 cases,deleted chromosome 5 involved in CCA – 29 cases,CCA without deletion of 5q – 10 cases.The worst overall survival was found in group 2 (median 3 months), followed by group 1 (median 5 months) and 3 (median 6 months).Patients with MDS and CCA should be considered as a unique entity with extremely poor prognosis. Exact molecular cytogenetic analysis by multiplex FISH of all chromosomal aberrations which are involved in CCA will lead to selection of the patients into new prognostic groups. Exploring the underlying mechanism of leukemogenesis could improve the therapeutic outcome for these patients and could contribute to the development of a new targeted treatment strategy.

Low Dose Decitabine Versus Best Supportive Care in Elderly Patients with Intermediate or High Risk MDS Not Eligible for Intensive Chemotherapy: Final Results of the Randomized Phase III Study (06011) of the EORTC Leukemia and German MDS Study Groups

Introduction: In 2002 the EORTC and the German MDS Study Group initiated a randomized phase III study comparing low dose Decitabine to supportive care in patients (pts) of 60 years or older with primary or secondary MDS or CMML. MDS patients with either 11–20% BM blasts or ≤ 10% blasts and poor cytogenetics could be included. Pts with a BM blast count between 21–30% without signs of disease progression for at least one month were also candidates for the study.Methods: Patients were centrally randomized; stratification factors were cytogenetics risk group, IPSS, MDS (primary vs secondary) and study centre, The treatment schedule was 15 mg/m2 Decitabine i.v. over 4 hours every 8 hours for the first 3 three consecutive days, of every 6 week-cycle, for a maximum of 8 cycles. Results were evaluated every 2nd cycle. When a complete remission was reached at least another 2 courses were given. The primary endpoint of the study was Overall Survival. AML free survival, Progression Free Survival (PFS), response rate, toxicity and QoL were secondary endpoints. A total of 185 deaths were required to detect a hazard ratio (HR) of 0.66 (alpha=5%, beta=20%). Intent-to-treat analysis was used.Results: Between 10.2002 and 5.2007 a total of 233 pts (149 male and 84 female) were recruited from 40 centres. The median age was 70 (60–90 years); RAEB-t was diagnosed in 32% of the pts. Most pts had an IPSS Intermediate-2 (55%) or high risk (38%). Poor risk cytogenetics was found in 46% of the patients. Prior therapy for MDS (not being intensive chemotherapy) was given in 20% of pts. The randomized groups were well balanced regarding stratification factors, age and FAB classification. The median follow up was 2.5 years. Time to Off Study was 180 (Decitabine) vs 112 days (SC arm). The median number of cycles given to the patients was 4 with 40%getting no more than 2 cycles. In a significant number of pts, subsequent treatment, consisting of transplant (10%) or induction chemotherapy (11%), was given.The distribution of best response in Decitabine vs SC arm was CR (13% vs 0%), PR (6% vs 0%), HI (15% vs 2%), SD (14% vs 22%), PD (29% vs 68%), hypoplasia (14% vs 0%), inevaluable (8% vs 8%). The 18 pts on Decitabine with a HI showed the following responses: 3-lineage (n=7), 2-lineage (n=5) and 1-lineage (n=6). The median time to response (CR/PR/HI) was 0.32 yrs and the response duration was 0.72 years. Median OS was 0.84 (Decitabine) vs 0.71 years (SC arm), estimated HR was 0.88, 95% CI 0.66–1.17, p=0.38 (logrank 2-sided). The PFS was significantly (p=0.004) longer in Decitabine vs SC arm: median was 0.55 vs 0.25 years, HR=0.68 (95% CI 0.52–0.88). Time to AML or Death was not significantly improved (p=0.24): median was 0.73 vs 0.51 years (HR=0.85, 95% CI 0.64–1.12).Toxicity. The toxicity was mainly cytopenia related toxicity that was either disease related or hematotoxicity; CTC grade 3–4 febrile neutropenia was 26% (Decitabine) vs 7% (SC arm) and Grade 3–4 infection was 59% vs 47%. Differences in non hematologic toxicities were mainly gastrointestinal: grade 1–2 nausea (28% vs 16%) and grade 1–2 vomiting (16% vs 9%). During the study period, 29 (Decitabine) vs 25 (SC arm) patients died: due to either progression to MDS/AML (7 vs 20), toxicity (9 vs 0), progression and/or toxicity (10 vs 1), other reasons (3 vs 4).Conclusions. Decitabine was found to be an effective drug in these high risk MDS patients with a overall RR of 34%, (similar to earlier studies), leading to a significant PFS improvement as compared to SC arm. The difference Decitabine vs SC arm regarding time to AML or Death was not significant. Due to shorter treatment duration (not being continued beyond 8 cycles) and maybe also due to subsequent treatments administered after disease progression, the difference regarding OS was lower (HR=0.88) and not statistically significant.

Phase I, Dose-Escalation Study of 2 Dosing Regimens of AS703569, An Inhibitor of Aurora and Other Kinases, Administered Orally in Patients with Advanced Hematological Malignancies

Background: AS703569 is a novel, orally bioavailable, potent ATP-competitive, small molecule that inhibits all three aurora kinase isoforms (A, B, and C), and shows inhibitory activity across other kinases involved in cell proliferation and survival, including FLT3, ABL1, ABL1 (mut. T315I), JAK-2, and FGFR3. AS703569 has been tested as a single agent and in combination with standard-of-care anticancer agents in leukemia cell lines, freshly isolated leukemic cells, and tumor xenograft models. The strong inhibition of proliferation and the triggering of apoptosis induced by AS703569 lead to significant anti tumor activity resulting in tumor regression or growth delay, and prolongation of animal survival. AS703569 is currently being tested in phase I studies as a single agent and in combination; the main objectives are to establish the MTD (based on dose-limiting toxicities [DLTs]) and evaluate the safety and PK/PD effects of different regimens.Study design: This is an open-label, phase I, two-arm, dose-escalation study in patients (pts) with AML, CML, MDS, and MPD. Patients were sequentially assigned to one of two AS703569 dosing regimens: Regimen 1: once daily (QD), days 1–3 and 8–10 of a 21-day cycle; Regimen 2: QD, days 1–6 of a 21-day cycle. In both treatment arms, AS703569 was administered at escalating dose levels (DL; 3, 6, 10, 15, 21, 28, and 47 mg/m2/day) using a 3+3 cohort design. Repeated cycles were permitted until disease progression or unacceptable toxicity.Patient characteristics: Pt characteristics are summarized in the Table. Pts had primary AML (n=20), secondary AML (n=13), CML (n=6), MDS (n=5), and MPD (n=1). Pts were heavily pretreated and had failed previous chemotherapy.Safety: The median number of AS703569 cycles received per pt was 2 for Regimen 1 (range 1–7) and 1 for Regimen 2 (range 1–6). In Regimen 1, at DL 7 (47 mg/m2/day, n=3), 2 subjects reported DLTs: 1 case of grade 3 diarrhea with hyponatremia and sepsis with a fatal outcome, and 1 case of grade 3 diarrhea with GI bleeding. In Regimen 2, at DL 7 (n=5), 3 subjects reported DLTs: 2 cases of grade 4 mucositis and 1 case of neutropenic infection. Consequently, the dose was de-escalated to 37 mg/m2/day for both regimens and enrollment is ongoing at this DL to confirm the MTD. Grade ≥3 toxicities reported throughout the study mainly included infections (18 pts), neutropenia and febrile neutropenia (17 pts), thrombocytopenia (15 pts), anemia (11 pts), and GI disorders including mucositis, diarrhea and GI bleeding (8 pts). Alopecia was reported in some pts.PK: Preliminary data for 37 pts (DL 1–6) show an increased exposure with dose, a Tmax of 2–4 h (range 0.5–8 h), and an effective half-life of ~10–20 h.Activity (preliminary data): In Regimen 1, 1 pt with refractory CML (mut. T315I) has received 7 treatment cycles and shown a hematological and cytogenetic response; 5 pts with AML received 5–7 cycles, 3 achieved reduction in BM and/or peripheral blasts. In Regimen 2, 1 pt with MDS received 6 cycles and achieved a PR; 2 pts with AML received 3 cycles and did not progress.Conclusions: These data indicate that AS703569, QD, days 1–3 and 8–10 every 21 days or on days 1–6 every 21 days is generally well tolerated in pts with advanced hematological malignancies. Most grade 3/4 toxicities are commonly seen in pts with advanced hematological malignancies and are in part linked to the underlying disease. A DL with an unacceptable frequency of DLTs was reached and enrollment continues at a lower DL to confirm the MTD. Early evidence of activity was observed in pts with CML, AML, and MDS.Regimen 1Regimen 2N2421Median (range) age, years69.5 (48–83)71 (49–82)Sex, M/F15/912/9ECOG PS, 0-1-25-12-73-12-6Median (range) previous lines of therapy3 (1–6)2 (1–6)

Genomic Rearrangements Associated with -5/del(5q) and -7/del(7q) in Myeloid Leukemias.

An important aspect of leukemia biology is the elucidation of the spectrum of chromosomal abnormalities and molecular mutations that cooperate in the pathways leading to leukemogenesis. To identify those chromosomal abnormalities that are associated with drug resistance and a poor outcome, we analyzed a cohort of 3,438 pts (primary MDS, 1155; AML de novo, 1832; and therapy-related MDS/t-AML, 451) ascertained between 1970–2007 at the University of Chicago. 866 (25%) had either -5/del(5q) (276, 8%), -7/del(7q) (313, 9%), or both (277, 8%). The incidence of loss of 5q, 7q, or both was 19% in primary MDS, 20% in AML de novo, and 61% in t-MDS/t-AML. Of note, 71% of the karyotypic abnormalities in these pts led to loss of chromosomal material. Balanced rearrangements accounted for 10% of the additional abnormalities, and the remaining 19% led to a gain of material. Abnormalities of chr 5 were associated with karyotypic instability. Pts with -5/del(5q) had an average of 7 karyotypic abnormalities, whereas pts with -7/del(7q) had an average of 3 abnormalities. Pts with both -5/del(5q) and -7/del(7q) had an average of 10 abnormalities. Only 13% of pts with an abnormality of chr 5 had -5/del(5q) as their sole karyotypic abnormality, whereas 41% of pts with an abnormality of chr 7 had -7/del(7q) as their sole karyotypic abnormality. In addition to increased complexity of the karyotype, abnormalities of chr 5 were associated with specific recurring abnormalities: -17/loss of 17p, 39%;-3/loss of 3p or 3q, 30%; -18/loss of 18q, 24%; -12/loss of 12p, 24%; +8, 23%; -13/del(13q), 18%; -20/del(20q), 18% (values refer to the percentage of each abnormality among pts with 5q loss). The relative frequency of these abnormalities in pts with -7/del(7q) ranged from 4–8%, and no specific abnormality was observed in more than 10% of cases with loss of 7q. These observations extend previous studies which demonstrated a high incidence of abnormalities of 17p, TP53 mutations, and complex karyotypes in t-MDS/t-AML characterized by abnormalities of chr 5 (Pedersen-Bjergaard J. NEJM 152:1491, 2005). Our observations, together with those in the literature, suggest that different molecular pathways are involved in the pathogenesis of primary MDS/AML and t-MDS/t-AML associated with abnormalities of chr 5 or 7. The subgroup of pts with abnormalities of chr 7 without chr 5 abnormalities typically has mutations of the RAS pathway (KRAS1, NRAS, NF1, PTPN11), methylation of the promoter of CDKN2B/p15, and a poor prognosis. In contrast, pts with loss of 5q, with or without abnormalities of chr 7, are characterized by complex karyotypes, TP53 mutations and -3/loss of 3p or 3q, +8, -12/loss of 12p, -13/del(13q), -17/loss of 17p, -18/loss of 18q, and -20/del(20q), and a poor prognosis. Emerging technologies, such as high throughput genomic analysis, may facilitate further delineation of the genetic pathways leading to myeloid diseases.Recurring Abnormalities in Patients with Abnormalities of Chromosomes 5 and/or 7Subgroup-3/loss of 3p or 3q+8/+8q-12/loss of 12p-13/del(13q)-17/loss of 17p-18/loss of 18q-20/del(20q)-5/del(5q) (276 pts)62 (22%)55 (20%)30 (11%)40 (14%)101 (36%)59 (21%)35 (13%)-7/del(7q) (313 pts)16(5%)25 (8%)12 (4%)11 (3.5%)15 (5%)13 (4%)22 (7%)-5/del(5q) & -7/del(7q) (277 pts)106 (38%)71 (26%)103 (37%)59 (21%)116 (42%)72 (26%)67 (24%)Total (866 pts)184 (21%)151 (17%)145 (17%)110 (13%)232 (27%)144 (17%)124 (14%)

Successful Engraftment Using Varied Stem Cell Sources, Low Toxicity, and Long-Term Survival Using a Bu/Flu/ATG Reduced Intensity Allogeneic Transplantation in High Risk Pediatric Patients Ineligible for Myelablative Therapy: Results of the Pediatric Blood and Marrow Transplant Consortium (PBMTC) Study ONC0313.

The role of reduced intensity conditioning (RIC) regimens in pediatric pts is unclear. To define the feasibility and toxicity of a bu/flu/ATG approach in pediatric pts ineligible for myeloablative transplant, we completed a trial at 25 North American and Australian institutions participating in the PBMTC. Forty six pediatric pts (age 2–20yrs, med 11) were enrolled with the following stem cell sources: 8 related donor (RD) BM (2 mismatched); 8 RD-PBSC; 10 unrelated donor (UD) BM; 8 UD-PBSC; 12 UD-CB. Qualifying indications included a previous allogeneic (n=22) or autologous (n=7) transplant, severe organ toxicity (n=8), invasive fungal infection (n=3), and other comorbidities (n= 6 pts, 4 with Down syndrome). Diagnoses included ALL (4 CR2; 11 CR3, 1 secondary), AML (7 CR2; 3 CR3; 3 secondary, 2 PR2+), MLL (1 CR3), CML (1 CR3), HD (3 CR3, 1 PR3), B-NHL (1 PR3), MDS (1 RA; 6 secondary), and JMML (1 PR2, 1 PR3). Patients received busulfan 0.8mg/kg/dose IV x 8 doses (target AUC 900–1100 uM/min), fludarabine 30mg/m2/d x 6 days, and thymoglobulin, 2.5 mg/m2/d x 1 day for RD and x 4 days for UD and UCB. GVHD prophylaxis consisted of cyclosporine (CSP) and mycophenylate mofetil (MMF, 15mg/kg bid). MMF was stopped at day +30 for RD and CB recipients and tapered between d +40–100 for UD recipients. CSP was tapered between d+42–100 for RD and d+100–180 for UD and UCB. Four pts rejected their grafts (9%), one after mismatched RD-BM, two after UD-BM and one after UCB. Two pts died prior to day 100 due to toxicity (4%) and the overall NRM was 11%. Acute GVHD occurred in 9/33 evaluable patients (grade I 9%, grade II 18%, no grade III-IV) and chronic GVHD occurred in 7/28 (25%) evaluable pts. Median follow up is 17 months (range 1–45 m). Two year EFS (events: rejection, relapse, death in remission) is 38% (SE 8) and 2yr OS is 51% (SE 9). No difference in outcome was noted based upon stem cell source, history of previous BMT vs. none, or ALL vs. myeloid disease vs. lymphoma. A trend toward improved survival was noted in “intermediate risk” patients (ALL CR2, AML CR2, and primary MDS without h/o previous BMT: 2yr OS 67 vs. 31%, intermediate vs. high risk, p=0.1). Patients who had undergone transplantation trended toward better survival when their previous myeloablative regimen did not contain TBI (2yr OS 82 vs. 31%, non-TBI vs. TBI, p=0.09). In conclusion, RIC using bu/flu/ATG in a cooperative group setting leads to engraftment in >90% of high risk pediatric pts using related or unrelated BM or PBSC, or unrelated CB. In spite of significant prior therapy, high risk disease, and a high rate of comorbidities in this cohort, the risk of NRM or GVHD is low. Prolonged survival has occurred not only in pts with myeloid disease (2yr OS 43% (SE 12)), but also in pts with ALL (2yr OS 49% (SE 15)), and lymphoma (2yr OS 50% (SE 35)). Flu/bu/ATG is a promising approach for pediatric pts ineligible for myeloablative transplant.

Multivariate Evaluation of the Prognostic and Therapeutic Relevance of Cytogenetics in a Merged European-American Cohort of 3860 Patients with MDS.

This study investigated the influence of cytogenetic findings on survival in MDS, after accounting for other known prognostic parameters and type of treatment. We identified 3210 patients with a known therapy regimen from our large database, including 3860 patients with MDS and secondary AML following MDS. This data pool was collected in the framework of a cooperative project merging data from the German-Austrian MDS study group (55% of pts.) and the MD Anderson Cancer Centre (MDA), Houston, USA (45% of pts.). Median age of all study patients was 65.9 years, the female-male ratio 1:1.53. After accounting for age, sex, % marrow blasts, de novo vs. primary MDS, treatment (supportive care, AML-type, and epigenetic therapy) and site of treatment(Germany/Austria vs.MDA) we looked at the effect of cytogenetic subgroups on survival. Survival data was available for 95.8% of all pts. The distribution of main cytogenetic categories was as follows: normal (1.727, 45%), 5q- (208, 5%), 5q- +1 abnormality (73, 2%), −7/7q- not complex (222, 6%), +8 not complex (203, 5%), complex with −5/−7 (627, 17%), other complex (195, 5%), 20q- not complex (69, 2%), and other not complex (475, 13%). Chemotherapy (c) was applied in 32.9% while 67.1% were treated with supportive care (sc) or epigenetic therapy. The cytogenetic prognosis according to IPSS-criteria was favourable in 1704 (53.1%) and unfavourable in 839 (26.13%) of the 3210 study patients. Multivariate analysis revealed the following non-cytogenetic parameters as unfavourable: age >60, male sex, blasts >5%, secondary MDS, AML-like chemotherapy, MDA as site (due to overrepresentation of high risk MDS). After accounting for these variables the following relative Hazard ratios (HR of 1.0 for normal karyotype) were calculated allowing a relative ranking of cytogentic findings: 5q-: 0.93, 5q- +1: 1.06, other not complex: 1.11, 20q-: 1.31, +8: 1.65, complex without −5/−7: 1.76 −7/7q-: 2.09, complex with −5/−7: 3.88. The effect of cytogenetics in pts. with either supportive care (sc) or chemotherapy (c) measured as relative HR (see above) were: 20q- (sc: 1.25, c: 1.51), 5q- (sc: 0.93, c: 0.73), other not complex (sc: 1.07, c: 1.04), −7/7q- (sc: 2.10, c: 2.09), +8 (sc: 2.05, c:1.54), complex without −5/−7 (sc: 2.23, c: 1.75), complex with −5/−7 (sc: 4.78, c: 3.77) showing that cytogenetics remains it's prognostic relevance independent from the therapy applied. In Kaplan-Meier-analyses median survival in pts. showing favourable karyotypes was 37.9 months with supportive treatment as compared to 26.4 months with chemotherapy (p<0.01). We observed no therapy-related survival differences with regard to patients of the unfavourable cytogenetic subgroup. The occurrence of complex abnormalities (n=670) was associated with an identical median survival comparing the therapy groups (c: 7.0, sc: 7.1 months). We also investigated groups with distinct abnormalities (5q-, −7/7q-, +8, 20q-) and found significant differences in survival between the therapy groups: Patients with 5q- and 20q- benefited from supportive care while −7/7q- was related with a better survival when chemotherapy was applied. Patients with trisomy 8 showed no differences in survival. Regarding these data, chemotherapy response, expressed by survival, is closely associated with cytogenetics. Complex abnormalities always show a dramatically reduced outcome, independent from the therapeutic strategy.

Gene Dosage of the Cell Cycle Regulatory Phosphatases Cdc25C and PP2A Determines Sensitivity to Lenalidomide in del(5q) MDS.

MDS with chromosome 5q deletion [del(5q)] is uniquely sensitive to clonal suppression by lenalidomide (LEN), yielding high rates of cytogenetic and erythroid response. Although haploinsufficiency for a candidate tumor suppressor gene within the common deleted segment (CDS) has been implicated in the pathogenesis of del(5q) MDS, no specific gene products account for the karyotype-dependent LEN sensitivity. Using primary AML cells, we showed that LEN is selectively cytotoxic to del(5q) cells, inducing cell cycle arrest at the G2 > G1 junctures and apoptosis in a concentration-dependent fashion. Now we show that the CDS-encoded Cdc25C and PP2A phosphatases (PPTs) serve as molecular targets for LEN. Cdc25C and PP2A are dual specificity PPTs that regulate cell cycle. The genes encoding the catalytic subunit alpha (PP2ACa), the dominant catalytic isoform, and the regulatory subunit B (beta isoform PR 52) of the PP2A holoenzyme reside within the del(5q) CDS. Real-time RT-PCR showed that Cdc25C and PP2ACa gene expression is significantly reduced in primary del(5q) AML and MDS BM-MNC compared to non-del5q and normal controls. A Cdc25C FISH probe confirmed presence of only a single allele in del(5q) specimens [n=5] vs. normal karyotype [n=5] with no overlap with the EGR1 locus. We found that LEN inhibited rHu-Cdc25C activity with IC90 inhibitory concentrations ≤10nM. Similarly, PP2A PPT activity was inhibited by LEN in enzyme immunoprecipitates from Ramos cells at sub-micromolar concentrations. In U937 cells, we confirmed intracellular Cdc25C and PP2A inhibition, showing concentration-dependent retention of the inhibitory p-Tyr15 -Cdc2 substrates for Cdc25C with corresponding phosphorylation of the PP2A substrate Ser216 Cdc25C, findings reproduced by treatment with the PP2A selective antagonist, fostreicin. Cdc25C immunoprecipitation showed that phosphorylation of Ser216 Cdc25C increased binding to the 14-3-3 protein with consequent cytoplasmic sequestration confirmed by fluorescence microscopy. Phosphorylation of histone H2A.X Ser139 was unchanged after LEN treatment, indicating that phosphorylation of the inhibitory Cdc25C serine does not arise from upstream DNA damage activated kinases. Importantly, siRNA suppression of Cdc25C gene expression in U937 cells promoted LEN-specific apoptosis in 45% of cells, which increased to 68% after fostreicin inhibition of PP2A. These data indicate that haplodeficiency for the Cdc25C and PP2ACa genes promotes selective sensitivity of del(5q) cells to LEN-induced apoptosis. Haplodeficiency of critical drug-able targets may represent a novel strategy for tumor selective therapy.

Analysis of Class I and II Histone Deacetylase Fails To Identify a Human Leukemia Specific Expression Profile.

Histone deacetylase (HDAC) inhibitors are being developed clinically for the treatment of leukemia. Because HDACs are composed of a large number of different proteins, and substrate specificity may differ among different HDAC inhibitors, it is important to understand if human leukemias are characterized by specific HDAC expression patterns. To study this, we have analyzed using real-time PCR and Western blots, all major class I and II HDACs in normal marrow controls (N=13, including 10 CD19+ B cell specimens), leukemia cell lines (N=25), samples from patients with AML (N=6), MDS (N=12), CLL (N=10) and human samples (N=6) obtained pretreatment and sequentially from patients with leukemia treated with two different phase I clinical trials of HDAC inhibitors: MGCD0103 and vorinostat. In general, normal controls were characterized by low levels of HDACs 1 to 10, although normal CD19+ B cells exhibited a significant increased expression of HDAC1 and 5. In leukemia cell lines, HDAC 1, 2 and 3 were expressed at higher levels than 4 to 10 but there were no differences between leukemia cell lines and normal controls or B cells. HDAC mRNA expression was not modified by cell proliferation or treatment with HDAC inhibitors. No specific HDAC expression profiles were detected in primary human AML or MDS samples. In contrast, CLL primary samples were characterized by an overexpression of HDAC 1,3,5 and 10, although this pattern was not significantly different than that of normal CD19+ B cells. Sequential analysis of human samples obtained from patients treated with two different HDAC inhibitors, vorinostat or MGCD0103 on two different clinical trials, did not affect expression profiles in patients with MDS or AML. Overall, mRNA expression results correlated with protein levels. In summary, our results indicate that AML or MDS are not characterized by a leukemia specific HDAC expression profile but that B cells and B cell leukemia are characterized by a significant overexpression of HDAC 1. This could explain the activity observed with HDAC inhibitors in B cell malignancies and serve as the bases for clinical studies of HDAC inhibitors in CLL.

A Complex Karyotype but Not Monosomy 7 Is an Independent Prognostic Factor in Advanced Childhood MDS.

Disclosure: No relevant conflicts of interest to declare.To study the clinical significance of recurrent chromosome aberrations in childhood MDS, cytogenetic data of 394 consecutive children with refractory cytopenia (RC) (N=215), RAEB (N=141) and RAEB-T (N=38) analyzed in the regional cytogenetic reference centers and registered in the prospective study EWOG-MDS 98 between 1998 and 2005 were evaluated. At diagnosis, a karyotype could be defined in 279/394 patients (pts) (71%). No karyotype was obtained in 16% of pts with RC compared to 8% pts with RAEB and RAEB-t (p<0.001). Clonal chromosome aberrations were more common in pts with advanced MDS (RAEB and RAEB-T, 61%) compared to RC (29%), and in pts with secondary (69%) compared to primary MDS (36%) (p<0.001). Monosomy 7 was the most frequent aberration occurring with similar frequency in RC (47% of abnormal karyotypes) compared to advanced MDS (49%) and in primary (53%) compared to secondary (41%) MDS. In addition, aberrations typical for de novo AML such as aberrations involving 11q23 or 3q, t(6;9) and del(9q) were noted in morphologically and clinically unequivocal MDS cases. Recurrent aberrations of adult MDS like isolated del(5q), del(20q) and -Y were very uncommon indicating a different pathogenesis of these cases. In pts with advanced MDS, there was no significant difference in overall survival (OS) of pts with normal karyotype (44% ± 18) compared to pts with monosomy 7 (58% ± 19) and patients with other karyotypes (61% ± 22). However, pts with advanced MDS and a complex karyotype (defined by ≥ 3 chromosome aberrations, presence of structural aberrations and excluding clonal evolution of monosomy 7) had a shorter OS (16% ±15, p<0.01). OS and event-free survival after hematopoietic stem cell transplantation (HSCT) in pts with complex karyotypes was inferior compared to that of pts with other cytogenetic aberrations (p=0.012 and 0.039, respectively). Within the group of pts with secondary MDS, complex karyotypes were found in MDS evolving from inherited bone marrow failure disorders or after radio-/ chemotherapy, but absent in familial MDS and cases evolving from acquired aplastic anemia. As shown in a multivariate Cox analysis, advanced MDS, secondary MDS, the presence of a complex karyotype and HSCT were identified as independent prognostic factors for OS. Thus, this study demonstrates the prognostic significance of cytogenetic findings in advanced childhood MDS independent of HSCT.

Prognostic Factors in Treatment-Related Myelodysplastic Syndromes (t-MDS) and Acute Myeloid Leukemia (t-AML).

In the current WHO classification patients (pts) with therapy-associated MDS are merged into a subgroup of AML, termed “AML with MDS, therapy-related”, regardless of dysplastic features, medullary blast count or cytogenetics. To validate the appropriateness of this approach, we combined the MDS/AML data sets of the Duesseldorf as well as the Goettingen data base. We identified 305 pts with t-MDS or t-AML. There were 138 males and 167 females, median age was 64 (22–90). When classified according to the WHO proposals for primary MDS (pMDS), 38% of the pts had AML (28% blast count >30%, 10% blast count 20–30% (RAEB-T)), 10% had RAEB II, 8% RAEB I, 2% CMML II, 3% CMML I, 6% RA, 1.5% RARS, 20% RCMD, 11% RCMD-RS and 0.5% had 5q- Syndrome. 60% of pts had received chemotherapy only, 12% radiotherapy, and 28% underwent combined radiochemotherapy prior to t-MDS/AML diagnosis. The median latency between treatment and diagnosis was 116 months in pts who received radiotherapy as compared to 81 months in pts treated with chemotherapy alone or in combination with radiation (p= 0.0005). Cytogenetics were available in 192 pts (63%). 58% had an abnormal karyotype, the median number of aberrant chromosomes was 2 (0–12). The most frequent aberrant chromosome was chromosome 5 (18%), followed by 7 (14%), 20 (7%) and 17 (7%). 48% of the pts had a low-risk, 18% an intermediate-risk, and 33% a high-risk karyotype according to IPSS. Median survival of the entire group was 10 months compared to 26 months in pMDS in our registry (p=0.00005). Important prognostic parameters for pMDS, like age, hemoglobin level, platelet count, neutrophile count, as well as classification and scoring systems (FAB, WHO, IPSS) could not show an impact on outcome in t-MDS/AML. Pts with <5% medullary blasts had a median survival of 16 months, with 5–9% of 8 months, with 10–19% of 8 months, with 20–29% of 6 months and pts with a blast count >30% had a median survival of 12months (p=n.s.). When we compared pts with a medullary blast count <5 vs ≥5 months the survival difference (15 vs 7 months) became significant (p=0,013). Pts with an elevated LDH level had a median survival of 7 as compared to 17 months in pts with normal LDH (p=0.0006). The karyotype subgroups (IPSS) showed significant survival differences between each of the groups: low-risk -34 months, intermediate-risk -25 months, high-risk -8 months. In a multivariate analysis only karyotype (p=0,011) and LDH level (p=0,014) remained independent prognostic parameters (blast count: p=0,961). These two variables can be combined in a score: LDH elevated= 1 point, high-risk karyotype= 1 point. This score leads to 3 subgroups (0, 1, or 2 points) with a significantly different prognosis of 42, 15, and 7 months (p=0,01). Our analysis shows that there is no substantial difference in survival between t-MDS and t-AML, justifying the combination of both entities in one AML subgroup. Current morphology based classification systems offer no prognostic information. On the other hand the established karyotype classification according to IPSS remains relevant for prognosis and combining this information with the LDH level leads to a simple score that is able to separate prognostically different risk-groups and thus should be validated further. 0%

Nurse Practitioners' and Physicians' Views of NPs as Providers of Primary Care to Veterans

To describe NPs' and MDs' perceptions of the role of NPs, the degree of collegiality between professions, and NPs' feeling of acceptance, three relationship components that may affect the acceptance of NPs as providers of primary care. A descriptive study including both closed- and open-ended questions plus several Likert-type questions conducted June-August 2004. Our sample included all primary care NPs (87) and MDs (162) within a Midwestern Veterans Health Administration (VHA) region. Data were collected from 153 providers. NPs saw their role as one of autonomous practice with physician back-up as needed, while MD respondents envisioned a role akin to a physician extender. Most of the physician respondents did not think NPs could provide adequate primary care to veterans who tend to have many comorbid conditions. Yet both groups considered their relationships to be collegial and most NPs felt accepted by physicians. MDs particularly valued NPs' teaching and interpersonal skills leading to greater patient satisfaction. To facilitate the teamwork of NPs and MDs while improving utilization of NPs as primary care providers, VHA officials should routinely clarify roles, monitor quality of care of both MDs and NPs, and provide feedback to all concerned.

C029 Hematopoietic stem cell transplantation for advanced primary MDS in children: results of a retrospective analysis from the EWOG-MDS group

C029 Hematopoietic stem cell transplantation for advanced primary MDS in children: results of a retrospective analysis from the EWOG-MDS group