Types Of MDS Research Articles

Matched-Pair Analysis of 186 MDS Patients Receiving Iron Chelation Therapy or Transfusion Therapy Only.

Abstract 1747▪▪This icon denotes an abstract that is clinically relevant.Poster Board I-773 IntroductionPatients with MDS, especially those with a lower-risk type of disease, are prone to develop iron overload, partly due to increased duodenal iron resorption triggered by ineffective erythropoiesis, but mainly as a consequence of chronic transfusion therapy. Transfusion dependency is clearly associated with a decreased likelyhood of survival. It is less clear how far that association is attributable to the severity of the underlying bone marrow disease as opposed to toxic effects of iron overload. A large retrospective study from Spain recently showed that iron overload (serum ferritin >1000 ng/μl) was a significant prognostic factor for overall survival and leukemia-free survival. On multivariate analysis, the impact of iron overload was independent of transfusion requirement. If iron overload itself has an adverse effect on survival, iron chelation (IC) should do the opposite. This was indeed suggested by a partly retrospective and partly prospective observational study from France which showed a strong survival benefit from chelation therapy in patients with lower-risk MDS. We gathered that short of a prospective phase III trial, a retrospective matched-pair analysis might provide the best available data to identify a survival effect of iron chelation therapy in MDS. MethodsOur matched-pair analysis included 93 patients with various types of MDS undergoing long-term chelation therapy, for whom we were able to identify 93 matched partners in the Düsseldorf MDS Registry (n=3552) who received supportive care only (SC, excluding iron chelation). Pairs were matched according to age at diagnosis, gender, MDS type according to WHO classification, and IPSS score. All 186 patients had iron overload, defined as serum ferritin of at least 500ng μl. Patients were followed up until death or until June 30, 2009. ResultsMedian age was 63 yrs in the iron chelation group and 67 yrs in the supportive care group (p=n.s.). In both groups, the distribution among WHO types was as follows: 4 RA, 7 RARS, 41 RCMD, 22 MDS with del(5q), 8 RAEB I, 7 RAEB-II, 4 CMML-I. Both groups showed the following IPSS risk profile distribution: 37% low risk, 46% intermediate-I, 14% intermediate-II, and 3% high risk.Median ferritin level in the chlelated group was 1954 (498-7580), median ferritin level in the non-chelated group was 945 (508-5800).In the IC group, patients received the following chelators: deferoxamine (n=54), deferiprone (n=5), deferasirox (n=32), deferoxamine or followed by deferasirox (n=12), and deferoxamine plus deferiprone (n=4).The mean duration of the iron chelation was 28 months for Deferasirox and 39 months for Deferoxamine.Among patients receiving iron chelation therapy, 52% died in the observation period, as compared with 58% in the SC group. Median survival time in the IC group was 74 months vs. 49 months in the SC group (p=0.002). There was no significant difference regarding the risk of evolution into acute myeloid leukemia (AML). The cumulative risk of AML transformation between the IC group and the SC group was 10% vs. 12% two years after diagnosis, and 19% vs. 18% five years after diagnosis (p=0.73). ConclusionsOur data support the idea that iron chelation therapy results in improved overall survival of MDS patients, mainly by reducing the risk of non-leukemic death. Since this was a retrospective analysis of registry data, we cannot determine exactly which clinical complications (e.g. cardiac events or infections) were diminished. This goal must be achieved by a well-designed prospective clinical trial. Our results do not seem to confirm that iron chelation therapy decreases the risk of leukemic transformation. However, such an effect may require elimination of labile plasma iron in order to suppress oxidative stress. LPI levels were not available in this retrospective matched-pair analysis but should be included in prospective studies. DisclosuresFox:Novartis: Consultancy, Honoraria, Participation in advisory boards in desferasirox trials, Speakers Bureau. Germing:Novartis: Honoraria, Research Funding, Speakers Bureau. Gattermann:Novartis: Honoraria, Participation in Advisory Boards on deferasirox clinical trials.

Varying Importance of Prognostic Factors in Subgroups of Myelodysplastic Syndromes Defined by Blast Count, Cytogenetic Risk Group, or WHO Classification.

Abstract 2776Poster Board II-752 Introduction:We wondered whether prognostic factors have similar relevance in different subpopulations of MDS patients. Methods:Our analysis was based on patients with primary, untreated MDS, including 181 RA, 169 RARS, 649 RCMD, 322 RSCMD, 79 5q-syndromes, 290 RAEB I, 324 RAEB II, 266 CMML I, 64 CMML II, and 209 RAEB-T. The impact of prognostic variables in univariate analysis was compared in subpopulations of patients defined by medullary blast count, namely <5%, ≥5% (table), ≥10%, and ≥20% (not shown), as well as 3 subpopulations defined by the cytogenetic risk groups according to IPSS (table). Multivariate analysis of prognostic factors was performed for cytogenetically defined subgroups and WHO-subtypes./<5% blasts≥5% blastsCytogenetic risk groupgoodintermediatepoorLog-RankpLog-Rankp/Log-RankpLog-RankpLog-RankpHemoglobin </≥10g/dl76<0,000190<0,0001/24,1<0,00010,740,382,60,1Sex m/w140,00020,40,52/31<0,000130,0800,9Age </≥60years64<0,000110,50,001/42<0,00014,10,0410,3LDH </≥200U/l55<0,000133<0,0001/30<0,000110,20,00140,04Platelets </≥50000/μl29<0,000135<0,0001/4,80,0276,80,0091130,0003ANC </≥1000/μl40,0430,08/0,80,80,80,372,90,08WBC </≥20000/μl21<0,00013,80,051/17,9<0,000115,20,00014,40,03Transfusion y/n72<0,000168<0,0001/11,70,00060,30,530,08Fibrosis y/n100,00110,20,001/4,90,021,50,20,40,5Karyotype-risk51<0,000145<0,0001///////Blast count </≥ 5%/////36,6<0,00019,80,0018,90,02Blast count </≥ 10%/////54,7<0,00016,20,0112,40,0004Blast count </≥ 20%/////58,4<0,00013,10,0890,0026 Results:Strong prognostic factors in all blast-defined subgroups were hemoglobin, transfusion dependency, increased WBC, age, and LDH. However, all variables became less important in patients with ≥20% blasts (RAEB-T) and increased WBC was rare. Platelet count and cytogenetic risk groups were relevant in patients with <5%, ≥5%, and ≥10% marrow blasts, but not in RAEB-T. Marrow fibrosis was important in patients with <5% or ≥5% blasts, but not ≥10%. Gender and ANC <1000/μl were significant only in patients with a normal blast count. Furthermore, we looked for the effect of the karyotypes, relevant for IPSS scoring (-Y, del5q, del20q, others, del7q/-7, complex), and found a comparable influence on survival, irrespective whether patients had < or ≥5% marrow blasts.In subpopulations defined by cytogenetic risk groups, several prognostic factors were highly significant in univariate analysis, if patients had a good risk karyotype. These included hemoglobin, sex, age, LDH, increased WBC, transfusion need, and blast count (cut-offs 5%, 10%, and 20%). In the intermediate risk group only LDH, platelets, WBC, and blasts were significant prognostic factors, while in the high risk group only platelets and blast count remained significant.Multivariate analysis was performed for the cytogenetic risk groups and for subgroups defined by WHO subtypes. The analysis considered blast count (</≥5%), hemoglobin, platelets, ANC, cytogenetic risk group, transfusion need, sex, and age. In the subgroup including RA, RARS, and 5q-syndrome, LDH, transfusion, and age in descending order were independent prognostic parameters. In the RCMD+RSCMD group, karyotype, age, transfusion, and platelets were relevant factors. In the RAEB I+II subgroup, the order was hemoglobin, karyotype, age, and platelets, while in CMML I+II only hemoglobin had independent influence. In RAEB-T none of the factors examined was of independent significance. Looking at cytogenetic risk groups, in the favorable group, several variables independently influenced survival, namely transfusion, blasts, age, sex, and LDH (in this order). Interestingly, in the intermediate and high risk group, only blast count and platelets retained a significant impact. Conclusion:Univariate analysis showed prognostic factors (except ANC) included in IPSS and WPSS are relevant in most subgroups defined by marrow blast percentage. However, they all lose their impact if the blast count exceeds 20%. Regarding cytogenetic risk groups, several prognostic factors lose their influence already in the intermediate risk group. This underscores the prognostic importance of MDS cytogenetics. Multivariate analysis showed MDS subpopulations defined by WHO types also differ with regard to prognostic factors. In particular, CMML and RAEB-T stand out against the other MDS types. Disclosures:Kuendgen:Celgene: Honoraria. Hildebrandt:Celgene: Research Funding. Gattermann:Novartis: Honoraria, Participation in Advisory Boards on deferasirox clinical trials. Germing:Novartis, Celgene: Honoraria, Research Funding.

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.

Lineage-Specific Activation of p53 in Response to Ribosomal Haploinsufficiency in Human Bone Marrow Cells.

Abstract 948Haploinsufficiency for the ribosomal protein genes RPS14 and RPS19 have been implicated in the erythroid defect in the 5q- syndrome and Diamond Blackfan Anemia, respectively. However, the mechanism by which defective ribosome biogenesis causes erythroid failure is unknown. In this study, we found that shRNA mediated knockdown of RPS14 or RPS19 in primary human CD34+ cells stabilize TP53 by day 4 after infection with concomitant arrest of these cells at G1 stage of cell cycle. The levels of TP53 attained are comparable to the levels observed following gamma irradiation (5Gy) of the CD34+ cells. Using quantitative PCR, we confirmed that stabilized TP53 activates expression of downstream target genes MDM2, p21, Bax and Wig-1. Furthermore, treatment of the CD34+ cells with Nutlin-3 phenocopies RPS14 or RPS19 knockdown, suggesting that the mechanism of TP53 activation is mediated by MDM2 pathway. Conversely, treatment with pifithrin-alpha, which inhibits the transactivation activity of TP53, rescues the effects of RPS14 or RPS19 knockdown. The in vitro activation of TP53 in CD34+ cells was restricted to erythroid cell lineage, consistent with the clinical phenotype of RPS14 or RPS19 haploinsufficiency. Moreover, immunohistochemical analysis of bone marrow biopsies from patient with the 5q- syndrome demonstrated intense staining of TP53 that was restricted to erythroid progenitor cells. Taken together our study indicates that inhibition of ribosomal biogenesis causes TP53 activation selectively in erythroid progenitor cells. Clinically, TP53 staining of patient samples could be used as a diagnostic marker for some types of MDS. Disclosures:No relevant conflicts of interest to declare.

The peculiarities of cytogenetic changes in different types of myelodysplastic syndrome

We carried out the cytogenetic investigation of bone marrow aspirate from 32 patients with different types of MDS. The patients were from 8 regions of Ukraine. 11 patients had abnormal karyotype, and the transformation to AML were observed in 5 of them (45.5%). 27% of all patients had chromosomal changes with 3 or more chromosomes involved. The highest percentage of the patients with chromosomal anomalies (66.7%) was in cases of RAEB. Chromosome deletions were the most frequently detected karyotype abnormalities. We consider the phenomenon of chromosome fragmentation as the cytogenetic approval of the increased level of apoptosis in patients with MDS. The risk of the transformation to AML was measured using new international score system IPSS.

Identification of Pathogenetically Important Genes within the Common Deleted Region (CDR) of the 5q- Syndrome.

The 5q- syndrome is characterized by refractory anemia, normal or high platelet count, hypolobulated megakaryocytes, a good prognosis and a low risk of leukemic transformation. Although the CDR has been defined to a 1.5 Mb interval on the long arm on chromosome 5 (5q33.1), the molecular pathogenesis of the disease is still unknown. The CDR contains 39 known-genes of which 33 have been shown to be expressed in hematopoietic stem cells. In order to elucidate the molecular mechanisms behind the 5q- syndrome, we performed real-time quantitative PCR on these 33 genes. Samples from the bone marrow of 12 patients with a sole deletion of 5q and 14 patients with MDS with normal karyotype were initially analyzed. The genes that showed the most pronounced decrease in expression in the 5q- samples were: SLC36A1 (89% down-regulated compared to non 5q-), G3BP (79%), ATOX1 (76%), CSF1R (76%), RPS14 (74%), PDGFRB (73%), TNIP1 (72%), SPARC (71%), ANAX6 (69%), NSDT (66%) and TIGD (60%). SPARC expression was found to be higher in both types of MDS samples compared to normal bone marrow (n=18) as well as compared to seven leukemic cell lines (HL-60, NB4, HEL, KG1, K562, U937 and TP-1). ATOX1 expression was highly over-expressed (20- to 80-fold) in the leukemic cell lines and modestly but significantly higher in normal bone marrow compared to both types of MDS. For G3BP, the expression was similar in normal bone marrow compared to the non-5q- samples but 1- to 10-fold higher in the cell lines. RPS14 was down-regulated in both types of MDS compared to normal bone marrow and leukemic cell lines. Thus, we have identified the most significantly down-regulated genes within the CDR of the 5q- syndrome. Based on our expression data, their known biological functions and on publicly available tissue expression data, genes such as G3BP, ATOX1, TNIP1, RPS14 and CSF1R are interesting targets for further studies. Biological studies are currently being performed on these genes with respect to their role during hematopoiesis with special focus on erythropoiesis.

Clinical Response to Oral Low-Dose Cyclosporin in Myelodysplastic Syndrome: Study of 31 Cases from India.

Aim: This prospective, single arm, institutional study was designed to evaluate the response to Cyclosporin A (CsA) in adult patients with primary MDS with cytopenias.Material and MethodsPatients aged 18 years or more, with primary MDS, normal renal and hepatic functions were eligible for inclusion after informed consent. The diagnosis of MDS was based on demonstrating features of dysplasia in one or more cell lines on peripheral blood smear and bone marrow examination. The criteria for cytopenia were one or more of the following: hemoglobin <10 g/dl; platelets <100x109/L; absolute neutrophil count <1.5x 109/L. Secondary causes of MDS were excluded by clinical and laboratory assessment. Other exclusion criteria were: response to therapeutic trial of vitamin B12 and folic acid, HIV infection and diagnosis of PNH. MDS was considered hypocellular if bone marrow (BM) cellularity was <30%, and in such cases dysplastic features had to be present in more than one cell line, so as to exclude hypoplastic anemia. CsA was used in doses of 3–5 mg/kg/day in 2 divided doses. Response was assessed using the International Working Group criteria for MDS (Cheson et al in Blood 2000, 96:3671–74), after a minimum follow up of 3 months.ResultsA total of 31consecutive patients with MDS who fulfilled inclusion criteria were assessed. Patient characteristics were: median age 38 years (range 20–70); male18, female 13; MDS type: RA-24, RAEB-7; BM: hypocellular-8 (25.8%), normocellular-19 (61.3%), hypercellular-4 (12.9%); transfusion dependent - 26 (83.8%).ResponseThere were no remissions. Hematological improvement (HI) was seen in different cell lines. Erythroid response (HI-E) was seen in 18 (58%):major response in 10 (32.2%); type- 8 RA, 2 RAEB; cellularity - hypocellular 4, normocellular 6minor response in 8 (25.8%); type- 7 RA, 1 RAEB; hypercellular-1, hypocellular-1, normocellular-6 andno response in 13 (41.9%); type RA- 9, RAEB-4; hypocellular- 3, normocellular-7, hypercellular-3.In terms of type of MDS, response occurred in 3/7 (42.8%) of RAEB (major in 2, minor in 1) and 15/24 (62.5%) of RA (major 8, minor 7). Neutropenia at onset was present in 14/31 (45.1%) patients only. Of these, neutrophil response (HI-N) major was seen in 1 (RA, hypocellular) who also showed major erythroid response. Thrombocytopenia at onset was present in 21/31 (67.7%) patients only. Of these, platelet response (HI-P) major was seen in 1 (RA, normocellular) and minor response was seen in 1 (RA, normocellular) and both also showed erythroid response. Median interval between diagnosis and treatment was 1 month (range 1–6). Median length of treatment: was 11 months (range 4–46). Effect in responders was seen in median of 3 months (range 1–6). There were no delayed responses seen after 6 months therapy. Relapse occurred in 9 patients. Two relapsed within 1 and 2 months of stopping treatment. 7 patients relapsed while on treatment at a median time of 6 months. There was no statistically significant difference in responses according to the type of MDS or BM cellularity using the Chi square test (p > 0.05).Conclusion: Anemia improved in 58% patients of MDS (RA and RAEB) and was sustained in 29% cases, irrespective of bone marrow cellularity. Further experience is needed to determine the duration of treatment, as relapses can occur both during therapy and on cessation of cyclosporin.

Hematologic Improvement (HI) by TLK199 (Telintra™), a Novel Glutathione Analog, in Myelodysplastic Syndrome: Phase 2 Study Results.

Introduction: Glutathione S-transferase (GST) P1-1 has shown to be an important negative regulator of cellular growth and differentiation. The effect is mediated through binding to Jun kinase (JNK) which causes a decrease in kinase activity. TLK199, a novel analog of glutathione, binds selectively to GSTP1-1 resulting in its dissociation from JNK and subsequent kinase activation. Exposure of hematopoietic progenitor cells to TLK199 led to activation of JNK followed by cellular growth and maturation. TLK199 has shown significant myelostimulant activity in vitro in human bone marrow cell cultures as well as in several in vivo preclinical models of myelopoeisis. In Phase 1, TLK199 treatment resulted in hematologic improvement (HI) in MDS patients at all dose levels.Methods: The objectives of this multicenter Phase 2 study in MDS were to determine the safety (by NCI-CTC) and efficacy (by modified IWG MDS response criteria) of two dose schedules of TLK199 HCl Liposomes for Injection administered at 600 mg/m2 over 60 minutes by constant rate IV infusion daily x 3 or daily x 5 every 3 weeks. Patients (pts) were treated until lack of response or unacceptable toxicity.Results: 52 MDS pts (33 M/19 F),(29 RA, 9 RARS, 8 RAEB, 3 RAEB-t, 1 CMML, 2 UK), median age 69 years (range 22–90), received 244+ cycles (1099+ treatments), median 4 (range 1–13+). Thirty-seven pts (71%) were red cell transfusion dependent and 10 pts (19%) were platelet transfusion dependent prior to entry. Pts had failed a median of 1 prior therapy (range 0–6) including: erythropoietin (27/52%), G-CSF (9/17%), thalidomide (10/19%), azacitidine (7/14%), steroids (6/12%), hormones (2/4%), and other therapies (14/27%). Thirty-nine pts were evaluable for efficacy, 32 pts (82%) experienced HI in one or more blood cell lineages, 14 of 16 pts (88%) with trilineage dysfunction, 8 of 13 pts (62%) with bilineage dysfunction, and all 10 pts (100%) with unilineage dysfunction experienced HI. Lineage response was HI-P (14 of 22/64%), HI-N (9 of 27/33%), and HI-E (22 of 35/63%). Responses were accompanied by clinical symptom improvement, decreases in RBC and platelet transfusion requirements including transfusion independence and improvements in bone marrow maturation, differentiation, M/E ratios, and dysplastic morphology. Most common adverse events were mild to moderate acute infusion related reactions commonly seen with liposomal formulations: back pain (9/17%), nausea (8/15%), chills (8/15%), and bone pain (6/12%).Conclusions: TLK199 is well tolerated and an active agent in all FAB types of MDS. These data support the further clinical development of TLK199 in MDS as well as in other hematologic malignancies characterized by cytopenias.

Neither the Response of Committed Progenitors to Growth Factors nor the Detection of Apoptosis in Bone Marrow Cells Can Predict the Clinical Response to Treatment in Patients with Rars.

Introduction - Aims: Patients with refractory anemia with ringed sideroblasts (RARS) treated with erythropoietin (rh-Epo), usually exhibit less favorable response, comparing to other types of MDS. The addition of G-CSF improves response rate and newly diagnosed patients, transfusion independent, with higher hemoglobin (Hb) and low plasma Epo levels (<200 mIU/ml) are the best candidates to respond to combination regimens. We investigated whether the in vitro response of committed progenitor cells to growth factors and the detection of apoptosis in BM cells could predict the clinical response to treatment in these patients.Patients and methods: Sixteen anemic patients with RARS (4 female, 12 male, median age 71 years) were included in the study. The median Hb was 8.8 g/dl and 12 patients were transfusion-dependent. Karyotype was available in 13 cases and it was normal in 10 and abnormal in 3. IPSS was low in 8 cases and intermediate-1 in 5. Bone marrow colony-forming cells (CFC) were cultured in classical semisolid medium (with Epo alone) and the growth pattern was compared to that in a medium enriched with SCF, G-CSF, GM-CSF, IL-3 and IL-6. The ratio of developed colonies/105 marrow mononuclear cells with the enriched vs. the standard medium was determined as Increment Index (I.I.). Presence of apoptosis was investigated in BM aliquots of 11 patients with a DNA fragmentation assay. Patients were treated with rh-Epo 100-300 IU/Kg plus G-CSG 0.1-0.2 μg/kg sc. in alternative days and response was evaluated after 6 months of treatment. The in vitro response of progenitor cells to growth factors was correlated with the in vivo response to treatment. Every kind of response was also correlated with the presence of apoptosis, as well as with the clinical and laboratory features of the patients.Results: The enriched medium led always to an increased total CFC (mean I.I. 3.55, range 1.5–12.3) and BFU-E number (mean I.I. 2.4, range 1.2–6.1). Apoptosis was detected in 7/11 marrow samples, and its presence was associated with decreased number of BFU-E and of total CFC colonies, with the standard (BFU-E: 6.7±4.2 vs. 15±19, p=0.042, total CFC: 17±9 vs. 34±60, p=0.012) and the enriched medium (BFU-E: 15±11 vs. 31±60, p=0.048, total CFC: 63±37 vs. 84±113, p=0.026). However, apoptosis had no impact in the I.I of both type of colonies. Six patients (37.5%) responded to treatment, and 2 of them became transfusion-independent. All but one responded patients had low IPSS, higher absolute neutrophil count (2.75±0.7 vs. 1.7±0.9 x 109/l, p=0.037), and significantly lower serum Epo levels (62±43 vs. 209±93 IU/ml, p=0.004). Two of 5 responders and 5/6 non-responders exhibited apoptotic model in their marrow (p: n.s.). There was no difference in the I.I. between responders and non-responders to treatment (BFU-E: 2.75±1.17 vs. 2.42±1.51, p: ns, CFC: 2.8±1.16 vs. 3.16±4.1, p: ns). One of the 6 responders and 3/10 non-responders evolved to a more aggressive MDS or AML. Total median survival was also not different between the two groups of patients (responders: 93 months, non-responders: 67 months, p=0.281).Conclusive remarks: Neither the in vitro response of BM progenitors to growth factors, nor the presence of apoptosis in BM cells, could predict the clinical response to treatment with the used combination of rh-Epo+G-CSF in this group of patients with RARS.

Surcharge martiale et syndromes myélodysplasiques (SMD)

Transfusion of RBC units, the only current treatment for many myelodysplastic syndromes, and excess intestinal absorption of Fe related to dyserythopoiesis often result in iron overload. This condition is associated with high rates of morbidity and mortality. High-risk patients include those with refractory anemia, sideroblastic anemia, 5q- syndrome, patients with a good prognosis (low or lower intermediate international prognosis score), patients having received over 100 RBC units, and patients under the age of 70. Deferoxamine, while it can prevent iron overload, is a strenuous treatment requiring 8-to-12 hour- overnight subcutaneous injections. When patients comply with the regimen, it efficiently prevents mortality due to iron overload, but must be implemented early in the disorder, usually before transfusing 20 RBC concentrates. A simple way of monitoring iron overload is to measure seric ferritin levels and record the number of RBC concentrates. The chelating treatment should be modulated according to age, MDS type, international prognosis score, number of RBC units received, ferritin levels, and most of all, patient tolerance. The direct subcutaneous approach is currently being evaluated by the French Group for Myelodysplasias for its efficiency to prevent disorders, but seems to be both efficient and well complied with (a national protocol is under way). The recent findings on the proteins implied in iron recycling by macrophages after destruction of RBCs, may in the long term, enable us to manage patients with less burdensome treatments and more effective new oral chelates.

Karyotype at diagnosis, subsequent leukemic transformation and survival in myelodysplastic syndrome

240 patients with MDS studied cytogenetically at diagnosis between 1981 and 1990 were followed until death or until April 1992 to evaluate the prognostic significance of FAB classification, age and karyotype. 61 patients (25.4%) subsequently transformed into AML and 176 (73.3%) died during the follow-up period. Patients with blastic MDS types had a shorter survival and a higher probability of leukemic transformation. The younger age increased the probability of leukemic transformation, but was associated with a longer survival. The absence of analyzable mitoses was associated with a shorter survival. The complex chromosomal abnormalities at the initial evaluation identified a subgroup of patients with a high risk of a short survival and/or subsequent leukemic transformation. In refractory anemia the presence of complex chromosomal abnormalities was linked with a relative risk of 3.58 of leukemic transformation and shorter survival as compared with other cytogenetically defined groups.