ALBERT

Description: Abstract 2927 Background: Immunological changes have a primary role in the initiation and progression of myelodysplastic syndromes (MDS). Cytokine levels, such as IL-7 and IFN-gamma, are associated with lower-risk disease. Treatment with lenalidomide has proven efficacy in red blood cell (RBC) transfusion-dependent lower-risk MDS patients with del(5q). Lenalidomide exerts anti-angiogenic, anti-proliferative, and pro-erythropoietic effects; in particular, it has been shown that lenalidomide inhibits the proliferation and function of T regulatory cells (Tregs). Finally, MDS patients undergoing lenalidomide treatment experience erythroid responses and suppression of the del(5q) clone. Aims: In a multicenter Italian phase II trial to evaluate safety and efficacy of lenalidomide in primary MDS patients with del(5q) and Low- or Int-1 risk IPSS, we investigated changes in the transcription of cytokines and their receptors during treatment. Methods: The starting dose of lenalidomide was 10 mg p.o once daily on a continuous daily schedule for a maximum of 12 months. Bone marrow (BM) aspirates were obtained on study entry and every 12 weeks. Assays were performed using TaqMan® Low Density Array Fluidic card (TaqMan® Human Array, Applied Biosystems, Foster City, CA, USA) based on Applied Biosystems PRISM® 7900HT comparative ddCT method, according to the manufacturer's instructions. Target gene expression levels were measured in triplicate and normalized against the expression of the 18S housekeeping gene from a BM pool of normal, healthy subjects at all timepoints. Median relative gene expression values in MDS patients were compared to healthy subjects, set as a value of 1. Results: We report data obtained at baseline and after 12 weeks. Informed consent was obtained in all patients. Twenty-seven patients (5 M, 22 F) were evaluated at baseline and after 12 weeks. Mean age was 72 ± 9 years. Mean Hb level was 8.5 ± 0.9 g/dL and 16 patients were RBC transfusion -dependent (requiring at least 4 RBC transfusions in the preceding 2 months). Seven patients had additional cytogenetic abnormalities. Twenty-one patients (80%) experienced erythroid responses by week 12. Significant variations in gene expression of cytokines and receptors were observed during treatment. Genes significantly regulated during lenalidomide treatment (P 〈 0.05) are shown in the Table. In particular, FAS, IL-7 and FOXP3 gene were generally under-expressed at baseline and significantly increased after 12 weeks. Accordingly, IL7R was over-expressed in all patients at baseline and its expression was significantly reduced during treatment. Furthermore, IFN-gamma expression increased during therapy. Summary: The protein encoded by FAS gene is a member of the TNF-receptor superfamily and its interaction with its ligand leads to apoptosis. Interleukin (IL)-7 is an essential cytokine that promotes the proliferation and survival of B- and T-lymphocyte progenitors. The IL7R gene on chromosome 5 (5p13) codifies for the IL7 receptor, which blocks apoptosis during differentiation and activation of T lymphocytes. It functions, in part, through the induction of the expression of the antiapoptotic protein Bcl-2. The protein encoded by the FOXP3 gene is a member of transcriptional regulators. Defects in this gene are the cause of X-linked autoimmunity-immunodeficiency syndrome. The results of the present study indicate that lenalidomide may act through immunological changes. Further detailed analyses in these patients may provide new insights into the pathogenesis of MDS with del(5q) and the long-term effects of lenalidomide treatment on immunological changes in BM cells. Disclosures: Oliva: Celgene: Consultancy.

Description: Abstract 2653 Background The impact of tumor presence on the immune competence of the host may be of particular relevance in the case of B cell neoplasia, as the tumor itself derives from immune system components; moreover, immune effector mechanisms are directly involved in determining the efficacy of chemioimmunoterapies. It has been previously noted that alterations of the absolute number of circulating monocytes and lymphocytes (peripheral blood monuclear cells, PBMC) are a of prognostic relevance in diffuse large B cell lymphoma (DLBCL). Aims To analyze the phenotypic and functional asset of PBMC in DLBCL at diagnosis, and to evaluate possible correlations of the immunological profile with tumor biological traits and patient's clinical features. Patients and Methods We compared 30 consecutive newly diagnosed DLBCL patients with 21 healthy, age- and sex-matched controls for: 1) absolute number (/μL) and percentage (over PBMC) of monocytes, B cells, T cell (CD4+, CD8+, CD4+CD8+ double positive, CD4-CD8- double negative, CD56+ T cells, and FOXP3+CD25bright regulatory T cells), and Natural Killer (NK) cell subsets (CD56dim, CD56bright, CD16+), measured by cell blood count and multi-parameter flow cytometric (FACS) analysis; 2) functional capability of individual T and NK cell subsets, by assessing the frequency of Interferon-gamma (IFN-γ) expressing cells and cytotoxic granule-containing cells; 3) natural and CD16-dependent NK cytotoxic activity, by 51Cr release assay, and 4) plasma concentration of selected cytokines, as evaluated with Bioplex. Results DLBCL patients showed several quantitative and functional alterations of the PBMC compartment. DLBCL patients showed a higher absolute monocyte number (p=.001), and a lower lymphocyte count (p=.001), thus resulting in a strongly reduced lymphocyte/monocyte ratio (p

Description: Abstract 2659 Background: Gene-expression-profiling defined at least two main groups within Diffuse-large-B-cell Lymphoma (DLBCL) patients who have substantially different outcomes: Activated-B-cell (ABC-type) and Germinal-Center-B-cell (GCB-type). The translation of gene-expression-profiling arrays into robust algorithm useful for clinical purposes is still in progress. The detection of IgM monoclonal component (IgM MC) in DLBCL has been previously described in a few reports, mainly because it was associated with autoimmune hemolytic anaemia. To our knowledge this is the first report describing the incidence and prognosis of a series of DLBCL with IgM MC. Aims: In this report we compared clinical and biological features of DLBCL patients with and without secretory IgM MC . Patients & Methods: Within a consecutive series of 132 patients, diagnosed between September 2004 and April 2012 with conventional DLBCL, 16 cases (12%) with a IgM MC were identified. We selected a set of 95 consecutive DLBCL patients, treated with 6–8 cycles of RCHOP-like for comparison of histological features and survival. Only cases with a follow up time 〉24 months were included, unless a DLBCL–related event (i.e. primary refractoriness or relapse) had occurred earlier. Biological material was obtained after receiving patient's consent. This study was approved by our Institutional-Review-Board. Immunohistochemistry and FISH: Paraffin sections were immunostained for CD3, CD5, CD20, CD10, CD30, CD79a, CD138, ALK-1, MUM1, BCL2, BCL6, IgM, Kappa and Lambda immunoglobulin light chains, using an automated immunostainer (DAKO, Denmark). The Hans algorithm was used in order to classify cases as GCB-type and non GCB-type. FISH with Vysis break-apart probe was used to assess c-MYC gene abnormalities in tissue sections (Abbott Molecular Inc. US). Statistics: univariate comparisons between groups were carried out with appropriate non parametric test. Survival analyses were done by the Kaplan-Meier method, the analyses of factor predicting survival were carried out by the log-rank test. Cox's regression was used for multivariate analyses. The SPSS19 package (SPSS Inc.Chicago IL) was used for elaborations. Histology, immunohistochemistry and FISH Results: In 14 out of 16 cases (87.5%) the IgM MC was related to the DLBCL clone. This was ascertained by immunostaining of cytoplasm for IgM, Kappa and Lambda immunoglobulin light chains. All the 14 cases were classified as non GCB-type. FISH analysis detected no c-MYC gene rearrangements in all the cases. Clinical Results: The incidence of bone marrow involvement, two or more extranodal sites, female sex, IPI score 3–5 and failure to achieve CR on RCHOP treatment were significantly more frequent in the IgM MC group. Noteworthy four out of 14 patients had central nervous system involvement at diagnosis or at relapse. All but one, with a previous diagnosis of marginal zone lymphoma, were de novo DLBCL. Twelve patients (85.7%) presented a DLBCL related event compared to 35 patients (37%) without IgM MC (p=.001). Seven patients (50%) died with primary refractory or relapsed-chemoresistant disease, another one died of an adverse event during chemotherapy. Two are alive on salvage treatment, two are in PFS at +30 and +13 months after salvage treatment with Bortezomib-RDHAP followed by high dose therapy. Only two patients are in PFS after first line RCHOP at +56 and +29 months respectively. Survival analysis: The estimated two-year EFS, PFS and OS were significantly worst for IgM MC group (22% Vs 70%, p

Description: Abstract 4951 Introduction. Azacitidine (AZA) has proven effective in myelodysplastic syndromes (MDS). The duration of haematological response is limited (median 13. 6 months) (Fenaux, 2009), although some patients (pts) show a prolonged response. The French Group (Itzykson 2011) identified some clinical and haematologic parameters (poor ECOG performance status, IPSS intermediate and poor risk cytogenetics, circulating blasts, high transfusion need) independently associated with a a poorer outcome, and these 4 criteria were integrated in a 3-group prognostic score, validated in other cohorts (van der Helm 2011; Breccia 2012). Moreover, a complex karyotype was also predictive of a shorter duration of response. However long term survival was also observed in some of the pts with poor risk features (Itzykson 2012). Methods. These data prompted us to retrospectively analyse our MDS pts treated with AZA who showed a favourable long-lasting response to AZA (i. e: duration of response ≥ 20 months), in order to enucleate the clinical and haematologic features of long-responder pts. The type of response was defined according to IWG criteria (Cheson 2006): Complete Remission (CR); Partial Remission (PR) and Hematologic Improvement (HI). The response duration was measured from the date of achievement of a first response (HI, PR or CR), (also in pts who subsequently achieved a higher response category) until the date of disease progression or death. Overall Survival (OS) was measured from the start of AZA treatment. Moreover, as some of us (Follo, 2009) demonstrated that phosphoinositide-phospholipase C (PI-PLC) beta1 may represent a target for AZA, in a subgroup of pts we quantified the degree of PI-PLCbeta1 methylation and gene expression before and during AZA administration. Results. Thirty-four pts (M/F: 20/14), from eight Institutions, with a median age of 72 (range 52–84) yrs, showed a response duration ≥ 20 months. At AZA onset, WHO diagnosis was: refractory anemia (RA): 1 pt; refractory cytopenia with multilineage dysplasia (RCMD): 1 pt; RCMD with ringed sideroblasts (RCMD-RS): 1 pt; refractory anemia with excess blasts (RAEB)-1: 8 pts; RAEB-2: 15 pts; cronic myelomonocytic leukemia(CMML): 4 pts; AML with 20–30% blasts: 3 pts, MDS with fibrosis (MDS-F): 1 pt. Four pts had therapy-related MDS. IPSS risk was: low: 3 pts; intermediate-1: 6 pts; intermediate-2: 20 pts, high: 5 pts. IPSS cytogenetic risk was: low: 21 pts (61. 8%); intermediate: 8 pts (23. 5%); high: 5 pts (14. 7%) (3 with complex karyotypes and 2 with isolated -7 or 7q-). ECOG-PS was poor (≥ 2) in 2 pts (5. 8%) and 〈 2 in the other 32 pts. Transfusion need was high (≥ 4 RBC units/8 weeks) in 17 pts (50%), and low or absent in the remaining 17 pts. Three pts (8. 8%) presented circulating blasts. Following Itzykson's AZA prognostic scoring system, the risk was low in 12 pts (35. 3%), intermediate in 21 pts (61. 8%), and high in 1 pt (2. 9%), respectively. Time from diagnosis to AZA onset was 〈 6 months in 21 pts, and 〉 6 months in 13 pts. The pts received a median of 22 cycles of AZA (range: 8–52). The median number of cyles to any first response was 4 (range: 2–10). Twenty pts (58. 8%) showed an at least two-fold increase of platelets after the first cycle of AZA. The best response achieved was: CR in 23 pts (67. 7%), PR in 2 pts (5. 8%), and HI in 9 pts (26. 5%). Cytogenetic remission was achieved in 7 pts (20. 6%). The median duration of response was 24. 5 (range: 23–88) months. A significant toxicity (grade 〉 2) was observed in 5 (14. 7%) pts. Twenty-two pts (64. 8%) are still maintaining hematologic response, 6 pts (17. 6%) are still alive but discontinued treatment because of disease progression, and 6 pts died, for AML (2 pts), infection (1 pt), haemorrhage (1 pt), myocardial infarction (1 pt), cachexy (1 pt), respectively. Median OS from the start of AZA was 35. 5 (range: 22–120) months. In a subgroup of pts, we observed an increase in PI-PLCbeta1 expression, that was maintained along with the hematologic response. Moreover, PI-PLCbeta1 early increase (during the cycles 1 to 3) was significantly associated with a higher duration of response. Conclusions. Although our data confirm the finding of other Authors, as the majority of long-responder patients showed pre-treatment favourable prognostic factors, a long-lasting hematologic response can be achieved even in a significant fraction of pts presenting one or more poor risk features (IPSS intermediate or high risk cytogenetics, high transfusion need). Disclosures: Finelli: Celgene Corporation: Research Funding, Speakers Bureau; Novartis: Speakers Bureau.

Description: Abstract 4958 Erythropoietin (EPO) have been widely employed in the treatment of patients with low-risk Myelodysplastic Syndromes (MDS) and anemia, with response rates ranging from 30 to 60%. These data, however, have been derived only from controlled clinical trials or unicentric single-arm studies; it is still lacking a wider survey evaluating the use of EPO in the real-life clinical practice. To address this issue, the Gruppo Romano Mielodisplasie (GROM) revised retrospectively 394 MDS patients (M/F 225/169, median age at diagnosis 73. 9 yrs, IR 67. 0 – 79. 3) treated with EPO from 1/2002 to 12/2010 by 11 Hematological Centers (5 university hospitals and 6 community-based hospitals) in the metropolitan area of Rome. According to WHO classification, there were 81 (20. 6%) patients with RA, 7 (1. 8 %) with SA, 160 (40. 7%) with RCMD, 17 (4. 3%) with RCMD-S, 75(19. 0%) with RAEB-1, 27 (6. 8%) with RAEB-2 and 27 (6. 8%) with isolated del5q. The IPSS score was calculated in the 307 patients with an available karyotype: 145 (47. 2%) patients were low-risk, 135 (44. 0%) int-1, 24 (7. 8%) int-2 and 3 (1. 0%) high-risk. Median interval from diagnosis to EPO start was 3. 7 months (IR 0. 9 – 12. 1). At EPO start, median age was 74. 5 yrs (IR 68. 3 – 79. 9) with a median haemoglobin level of 8. 9 g/dl (IR 8. 2 – 9. 6). Creatinine level was elevated in 64 (16. 2%) cases: 138 patients (35. 3%) had a previous transfusion requirement. Median serum EPO level was 50. 0 mU/L (IR 26. 2 – 110. 0). The initial doses of EPO were ≤ 40. 000 UI/week in 259 patients (65. 7%) (standard doses, α-EPO in 104 patients, β-EPO in 143 patients, darbepoietin in 12 patients) and 80000 UI/week in 135 patients (34. 3%) (high doses, α-EPO in 130 patients, β-EPO in 5 patients). An erythroid response was observed in 228 (57. 9%) patients, with Hb increase 〉 1. 5 g/dl in 210 patients (53. 3%) and disappearance of transfusion requirement in 18 (4. 6%): patients receiving initial high doses had a higher response rate compared to patients receiving standard doses [94/135 (69. 6%) vs 134/259 (51. 7%), p=0. 002]. Only 5 thrombotic events (1. 2%) were reported during the treatment. Predicting factors for erythroid response were no previous transfusion requirement (p

Description: Abstract 3822 Poster Board III-758 BACKGROUND The heterogeneous nature of myelodysplastic syndromes (MDS), age- and disease-related factors (complications and progression to acute leukemia) are associated with the complexity of quality of Life (QoL). Patients are offered mainly non-curative or experimental drugs and/or supportive care. The exploration of QoL in MDS is a prerequisite for adequate therapeutic choice. METHODS We designed an observational study in MDS patients with IPSS risk score ≤2 to evaluate determinants of QoL and its correlates. Clinical and laboratory data were collected up to 18 months and QoL instruments (QOL-E v.2, LASA scale, and EQ-5D) were completed by patients and physicians (both blind to each other's responses) at baseline, months 1, 3, 6, 12, and 18. After diagnosis, treatment was assigned based on investigators' judgment. RESULTS Of 148 patients enrolled (mean age 72 years, 56% males), 115 (78%) patients were anemic at diagnosis and 38 (26%) had already received transfusions. Mean (± SD) Hb was 10.3 ± 2.1, ANC 2.3 ± 1.9×103/μL and PLT count 155 ± 118×103/μL. Charlson's Comorbidity Score was 〉 1 in 33 (22%). Physical and functional QoL, health, energy, activity and general states were generally poor (

Description: INTRODUCTION: Patients with myelodysplastic syndromes (MDS) are at continuous risk of complications and must face the reality of a relatively low survival while still mainly depending on supportive care. The chronic nature of MDS, the risk of progressive evolution, advanced age, anemia and the rapid changes in physical status make the MDS patient unique within the cancer population. Quality of Life (QoL) in MDS is undoubtedly compromised by functional, psychological, and disease-specific components. Treatment options are still scarce in this elderly population and hematologists must select candidates for experimental therapy. Patients’ preferences are requisites for therapeutic choice so that it is essential that clinicians understand patients’ perceptions. STUDY DESIGN: We designed a multicenter Italian 18-month prospective observational study in 150 MDS patients from diagnosis to evaluate the correlation between QoL changes and changes in Hb and other MDS-related variables. Comparison between the patients’ and the physicians’ perception of QoL, QoL changes related to adaptation, progression and treatment response, and feasibility, consistency and validity of the QoL instruments were evaluated. Selection criteria included adult age, MDS at diagnosis with IPSS score 〈 2, at least 1 cytopenia, ability to complete the QoL questionnaires and ECOG PS 〈 3. METHODS: The QoL instruments (QOL-E v.2, LASA scale, and EQ-5D) were completed by patients and physicians (both blind to each other’s responses) at baseline, months 1, 3, 6, 12, and 18. Clinical and laboratory data were collected throughout the study. RESULTS: Median age was 74 (IQ range 67–79); 85 were males (57%). Patients were classified according to WHO: 48 RA (32%), 30 RCMD (20%), 21 RAEB-1 (14%), 7 RAEB-2 (5%), 6 5q-syndrome (4%), 4 RARS (3%), 3 CMML (2%), 1 RCMD/RS (1%), 30 MDS-U (20%). Fifty-six patients (37%) had IPSS low risk, 62 (41%) Int-1 and 14 (9%) Int-2. In 18 (12%) patients IPSS was not evaluable due to karyotype. Thirty-nine patients (26%) were transfusion-dependent (TD) and 28 (72%) had at least 1 additional cytopenia. In the transfusion-free (TF) patients, median Hb was 10.5 g/dL (IQ range 9.2–12.6); 77 patients (69%) were anemic (Hb 〈 12.0 g/dL) and 48 (43%) had at least 1 additional cytopenia. ECOG PS was significantly better in TF patients (p=0.0061). Charlson’s comorbidity index was 0 in 78 patients (52%), 1 in 38 patients (25%), 2 in 20 patients (13%) and ≥ 3 in 14 patients (9%). Median serum epo was 50.4 U/L (N=94). Of the 29 QOL-E items, 25 items had a response rate 〉 90%. Though 26 of the 29 QOL-E items showed significant correlations between patients’ and physicians’ scores, there were significant score differences in 9 (31%) of the items with a general trend of physicians to overestimate patients’ problems. Several QoL scores correlated with Hb levels and were significantly lower in TD patients than in TF patients (Table). Table. Patient QoL scores in transfusion-dependent (TD) and transfusion-free (TF) patients and correlations with Hb values. QOL domain Whole group Correlation with Hb r (p) TD patients (n = 39) TF patients (n = 111) p QOL-E, scores Q1 33 (33–67) 0.186 (0.023) 33 (0–33) 33 (33–67) 0.036 Q2 67 (67–100) −0.032 (0.70) 67 (33–100) 67 (67–67) 0.11 Physical 63 (38–75) 0.286 (0.0004) 50 (38–63) 63 (50–75) 0.0072 Social 50 (25–63) 0.197 (0.017) 44 (17–63) 50 (38–63) 0.064 Sexual 100 (50–100) 0.250 (0.011) 50 (0–100) 100 (75–100) 0.0011 Fatigue 81 (71–86) 0.236 (0.0038) 78 (67–86) 81 (71–90) 0.14 MDS-specific 81 (71–90) 0.287 (0.0005) 74 (63–83) 83 (74–93) 0.0005 LASA, scores Energy 48 ± 25 0.285 (0.0004) 42 ± 25 50 ± 25 0.081 Activity 54 ± 27 0.226 (0.0055) 50 ± 29 56 ± 26 0.24 General 53 ± 27 0.304 (0.0002) 44 ± 25 57 ± 27 0.0093 EQ-5D, scores Mobility 50 (50–100) 0.119 (0.15) 50 (50–100) 75 (50–100) 0.45 Self-Care 100 (100–100) 0.148 (0.074) 100 (100–100) 100 (100–100) 0.14 Usual Activity 100 (50–100) 0.129 (0.12) 50 (50–100) 100 (50–100) 0.0050 Pain/Discomfort 50 (50–100) −0.027 (0.75) 100 (50–100) 50 (50–100) 0.48 Anxiety/Depression 50 (50–100) 0.010 (0.90) 50 (50–100) 50 (50–100) 0.88 VAS Health State 60 ± 20 0.212 (0.010) 52 ± 19 63 ± 19 0.0020 Data are reported as mean ± standard deviation or median and interquartile range as appropriate. CONCLUSIONS: QoL is compromised in MDS and is associated with Hb values and transfusion-dependence. Patient preferences must be evaluated when considering treatment options since hematologists seem to overestimate patients’ perception of healthrelated problems. The disease-specific questionnaire, QOL-E, and the LASA scale are valid tools for the evaluation of QoL in MDS patients.

Description: Abstract 2763 Poster Board II-739 Introduction: Chronic anemia of myelodysplastic syndromes (MDS) is associated with poor quality of life (QoL) and an inferior clinical course. Transfusion dependence in lower-risk patients is associated with reduced survival as a result of iron overload, heart failure, and progression to acute myeloid leukaemia. Lenalidomide is approved for the treatment of transfusion-dependent anemia in patients with International Prognostic Scoring System (IPSS) Low- or Intermediate (Int)-1-risk MDS with deletion 5q [del(5q)]. Rapid and durable responses include transfusion independence with a rise in Hb, suppression of the del(5q) clone, and improvement in bone marrow morphological features. We present preliminary results of a prospective single-arm trial investigating the effect on QoL, efficacy, and safety of lenalidomide in the treatment of 49 adult patients with IPSS Low- and Int-1-risk MDS with del(5q) with/without additional cytogenetic abnormalities and Hb 〈 10 g/dL. Methods: Exclusion criteria include: ANC 〈 500/mm3; PLT count 〈 50,000/mm3; prior chemotherapy; and ongoing treatment with rHuEpo. Lenalidomide was administered orally at a starting dose of 10 mg/day. If necessary, dosing was reduced to 5 mg/day or 5 mg on alternate days. Treatment will be continued for a maximum of 12 months or until evidence of unacceptable non-hematological adverse events, lack of response, disease progression, or relapse following erythroid improvement. QoL was assessed at study entry and weeks 8, 12, and 24 using the QOL-E v.2 questionnaire. QoL scores are standardized in a 0–100 scale with lower scores representing a worse QoL. Response was evaluated according to the modified International Working Group (IWG) response criteria. Results: Twenty patients (5 M, 15 F, mean age 72 ± 10 years) are evaluable for erythroid responses and cytogenetic changes at 12 weeks and 13 patients have reached a 24-week follow-up. At baseline, mean disease duration was 3.4 ± 2.3 years. Seventeen patients were transfusion dependent (TD), 3 were transfusion free (TF). ECOG performance status was 0 in 14 patients and 1 in 6 patients. After 12 weeks from study entry, 17 (85%) patients obtained an erythroid response with a mean Hb level increase from baseline 8.6 ± 0.9 g/dL to 11.1 ± 2.4 (p=0.001). By 24 weeks, 11 of the 13 patients re-evaluated were erythroid responders obtaining transfusion independence and significant improvements in Hb (mean change from baseline 3.7 ± 2.7 g/dL, and increase to mean 11.1 ± 2.4 g/dL (p

Description: The use of all-trans retinoic acid (ATRA) in combination with chemotherapy has markedly improved the prognosis for patients with acute promyelocytic leukemia (APL); the higher complete remission (CR) and survival rates now reported in this disease almost approach those obtained for other highly curable hematologic malignancies. Of 77 patients with APL who were consecutively treated at a single institution and who achieved CR after induction and consolidation therapy, 5 (6.5%) acquired therapy-related myelodysplasia (tMDS), acute myelogenous leukemia (AML), or both (tMDS–AML). Of these, 3 of 46 (6.5%) patients received front-line chemotherapy with or without ATRA and acquired tMDS–AML while in first remission of APL. Two underwent repeated chemotherapy cycles with ATRA because of APL relapse and acquired tMDS–AML while in the second or third remission of APL. In 2 patients, clinical and biologic characteristics of tMDS–AML were as expected for postalkylating forms (long latency, MDS phase preceding AML, karyotypic aberrations involving chromosomes 5 or 7), even though one of them had not previously received alkylating drugs. Three of the 5 patients died shortly after tMDS–AML diagnosis, one is alive with tMDS, and one is alive and in CR after allogeneic bone marrow transplantation. The occurrence of tMDS–AML after successful therapy for APL is an emerging problem. The availability of prognostic score systems at initial diagnosis and monitoring of residual disease by polymerase chain reaction might allow better tailoring of treatment intensity in APL to spare unnecessary toxicity and to minimize the risk for tMDS–AML in patients who are presumably cured.