Adequate iron chelation therapy for at least six months improves survival in transfusion-dependent patients with lower risk myelodysplastic syndromes.

BACKGROUND: Most patients with myelodysplastic syndromes (MDS) require transfusions at the risk of iron overload and associated organ damage, and death. Emerging evidence indicates that iron chelation therapy (ICT) could reduce mortality and improve survival in transfusion-dependent MDS patients, especially those classified as International Prognostic Scoring System (IPSS) Low or Intermediate-1 (Low/Int-1). METHODS: Follow-up of a retrospective study. Sample included 127 Low/Int-1 MDS patients from 28 centers in Belgium. Statistical analysis stratified by duration (≥6 versus <6 months) and quality of chelation (adequate versus weak). RESULTS: Crude chelation rate was 63% but 88% among patients with serum ferritin ≥1000 µg/L. Of the 80 chelated patients, 70% were chelated adequately mainly with deferasirox (26%) or deferasirox following deferoxamine (39%). Mortality was 70% among non-chelated, 40% among chelated, 32% among patients chelated ≥6 m, and 30% among patients chelated adequately; with a trend toward reduced cardiac mortality in chelated patients. Overall, median overall survival (OS) was 10.2 years for chelated and 3.1 years for non-chelated patients (p<0.001). For patients chelated ≥6 m or patients classified as adequately chelated, median OS was 10.5 years. Mortality increased as a function of average monthly transfusion intensity (HR=1.08, p=0.04) but was lower in patients receiving adequate chelation or chelation ≥6 m (HR=0.24, p<0.001). CONCLUSION: Six or more months of adequate ICT is associated with markedly better overall survival. This suggests a possible survival benefit of ICT in transfusion-dependent patients with lower-risk MDS.

Bortezomib combined with low-dose cytarabine in Intermediate-2 and high risk myelodysplastic syndromes. A phase I/II Study by the GFM.

Marrow cells from patients with higher-risk myelodysplastic syndrome (MDS) exhibit constitutive nuclear factor (NF)-κB activation. The proteasome inhibitor, bortezomib, has limited efficacy as a single agent in acute myeloid leukaemia. Its activity on leukaemic cell lines is potentiated by chemotherapy. We treated 43 higher-risk MDS patients with bortezomib (1·5 mg/m(2) , days 1, 4, 8 and 11) and low dose cytarabine arabinoside (LDAC; 10 mg/m(2) , then 20 mg/m(2) from days 1-14), every 28 d for four cycles. Median follow-up was 29·7 months. Responses were seen in 12 of the 43 patients (28%), including complete response (CR, n = 1), marrow-CR (n = 3), partial response (PR, n = 5) and haematological improvement (HI, n = 3). Responses were seen in 12 (36%) of the 33 previously untreated patients (11% CR, 13% PR, 2·5% HI), compared to none in the 12 previously treated patients (P < 0·01). Responders had better overall survival (median 18·2 vs. 10 months). One CR and 3 marrow-CRs were seen in patients with complex karyotypes. Main toxicity was haematological, responsible for infection in six patients and bleeding in 3. Three patients with Grade 1-2 pre-treatment haematotoxicity developed Grade 3-4 toxicity. Neuropathy was seen in 12% of patients. The addition of bortezomib to LDAC in higher-risk MDS may improve results obtained with LDAC alone, especially in patients with unfavourable karyotypes.

Iron status and treatment modalities in transfusion-dependent patients with myelodysplastic syndromes.

Transfusion dependency and iron overload are common among patients with myelodysplastic syndromes (MDS) treated with red blood cell (RBC) transfusions. Transfusion dependency is associated with leukemic progression and shorter survival. Guidelines recommend iron chelation therapy to manage iron overload, however little is known about the chelation patterns in daily clinical practice. The objective of this multicenter, retrospective, cross-sectional, observational study was to evaluate iron status and its management in transfusion-dependent MDS patients. A total of 193 patient records from 29 centers were eligible for inclusion. Median patient age was 76, and median age at diagnosis of MDS was 74. Patients had received an average of 13.4 ± 7.6 RBC units in the past 4 months; 44% had received more than 50 units since their MDS diagnosis. Medium serum ferritin was 1,550 µg/L. Ninety patients (46.6%) received iron chelation therapy with either deferoxamine (41%), deferasirox (36%), and deferoxamine followed by deferasirox (23%). There were no statistically significant differences between chelated and nonchelated patients in terms of International Prognostic Scoring System (IPSS), French-American-British (FAB), and/or World Health Organization (WHO) status, though chelated patients had received more RBC transfusions (p = 0.014). Iron chelation therapy may be underutilized in transfusion-dependent patients. Undertreatment can be reduced by complementing sound clinical judgment with the generally accepted guidelines of a serum ferritin level >1,000 µg/L and/or two or more RBC transfusions per month for the past year; considering patients on the basis of their IPSS, FAB, and/or WHO status; and individually tailored treatment regimens. Prospective randomized trials are necessary to establish causally the efficacy of iron chelation therapy in MDS.

Early introduction of ESA in low risk MDS patients may delay the need for RBC transfusion: a retrospective analysis on 112 patients.

ESAs are increasingly used to treat anemia of lower risk MDS, even before RBC transfusion requirement. From a previously published patient cohort treated with ESAs, we selected 112 patients with de novo low or int-1 IPSS MDS with Hb<10 g/dl, serum EPO<500 UI/l and who had never been transfused. Erythroid response rate at 12 weeks was 63.1% (IWG 2006). In multivariate analysis, an interval between diagnosis and ESA onset<6 months, Hb level>9 g/dl, and serum EPO<100 UI/l predicted better response to ESA while shorter interval between diagnosis and ESA onset (p=0.01), lower serum EPO (p=0.04) and WHO diagnosis of RCMD-RS (p=0.03) were associated with longer response. Median interval from diagnosis to transfusion dependency was 80 months and 35 months, respectively, in patients with onset of ESA < 6 months and ≥ 6 months from diagnosis (p=0.007). Those results support early onset of ESA in lower risk MDS, to better avoid the consequences of anemia. Early introduction of ESA may also delay the need for RBC transfusions, hypothetically by slowing the disease course, but prospective studies are required to further assess this point.

Efficacy and safety of lenalidomide in intermediate-2 or high-risk myelodysplastic syndromes with 5q deletion: results of a phase 2 study.

Higher-risk MDS with del5q carry a poor prognosis. In this phase 2 trial, 47 patients with higher-risk MDS received lenalidomide 10 mg/day. International Prognostic Scoring System was high in 60%, intermediate-2 risk in 40%. del 5q was isolated, with one additional and more than one additional abnormality in 19%, 23%, and 58% patients, respectively. Thirteen (27%) patients achieved hematologic response, including 7 hematologic complete remission (CR) (with complete [4] or partial [3] cytogenetic response), 2 marrow CR and 4 hematologic improvement erythroid, and 12 became red blood cell (RBC) transfusion independent, for a median duration of 6.5 months. Median CR duration was 11.5 months. Six of 9 (67%) patients with isolated del 5q achieved CR, versus 1 of 11 and none of 27 patients with one or more than one additional abnormality, respectively (P < .001). Seven of 20 (35%) with initial platelets more than 100,000/mm(3) obtained CR, compared with none of the 27 with lower platelet counts less than 100,000/mm(3) (P = .001). Our data support a potential role of lenalidomide in higher-risk MDS with isolated del 5q.

Farnesyl transferase inhibitor (lonafarnib) in patients with myelodysplastic syndrome or secondary acute myeloid leukaemia: a phase II study.

Although an activating mutation of Ras is commonly observed in myelodysplastic syndrome (MDS), the role of Ras in the natural history of MDS remains largely unknown. We prospectively studied efficiency and tolerance of lonafarnib, a compound able to inhibit Ras signalling pathway through an inhibition of farnesyl transferase, in patients with MDS or secondary acute myeloid leukaemia (sAML). Lonafarnib was administered orally at a dose of 200 mg twice daily for three courses of 4 weeks (separated by 1 to 4 weeks without treatment). Sixteen patients were included: FAB/RAEB (n = 10), RAEB-T (n = 2), sAML (n = 2) and chronic myelomonocytic leukaemia (CMML; n = 2); WHO/RAEB-1 (n = 4), RAEB-2 (n = 5), AML (n = 5), CMML (n = 2). Median age was 70 (53-77) years. The karyotype was complex or intermediate in 11 patients, and the International Prognostic Scoring Systems (IPSS) risk groups were low in two patients, INT-1 in one patient, INT-2 in four patients and high in six patients (unknown or not applicable in three patients). Among the 14 patients tested, five had Ras mutations in codons 12, 13 or 61 of N-Ras, K-Ras or H-Ras. One patient was excluded of the analysis for protocol violation, and 15 patients were assessable for tolerance. Gastrointestinal toxicities (diarrhoea, nausea and anorexia) and myelosuppression were the major side effects. Other toxicities included infections, fatigue, increase of liver enzymes, arrhythmia and skin rash. One patient died of infection, and the treatment was stopped in one other who developed atrial fibrillation. Doses were reduced in all but one patient treated with more than one course of farnesyl transferase inhibitor. Responses were assessable in 12 patients. A partial response in one sAML patient and a very transient decrease of blast cell count with normalisation of karyotype in one MDS patient were observed. No relation between improvement of marrow parameters and detected Ras mutations was observed. Lonafarnib alone, administered following our schedule, has shown limited activity in patients with MDS or secondary AML. Gastrointestinal and haematological toxicities appear the limiting toxicity in this population of patients.

Predictive factors of response and survival in myelodysplastic syndrome treated with erythropoietin and G-CSF: the GFM experience.

We analyzed prognostic factors of response, response duration, and possible impact on survival of epoetin alpha, epoetin beta, or darbepoetin alpha (DAR) with or without granulocyte colony-stimulating factor in 403 myelodysplastic syndrome (MDS) patients. Sixty-two percent (40% major and 22% minor) and 50% erythroid responses were seen, and median response duration was 20 and 24 months according to IWG 2000 and 2006 criteria, respectively. Significantly higher response rates were observed with less than 10% blasts, low and int-1 International Prognostic Scoring System (IPSS), red blood cell transfusion independence, serum EPO level less than 200 IU/L, and, with IWG 2006 criteria only, shorter interval between diagnosis and treatment. Significantly longer response duration was associated with major response (IWG 2000 criteria), IPSS low to INT-1, blasts less than 5%, and absence of multilineage dysplasia. Minor responses according to IWG 2000 were reclassified as "nonresponders" or "responders" according to IWG 2006 criteria. However, among those IWG 2000 minor responders, response duration did not differ between IWG 2006 responders and nonresponders. Multivariate adjusted comparisons of survival between our cohort and the untreated MDS cohort used to design IPSS showed similar rate of progression to acute myeloid leukemia in both cohorts, but significantly better overall survival in our cohort, suggesting that epoetin or DAR treatment may have a favorable survival impact in MDS.

Contribution of flow cytometry to the diagnosis of malignant and non malignant conditions in lymph node biopsies.

In order to assess the contribution of FC to the diagnosis of lymph node disorders we retrospectively compared the pathological and the FC diagnosis made in 118 consecutive lymph node biopsies. Pathological diagnosis included non malignant conditions (n = 43), B-cell Non Hodgkin lymphoma (NHL) (n = 30), T-cell NHL (1 case), carcinoma (n = 18), Hodgkin lymphoma (HL) (n = 15), melanoma (n = 2), chronic myelocytic leukemia (n = 12), miscellaneous non-lymphoid tissues (n = 6) and undetermined conditions (n = 2). Among the 116 assessable samples, FC was in agreement with histology in 102 cases (87.9%; 95%CI = 81-93) which included 38 benign conditions (90%; 95% CI = 77-97%), 29 NHL (96.7%; 95% CI = 83-100), 18 carcinomas (100%; 95% CI = 81-100), and 12 HL (80.0%; 95% CI = 52-96). Discrepancies (14 cases) included 3 HL undiagnosed by FC and 2 granulomatous adenitis with an erroneous FC diagnosis of HL. Finally, a malignant condition was suspected only by FC in 5 cases (1 carcinoma, 2 B-cell and 2 T-cell NHL) and subsequently demonstrated by additional diagnostic procedures. In conclusion, this study confirms that FC performed on fresh lymph node samples is a powerful diagnostic tool in patients with malignant lymphoma. A few cases left undiagnosed by classical pathological analysis can be recognized by FC. Carcinoma is readily identified by FC analysis, while some benign conditions and Hodgkin lymphoma can be misdiagnosed with the use of FC, although the potential of FC to properly recognize HL is improving compared to previously reported studies. FC is a useful adjunct to pathological analysis of lymph node specimens.