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Treatment with azacitidine (AZA) has been suggested to be of benefit for higher-risk myelodysplastic syndrome (HR-MDS) patients with chromosome 7 abnormalities (Abn 7). This retrospective study of 235 HR-MDS patients with Abn 7 treated with AZA (n = 115) versus best supportive care (BSC; n = 120), assessed AZA treatment as a time-varying variable in multivariable analysis. A Cox Regression model with time-interaction terms of overall survival (OS) at different time points confirmed that, while chromosome 7 cytogenetic categories (complex karyotype [CK] versus non-CK) and International Prognostic Scoring System risk (high versus intermediate-2) retained poor prognosis over time, AZA treatment had a favourable impact on OS during the first 3 years of treatment compared to BSC (Hazard ratio [HR] 0·5 P < 0·001 at 1 year, 0·7 P = 0·019 at 2 years; 0·73 P = 0·029 at 3 years). This benefit was present in all chromosome 7 categories, but tended to be greater in patients with CK (risk reduction of 82%, 68% and 53% at 1, 3 and 6 months in CK patients; 79% at 1 month in non-CK patients, P < 0·05 for all). AZA also significantly improved progression-free survival (P < 0·01). This study confirms a time-dependent benefit of AZA on outcome in patients with HR-MDS and cytogenetic abnormalities involving chromosome 7, especially for those with CK., (© 2018 John Wiley & Sons Ltd.)

Purpose Most anemic patients with non-deleted 5q lower-risk myelodysplastic syndromes (MDS) are treated with erythropoiesis-stimulating agents (ESAs), with a response rate of approximately 50%. Second-line treatments, including hypomethylating agents (HMAs), lenalidomide (LEN), and investigational drugs, may be used after ESA failure in some countries, but their effect on disease progression and overall survival (OS) is unknown. Here, we analyzed outcome after ESA failure and the effect of second-line treatments. Patients and Methods We examined an international retrospective cohort of 1,698 patients with non-del(5q) lower-risk MDS treated with ESAs. Results Erythroid response to ESAs was 61.5%, and median response duration was 17 months. Of 1,147 patients experiencing ESA failure, 653 experienced primary failure and 494 experienced relapse after a response. Primary failure of ESAs was associated with a higher risk of acute myeloid leukemia (AML) progression, which did not translate into an OS difference. Of 450 patients (39%) who received second-line treatment, 194 received HMAs, 148 received LEN, and 108 received other treatments (MISC), whereas 697 received RBC transfusions only. Five-year AML cumulative incidence was 20.3%, 20.3%, and 11.3% for those receiving HMAs, LEN, and MISC, respectively ( P = .05). Five-year OS for patients receiving HMA, LEN, and MISC was 36.5%, 41.7%, and 51%, respectively ( P = .21). In a multivariable analysis adjusted for age, sex, revised International Prognostic Scoring System score, and progression at ESA failure, there was no significant OS difference among the three groups. Conclusion In this large, multicenter, retrospective cohort of patients with non-del(5q) lower-risk MDS treated with ESAs, none of the most commonly used second-line treatments (HMA and LEN) significantly improved OS. Early failure of ESAs was associated with a higher risk of AML progression.

After failure of erythropoiesis-stimulating agents (ESAs), lenalidomide (LEN) yields red blood cell (RBC) transfusion independence (TI) in 20-30% of lower-risk non-del5q myelodysplastic syndrome (MDS). Several observations suggest an additive effect of ESA and LEN in this situation. We performed a randomized phase III study in 131 RBC transfusion-dependent (TD, median transfusion requirement six RBC units per 8 weeks) lower-risk ESA-refractory non-del5q MDS. Patients received LEN alone, 10 mg per day, 21 days per 4 weeks (L arm) or LEN (same schedule) + erythropoietin (EPO) beta, 60,000 U per week (LE arm). In an intent-to-treat (ITT) analysis, erythroid response (HI-E, IWG 2006 criteria) after four treatment cycles (primary end point) was 23.1% (95% CI 13.5-35.2) in the L arm and 39.4% (95% CI 27.6-52.2) in the LE arm (P=0.044), while RBC-TI was reached in 13.8 and 24.2% of the patients in the L and LE arms, respectively (P=0.13). Median response duration was 18.1 and 15.1 months in the L and LE arms, respectively (P=0.47). Side effects were moderate and similar in the two arms. Low baseline serum EPO level and a G polymorphism of CRBN gene predicted HI-E. Combining LEN and EPO significantly improves erythroid response over LEN alone in lower-risk non-del5q MDS patients with anemia resistant to ESA.

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., (© 2012 Blackwell Publishing Ltd.)

We evaluated the prognostic value of serum ferritin (SF) level at diagnosis in 318 newly diagnosed IPSS low and int 1 (lower) risk MDS patients included in the French MDS registry, who did not require RBC transfusions and had baseline SF level determination. Increased baseline SF level (>300 ng/ml) was correlated with male gender, more pronounced anaemia, and diagnosis of RARS but had no negative impact on progression to AML or survival., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Isolated 20q deletion is common in MDS and considered of good prognosis, but no large series have been reported. We compared characteristics of 62 MDS patients with isolated del 20q, 36 patients with del 20q and other cytogenetic abnormalities, and 1335 MDS patients without del20q. Significant differences between MDS with isolated del 20q and patients without del 20q were lower platelet count (mean 144 vs. 196 G/l, p=0.005), lower marrow blast count (mean 3.9% vs. 5.6%, p=0.0008), and higher reticulocyte count (mean 72.5 vs. 51.7 G/l, p=0.04). Ten (16%) patients with isolated del 20q had Hb>12 g/dl and platelets <100 G/l, compared to 7.3% of patients without del 20q (p=0.025). Review of marrow slides of those 10 patients showed that could be readily identified as MDS prior to cytogenetics. Fourteen percent of patients with isolated del 20q progressed to AML compared to 11% with one and 24% with several additional abnormalities. Median survival was 54 months in patients with isolated del 20q, not reached and 12 months for del 20q with one and several additional abnormalities, respectively (p=0.035) confirming the favorable prognosis of del 20q without complex abnormalities., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

With improved treatment of acute promyelocytic leukemia (APL) by all trans retinoic acid (ATRA) combined to anthracycline-aracytin chemotherapy (CT), a larger number of those patients may be at risk of late complications. Recently, the Rome group reported five cases of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML, non-APL) occurring during the course of 77 APL patients (6.5%) in complete remission (CR). From 1991 to 1998, we treated 677 newly diagnosed cases of APL, and 617 of them achieved CR with ATRA combined to CT (n=579) or CT alone (n=38); 246 of them received subsequent maintenance CT with 6 mercaptopurine and methotrexate. With a median follow-up of 51 months, 6 patients (0.97%) developed MDS, 13-74 months after the diagnosis of APL. In all six cases, t(15;17) and PML-RARalpha rearrangement were absent at the time of MDS diagnosis, and karyotype mainly showed complex cytogenetic abnormalities involving chromosomes 5 and/or 7, typical of MDS observed after treatment with alkylating agents, although none of the six patients had received such agents for the treatment of APL. Our findings suggest that MDS can indeed be a long-term complication in APL, although probably at lower incidence than that previously reported.

Treatment with alkylating agents or radiophosphorous (32P) has been shown to carry a certain leukemogenic risk in myeloproliferative disorders (MPDs), including essential thrombocytemia (ET). The leukemogenic risk associated to treatment with hydroxyurea in ET, on the other hand, is generally considered to be relatively low. Between 1970 and 1991, we diagnosed ET in 357 patients, who were monitored until 1996. One or several therapeutic agents had been administered to 326 patients, including hydroxyurea (HU) in 251 (as only treatment in 201), pipobroman in 43, busulfan in 41, and 32P in 40. With a median follow-up duration of 98 months, 17 patients (4.5%) had progressed to acute myeloid leukemia (AML; six cases) or myelodysplastic syndrome (MDS; 11 cases). Fourteen of these patients had received HU, as sole treatment in seven cases, and preceded or followed by other treatment in seven cases, mainly pipobroman (five cases). The remaining three leukemic progressions occurred in patients treated with 32P (two cases) and busulfan (one case). The incidence of AML and MDS after treatment, using 32P alone and 32P with other agents, busulfan alone and with other agents, HU alone and with others agents, and pipobroman alone and with other agents was 7% and 9%, 3% and 17%, 3.5% and 14%, and 0% and 16%, respectively. Thirteen of 17 patients who progressed to AML or MDS had successful cytogenetic analysis. Seven of them had rearrangements of chromosome 17 (unbalanced translocation, partial or complete deletion, isochromosome 17q) that resulted in 17p deletion. They also had a typical form of dysgranulopoiesis combining pseudo Pelger Hüet hypolobulation and vacuoles in neutrophils, and p53 mutation, as previously described in AML and MDS with 17p deletion. Those seven patients had all received HU, as the only therapeutic agent in three, and followed by pipobroman in three. The three patients who had received no HU and progressed to AML or MDS had no 17p deletion. A review of the literature found cytogenetic analysis in 35 cases of AML and MDS occurring after ET, 11 of whom had been treated with HU alone. Five of 35 patients had rearrangements that resulted in 17p deletion. Four of them had been treated with HU alone. These results show that treatment with HU alone is associated with a leukemic risk of approximately 3.5%. A high proportion of AML and MDS occurring in ET treated with HU (alone or possibly followed by pipobroman) have morphologic, cytogenetic, and molecular characteristics of the 17p- syndrome. These findings suggest that widespread and prolonged use of HU in ET may have to be reconsidered in some situations, such as asymptomatic ET.