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Hematologic responses to hypomethylating agents are often delayed in patients with myelodysplastic syndrome or acute myeloid leukemia. Fetal hemoglobin is a potential novel bio-marker of response: recently, we demonstrated that a high fetal hemoglobin level prior to decitabine treatment was associated with superior outcome. Here we investigated whether early fetal hemoglobin induction during decitabine treatment also had prognostic value, and studied the potential of decitabine to induce erythroid differentiation and fetal hemoglobin expression in vitro. Fetal hemoglobin levels were measured by high-performance liquid chromatography in patients with higher-risk myelodysplastic syndrome (n=16) and acute myeloid leukemia (n=37) before treatment and after each course of decitabine. Levels above 1.0% were considered induced. Patients achieving complete or partial remission as best response had attained a median fetal hemoglobin of 1.9% after two courses of treatment, whereas the median value in patients who did not reach complete or partial remission was 0.8% (P=0.015). Fetal hemoglobin induction after two courses of decitabine treatment was associated with early platelet doubling (P=0.006), and its subsequent decrease with hematologic relapse. In patients with myelodysplastic syndrome, induction of fetal hemoglobin after course 2 of treatment was associated with longer overall survival: median of 22.9 versus 7.3 months in patients with or without induction of fetal hemoglobin, respectively [hazard ratio=0.2 (95% confidence interval: 0.1–0.9); P=0.03]. In vitro decitabine treatment of two bi-potential myeloid leukemia cell lines (K562 and HEL) resulted in induction of an erythroid (not megakaryocytic) differentiation program, and of fetal hemoglobin mRNA and protein, associated with GATA1 gene demethylation and upregulation. In conclusion, fetal hemoglobin may provide a useful dynamic biomarker during hypomethylating agent therapy in patients with myelodysplastic syndrome or acute myeloid leukemia.

Flow cytometric analysis is a recommended tool in the diagnosis of myelodysplastic syndromes. Current flow cytometric approaches evaluate the (im)mature myelo-/monocytic lineage with a median sensitivity and specificity of ~71% and ~93%, respectively. We hypothesized that the addition of erythroid lineage analysis could increase the sensitivity of flow cytometry. Hereto, we validated the analysis of erythroid lineage parameters recommended by the International/European LeukemiaNet Working Group for Flow Cytometry in Myelodysplastic Syndromes, and incorporated this evaluation in currently applied flow cytometric models. One hundred and sixty-seven bone marrow aspirates were analyzed; 106 patients with myelodysplastic syndromes, and 61 cytopenic controls. There was a strong correlation between presence of erythroid aberrancies assessed by flow cytometry and the diagnosis of myelodysplastic syndromes when validating the previously described erythroid evaluation. Furthermore, addition of erythroid aberrancies to two different flow cytometric models led to an increased sensitivity in detecting myelodysplastic syndromes: from 74% to 86% for the addition to the diagnostic score designed by Ogata and colleagues, and from 69% to 80% for the addition to the integrated flow cytometric score for myelodysplastic syndromes, designed by our group. In both models the specificity was unaffected. The high sensitivity and specificity of flow cytometry in the detection of myelodysplastic syndromes illustrates the important value of flow cytometry in a standardized diagnostic approach. The trial is registered at www.trialregister.nl as NTR1825; EudraCT n.: 2008-002195-10

In a prospective multicenter phase II study, we evaluated the effect of three courses of vincristine, doxorubicin and dexamethasone followed by high-dose melphalan and autologous stem cell transplantation on an intention-to-treat basis. Sixty-nine newly diagnosed patients with amyloid light chain amyloidosis were included between November 2000 and January 2006: 37 men and 32 women with a median age of 56 years, including 46% of patients with cardiac and 22% of patients with involvement of 3 or 4 organs. Initial results presented in 2008 showed a 4-year overall survival rate of 62% among all the patients, while the 4-year survival rate after transplantation was 78%. Here we report the long-term follow-up data after a median follow up of 115 months of the patients still alive. Median survival of all patients was 96 months from registration and for the transplanted patients ten years from the date of transplantation. Twelve (12%) patients died during induction therapy with vincristine, doxorubicin and dexamethasone, including 8 patients (12%) due to treatment-related mortality. Two patients died within one month following high-dose melphalan. We conclude that vincristine, doxorubicin and dexamethasone should not be applied as induction therapy for intensification in amyloid light chain amyloidosis. However, a 2-step approach consisting of a non-intensive less toxic induction therapy followed by high-dose melphalan and autologous stem cell transplantation may result in extended survival in newly diagnosed patients with amyloid light chain amyloidosis (clinicaltrials.gov identifier: 01207094).

Background The treatment of acute myeloid leukemia of older, medically non-fit patients still poses a highly unmet clinical need, and only few large, prospective studies have been performed in this setting. Given the established activity of hypomethylating agents such as 5-aza-2'-deoxycytidine (decitabine) in myelodysplastic syndromes and acute myeloid leukemia with 20–30% bone marrow blasts, we investigated whether this drug is also active in patients with more than 30% blasts.Design and Methods To evaluate the efficacy and toxicity of decitabine in patients over 60 years old with untreated acute myeloid leukemia ineligible for induction chemotherapy, 227 patients (median age, 72 years), many with comorbidities, adverse cytogenetics and/or preceding myelodysplastic syndrome were treated with this hypomethylating agent. During the initial decitabine treatment (135 mg/m2 total dose infused intravenously over 72 hours every 6 weeks), a median of two cycles was administered (range, 1–4). All-trans retinoic acid was administered to 100 patients during course 2. Fifty-two patients who completed four cycles of treatment subsequently received a median of five maintenance courses (range, 1–19) with a lower dose of decitabine (20 mg/m2) infused over 1 hour on 3 consecutive days every 4–6 weeks.Results The complete and partial remission rate was 26%, 95% CI (20%, 32%), and an antileukemic effect was noted in 26% of patients. Response rates did not differ between patients with or without adverse cytogenetics; patients with monosomal karyotypes also responded. The median overall survival from the start of decitabine treatment was 5.5 months (range, 0–57.5+) and the 1-year survival rate was 28%, 95%CI (22%,34%). Toxicities were predominantly hematologic.Conclusions Decitabine is well tolerated by older, medically non-fit patients with acute myeloid leukemia; myelosuppression is the major toxicity. The response rate and overall survival were not adversely influenced by poor-risk cytogenetics or myelodysplastic syndrome. Because of these encouraging results, randomized studies evaluating single-agent decitabine versus conventional treatment are warranted. The study is registered with the German Clinical Trials Registry, number DRKS00000069.

Background In order to improve the molecular response rate and prevent resistance to treatment, combination therapy with different dosages of imatinib and cytarabine was studied in newly diagnosed patients with chronic myeloid leukemia in the HOVON-51 study.Design and Methods Having reported feasibility previously, we hereby report the efficacy of escalated imatinib (200 mg, 400 mg, 600 mg or 800 mg) in combination with two cycles of intravenous cytarabine (200 mg/m2 or 1000 mg/m2 days 1 to 7) in 162 patients with chronic myeloid leukemia.Results With a median follow-up of 55 months, the 5-year cumulative incidences of complete cytogenetic response, major molecular response, and complete molecular response were 89%, 71%, and 53%, respectively. A higher Sokal risk score was inversely associated with complete cytogenetic response (hazard ratio of 0.63; 95% confidence interval, 0.50–0.79, P

Background and Objectives The Dutch-Belgian HOVON group performed a randomized phase 3 trial to compare single non-myeloablative intensive treatment with double, intensive treatment in previously untreated patients with multiple myeloma (MM).Design and Methods Three hundred and three patients with stage II/III MM were randomized after VAD induction chemotherapy to receive two cycles of non-myeloablative intermediate-dose melphalan (70 mg/m2) (single treatment) or the same regimen followed by cyclophosphamide 120 mg/kg iv plus total body irradiation (TBI) 9 Gy and autologous stem cell transplantation (double, intensive treatment). In both treatment arms interferon αIIa was given as maintenance until relapse/progression.Results A significantly higher proportion of patients achieved a complete remission (CR) on protocol treatment with double, intensive therapy (32% vs 13%, p