Jan Lemmens

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.

Monocytes are activated in patients with myelodysplastic syndromes and can contribute to bone marrow failure through CD40-CD40L interactions with T helper cells.

Immune mechanisms have been shown to contribute to the process of myelodysplastic syndromes (MDS)-related bone marrow (BM) failure. The aim of this study was to evaluate the possible contribution of activated monocytes through CD40–CD40L(CD154) interactions with activated T helper cells. We demonstrated in 77 predominantly lower risk MDS patients that the CD40 receptor was expressed significantly higher on monocytes and that CD40L was expressed significantly higher on T helper cells in peripheral blood (PB) and BM. Increased levels of CD40 and CD40L were detected in the same patients. In addition, stimulation of the CD40 receptor on purified PB monocytes led to a significantly higher tumor necrosis factor alpha production in patients. Co-culture of BM mononuclear cells of 21 patients in the presence of a blocking CD40 monoclonal antibody (ch5D12) led to a significant increase in the number of colony-forming units. A correlation was seen between increased CD40 expression on monocytes with patients’ age below 60 years and with the cytogenetic abnormality trisomy 8. These results demonstrate that CD40 expression on monocytes may identify a subgroup of MDS patients in whom immune-mediated hematopoietic failure is part of the disease process. As such, the CD40–CD40L-based activation of monocytes might be a target to counteract MDS-related BM failure.

The t(14;20)(q32;q12): a rare cytogenetic change in multiple myeloma associated with poor outcome

and concurrent sepsis causing diagnostic delay and significant morbidity. We believe that these predisposing events are common to all patients receiving high-dose chemotherapy for CNS lymphomas and that this complication is under-recognized. Evidence shows that cancer and its treatment is the leading case of WE in the paediatric population and that the diagnosis is commonly missed (Vasconcelos et al, 1999). We propose that prophylactic, parenteral thiamine should be administered to all patients receiving second-line anti-emetic therapy during high-dose chemotherapy for CNS malignancy.

Myelofibrosis patients in Belgium: disease characteristics.

Abstract Objective: To date, only a small number of epidemiological studies on myelofibrosis have been performed. The current study aimed to characterize the myelofibrosis patient population in Belgium according to pre-defined disease parameters (diagnosis, risk categories, hemoglobin <10 g/dl, spleen size, constitutional symptoms, platelet count, myeloblast count), with a view to obtaining a deeper understanding of the proportion of patients that may benefit from the novel myelofibrosis therapeutic strategies. Methods: A survey was used to collect data on prevalence and disease parameters on all myelofibrosis patients seen at each of 18 participating hematologic centers in 2011. Aggregated data from all centers were used for analysis. Analyses were descriptive and quantitative. Results: A total of 250 patients with myelofibrosis were captured; of these, 136 (54%) were male and 153 (61%) were over 65 years old. One hundred sixty-five (66%) of myelofibrosis patients had primary myelofibrosis and 85 (34%) had secondary myelofibrosis. One hundred ninety-three myelofibrosis patients (77%) had a palpable spleen. About a third of patients (34%) suffered from constitutional symptoms. Two hundred twenty-two (89%) myelofibrosis patients had platelet count ≧50 000/μl and 201 (80%) had platelet count ≧100 000/μl. Of 250 patients, 85 (34%) had a myeloblast count ≧1%. Six (2%) patients had undergone a splenectomy. Thirteen (5·2%) patients had undergone radiotherapy for splenomegaly. Conclusions: The results of this survey provide insight into the characteristics of the Belgian myelofibrosis population. They also suggest that a large proportion of these patients could stand to benefit from the therapies currently under development.

CML with e6a2 BCR-ABL1 transcript: an aggressive entity?

Dear Editor, The BCR-ABL1 fusion gene is characteristic of CML. Four different breakpoint cluster regions (bcr) have been described in BCR. The most common BCR breakpoints, in 95% of CML cases, occur in M-BCR, i.e., introns 13 or 14, resulting in an e13a2 (b2a2) or an e14a2 (b3a2) BCR-ABL1 transcript. “Atypical” transcripts, e8a2, e19a2, e13a3, e14a3, e1a3, and e6a2 BCR-ABL1, account for less than 1% of CML cases [1, 2]. Only 11 CML patients have been reported with the e6a2 variant. A male predominance and a worse outcome have been suggested for this variant [3]. Here, we describe an additional CML case with an e6a2 fusion transcript. This 57-year-old male patient presented with hepatosplenomegaly, weight loss, cough, and fever. Laboratory examination showed a hemoglobin level of 12.1 g/dL, a white blood cell count of 43.5×10*9/L with 5% myeloblasts and 10% eosinophils, a platelet count of 129×10*9/L, and an LDH of 3,363 U/L (normal value, 313–618 U/L). An abdominal CT scan confirmed the hepatomegaly (craniocaudal diameter of 24 cm) and splenomegaly (bipolar diameter of 20 cm). Sokal score was 2.11, and Hasford score, 2,211.6 (both high risk). Bone marrow aspirate showed a hypocellular marrow with 10% myeloblasts and marked eosinophilia. On trephine biopsy, a myeloproliferative disease with striking fibrosis was seen. Taqman RQ-PCR was negative for e13a2/e14a2 transcripts and weakly positive for the e1a2 transcript in peripheral blood. A subsequent cytogenetic analysis showed the t(9;22)(q34;q11) translocation in all metaphases and trisomy of chromosome 8 in 6 out of 10 metaphases, indicating clonal evolution. Fluorescent in situ hybridization (FISH), using the Vysis LSI BCR/ABL1 extra signal dual color translocation probe, revealed, in addition to the expected fusion signal on der(22), a small fusion on der(9), further suggesting the presence of a variant breakpoint, located centromeric to M-BCR (Fig. 1). Qualitative reverse transcription polymerase chain reaction (RT-PCR), using forward primers in BCR exon 1 and reverse primers in ABL1 exon 2, confirmed the presence of a variant transcript of 502 bp. This was identified as e6a2 after Sanger sequencing. Based on these findings, a diagnosis of CML in an accelerated phase was made, and the patient was started on imatinib 600 mg daily. Three months later, while still on imatinib, he was readmitted with CML in blast crisis. He had cutaneous chloromas, severe abdominal pain, a productive cough, and life-threatening dyspnea, necessitating intubation and mechanical ventilation. Peripheral leukocyte count was 465× 10*9/L with 29% myeloblasts; he had severe anemia (Hb, 6.5 g/L), thrombocytopenia (75×10*9/L), and an LDH of 10,612 U/L. Chest CT scan revealed multiple pathologically enlarged mediastinal and hilar lymph nodes. Fundoscopic examination showed features of hyperviscosity. Peripheral blood karyotype and FISH now showed an extra derivative der(22)t(9;22) in ~50% of cells. Following leukapheresis and PV is a senior clinical investigator of the Fund for Scientific ResearchFlanders (Belgium) (FWO Vlaanderen). K. A. Beel : J. Maertens Department of Hematology, Internal Medicine, University Hospital Leuven, Leuven, Belgium

Results from the Belgian mantle cell lymphoma registry.

Introduction: Mantle cell lymphoma is a B-cell non-Hodgkin’s lymphoma characterized by a t(11;14), resulting in overexpression of cyclin D1. Conventional chemotherapy obtains frequent (but short) remissions, leading to a poor median overall survival (OS) of 3–5 years. To obtain more information about the prevalence and current treatment of Mantle cell lymphoma (MCL) in Belgium, we collected data in a Belgian registry of MCL. Materials and methods: All Belgian MCL patients, t(11;14) and/or cyclin D1 positive, seen in hematology departments over a one-year period (April 2013–March 2014) were included. Data about patient characteristics, histology, treatment lines, and response were compiled and retrospectively analyzed. Results: Four hundred and four patients were included with a median age at diagnosis of 64 years (range 23–96 years) and a male predominance (72%). For 2013, we calculated a prevalence of at least 36.2 per million and an incidence of at least 7.0 per million in the Belgian population. Characteristics at diagnosis involved lymphadenopathy (82%), splenomegaly (44%), B-symptoms (39%), and hepatomegaly (10%). Bone marrow invasion was present at diagnosis in 77%. Stage at diagnosis was advanced in the majority of cases. The median number of treatment lines was 1. Type of first line treatment included a combination of anthracyclin and cytarabine-based regimen (34%), anthracyclin (39%), and other. Rituximab was used in 88% of first line treatments. In 44% first line treatment was followed by autologous stem cell transplantation. Conclusion: The analysis of this Belgian MCL registry provides insight in the epidemiology, demographics, and current treatment of our Belgian MCL population.