Pascal Pierre

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.

The fusion proteins TEL-PDGFRβ and FIP1L1-PDGFRα escape ubiquitination and degradation

Upon growth factor-induced activation, receptor tyrosine kinases such as the PDGF and FGF receptors are targeted for lysosomal degradation via a mechanism that involves ubiquitination of receptor lysines. In this study, it is shown that constitutively active oncogenic fusion proteins that contain PDGF or FGF receptor moieties, caused by specific chromosomal translocations in chronic myeloid neoplasms, escape this negative regulatory mechanism. Background Chimeric oncogenes encoding constitutively active protein tyrosine kinases are associated with chronic myeloid neoplasms. TEL-PDGFRβ (TPβ, also called ETV6-PDGFRB) is a hybrid protein produced by the t(5;12) translocation, FIP1L1-PDGFRα (FPα) results from a deletion on chromosome 4q12 and ZNF198-FGFR1 is created by the t(8;13) translocation. These fusion proteins are found in patients with myeloid neoplasms associated with eosinophilia. Wild-type receptor tyrosine kinases are efficiently targeted for degradation upon activation, in a process that requires Cbl-mediated monoubiquitination of receptor lysines. Since protein degradation pathways have been identified as useful targets for cancer therapy, the aim of this study was to compare the degradation of hybrid and wild-type receptor tyrosine kinases. Design and Methods We used Ba/F3 as a model cell line, as well as leukocytes from two patients, to analyze hybrid protein degradation. Results In contrast to the corresponding wild-type receptors, which are quickly degraded upon activation, we observed that TPβ, FPα and the ZNF198-FGFR1 hybrids escaped down-regulation in Ba/F3 cells. The high stability of TPβ and FPα hybrid proteins was confirmed in leukocytes from leukemia patients. Ubiquitination of TPβ and FPα was much reduced compared to that of wild-type receptors, despite marked Cbl phosphorylation in cells expressing hybrid receptors. The fusion of a destabilizing domain to TPβ induced protein degradation. Instability was reverted by adding the destabilizing domain ligand, Shield1. The destabilization of this modified TPβ reduced cell transformation and STAT5 activation. Conclusions We have shown that chimeric receptor tyrosine kinases escape ubiquitination and down-regulation and that their stabilization is critical to efficient stimulation of cell proliferation.

The fusion proteins TEL-PDGFRbeta and FIP1L1-PDGFRalpha escape ubiquitination and degradation

Upon growth factor-induced activation, receptor tyrosine kinases such as the PDGF and FGF receptors are targeted for lysosomal degradation via a mechanism that involves ubiquitination of receptor lysines. In this study, it is shown that constitutively active oncogenic fusion proteins that contain PDGF or FGF receptor moieties, caused by specific chromosomal translocations in chronic myeloid neoplasms, escape this negative regulatory mechanism. Background Chimeric oncogenes encoding constitutively active protein tyrosine kinases are associated with chronic myeloid neoplasms. TEL-PDGFRβ (TPβ, also called ETV6-PDGFRB) is a hybrid protein produced by the t(5;12) translocation, FIP1L1-PDGFRα (FPα) results from a deletion on chromosome 4q12 and ZNF198-FGFR1 is created by the t(8;13) translocation. These fusion proteins are found in patients with myeloid neoplasms associated with eosinophilia. Wild-type receptor tyrosine kinases are efficiently targeted for degradation upon activation, in a process that requires Cbl-mediated monoubiquitination of receptor lysines. Since protein degradation pathways have been identified as useful targets for cancer therapy, the aim of this study was to compare the degradation of hybrid and wild-type receptor tyrosine kinases. Design and Methods We used Ba/F3 as a model cell line, as well as leukocytes from two patients, to analyze hybrid protein degradation. Results In contrast to the corresponding wild-type receptors, which are quickly degraded upon activation, we observed that TPβ, FPα and the ZNF198-FGFR1 hybrids escaped down-regulation in Ba/F3 cells. The high stability of TPβ and FPα hybrid proteins was confirmed in leukocytes from leukemia patients. Ubiquitination of TPβ and FPα was much reduced compared to that of wild-type receptors, despite marked Cbl phosphorylation in cells expressing hybrid receptors. The fusion of a destabilizing domain to TPβ induced protein degradation. Instability was reverted by adding the destabilizing domain ligand, Shield1. The destabilization of this modified TPβ reduced cell transformation and STAT5 activation. Conclusions We have shown that chimeric receptor tyrosine kinases escape ubiquitination and down-regulation and that their stabilization is critical to efficient stimulation of cell proliferation.

Savene® (dexrazoxane) use in clinical practice

IntroductionAnthracycline extravasation (ACEV) is a rare but potentially devastating event which can result in severe injuries including ulceration and necrosis, slow-healing lesions, serious joint damage and permanent disfigurement. It can delay further scheduled chemotherapy and affect cancer treatment outcome. Savene® (dexrazoxane) is the only approved antidote for ACEV in Europe (Totect® in the USA) and is administered by intravenous infusion. Its efficacy has been demonstrated in clinical trials with biopsy-verified ACEV with a 98% success rate (no need for surgical debridement) allowing for immediate continuation of chemotherapy in 71% of patients. Adverse events, mainly haematological toxicity, were rapidly reversible. The objective of the study was to assess, in clinical practice, the efficacy and safety profile of Savene® for ACEV in different Belgian hospitals.Patients and methodsA survey of Savene® use was conducted in Belgium from 2007 to 2010 by using a questionnaire sent to 44 hospitals.Main resultsData were obtained for 41 cancer patients, 68% (28/41) had ACEV from central venous catheters. Surgical debridement due to ACEV could be avoided in 26 out of 28 extravasations from a central venous access and in 95% (39/41) of the total population treated with Savene®. Planned chemotherapy was maintained in 73% (30/41) of patients. Eight adverse events were reported in four patients treated with Savene®, six events were assessed to be of common toxicity criteria grades 1–2 (nausea, leucopenia and arm pain) and two events (neutropenia and pancytopenia) were assessed to be grade 3.ConclusionThese data are comparable with the data from previous clinical trials and confirm the efficacy and safety profile of Savene® in clinical practice for the treatment of anthracycline extravasation, including extravasations from central venous catheters.

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.

Anaplastic lymphoma kinase-positive anaplastic large cell lymphoma with the variant RNF213-, ATIC- and TPM3-ALK fusions is characterized by copy number gain of the rearranged ALK gene

Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma is characterized by 2p23/ALK aberrations, including the classic t(2;5)(p23;q35)/NPM1-ALK rearrangement present in ~80% of cases and several variant t(2p23/ALK) occurring in the remaining cases. The ALK fusion partners play a key role in the constitutive activation of the chimeric protein and its subcellular localization. Using various molecular technologies, we have characterized ALK fusions in eight recently diagnosed anaplastic large cell lymphoma cases with cytoplasmic-only ALK expression. The identified partner genes included EEF1G (one case), RNF213/ALO17 (one case), ATIC (four cases) and TPM3 (two cases). Notably, all cases showed copy number gain of the rearranged ALK gene, which is never observed in NPM1-ALK-positive lymphomas. We hypothesized that this could be due to lower expression levels and/or lower oncogenic potential of the variant ALK fusions. Indeed, all partner genes, except EEF1G, showed lower expression in normal and malignant T cells, in comparison with NPM1. In addition, we investigated the transformation potential of endogenous Npm1-Alk and Atic-Alk fusions generated by clustered regularly interspaced short palindromic repeats/Cas9 genome editing in Ba/F3 cells. We found that Npm1-Alk has a stronger transformation potential than Atic-Alk, and we observed a subclonal gain of Atic-Alk after a longer culture period, which was not observed for Npm1-Alk. Taken together, our data illustrate that lymphomas driven by the variant ATIC-ALK fusion (and likely by RNF213-ALK and TPM3-ALK), but not the classic NPM1-ALK, require an increased dosage of the ALK hybrid gene to compensate for the relatively low and insufficient expression and signaling properties of the chimeric gene.

The fusion proteins TEL-PDGFR and FIP1L1-PDGFR escape ubiquitination and degradation

Upon growth factor-induced activation, receptor tyrosine kinases such as the PDGF and FGF receptors are targeted for lysosomal degradation via a mechanism that involves ubiquitination of receptor lysines. In this study, it is shown that constitutively active oncogenic fusion proteins that contain PDGF or FGF receptor moieties, caused by specific chromosomal translocations in chronic myeloid neoplasms, escape this negative regulatory mechanism. Background Chimeric oncogenes encoding constitutively active protein tyrosine kinases are associated with chronic myeloid neoplasms. TEL-PDGFRβ (TPβ, also called ETV6-PDGFRB) is a hybrid protein produced by the t(5;12) translocation, FIP1L1-PDGFRα (FPα) results from a deletion on chromosome 4q12 and ZNF198-FGFR1 is created by the t(8;13) translocation. These fusion proteins are found in patients with myeloid neoplasms associated with eosinophilia. Wild-type receptor tyrosine kinases are efficiently targeted for degradation upon activation, in a process that requires Cbl-mediated monoubiquitination of receptor lysines. Since protein degradation pathways have been identified as useful targets for cancer therapy, the aim of this study was to compare the degradation of hybrid and wild-type receptor tyrosine kinases. Design and Methods We used Ba/F3 as a model cell line, as well as leukocytes from two patients, to analyze hybrid protein degradation. Results In contrast to the corresponding wild-type receptors, which are quickly degraded upon activation, we observed that TPβ, FPα and the ZNF198-FGFR1 hybrids escaped down-regulation in Ba/F3 cells. The high stability of TPβ and FPα hybrid proteins was confirmed in leukocytes from leukemia patients. Ubiquitination of TPβ and FPα was much reduced compared to that of wild-type receptors, despite marked Cbl phosphorylation in cells expressing hybrid receptors. The fusion of a destabilizing domain to TPβ induced protein degradation. Instability was reverted by adding the destabilizing domain ligand, Shield1. The destabilization of this modified TPβ reduced cell transformation and STAT5 activation. Conclusions We have shown that chimeric receptor tyrosine kinases escape ubiquitination and down-regulation and that their stabilization is critical to efficient stimulation of cell proliferation.