Fabienne Trullemans

Clinical findings and magnetic resonance imaging in severe cyclosporine‐related neurotoxicity after allogeneic bone marrow transplantation

Abstract: Objectives: Severe neurotoxicity is a recognized complication of cyclosporin A (cyclosporine, CSA). Neuroimaging studies typically show reversible brain lesions, predominantly confined to the white matter. Our aim was to delineate clinical characteristics and to specify results of magnetic resonance imaging (MRI) and computerised tomography (CT) scan findings. Methods: Cases of severe cyclosporine‐related neurotoxicity (SNCT) were identified among a series of 129 consecutive allogeneic transplant recipients. Clinical features were analysed, including CSA levels, electrolytes, cholesterolemia and magnesemia. MRI and/or CT scans were obtained within 24 h to 4 d after the onset of neurotoxicity. Results: Six patients (4.6%) developed a prodromal phase (headache and/or hypertension), followed by SCNT, including generalized seizures (n = 5), occipital blindness (n = 1) and hemiparesis (n = 1). There was no correlation between the laboratory findings and the onset of SNCT. All patients were on corticosteroid treatment. MRI studies showed hyperintensity lesions, predominantly in the posterior cerebrum, with both subcortical and cortical involvement in 4 out of 5 patients. Cerebellar involvement (n = 4) was also a frequent finding. The signal abnormalities, corresponding to the anastomotic border zones between major cerebral and cerebellar arteries, were limited to the respective cortical areas. Conclusion: Association of corticosteroids is a trigger in the development of SCNT. MRI is recommended for the early identification of the transient brain lesions in patients with a prodromal phase. The more specific distribution of the lesions in the anastomotic border zones suggests vascular injury as a contributing factor in the pathology of SNCT.

Multiple myeloma--an update on diagnosis and treatment.

Multiple myeloma is a plasma cell (PC) malignancy characterized by the accumulation of monoclonal PCs in the bone marrow and the production of large amounts of a monoclonal immunoglobulin or paraprotein. In the past years, new approaches in the diagnosis and treatment were introduced aiming to identify high‐risk patients who need proper anti‐myeloma treatment. Intensive therapy including autologous hematopoietic stem cell transplantation and the new agents bortezomib, thalidomide, and lenalidomide have improved patients’ responses. Further optimalization of the different treatment schedules in well‐defined patient groups may prolong their survival. Patient stratification is currently based on patient characteristics, extent of myeloma disease, and associated cytogenetic and laboratory anomalies. More and more gene expression studies are introduced to stratify patients and to individualize therapy.

An early increase in serum levels of C-reactive protein is an independent risk factor for the occurrence of major complications and 100-day transplant-related mortality after allogeneic bone marrow transplantation

We monitored levels of C-reactive protein (CRP) in 96 consecutive adult allogeneic BMT patients (age 15–50 years) transplanted in our unit. Major transplant-related complications (MTC) occurred in 32% of cases and included: hepatic veno-occlusive disease, pneumonitis, severe endothelial leakage syndrome and >II acute GVHD. Transplant-related mortality (TRM) before day 100 post-BMT was 13.5%. Variables included in a stepwise logistic regression model were: gender, age, disease category, donor type, T cell depletion, TBI, use of growth factors, bacteremia, mean CRP-levels >50 mg/l between days 0 and 5 (CRP day 0–5) and >100 mg/l between days 6 and 10 (CRP day 6–10) post-BMT. Only high CRP-levels (for MTC and TRM) (P < 0.001) and donor-type (for TRM) (P = 0.02) were independent risk factors. The estimated probability for MTC was 73% (CRP day 6–10 >100 mg/l) vs 17% (CRP day 6–10 <100 mg/l). Using the same cut-off levels, the probabilities for TRM were 36.5% vs 1% in the identical sibling donor situation and 88% vs 12.5% in other donor-type transplants. We conclude that the degree of systemic inflammation, as reflected by CRP-levels, during the first 5–10 days after BMT identifies patients at risk of MTC and TRM. Our data may be useful in selecting patients for clinical trials involving pre-emptive anti-inflammatory treatment.

Monitoring of C-reactive protein after allogeneic bone marrow transplantation identifies patients at risk of severe transplant-related complications and mortality

Patterns of C-reactive protein (CRP) release were derived from frequent CRP measurements in a cohort of 66 consecutive patients receiving allogeneic bone marrow transplants (BMT) in our unit. Based on a retrospective study of clinical events occurring within the first 40 days after BMT, patients with major transplant-related complications (MTC+ group, n = 22) could be separated from those with fever or mild complications only (MTC− group, n = 44). Treatment-related mortality in the MTC+ group was significantly higher: 32 vs 0% (P < 0.001). major complications included veno-occlusive liver disease (vod), severe endothelial leakage syndrome (els), pneumonitis and acute gvhd >II. The severity of complications was reflected by the patterns of CRP release with continuously high levels preceding the maximal signs and symptoms of MTC. Univariate analysis showed that, among other variables (sex, age, disease status at transplant, ±TBI in the conditioning regimen, ± use of myeloid growth factors after BMT, time to reach PN >200/mm3), three factors were significantly associated with MTC: maximal levels of CRP during the post-transplant episode (CRPmax) (296.6 ± 91.8 vs 88.9 ± 55.8 mg/100 ml, P < 0.001), the use of unmanipulated graft (no t depletion) (46.9 vs 12.5%, P < 0.009) and the crp level on the day of bmt (crpo) (42.7 ± 55.4 vs 18.2 ± 19.5, P = 0.045). In multivariate analysis, using a stepwise logistic regression model including the same variables, CRPmax appeared to be the strongest independent variable (P < 0.001) and a reliable (94% accuracy) parameter to assess the risk of mtc. based on this model, crp levels of 200 and 300 mg/100 ml are associated with a risk of 48 and 94% of developing mtc, respectively. we conclude that crp monitoring after bmt identifies patients at risk of severe transplant-related complications and mortality.

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.

Different expression of adhesion molecules on CD34+ cells in AML and B-lineage ALL and their normal bone marrow counterparts

Abstract:  The expression of adhesion molecules on CD34+ cells in acute myeloid leukemia (AML) and B‐lineage acute lymphoblastic leukemia (B‐lineage ALL) was compared with that on the myeloid and B‐lymphoid CD34+ cells in normal bone marrow. Bone marrow aspirates of 10 patients with AML, 8 patients with B‐lineage ALL and of 6 healthy volunteers were examined. The phenotype of the CD34+ cells was determined with a double immunofluorescence method and flow cytometry. CD34+ cells in AML and B‐lineage ALL showed a lower expression of VLA‐2 and VLA‐3 and a higher expression of ICAM‐1 and LFA‐3 than their normal bone marrow counterparts. AML CD34+ cells had less L‐selectin but more VLA‐5 on their surface membrane than normal myeloid CD34+ cells. B‐lineage ALL CD34+ cells showed an overexpression of LFA‐3. In individual patients deficiencies or over‐expression of the β1 integrin chain, VLA‐4, PECAM‐1 or HCAM also occurred. An abnormal adhesive capacity of the leukemic cells may influence their proliferation, their localisation and apoptosis. An aberrant expression of adhesion molecules may be used for the detection of minimal residual leukemia in these patients.

Growth factor receptor profile of CD34+ cells in AML and B‐lineage ALL and in their normal bone marrow counterparts

Abstract: Leukaemic cells show a low clonogenic activity and a heterogeneous proliferative response to growth factors. We investigated whether this could be due to an altered expression of growth factor receptors on the leukaemic precursors. Receptors for G‐CSF, stem cell factor (SCF), IL‐3, IL‐6 and IL‐7 were detected on CD34+ cells in AML and B‐lineage ALL with monoclonal antibodies and flow cytometry. The expression was compared with that on myeloid and B‐lymphoid CD34+ cells in normal bone marrow. Leukaemic CD34+ cells expressed the same receptors as their normal counterparts. AML and B‐lineage ALL could be distinguished by the growth factor receptor profile of their CD34+ cells. SCFR, G‐CSFR and IL‐6Rα were found in AML, IL‐7R in B‐lineage ALL and IL‐3Rα in both. IL‐3Rα was upregulated in AML and B‐lineage ALL CD34+ cells, while samples with low or high expression were present for the other receptors. This variable expression could correlate with the heterogeneous response of leukaemic cells to growth factors. Functional studies on isolated CD34+ cells are needed to investigate this further.

Late and localized extramedullary relapse of a light chain kappa myeloma after syngeneic bone marrow transplantation.

We report the case of a 54-year-old female patient with stage IIIA kappa light chain myeloma (MM) who relapsed 7 years after syngeneic bone marrow transplantation (BMT). The relapse occurred as a voluminous soft tissue plasmacytoma in the leg, developing after local trauma. The patient was successfully treated with local radiotherapy and has remained progression-free for more than 2 years. This case represents one of the longest survivors, in complete remission, after syngeneic transplantation for MM. The presentation of recurrent disease as localized plasmacytoma with extramedullary growth is unusual in the post-transplant setting. Bone Marrow Transplantation (2000) 25, 115–117.

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.

The impact of partial T cell depletion on overall transplant-related toxicity, graft function and survival after HLA-identical allogeneic bone marrow transplantation in standard risk adult patients with leukemia

In this single-center study, a consecutive cohort of 59 adult patients transplanted with HLA-identical bone marrow and receiving graft-versus-host disease (GVHD) prophylaxis with either standard cyclosporine/methotrexate (n = 33) or partial T cell depletion (E-rosetting) (TCD, n = 26 were analyzed). Only patients with chronic myeloid leukemia in first chronic phase or acute leukemia/myelodysplasia in first or second remission were included. Except for age (median 28 vs 42 years), both groups were comparable in terms of diagnosis, conditioning regimen and growth factor support. TCD significantly reduced >grade II acute GVHD (0 vs 24%, P = 0.02), chronic GVHD (8.5 vs 45%, P = 0.007) and other major bone marrow transplant (BMT)-related complications (4 vs 36%, P = 0.005). TCD decreased overall transplant-related mortality (11.5 vs 36%, P = 0.04). In the TCD group faster neutrophil (13 vs 22 days, P = 0.02) and platelet recoveries (18 vs 26 days, P < 0.001) were noted. The relapse risk was higher after TCD (57.5 vs 21.5%, P = 0.04). Overall survival probability at 10 years was identical in both groups (54 vs 53.5%, P = 0.33). We found a relationship between the number of T cells in the graft and the occurrence of major complications (P < 0.001) and relapse (P = 0.03). This comparative analysis shows that graft-derived T cells have a major role in overall BMT-related toxicity and that partial TCD is an acceptable approach in terms of survival for patients between 40 and 50 years of age. Bone Marrow Transplantation (2001) 28, 917–922.