HEMATOTHESIS

A multicentric observational study on the management of hyperleukocytic acute myeloid leukaemia in Belgium

SUMMARY

INTRODUCTION

In hyperleukocytic acute myeloid leukaemia (AML) the risk of leukostasis is high due to the rapid increase in WBC count and the size of the myeloid blasts. It is associated with poor prognosis due to an increased risk of early death and relapse. Immediate initiation of cytoreductive treatment is essential to improve outcome, but evidence to prefer hydroxyurea, leukapheresis, intensive chemotherapy (IC) or a combination treatment, is lacking. Therefore, we decided to investigate the current approach of hyperleukocytic AML in Belgium.

METHODS

A brief questionnaire on the management of hyperleukocytic AML was sent to all Belgian centres currently treating AML with IC and was replied by ten centres. Four centres agreed to a more detailed retrospective analysis. All newly diagnosed AML patients presenting with hyperleukocytosis between January 2013 and April 2019 were included. Patient and disease characteristics were collected, as well as treatment choice and outcome parameters.

RESULTS

We included 121 patients with a median WBC count of 116,360/µL. Mortality at day 21 was 20% and overall mortality was 64% at a median follow-up of six months. Twenty percent received leukapheresis, which was started within 24 hours. There was no difference in age distribution, treatment intensity or time to start IC between patients receiving leukapheresis or not. Although the leukapheresis group had a more severe presentation with a higher median WBC and blast count and a worse performance status, there was no difference in response to therapy, early or long-term mortality. In a multivariate analysis, age at diagnosis and treatment modality (IC vs non-IC) were the only independent parameters that significantly affected early death.

CONCLUSION

Evidence on optimal treatment options in hyperleukocytic AML is lacking. We could not demonstrate any added value of leukapheresis. To improve the prognosis of this dramatic presentation, national or even European databases should be used to document and learn from the outcome of current practice.

(BELG J HEMATOL 2020;11(7):325-34)

In search of novel working mechanisms of proteasome inhibitors in multiple myeloma

SUMMARY

Proteasome inhibitors (PIs) constitute one of the cornerstones of the treatment of multiple myeloma (MM), with bortezomib, carfilzomib and ixazomib being approved for clinical use. Due to the relatively recent introduction of PIs to clinical practice, many aspects of the pleiotropic effects of PIs still remain unexplored, particularly for the second-generation PIs carfilzomib and ixazomib. Since MM still remains incurable and many patients will eventually develop treatment-refractory disease, the search for validated biomarkers to predict treatment response is of great clinical importance. In the first aim of this project, we evaluated the effect of proteasome inhibitors on erythropoiesis. During the follow-up of MM patients treated with PIs in the first part of this project, we observed a consistent and highly significant increase in the reticulocyte count during treatment with carfilzomib-based regimens in patients with relapsed multiple myeloma. This observation was not made in a matched cohort of bortezomib-treated patients. In subsequent ex vivo experiments, we demonstrated that carfilzomib exposure significantly impaired terminal erythroid maturation, independent of erythroid commitment, expansion or differentiation. Our results therefore report the first pharmacologically induced delay in erythroid maturation as a mechanism for carfilzomib-induced reticulocytosis in patients with multiple myeloma. These findings might therefore lead to new therapeutic applications for carfilzomib in disorders of mature erythrocytes, such as sickle cell anaemia. In the second part of this project, we evaluated proteasome activity as a potential biomarker for PI drug sensitivity. For this purpose, we measured proteasome activity in primary myeloma cells, purified from the bone marrow of patients with MM. Baseline proteasome activity was not significantly different in myeloma cells derived from treatment-responsive or –refractory MM patients. The degree of proteasome inhibition by PIs was similar in both groups. As a result, the clinical applicability of proteasome activity as a biomarker for drug sensitivity in MM currently remains limited. Nevertheless, these data also suggest that drug sensitivity to PIs is in part proteasome-independent, indicating that our understanding of PI drug resistance should be further improved. In a follow-up project to the present thesis, we have designed several genome-wide screening experiments using CRISPR-Cas9 technology to gain novel insights in the mechanisms driving drug resistance to PIs in MM.

(BELG J HEMATOL 2020;11(3):133–5)

Erythropoiesis and iron metabolism after haematopoietic stem cell transplantation

After haematopoietic stem cell transplantation (HCT), many patients present anaemia, which can persist for months due to an inadequate erythropoietin production for the degree of the anaemia. In this thesis, we performed two randomised studies with erythropoiesis-stimulating agents therapy after allogeneic (including myeloablative and non-myeloablative conditioning) and autologous transplantation. We showed a great efficacy of this growth factor to ensure full erythroid reconstitution when initiated soon after engraftment and not immediately after the transplant. Furthermore, as iron parameters are quite disturbed following HCT, we sought to study iron metabolism after HCT (which has not been much investigated), integrating the role of hepcidin, the key regulator in iron metabolism. Hence, we demonstrated that hepcidin levels prior to and following autologous HCT were influenced by iron stores and changes in erythropoietic activity.

(BELG J HEMATOL 2019;10(2):89–95)

Impact of new treatment guidelines pertaining to the indication for allogeneic stem cell transplantation in intermediate-risk acute myeloid leukaemia at Ghent University Hospital: A retrospective analysis

SUMMARY

Since several years, it has become clear that intermediate-risk acute myeloid leukaemia patients in an acceptable clinical condition can benefit from allogeneic stem cell transplantation thanks to the improvement in relapse free survival. This study retrospectively analysed the outcome of all intermediate-risk acute myeloid leukaemia patients treated with intensive chemotherapy at the Ghent University Hospital between 01-01-2013 and 30-04-2017 in an effort to determine the impact of a new in-hospital treatment guideline adopted in April 2015. This guideline recommends all intermediate-risk acute myeloid leukaemia patients who are fit for intensive therapy to proceed to allogeneic stem cell transplantation in first complete remission. Unfortunately, we could not demonstrate an improvement in the relapse free survival after implementation of the treatment guideline. Nevertheless, exploratory analysis of the entire group suggests a survival benefit from allogeneic stem cell transplantation, with significantly improved relapse free survival and a trend towards a better overall survival.

(BELG J HEMATOL 2018;9(7):285–9)

Whole-body diffusion-weighted magnetic resonance imaging for staging and early treatment response assessment in malignant lymphoma

SUMMARY

Diffusion-weighted magnetic resonance imaging (DW/MRI) is a radiation-free functional imaging technique reflecting tissue cellularity by probing the diffusion of water molecules on a microstructural level. This can be assessed visually, but also quantified by calculating the apparent diffusion coefficient (ADC). Although established in many solid tumours and multiple myeloma, its role in disease assessment in malignant lymphoma has yet to be determined. Therefore, the main purpose of this work was twofold: exploring the performance of whole-body DW/MRI (WB-DW/MRI) in staging malignant lymphoma and assessing treatment response early during treatment with 18F-FDG-PET/CT in combination with bone marrow biopsy results serving as the gold standard. Regarding staging, we found that WB-DW/MRI is a feasible imaging technique. Visual image analysis sufficed to accurately detect extranodal disease, while adequate nodal characterisation required ADC calculations. Lymph node characterisation was further improved by using a more elaborate quantitative analysis based on ADC parameters derived from whole-lesion ADC histogram analysis next to the commonly used mean ADC. In the context of treatment response assessment, mean ADC changes between the baseline and interval scan performed after one cycle of (immuno)chemotherapy significantly correlated with progression-free-survival in patients with aggressive non-Hodgkin lymphoma (NHL). For Hodgkin lymphoma, taking into account the typical intralesional heterogeneity, an advanced 3-D texture analysis was performed, which demonstrated that ADC parameters associated with tumour heterogeneity (energy, local homogeneity, and entropy) were predictive of outcome in contrast to conventional ADC parameters.

(BELG J HEMATOL 2018;9(6):242–4)

A nursing intervention that reduces symptom burden during chemotherapy

SUMMARY

The aim of this dissertation was to develop and evaluate a nursing intervention that reduces symptom burden during chemotherapy. We developed an intervention that uses motivational interviewing to support self-efficacy and to improve symptom self-management. In a quasi-experimental study in adult patients treated with chemotherapy, the intervention significantly reduced overall symptom distress and symptom severity at all three time points in the study (three, six and twelve weeks after the start of the treatment).

(BELG J HEMATOL 2018;9(5):192–4)

Is it possible to predict who may never need treatment for B-CLL?

SUMMARY

Chronic lymphocytic leukaemia has a very heterogeneous disease evolution. Prognostic factors of B-CLL overall survival have been extensively studied. However, much less is known about prognostic factors that can identify patients who will never develop an indication for treatment, at the time of their initial diagnosis. In this study we give an overview of variables that have a predictive value for treatment free survival. Subsequently, we try to develop a novel prognostic index, to address the question ‘who will never need treatment for B-CLL?’.

(BELG J HEMATOL 2018;9(3):124–9)