REVIEW HEMATOLOGY

The clinical relevance of calreticulin mutations in myeloproliferative neoplasms

SUMMARY

Calreticulin mutations are driver mutations detected in around 20–25% of essential thrombocythemia and in 25–30% of primary myelofibrosis patients. The most recurrent mutations are type-1 (a deletion of 52 bp in the exon 9) and type-2 (an insertion of 5 bp in the exon 9). This review describes the distinct clinical features, prognosis and outcome of calreticulin mutated patients from JAK2V617F or MPL (thrombopoietin receptor) mutated patients. The subtypes of calreticulin mutations were also associated with distinct clinical characteristics. Several treatment guidelines were adapted for calreticulin-mutated patients. The mechanism by why the three driver mutations, which all activate JAK/STAT signalling pathway can trigger diseases with quite different features is still not known. The recent progress in the understanding of calreticulin mutation biology will allow the development of new target therapies with the hope to cure the disease in the next years.

(BELG J HEMATOL 2022;13(8):293–301)

Rational approach of older patients with chronic lymphocytic leukaemia

SUMMARY

The majority of CLL patients are elderly, with a median age of those requiring a first line treatment, close to 76 years old. Nowadays, multiple treatment options are available for this disease, ranging from chemo immunotherapy regimens to biological therapies. The treatment decision in an older CLL patient is a four-step procedure, starting firstly with the assessment of treatment criteria. The second step is to evaluate the life-expectancy of the patient, its autonomy, vulnerabilities and the socio-economic status. The subsequent step is to define treatment options according to prognostic factors. Last, but not least, the patient should be involved in the final decision to know to what extend he is willing to receive a treatment with a potential curative or palliative intent. The assessment of an elderly CLL patient is a complex procedure, not only comprehending the evaluation of biological and hematological parameters but also clinical, social and psychological features, which equally contribute to the selection of the most valuable strategy.

(BELG J HEMATOL 2021;12(4):147-54)

A Belgian retrospective analysis of the use of venetoclax monotherapy in patients with chronic lymphocytic leukaemia in routine clinical practice

SUMMARY

Chronic lymphocytic leukaemia (CLL) is a slow-progressing cancer that results in uncontrolled proliferation and accumulation of B-lymphocytes in the blood and bone marrow and is the most common form of leukaemia in the western world. CLL patients harbouring a deletion of chromosome 17 (del17p) or the TP53 mutation, who progress after treatment with immunological, chemotherapeutic as well as targeted agents such as ibrutinib have poor prognosis signifying a population with an unmet medical need. Clinical studies showed that venetoclax, a selective; orally bioavailable Bcl-2 inhibitor, induces CLL cell apoptosis, and offers an alternative therapeutic option for CLL, either as a monotherapy or in combination with rituximab. BRAVe was a multicentre, observational retrospective study, conducted in Belgium. The main objectives of this study were to evaluate the safety and effectiveness of venetoclax monotherapy in Belgian patients with CLL, as well as the utilisation of resources in a real life setting. The results show a manageable/favourable safety profile for venetoclax with limited burden for patients and sites, and a good overall response rate in pre-treated CLL patients in the relapsed/refractory setting.

(BELG J HEMATOL 2020;12(3):106-11)

ThromboGenomics implementation in Belgium

SUMMARY

The international study ThromboGenomics has developed and tested a targeted high-throughput sequencing (HTS) multi-gene panel test for diagnostics of patients with rare bleeding, thrombotic or platelet disorders (BTPD). After the initial validation of this research platform, 2396 index patients were sequenced and a mean diagnostic rate of 49.2% was reached for all thrombotic, coagulation, platelet count and function disorder patients while this rate dropped to 3.2% for patients with unexplained bleeding disorders that were characterised by normal haemostasis test results. Since early 2019, a similar HTS test for BTPD has been implemented in Belgium in a clinical diagnostic setting. This test screens 96 diagnostic-grade genes and is updated yearly with novel genes. Upon inclusion, clinicians can opt for one of the three panels: 1) (anti)coagulation panel test for abnormal bleeding or thrombosis, 2) platelet disorder panel test for inherited thrombocytopenia or known platelet dysfunctions and 3) the unexplained bleeding panel test but with evidence for Ehlers-Danlos Syndrome or Rendu-Osler-Weber disease. Inclusion and exclusion criteria for patients eligible for such HTS will be discussed. The submission of detailed information about clinical phenotype, family history and laboratory test results is critical for the interpretation of the genetic results. The aim is to provide results to clinicians and patients with a detailed report that discusses variant interpretation.

(BELG J HEMATOL 2020;12(3):99-105)

Stem cell-derived natural killer cell immunotherapy

SUMMARY

Natural killer cells are increasingly recognised as an attractive source of allogeneic immune effector cells in cancer immunotherapy. Over the past decade, several adoptive transfer trials using allogeneic NK cells from different sources have shown safety with little evidence of toxicities such as graft-versus-host disease, cytokine release syndrome or neurotoxicity that are often seen in T cell therapy. While clinical effects have been observed, improvements are warranted to increase relapse free survival and potentially cure cancer patients. Genetic engineering shows great potential for improving NK cell therapy through chimeric antigen receptors or knocking out immune checkpoints and MHC-I. Especially stem cell-derived natural killer cells are an ideal template as they can be cultured without T and B cell contamination and are relatively easy to genetically engineer compared to mature NK cells. Next to improving anti-tumour specificity, persistence can be improved by including cytokine domains in the chimeric antigen receptor, which is a great benefit over NK cell lines that need to be lethally irradiated to prevent uncontrolled proliferation. Importantly, the safety profile of adoptive NK cell transfer allows for minimal matching, which opens the door for large-scale production and cryopreservation to create an off-the-shelf therapy.

(BELG J HEMATOL 2020;12(2):59-65)

Tyrosine kinase inhibitor discontinuation in patients with chronic myelogenous leukaemia: A retrospective study and review of the literature

ABSTRACT

BACKGROUND: Tyrosine kinase inhibitors (TKIs) have improved the survival of patients with chronic myeloid leukaemia (CML). TKIs can be successfully discontinued in some CML patients who have achieved a stable deep molecular response.

OBJECTIVE: The purpose of this article is twofold. On the one hand, this review provides an overview of current use and discontinuation of TKIs in patients with CML. On the other hand, we retrospectively investigated the use and possible discontinuation of TKIs in a specific patient population with CML at the University Hospital of Leuven.

METHODS: A literature search was carried out in May 2019 to identify all relevant articles. Articles were searched on PubMed, Embase, Web of Science and Cochrane Library. Additionally, the articles found in the reference list were used.

RESULTS: This review included ten articles (two on imatinib, four on dasatinib, four on nilotinib), with 970 patients. Treatment free remission (TFR) ratio varied from 41–68% after one year. One study published the results of TFR after three years. In UZ Leuven, the TFR ratio was 60% after 106 weeks.

CONCLUSION: Tyrosine kinase inhibitor (TKI) therapy can be safely terminated in selected patient groups. About half of the patients retain the molecular remission after discontinuation of TKI therapy.

(BELG J HEMATOL 2020;12(2):52-8)

BCMA targeting in multiple myeloma

SUMMARY

Over the past decade, significant progress was made in the treatment of patients with multiple myeloma (MM). Nevertheless, research efforts continue in an attempt to develop treatment options with novel mechanisms of action that have higher efficacy, can evade resistance to prior lines of treatment and are well tolerated. As the B-cell maturation antigen (BCMA) is preferentially expressed by mature B-lymphocytes and is overexpressed in MM patients, it provides an interesting therapeutic target in MM. Thus far, three treatment modalities have been developed for BCMA targeting; bispecific antibody constructs, antibody-drug conjugates and chimeric antigen receptor (CAR) T-cell therapy, each with its own advantages and challenges. This review provides an overview of the (preliminary) clinical data that were generated with these different treatment modalities.

(BELG J HEMATOL 2020;11(8):387-97)