REVIEW HEMATOLOGY

Recent advances in the genomic and epigenomic biology of juvenile myelomonocytic leukaemia

SUMMARY

Juvenile myelomonocytic leukaemia is a heterogeneous disease caused by constitutional activation of the Ras signal transduction pathway. The clinical course of the disease is variable and non-specific. In the majority of patients prompt hematopoietic stem cell transplantation is necessary for long-term survival, whereas in a minority the disease will resolve without treatment. In more than 90% of the patients, mutations in one or more of the following genes can be found (somatic NRAS, KRAS and PTPN11, germline NF1 and CBL). However, these canonical mutations are insufficient to explain the phenotypic heterogeneity of this disease. More recently, secondary mutations, non-coding RNA expression, and genomic DNA methylation have led to a better understanding of the pathobiology of the disease, and shown to play a role in the classification and prognostication of this rare disease. In addition, this novel information has been crucial for novel drug development and introduction of novel patient-tailored therapies, which are currently being tested in vitro or in vivo in clinical trials.
(BELG J HEMATOL 2020;11(2):49–55)

Fertility preservation in women before cancer therapy

SUMMARY

In recent decades, major progress has been made in cancer diagnosis and therapy, significantly extending the life expectancy of cancer patients and thereby dramatically increasing demand for fertility preservation. Indeed, of all cancers arising in women worldwide, ~15% occur in those aged <45 years, while ~40% of cancers affecting girls <20 years of age are of haematological origin. Furthermore, patients requiring chemotherapy and/or radiotherapy are at risk of premature ovarian failure. This review discusses different strategies aiming to preserve and protect fertility: embryo and oocyte cryopreservation; ovarian tissue cryopreservation; fertility-sparing surgery; gonadoprotective strategies; and new avenues of research like the artificial ovary and in vitro maturation of primordial follicles.

(BELG J HEMATOL 2020;11(2):44–8)

A single-center retrospective study of patients with systemic mastocytosis at University Hospital Leuven

SUMMARY

Systemic mastocytosis is a rare heterogeneous disorder characterised by abnormal proliferation of mast cells. It can be divided in subtypes with different phenotypes and prognoses. This article is a retrospective descriptive study of 37 patients with systemic mastocytosis according to the WHO criteria of 2008 at UZ Leuven. Twenty-eight patients had indolent systemic mastocytosis (75.7%), four smouldering systemic mastocytosis (10.8%), three aggressive systemic mastocytosis (8.1%) and two systemic mastocytosis with associated haematological neoplasia (5.4%). In one out of five patients, the diagnosis was made based on at least three minor criteria. The sensitivity of CD25 expression was 100%. In 75.7% a KITD816V mutation was detected. The value of serum tryptase was associated with the subtype of systemic mastocytosis. Seventy-eight percent had cutaneous lesions. Forty-eight percent experienced at least one anaphylactic reaction. Osteoporosis was reported in 24.6%. Eighty-nine percent and 64.9% of patients were treated with respectively H1 and H2 antihistamines. Cytoreductive treatment was administered to nine patients (24.3%). Three patients received as first-line treatment midostaurine, three imatinib, one cladribine, one nilotinib and one masitinib. This study reflects the heterogeneity of this condition and emphasises the importance of a multidisciplinary approach in a specialised center for early diagnosis and treatment of disease-associated manifestations.

(BELG J HEMATOL 2019;10(7):265–76)

Adult T-cell leukaemia-lymphoma: Pathogeny and clinical recommendations

SUMMARY

Human T-cell leukaemia virus type 1 (HTLV-1) was the first human oncogenic virus discovered. It is endemic in some regions of the world but increasingly prevalent in our countries as globalisation is progressing. After several decades of asymptomatic carrying, approximately 2–5% of infected individuals will develop adult-T-cell leukaemia-lymphoma (ATL). Despite significant progress in the physiopathology and therapeutic interventions, the prognosis of this rare disease is dismal. An update of classification, clinical features, diagnosis and recent treatment recommendations is outlined in this review.

(BELG J HEMATOL 2019;10(7):277–84)

Targeted next generation DNA sequencing for the detection of clonal haematopoiesis in idiopathic cytopaenia of undetermined significance (ICUS)

SUMMARY

Patients lacking diagnostic criteria for myelodysplastic syndrome, but who show an unexplained persistent cytopaenia are classified as patients suffering from idiopathic cytopaenia of undetermined significance (ICUS). A fraction of these patients carry somatic mutations in genes which are also mutated in myeloid neoplasms. The significance of these mutations in ICUS patients is not well known and only few research papers have tried to correlate them with clinical outcome. ICUS patients carrying somatic mutations seem to have a higher progression rate to myeloid malignancies compared to unmutated patients. Some mutation profiles also show lower overall survival, similar to patients with (low-risk) myelodysplastic syndrome. Therefore, it seems useful to screen for somatic mutations in cytopaenic patients. The goal of this paper is to review recent literature regarding the significance of somatic mutations in cytopaenic patients and propose a screening protocol by evaluating a test protocol at the AZ Sint-Jan hospital Brugge-Oostende.

(BELG J HEMATOL 2019;10(6):231–40)

Defeating cytomegalovirus, the transplantation troll: can letermovir do the job?

Letermovir (AIC246, MK-8228) is a novel anti-cytomegalovirus (CMV) agent that inhibits CMV replication by targeting the viral terminase complex. In December 2017, letermovir was approved by the Food and Drug Administration (FDA) for the prophylaxis of CMV infection and disease in adult CMV-seropositive recipients of an allogenic haematological stem cell transplantation. Letermovir shows a favourable pharmacokinetic profile in haematological stem cell transplantation recipients after oral administration. The recommended dose for CMV-prophylaxis is once daily 480 mg (oral or intravenous). Letermovir demonstrated superiority in a placebo (plus polymerase chain reaction-monitoring and pre-emptive therapy)-controlled phase III randomised clinical trial. Letermovir is an inhibitor of the cytochrome P450 (CYP)3A family, CYP2B8 and an inducer of the CYP2C9/19. Dose-adjustments (240 mg/day) are necessary when letermovir is combined with cyclosporine. Combinations of letermovir with either voriconazole, midazolam and rosiglitazone require close monitoring of the plasma levels of the latter agents. Letermovir-resistant CMV mutants share mutations that are mostly located between the codon range 230–370 of the UL56 gene. Letermovir is not nephrotoxic nor myelotoxic, but slightly higher rates of atrial fibrillation and tachycardia have been described. In conclusion, letermovir is the first FDA approved anti-CMV agent for prophylaxis in haematological stem cell transplantation patients.

(BELG J HEMATOL 2019;10(4):136–45)

Acquired haemophilia A

Acquired haemophilia A is a potentially severe condition characterised by spontaneous bleeding episodes. Direct recognition and prompt treatment are mandatory. Diagnostic coagulation assays show an isolated prolonged activated partial thromboplastin time, not correcting in a mixing assay. An isolated decrease of factor VIII activity together with the presence of a neutralising antibody confirm the diagnosis. Treatment consists of cessation of a possible bleed and the eradication of the neutralising antibody.

(BELG J HEMATOL 2019;10(4):146–52)