Heterozygous RTEL1 variants in bone marrow failure and myeloid neoplasms.

Biallelic germline mutations in RTEL1 (regulator of telomere elongation helicase 1) result in pathologic telomere erosion and cause dyskeratosis congenita. However, the role of RTEL1 mutations in other bone marrow failure (BMF) syndromes and myeloid neoplasms, and the contribution of monoallelic RTEL1 mutations to disease development are not well defined. We screened 516 patients for germline mutations in telomere-associated genes by next-generation sequencing in 2 independent cohorts; one constituting unselected patients with idiopathic BMF, unexplained cytopenia, or myeloid neoplasms (n = 457) and a second cohort comprising selected patients on the basis of the suspicion of constitutional/familial BMF (n = 59). Twenty-three RTEL1 variants were identified in 27 unrelated patients from both cohorts: 7 variants were likely pathogenic, 13 were of uncertain significance, and 3 were likely benign. Likely pathogenic RTEL1 variants were identified in 9 unrelated patients (7 heterozygous and 2 biallelic). Most patients were suspected to have constitutional BMF, which included aplastic anemia (AA), unexplained cytopenia, hypoplastic myelodysplastic syndrome, and macrocytosis with hypocellular bone marrow. In the other 18 patients, RTEL1 variants were likely benign or of uncertain significance. Telomeres were short in 21 patients (78%), and 3' telomeric overhangs were significantly eroded in 4. In summary, heterozygous RTEL1 variants were associated with marrow failure, and telomere length measurement alone may not identify patients with telomere dysfunction carrying RTEL1 variants. Pathogenicity assessment of heterozygous RTEL1 variants relied on a combination of clinical, computational, and functional data required to avoid misinterpretation of common variants.

The impact of donor factors on primary non-engraftment in recipients of reduced intensity conditioned transplants from unrelated donors.

BACKGROUND AND OBJECTIVES: Primary graft failure is a serious complication following hematopoietic cell transplants, particularly when using unrelated donors. We analyzed factors affecting primary graft failure in recipients of hematopoietic cell transplants from unrelated donors, which were performed using reduced intensity conditioning. DESIGN AND METHODS: This was a retrospective analysis of 144 patients whose transplants took place between March 1998 and October 2004. The data were analyzed in January 2005. RESULTS: The median age of the patients was 51 years. The diagnoses were varied. Conditioning regimens were fludarabine, melphalan, campath (n=80), fludarabine, busulphan, campath (n=38), fludarabine, BEAM, campath (n=9) and other (n=17). The donor was 10/10 allele matched in 95/144 (66%) cases; 94 donated bone marrow and 50 peripheral blood stem cells. The 3-year probability of overall survival was 43%. The median follow-up was 724 days (range: 91-1651 days). Of evaluable patients, 7/140 (5%) failed to achieve myeloid engraftment. Primary graft failure was significantly associated with the use of a mismatched donor (6/47,13% versus 1/93, 1%, p=0.006), as well as: bone marrow as the source of stem cells (p=0.046), chronic myeloid leukemia compared to other diagnoses (p=0.022), and a female rather than a male donor (p=0.019). In multivariate analysis chronic myeloid leukemia, HLA mismatched and/or female donors remained significantly associated with primary graft failure. Single HLA mismatches were tolerated, however in multiply mismatched grafts, overall survival was worse (p=0.005); transplanted-related mortality (p=0.005) and chronic graft-versus-host disease (p=0.025) were increased. INTERPRETATION AND CONCLUSIONS: These data have implications for the choice of donor and stem cell source in transplants performed using reduced intensity conditioning regimens, suggesting that the use of bone marrow, female donors and HLA-mismatched grafts increase the risk of primary graft failure, and should be avoided in certain situations.

Trisomy 10 and acute myeloid leukemia.

We report the second case of trisomy 10 as the sole abnormality in acute erythroblastic leukemia (AML M6). Trisomy 10 is a rare recurring numerical chromosomal abnormality is probably linked to a myeloblast subset with CD7+ and CD33+ immunophenotype. Most of the 15 cases reported to date in the literature have been M0, M1, or M2, with one showing AML M6 morphology.

Recurrent infections in sickle cell disease: haematological and immune studies

Some haematological and immunological indices were compared in 19 children with sickle cell disease and a history of recurrent infections and in 16 children with sickle cell disease without any known infections. The recurrent infection group had significantly greater pitted red cell counts and greater absolute monocyte counts. No differences were apparent in routine haematological indices, foetal haemoglobin, immunoglobulin, or complement levels between the groups. The interpretation of these results is discussed (AU)