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Haploinsufficiency of GATA2 caused by heterozygous loss-of-function mutations is associated with cytopenias and predisposition to myelodysplasia and AML with other variable extrahematopoietic manifestions, including lymphedema, pulmonary alveolar proteinosis, and hearing loss. The authors report on 2 siblings with the disorder whose father was asymptomatic because of an acquired missense mutation in the affected allele that was restricted to hematopoietic cells; surprisingly, he also had no extrahematopoietic complications.

The acquisition of pathogenic variants in the TERTpromoter (TERTp)region is a mechanism of tumorigenesis. In nonmalignant diseases, TERTpvariants have been reported only in patients with idiopathic pulmonary fibrosis (IPF) due to germline variants in telomere biology genes.

•Clonal signatures of TBD associate with age and the underlying genotype, and are markers of malignant clonal evolution and poor survival.•In contrast to POT1/PPM1D/TERTpmutations, Chr1q+, U2AF1S34, and TP53somatic mutations are key drivers of cancer development in TBD.

Despite significant progress in transplantation by the addition of alternative hematopoietic stem cell sources, many patients with inherited bone marrow failure syndromes are still not eligible for a transplant. In addition, the availability of sequencing panels has significantly improved diagnosis by identifying cryptic inherited cases. Androgens are the main nontransplant therapy for bone marrow failure in dyskeratosis congenita and Fanconi anemia, reaching responses in up to 80% of cases. Danazol and oxymetholone are more commonly used, but virilization and liver toxicity are major adverse events. Diamond-Blackfan anemia is commonly treated with corticosteroids, but most patients eventually become refractory to this treatment and toxicity is limiting. Growth factors still have a role in inherited cases, especially granulocyte colony-stimulating factor in congenital neutropenias. Novel therapies are warranted and thrombopoietin receptor agonists, leucine, quercetin, and novel gene therapy approaches may benefit inherited cases in the future.

•We developed a machine-learning algorithm to guide differential diagnosis of BMF.•Acquired vs inherited prediction relied on 25 variables recorded through a comprehensive history, and physical and laboratory evaluation encompassing organ systems at the time of first evaluation.

Introduction:Telomere biology (TBD) disorders are caused by pathogenic germline variants in genes related to telomere maintenance. In TBD, clonal hematopoiesis (CH) has been hypothesized to compensate for restricted cell fitness and to lead to development of myelodysplastic syndromes and acute myeloid leukemia (MDS/AML). We sought to characterize the clonal landscape and dynamics by deep sequencing of a large cohort of TBD patients with a broad spectrum of phenotypes and ages.

Genetic testing has been increasingly used to assist with differential diagnosis of acquired vs inherited bone marrow failure syndromes (IBMFS), a group of rare and heterogeneous diseases. However, the assay is still costly and not routinely available for many hematologists. To improve decision-making for genetic testing, we developed a genomic-based machine-learning model based on a two-step data-driven clustering and classification process to predict the likelihood of BMF patients having either an acquired or inherited disease based on 27 clinical and laboratory variables recorded at initial clinical encounter.

Calado: Instituto Butantan: Consultancy; Agios: Membership on an entity's Board of Directors or advisory committees; Alexion Brasil: Consultancy; Novartis Brasil: Honoraria; Team Telomere, Inc.: Membership on an entity's Board of Directors or advisory committees; AA&MDS International Foundation: Research Funding. Young: Novartis: Research Funding.

Calado: Instituto Butantan: Consultancy; AA&MDS International Foundation: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Novartis Brasil: Honoraria; Alexion Brasil: Consultancy; Team Telomere, Inc.: Membership on an entity's Board of Directors or advisory committees. Young: Novartis: Research Funding.

Introduction: Burkitt lymphoma (BL) has become an AIDS-defining disease by Centers for Disease Control (CDC) definition since 1993, emphasizing the strong relationship between this subtype of non-Hodgkin Lymphoma (NHL) and the Human Immunodeficiency Virus (HIV) infection. Although it is widely recognized that the HIV-associated BL represents a distinct entity and a more difficult-to-treat disease, reported results from developed countries seem to corroborate that these regimens do not need to be tailored to the HIV-positive population. There is no available data on outcomes of this population in developing countries. In this study, we report a real-world cohort of adult HIV-associated BL patients in Brazil.

We want to determine if treatment with male hormone nandrolone decante is safe and improves hematologic response as first-line treatment in patients with telomere disease.

Delamain: Novartis: Honoraria.

Telomerase reactivation by acquisition of mutations in the TERTpromoter (TERTp)region is a mechanism of tumorigenesis. The most common TERTpmutations are located in positions -146, -124, and -57 upstream the initiation codon. In non-malignant diseases, TERTpmutations only have been reported in patients with idiopathic pulmonary fibrosis (IPF) caused by germline mutations in telomere biology genes, that are also etiologic in a broader spectrum of diseases collectively named telomeropathies (such as IPF, aplastic anemia [AA], dyskeratosis congenita [DC], and cirrhosis).

Young: CRADA with Novartis: Research Funding; National Institute of Health: Research Funding; GlaxoSmithKline: Research Funding.

Inherited and acquired bone marrow failure syndromes (BMF) may be difficult to distinguish due to heterogeneity and overlap of clinical phenotypes. Genomic screening has been increasingly used to identify mutations in BMF-related genes that are known to be etiologic in inherited BMF. However, genomic testing is expensive, results may not return for several seeks, and findings can be difficult to interpret as some reported variants are of unclear clinical significance. To guide the decision-making for genetic testing and results interpretation, we aimed to identify clinical and molecular parameters associated with a higher probability of patients having an inherited disease. We screened 323 BMF patients from two independent cohorts for germline mutations in BMF-related genes using a targeted next-generation sequencing (NGS) assay, and correlated the results with patients' prior diagnosis, family history, telomere length (TL), karyotype, and the presence of a paroxysmal nocturnal hemoglobinuria (PNH) clones.

Dunbar: National Institute of Health: Research Funding. Young:CRADA with Novartis: Research Funding; GlaxoSmithKline: Research Funding; National Institute of Health: Research Funding.

No relevant conflicts of interest to declare.

In patients with severe acquired aplastic anemia (AA) not eligible for hematopoietic stem cell transplant (HSCT), immunosuppression with horse antithymocyte globulin (h-ATG) and cyclosporine (CsA) is standard and is associated with a high response rate of about 60-70% at 6 months (Scheinberg et al.N Engl J Med 365: 430, 2011). Patients who are unresponsive to initial h-ATG can be rescued with rabbit ATG (r-ATG) in a third of cases (Scheinberg et al. Br J Haematol 133: 622, 2006). Since 2007, h-ATG is no longer available in most Latin American, Asian and European countries, with rabbit ATG (r-ATG) the only ATG formulation available in these markets. However, the outcome with r-ATG as first therapy in SAA is significantly inferior to that of h-ATG with worst response rate and overall survival (Scheinberg et al.N Engl J Med 365: 430, 2011). The salvage rate for patients who failed initial r-ATG is low with alemtuzumab and horse ATG [Scheinberg et al. Blood 119: 345, 2012; Am J Hematol 89: 467, 2014]. However, the salvage rate of a repeat course of r-ATG after initial r-ATG is unknown. Thus, we conducted a retrospective analysis in marrow failure referral Brazilian and Argentinian centers to address this question. The primary endpoint was hematologic response at 3 and 6 months, which was defined as transfusional independence and no longer meeting criteria for severe AA. Secondary endpoints included relapse, clonal evolution, and overall survival. Since 2005, 37 patients (32 refractory and 5 relapsed; 57% males, median age, 17 years; range 3-63 years) were re-treated with r-ATG (Thymoglobuline¨, Genzyme, Cambridge, MA, USA) with median dose of 3.5 mg/kg/d (range 1.67-5.0) for 5 days and oral cyclosporine adjusted to maintain blood levels between 150 and 400 ng/mL for 6 months. Corticosteroids, usually methylprednisolone, were given for at least 2 weeks to prevent serum sickness and trimethoprim–sulfamethoxazole was administered as Pneumocystis jiroveciprophylaxis. Only patients that completed the 5 day r-ATG course were included in the analysis. Second treatment was administered at a median of 283 days from first r-ATG/CsA (range 118-2379 days). After a median follow-up of 726 days (range 7-2320 days), the overall response rates at 3 and 6 months for initial r-ATG refractory patients was 5/32 (16%) and 7/32 (22%), respectively, and for those who relapsed 60% (3/5) (Table). Among all responders, 2 (20%) relapsed at 170 and 897 days after second treatment. In total, clonal evolutions were observed in 6 patients; 5 in non-responders (4 to monosomy 7; 1 trisomy 8 and 21), and 1 in a responder (myelodysplastic syndrome with normal karyotype). Three non-responders underwent matched-unrelated donor allogeneic HSCT. Twelve patients died, all who were non-responders to repeat r-ATG. Overall survival at 4.1 years (censored at the time of HSCT) was 58% (95% CI, 36-75%) (Figure). Our findings indicate that only a minority of r-ATG refractory AA patients may be successfully rescued with a second course of the same immunosuppression. Similar low salvage rates have been reported with alemtuzumab and h-ATG for those refractory to initial r-ATG. In the aggregate, these data show that: 1) other therapies should be considered for those refractory to initial r-ATG such as alternative donor HSCT, thrombopoietin agonists, or other experimental therapies; 2) the high success rate of initial h-ATG therapies cannot be recapitulated when r-ATG is administered first given the low salvage rate with alemtuzumab, h-ATG and now (current data) with r-ATG; 3) for patients that relapse after first r-ATG treatment, second course r-ATG may be a reasonable option.