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Genetic predisposition to acute myeloid leukemia (AML) concerns a minority of adult patients. Development of high-throughput sequencing technologies over the last ten years allowed identification o...

The germline predisposition associated with the autosomal dominant inheritance of the 14q32 duplication implicating ATG2B/GSKIP genes is characterized by a wide clinical spectrum of myeloid neoplasms. We analyzed 12 asymptomatic carriers and 52 patients aged 18-74 years from six families, by targeted sequencing of 41 genes commonly mutated in myeloid malignancies. We found that 75% of healthy carriers displayed early clonal hematopoiesis mainly driven by TET2 mutations. Molecular landscapes of patients revealed two distinct routes of clonal expansion and leukemogenesis. The first route is characterized by the clonal dominance of myeloproliferative neoplasms (MPN)-driver events associated with TET2 mutations in half of cases and mutations affecting splicing and/or the RAS pathway in one-third of cases, leading to the early development of MPN, mostly essential thrombocythemia, with a high risk of transformation (50% after 10 years). The second route is distinguished by the absence of MPN-driver mutations and leads to AML without prior MPN. These patients mostly harbored a genomic landscape specific to acute myeloid leukemia secondary to myelodysplastic syndrome. An unexpected result was the total absence of DNMT3A mutations in this cohort. Our results suggest that the germline duplication constitutively mimics hematopoiesis aging by favoring TET2 clonal hematopoiesis.

Adult T-cell Leukemia/Lymphoma (ATLL) is a sight- and life-threatening complication of human T-cell lymphotropic virus type 1 (HTLV-1) infection. Ophthalmic manifestations include uveitis, optic nerve oedema, retinal vasculitis, and lymphomatous infiltration. Orbital lesions are rare. We report the case of an orbital tumor revealing systemic ATLL in a 45-year-old Dominican patient who died despite treatment. Apart from late-grade cutaneous T-cell lymphoma, ATLL is the only T-lymphoma to develop in the orbit. Diagnosis is based on serologic evidence of HTLV-1 infection, cytology, and blood sample analysis. Biopsy is deemed necessary. Given the poor prognosis of ATLL and the worldwide presentation of HTLV-1, physicians should consider ATLL in the differential diagnosis of orbital malignant tumor and look for HTLV-1 infection in populations at risk.

In 2015, a germline copy number variation of chromosome 14 (CNVdup14) including ATG2B and GSKIP genes was described as a predisposition genetic factor responsible of familial myeloproliferative neoplasms from French West Indies (Saliba et al, Nat Gen 2015), frequently progressing to AML. In this study, we looked at the presence of this CNVdup14 in a cohort of Caribbean islands patients (pts) with non-secondary aggressive hematological malignancies (HM). We also studied the expression of ATG2B and GSKIP genes in a cohort of acquired AML pts. This is a retrospective multicenter study of adults Caribbean islands pts treated at Gustave Roussy Cancer Center (Villejuif, France) and at the French West Indian hospitals (Martinique and Guadeloupe) between May 2000 and May 2018. We included pts with AML, acute undifferentiated leukemia (AUL), acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LL). Pts with personal history of myeloproliferative or myelodysplastic syndromes before the onset of aggressive HM were not included in this study. The presence of the CNVdup14 was carried out by PCR analyses in all the pts. For the second part of the study, expression of ATG2B and GSKIP genes were assessed in newly diagnosed de novo AML pts with normal karyotype or trisomy 8 (samples from the GOELAMSTHEQUE) by quantitative RT-PCR and expressed as relative expression PPIA/HPRT/H2A.Z. One hundred pts were analyzed. Median age was 52 years (IQ 40-62) with male predominance (61%). Fifty eight pts came from Martinique, 42 pts from the rest of the Caribbean islands (including 28, 4, 3, 2 pts from Guadeloupe, Haiti, Saint Martin, Dominican Republic, respectively). Seventy eight pts had AML. Among them, according to revised MRC cytogenetic classification, 11 (14%) were favorable, 47 (60%) intermediate and 20 (26%) adverse. Seventeen pts had ALL, 3 LL, and 2 AUL. On the entire cohort, all except nine pts were treated with intensive chemotherapy, 80 reached complete remission, 29 relapsed, 46 pts died. Thirty two pts received hematopoietic stem cell transplantation (HSCT). Six pts were positive for the CNVdup14 by PCR (confirmed by SNP array in the 5 pts with leftover DNA available). All had an AML (no pts with favorable AML) and were originated from Martinique. These pts represented 14% of the 43 AML from Martinique in our cohort (17% if we excluded favorable AML). One was known to be part of an ATG2B/GSKIP family, 2 pts had no familial history of myeloid malignancies and 2 new families were discovered. Median white blood cell, hemoglobin and platelets counts were 17.7 G/l (IQ 6.7-48), 8.15 g/dl (6.9-9.7) and 58 G/l (20-132), respectively. Median age at AML diagnosis was 49 years (34-55), 3/6 (50%) had extramedullary localization compared to 11/78 (14%) for others AML pts. Karyotype was normal for 4, or showed a monosomy 7 for 2 pts. NGS panel showed distinct abnormalities compared to the entire cohort (Fig A). None had JAK2, MPL, CALR, P53, RUNX1, DNMT3A, FLT3-ITD mutations. All harbored an epigenetic and/or spliceosome mutation (IDH n=3, TET2 n=3, ASLX1 n=3, SRSF2 n=3). Five out of the six pts received intensive treatment and 4 achieved complete remission. Two received HSCT, 2 relapsed and 4 died. Median overall survival (OS) of the entire cohort was 35.7 months (22.5-89.5) and progression free survival (PFS) 27.6 months (15.6 -56.1). As CNVdup14 pts had AML only, we next evaluated survival according to the predisposition status in the AML cohort. Pts with CNVdup14 had a median OS and PFS of 19 (6.5-29) and 11.4 (6.5-29) months, respectively, compared with 52.6 (22.9-100.2) and 30 months (15.6-60) in CNV wild-type counterparts (PFS Fig B). We next evaluated ATG2B and GSKIP expression in a cohort of 46 random de novo AML pts (GOELAMS-LAM-IR-2006 multicenter trial). Median expression of ATG2B and GSKIP were 4.8 (2.6-12.9) and 5.3 (0.3-5.1) respectively. No CNVdup14 was detected. Interestingly we found a correlation between the two genes expression (Pearson Correlation Coefficients 0.55 and linear regression p< 0.001, Fig C). Expression of ATG2B and GSKIP was also correlated with leukocytosis (p=0.003 and p=0.07) (Fig D). We found no impact on OS and PFS. For the first time, we described a high percentage of the germline CNVdup14 in de novo AML pts from Martinique (14%). Moreover evaluation of ATG2B and GSKIP expression suggested that the role of theses 2 genes in leukemogenesis is not limited to pts with the CNVdup14. Figure. Figure. Disclosures de Botton: Agios: Research Funding; Celgene: Honoraria, Research Funding. Benabelali:CERBA laboratory: Employment.

We report here two cases of thrombocytopenic purpura at onset of Zika virus infection. A 26-year-old woman and a 21-year-old man had thrombocytopenia above 5×10(9) platelets/L. Hemorrhagic symptoms were mucosal and subcutaneous bleeding and gross hematuria and they reported episode of conjunctivitis. In both cases blood and bone marrow analysis suggested thrombocytopenic purpura, blood PCR tests for Dengue (DENV), Chikungunya (CHIKV) and Zika virus (ZIKV) were negative. In both cases urinary PCR for ZIKV was positive, Prednisolone yielded early remission. Only three similar cases have been reported so far. In the Caribbean, DENV is also epidemic and responsible for severe thrombocytopenia. Coinfections can occur. Our report underlines the need to include a ZIKV assay in the diagnostic work-up of thrombocytopenic purpura in epidemic areas.