Characteristics, combinations, treatments, and survival of second primary hematological neoplasm: a retrospective single-center cohort of 49 patients (Hemo2study).

The coexistence of dual hematological neoplasms is very rare. Sequential or synchronous neoplasms in hematology are an uncommon and complex clinical situation. The aim of the Hemo2 study was to describe the clinical characteristics and analyze the outcome of these patients. We performed a retrospective review of all patients diagnosed with sequential or synchronous hematological malignancies in the university hospital of Tours, between 2007 and 2018. We identified 49 patients in our study, with a prevalence of 0.89%. Sequential and synchronous combinations were found in 36 (73%) and 13 (27%) patients, respectively. One patient presented three sequential neoplasms. The median cumulative incidence was 6 years (95% CI 3-7). Among all neoplasms diagnosed (n = 99), we found 79 lymphoid neoplasms (LNs) (80%) and 20 myeloid neoplasms (MNs) (20%). Sex ratio was 1.88 with 65% of males and 35% of females. The most common LNs were Hodgkin lymphoma (n = 16; 16%) and multiple myeloma (n = 11; 11%). The most frequent MN was essential thrombocythemia (n = 5; 5%). The most common combination was Hodgkin lymphoma and follicular lymphoma in five (10%) patients. The overall survival from the first diagnosis (OS1) at 5 years was 82.4% (95% CI 72.1-94.3). The median overall survival from the second diagnosis (OS2) was 98 months (95% CI 44-NR) and 5-year OS2 was 58.7% (95% CI 45.5-75.7). Median progression-free survival from the second diagnosis (PFS) was 47 months (95% CI 27-NR) with 5-year PFS of 49% (95% CI 35.9-67). OS and PFS did not statistically differ between synchronous and sequential dual neoplasms. In this cohort, that the death relative risk (RR) was significantly lower if the second neoplasm appeared after more than 4 years following the first diagnosis (OR 0.37 (95% CI 0.16-0.90)). The Hemo2study confirmed the rarity of dual hematological neoplasms. In this cohort, HL and FL were the most frequent combinations. Our results may support that synchronous and sequential dual neoplasms bear the same prognosis. Further studies are needed to better characterize these uncommon clinical situations.

Quantitative chimerism in CD3-negative mononuclear cells predicts prognosis in acute myeloid leukemia patients after hematopoietic stem cell transplantation.

Relapse is a major complication of acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (SCT). The objective of our study was to evaluate chimerism monitoring on the CD3-negative mononuclear cells by RQ-PCR to predict relapse of patients allografted for AML and to compare its performance with WT1 quantification. A cohort of 100 patients undergoing allogenic SCT for AML was retrospectively analyzed in a single institution. Patients without complete chimerism, defined as less than 0.01% of recipient's DNA in CD3-negative cells, had a significantly higher risk of relapse and a lower overall survival (p < 0.001). An increase in the percentage of recipient DNA in CD3-negative cells was associated with an increased risk of relapse (p < 0.001) but not with overall survival. Comparable performances between monitoring of CD3-negative cell chimerism and WT1 expression to predict relapse was observed up to more than 90 days before hematological relapse, with sensitivity of 82% and 78%, respectively, and specificity of 100% for both approaches. Quantitative specific chimerism of the CD3-negative mononuclear fraction, enriched in blastic cells, is a new and powerful tool for monitoring measurable residual disease and could be used for AML patients without available molecular markers.

Bone marrow oxidative stress and specific antioxidant signatures in myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal stem cell disorders with an inherent tendency for transformation in secondary acute myeloid leukemia. This study focused on the redox metabolism of bone marrow (BM) cells from 97 patients compared with 25 healthy controls. The level of reactive oxygen species (ROS) was quantified by flow cytometry in BM cell subsets as well as the expression level of 28 transcripts encoding for major enzymes involved in the antioxidant cellular response. Our results highlight increased ROS levels in BM nonlymphoid cells and especially in primitive CD34posCD38low progenitor cells. Moreover, we identified a specific antioxidant signature, dubbed "antioxidogram," for the different MDS subgroups or secondary acute myeloblastic leukemia (sAML). Our results suggest that progression from MDS toward sAML could be characterized by 3 successive molecular steps: (1) overexpression of enzymes reducing proteic disulfide bonds (MDS with <5% BM blasts [GLRX family]); (2) increased expression of enzymes detoxifying H2O2 (MDS with 5% to 19% BM blasts [PRDX and GPX families]); and finally (3) decreased expression of these enzymes in sAML. The antioxidant score (AO-Score) defined by logistic regression from the expression levels of transcripts made it possible to stage disease progression and, interestingly, this AO-Score was independent of the revised International Scoring System. Altogether, this study demonstrates that MDS and sAML present an important disturbance of redox metabolism, especially in BM stem and progenitor cells and that the specific molecular antioxidant response parameters (antioxidogram, AO-Score) could be considered as useful biomarkers for disease diagnosis and follow-up.

Analysis of TCR, pT alpha, and RAG-1 in T-acute lymphoblastic leukemias improves understanding of early human T-lymphoid lineage commitment.

T-acute lymphoblastic leukemias (T-ALLs) derive from human T-lymphoid precursors arrested at various early stages of development. Correlation of phenotype and T-cell receptor (TCR) status with RAG-1 and pT alpha transcription in 114 T-ALLs demonstrated that they largely reflect physiologic T-lymphoid development. Half the TCR alpha beta lineage T-ALLs expressed a pre-TCR, as evidenced by RAG-1, pT alpha, and cTCR beta expression, absence of TCR delta deletion, and a sCD3(-), CD1a(+), CD4/8 double-positive (DP) phenotype, in keeping with a population undergoing beta selection. Most TCR gamma delta T-ALLs were pT alpha, terminal deoxynucleotidyl transferase (TdT), and RAG-1(lo/neg), double-negative/single-positive (DN/SP), and demonstrated only TCR beta DJ rearrangement, whereas 40% were pT alpha, TdT, and RAG-1 positive, DP, and demonstrated TCR beta V(D)J rearrangement, with cTCR beta expression in proportion. As such they may correspond to TCR alpha beta lineage precursors selected by TCR gamma delta expression, to early gamma delta cells recently derived from a pT alpha(+) common alpha beta/gamma delta precursor, or to a lineage-deregulated alpha beta/gamma delta intermediate. Approximately 30% of T-ALLs were sCD3/cTCR beta(-) and corresponded to nonrestricted thymic precursors because they expressed non-T-restricted markers such as CD34, CD13, CD33, and CD56 and were predominantly DN, CD1a, pT alpha, and RAG-1 low/negative, despite immature TCR delta and TCR gamma rearrangements. TCR gene configuration identified progressive T-lymphoid restriction. T-ALLs, therefore, provide homogeneous expansions of minor human lymphoid precursor populations that can aid in the understanding of healthy human T-cell development.