Clinical and prognostic significance of small paroxysmal nocturnal hemoglobinuria clones in myelodysplastic syndrome and aplastic anemia

Abstract

In this large single-centre study, we report high prevalence (25%) of, small (<10%) and very small (<1%), paroxysmal nocturnal hemoglobinuria (PNH) clones by high-sensitive cytometry among 3085 patients tested. Given PNH association with bone marrow failures, we analyzed 869 myelodysplastic syndromes (MDS) and 531 aplastic anemia (AA) within the cohort. PNH clones were more frequent and larger in AA vs. MDS (p = 0.04). PNH clone, irrespective of size, was a good predictor of response to immunosuppressive therapy (IST) and to stem cell transplant (HSCT) (in MDS: 84% if PNH+ vs. 44.7% if PNH−, p = 0.01 for IST, and 71% if PNH+ vs. 56.6% if PNH− for HSCT; in AA: 78 vs. 50% for IST, p < 0.0001, and 97 vs. 77%, p = 0.01 for HSCT). PNH positivity had a favorable impact on disease progression (0.6% vs. 4.9% IPSS-progression in MDS, p < 0.005; and 2.1 vs. 6.9% progression to MDS in AA, p = 0.01), leukemic evolution (6.8 vs. 12.7%, p = 0.01 in MDS), and overall survival [73% (95% CI 68–77) vs. 51% (48–54), p < 0.0001], with a relative HR for mortality of 2.37 (95% CI 1.8–3.1; p < 0.0001) in PNH negative cases, both in univariate and multivariable analysis. Our data suggest systematic PNH testing in AA/MDS, as it might allow better prediction/prognostication and consequent clinical/laboratory follow-up timing.

The predictive value of PNH clones, 6p CN-LOH, and clonal TCR gene rearrangement for aplastic anemia diagnosis

“…[63][64][65] Similarly, pediatric RCC patients who have PNH clones were previously reported to have improved responses to IST, suggesting that their marrow dysfunction is likely immune-mediated. 33,66 The close link of PNH Gran and acquired 6p CN-LOH MHC to the autoimmune pathogenesis of AA can facilitate efficient identification of patients with AA-type autoimmune marrow failure among those diagnosed with RCC or hypoplastic MDS.…”

“…We used a cutoff of PNH Gran that corresponded to our assay sensitivity (.0.05%) because the presence of even minor PNH populations has been previously shown to be predictive of immunosuppressive therapy response in AA. [31][32][33] In patients with detectable PNH Gran clones, the median interval from presentation to first available PNH testing was 0 months (ie, at diagnosis), ranging from initial presentation to 74 months after original diagnosis.…”

Large Granular Lymphocyte Expansion in Myeloid Diseases and Bone Marrow Failure Syndromes: Whoever Seeks Finds

“…This phenomenon is common to other clonal entities such as paroxysmal nocturnal hemoglobinuria (PNH). Here, a multistep pathogenesis is postulated encompassing the acquisition of a somatic mutation of PIG-A gene, the autoimmune attack to normal stem cells, and the selection/expansion of the PNH clone favored by immunosuppression and/or acquisition of co-mutations (56). Similarly, in LGL clones, somatic mutations of STAT3 and STAT5b have been demonstrated, that seem however not sufficient to cause the disease, without additional contribution of environmental factors, cytokine dysregulation, and therapies.…”

Immune Phenomena in Myeloid Neoplasms: An “Egg or Chicken” Question

“…Additionally, the bone marrow environment (dominated by an auto-immune signature) seems to play an important role in a further growth advantage of the PNH clone ( 46 ). Bone marrow microenvironment and autoimmune phenomena may play a role also in MDS, where mainly small PNH clones are described, without an overt hemolytic disease ( 45 ). Consistently, anti- erythroblast antibodies have been demonstrated in about 2/3 of early MDS together with increased values of the pro-apoptotic protein Bax and decreased levels of Bcl‐2 levels, and their BM culture supernatants induced dyserythropoietic signs, erythroblastic clustering, and increased overall in cultured normal BM ( 47 , 48 ).…”