Background: Small populations of paroxysmal nocturnal hemoglobinuria (PNH)-type cells (<1.0%) are frequently found in bone marrow failure syndromes (BMF) including aplastic anemia (AA) and low-risk myelodysplastic syndromes (MDS) without evident hemolytic symptoms. The presence of small PNH-type cells has been reported to predict better response to immunosuppressive therapy (IST) both retrospectively (Blood 2006 107:1308-1314) and prospectively (Br J Haematol 2014 164:546-54), but its clinical significance is still to be elucidated. In addition, the kinetics of those small PNH-type cells have not been well studied. To better understand the clinical significance and the kinetics of PNH-type cells in BMF, we conducted a nationwide, multicenter, prospective, observational clinical study named SUPREMACY.

Methods: Patients diagnosed with PNH, AA, MDS or indistinguishable BMF without malignant diseases were prospectively recruited to the study between April 1 st, 2016 and December 31 st, 2019 in Japan. Participants were excluded from the study if treated with eculizumab or ravulizumab. Peripheral blood samples were obtained with informed consent and sent to the single laboratory every 12months (mos) for 36 mos. A high-resolution flow cytometry assay known as OPTIMA method (Ann Hematol 97(12):2289-2297) was used to precisely detect a small population of GPI(-) cells, which defines ≥0.003% PNH-type granulocytes (Gran) and ≥0.005% erythrocytes as an abnormal increase. The quality of life (QOL) of the pts was assessed using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) instruments. All other lab data and clinical information were obtained at each participating institute or hospital on sample collection, and were accumulated by the Japan PNH Study Group for analysis.

Results: Total 1,985 pts were registered and 1,813 pts were eligible for analysis. Median age was 67 with 50.5% male patients. PNH-type cells were positive in 50.4% (235/466) of AA, 19.7% (70/355) of MDS, 22.3% (61/273) of suspected PNH, and 33.9% (232/685) of undiagnosed BMF. PNH-type cells were increased in nearly 30% of the pts with RCUD, RCMD, MDS-U, and 5q-, but not in RARS, RAEB-1, or RAEB-2. Time-course data of the size of PNH-type cells were available in 651 pts at 12mos and in 210 pts at 36mos. Small (<1.0%) PNH-type granulocytes (sPNHg) stayed below 1.0% at 36mos in 81/86 (94.2%) pts, but increased in 5/86 (5.8%) by median 2.75% or by average 17.86% at 36mos. Clinical data for IST were available in 277 pts (12mos) and 99 pts (36mos). Pts with PNH-type cells showed a better response rate [Complete response (CR) + Partial response (PR), 159/201 (79.1%) at 12mo, 68/73 (93.2%) at 36mo] to IST compared to the pts without PNH-type cells [48/76 (63.2%) at 12mos, 17/26 (65.4%) at 36mos] (P<0.01, Chi-square test)(Figure 1). Changes of QOL data were compared between the pts with sPNHg [PNH(+)] and the pts without PNH-type cells [PNH(-)] at 36mos, and PNH(+) showed significant improvement in FACIT-Fatigue score (n=36, p=0.0348, Chi-square test) and in 6 items of EORTC QLQ-C30 (global health status, emotional functioning, social functioning, fatigue, and financial difficulties)(n=40) but no significant change of QOL was observed except in one item (constipation) in PNH(-) (n=36)(Table 1).

Conclusion: PNH-type cells were detected exclusively in AA and low-risk MDS, supporting the hypothesis that the increase of PNH-type cells in BMF underpin the benign immune-mediated feature of the disease. The presence of PNH-type cells predicts a better response to IST in BMF, which is consistent with previous reports. Detection of subclinical PNH-type cells was associated with an improvement of QOL scores in multiple items at 36mos. Those small populations of PNH-type cells stayed subclinical in most of the cases, but caution should be exercised in monitoring the sizes as some may evolve into clinical PNH.


Ueda:Chugai Pharmaceutical: Consultancy, Honoraria, Research Funding; Alexion Pharma: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Yonemura:Alexion Pharma: Honoraria, Research Funding; Chugai Pharmaceutical: Research Funding; Novartis Pharma: Honoraria. Obara:Novartis Pharma: Honoraria; Chugai Pharmaceutical: Honoraria, Research Funding; Alexion Pharma: Honoraria, Research Funding. Ando:Novartis: Honoraria; Kyowa Kirin: Research Funding; Chugai Pharmaceutical: Research Funding; Celgene: Honoraria; Astellas Pharma: Honoraria; Takeda Pharmaceutical: Research Funding. Kawaguchi:Alexion Pharma: Honoraria. Nishimura:Alexion Pharma: Consultancy; Chugai Pharmaceutical: Consultancy; Novartis Pharma: Consultancy; Roche: Consultancy; apellis pharmaceuticals: Consultancy; Biocryst: Consultancy; Sanofi: Consultancy. Nakao:Kyowa Kirin: Honoraria; Novartis Pharma: Honoraria; Symbio: Consultancy; Alexion Pharma: Research Funding.

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