THE RELATIONSHIP BETWEEN THE PRETREATMENT PNH CLONE SIZE AND CLINICAL COURSE IN PATIENTS WITH BONE MARROW FAILURE SYNDROMES: INTERIM ANALYSIS OF JAPANESE MULTICENTER PROSPECTIVE STUDY
Author(s): ,
Yasutaka Ueda
Affiliations:
Hematology and Oncology,Osaka University Graduate School of Medicine,Suita,Japan;Japan PNH Study Group,Tokyo,Japan
,
Kohei Hosokawa
Affiliations:
Hematology,Kanazawa University,Kanazawa,Japan;Japan PNH Study Group,Tokyo,Japan
,
Ken Ishiyama
Affiliations:
Hematology,Kanazawa University,Kanazawa,Japan;Japan PNH Study Group,Tokyo,Japan
,
Hiroyuki Takamori
Affiliations:
Hematology and Oncology,Osaka University Graduate School of Medicine,Suita,Japan;Japan PNH Study Group,Tokyo,Japan
,
Yuji Yonemura
Affiliations:
Transfusion Medicine and Cell Therapy, Blood Transfusion Service,Kumamoto University School of Medicine,Kumamoto,Japan;Japan PNH Study Group,Tokyo,Japan
,
Naoshi Obara
Affiliations:
Hematology,Faculty of Medicine, University of Tsukuba,Tsukuba,Japan;Japan PNH Study Group,Tokyo,Japan
,
Hideyoshi Noji
Affiliations:
Hematology,Fukushima Medical University,Fukushima,Japan;Japan PNH Study Group,Tokyo,Japan
,
Hiroshi Takahashi
Affiliations:
Hematology,Fukushima Medical University,Fukushima,Japan;Japan PNH Study Group,Tokyo,Japan
,
Yukari Shirasugi
Affiliations:
Hematology and Oncology,Tokai University School of Medicine,Isehara,Japan;Japan PNH Study Group,Tokyo,Japan
,
Takahisa Matsuda
Affiliations:
Alexion Pharma G.K.,Tokyo,Japan
,
Kiyoshi Ando
Affiliations:
Hematology and Oncology,Tokai University School of Medicine,Isehara,Japan;Japan PNH Study Group,Tokyo,Japan
,
Tsutomu Shichishima
Affiliations:
Hematology,Fukushima Medical University,Fukushima,Japan;Japan PNH Study Group,Tokyo,Japan
,
Takayuki Ikezoe
Affiliations:
Hematology,Fukushima Medical University,Fukushima,Japan;Japan PNH Study Group,Tokyo,Japan
,
Shigeru Chiba
Affiliations:
Hematology,Faculty of Medicine, University of Tsukuba,Tsukuba,Japan;Japan PNH Study Group,Tokyo,Japan
,
Haruhiko Ninomiya
Affiliations:
Hematology,Faculty of Medicine, University of Tsukuba,Tsukuba,Japan;Japan PNH Study Group,Tokyo,Japan
,
Tatsuya Kawaguchi
Affiliations:
Medical Technology,Kumamoto Health Science University,Kumamoto,Japan;Japan PNH Study Group,Tokyo,Japan
,
Jun-ichi Nishimura
Affiliations:
Hematology and Oncology,Osaka University Graduate School of Medicine,Suita,Japan;Japan PNH Study Group,Tokyo,Japan
,
Yuzuru Kanakura
Affiliations:
Hematology and Oncology,Osaka University Graduate School of Medicine,Suita,Japan;Japan PNH Study Group,Tokyo,Japan
Shinji Nakao
Affiliations:
Hematology,Kanazawa University,Kanazawa,Japan;Japan PNH Study Group,Tokyo,Japan
EHA Library. Ueda Y. Jun 15, 2019; 266732; PS1115
Dr. Yasutaka Ueda
Dr. Yasutaka Ueda
Contributions
Abstract

Abstract: PS1115

Type: Poster Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 17:30 - 19:00

Location: Poster area

Background
Paroxysmal nocturnal hemoglobinuria (PNH) is caused by a clonal expansion of stem cell(s) with PIGA mutation. PIGA mutation itself doesn’t confer growth advantage on PNH clones in mice models, and what drives PNH clonal expansion has been a long-standing issue. We have previously reported the high prevalence of increased PNH-phenotype cells in bone marrow failure syndromes (BMF) including aplastic anemia (AA) and myelodysplastic syndromes (MDS), but the kinetics of PNH clone in BMF remains to be elucidated.

Aims
To determine what affects PNH clonal dynamics by conducting a prospective multi-central clinical trial, SUPREMACY.

Methods
Patients (pts) diagnosed with PNH, AA, MDS or other BMF were prospectively recruited to this study. All the pts were eculizumab naive. Blood samples to assess PNH clone size were sent to the single central laboratory, and assessed using high-precision flow cytometry (Ann Hematol. 2018 97:2289-2297) for the PNH-type cell positivity (granulocytes, ≧0.003%; red blood cells, ≧0.005%; monocytes, ≧0.01%) every 12 months. All other lab data and clinical information were collected at the time of the PNH-clone size assessment from each participating institution or hospital, and were analyzed at Japan PNH Study Group.

Results
Between April 2016 and September 2018, 1,171 pts were enrolled into this study. The median age was 67 years with 50.0% males. PNH-type cells were positive in 55.8% (159/285) of AA, 20.3% (49/242) of MDS, 100% (29/29) of PNH, 22.7% (39/172) of suspected PNH, and 36.1% (160/443) of undiagnosed BMF. 235 pts were eligible for this interim analysis of the change in the percentage of PNH-type cells. At 12 months, 16 out of 102 PNH (+) pts became PNH (-), whereas none of 133 PNH (-) pts became PNH (+). Of the 102 PNH (+) pts whose blood samples were serially examined, the percentage of PNH-type granulocytes increased in 40 pts (PNHginc pts), while it decreased in 61 pts (PNHgdec pts) and remained the same in one patient. At the time of registration (0 month), PNHginc pts had a higher percentage of PNH-type granulocytes than PNHgdec pts (median: 0.470 % vs 0.059 %, P<0.01; mean: 12.534 % vs 4.012 %, P=0.0362). There were more pts with large (≧1%) PNH-type cells in PNHginc pts [40.0% (16/40)] than in PNHgdec pts [21.3% (13/61)] (P=0.0423). Clinical data regarding response to immunosuppressive therapy (IST) were available with 94 pts. PNH (+) pts showed a better response rate [CR+PR, 57/67 (85.1%)] to IST compared to PNH (-) pts [16/27 (59.3%)] (P<0.01). The changes of the percentage of PNH-type granulocytes were not statistically different between those with IST (n=67, median -0.004% ) and those without IST (n=35, median -0.005 % ) (P=0.9046), or between those who respond to IST (CR+PR: n=57, median -0.004%) and those who did not (NR: n=10, median -0.002%)(P=0.6036).

Conclusion
Increased PNH type-cells were highly prevalent among pts with BMF, and the presence of increased PNH-type cells predicted better response to IST, both of which were consistent with previous reports. There was a tendency toward higher chance of PNH clones to expand in pts whose PNH clone size was large than in those whose PNH clone size was small at the time of registration. The effect of IST to the kinetics of PNH-type cells were not observed. These observations suggest that clonal dynamics of PNH-type cells might be different depending on their clone size before treatment. This is the first interim analysis of the study, and further accumulation of cases is needed to clarify those issues.

Session topic: 12. Bone marrow failure syndromes incl. PNH - Clinical

Keyword(s): Bone marrow failure, Flow cytometry, Immunosuppressive therapy, Paroxysmal nocturnal hemoglobinuria (PNH)

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