Aplastic Anemia Associated with PNH-Clone - a Single Centre Experience

Abstract

Introduction: Pathogenetic relationship of aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH) was registered a long time ago. Approximately in 50-60% of patients with AA is detected PNH-clone, and during long-term observation the transformation of AA into classic PNH is likely. At the time of diagnosis PNH-clone sizes range from small proportion of PNH-cells, requiring only monitoring, up to combination of clinically manifested AA and PNH requring combined therapy. Nevertheless, the peculiar characteristics of the disease in cases of different AA-PNH-combinations still remain unclear. Aim: to evaluate the relationship between size and dynamics of PNH-clone with clinical features of AA/PNH. Materials and methods: We have evaluated blood samples of 81 patients with AA (whole group) for the presence of PNH-clone using flow cytometry according to ICCS standards. 23 patients aged 23 to 54 years (median 46 years) were under constant observation for 3 years or more, control examination was performed once every 6 months (dynamic observation group). Of them 17 had severe AA (SAA) and 6 - nonsevere AA (NAA). Twelve patients received standard immunosupressive therapy (IST) for the treatment of AA, other patients were in remission and did not require IST. Results: In the whole group of patients (n=81) 47 patients (58%) were AA/PNH-positive (PNHpos) with clone size ranging from 0.01% to 97.9%. PNH-clone less than 1% was identified in 10% of subjects; PNH-clone more than 10% was observed in 50% of subjects. In dynamic observation group 18 patients were AA/PNHpos with initial clone size from 0.1% to 95.9%, and 5 patients - AA/PNH negative (AA/PNHneg). In AA/PNHneg patients pathological clone still has not been detected in repeated studies for the observed period. Among patients with AA/PNHpos stable clone was observed in 11 subjects (61%), it increased to 10% and more in 5 subjects (28%) and decreased in 2 patients (11%) with small PNH-clone. Clinical and laboratory signs of chronic intravascular hemolysis were usually observed in patients with pathological clone over 25%. PNH-clone less than 10% was not accompanied by significant deviations in clinico-laboratory indices. Most of patients in whom PNH-clone size increased, had remission of AA. Four patients had clonal evolution to manifest classical PNH, of them in 2 patients with SAA аplasia of hematopoiesis persisted. In one patient, with complete remission of SAA lasting more than 3 years and minor PNH-clone, was observed transformation into myeloid leukemia leading to death. Ekulizumab was prescribed to 4 patients: 2 with clinically manifest hemolysis and clone size > 90% (1 - in conjunction with IST for AA), and 2 with clone size 24% and 70% and LDH > 1.5 ULN due to unplanned pregnancies (both on Cyclosporin therapy). All of them achieved the target level of LDH <1.5 ULN in the first 2 weeks of therapy. Of 2 transfusion-dependent patients, one still does not require transfusion support after the Ekulizumab initiation, and in other patient transfusion dependency decreased, despite refractory TAA. In one patient with PNH-clone 70% Ekulizumab therapy was initiated in III trimester of pregnancy, delivery was without complications, full-term baby, 8-9 points Apgar. In the 2nd pregnant patient with PNH-clone 24% Ekulizumab was prescribed because of pre-eclampsia and LDH>4 ULN at 21-22 weeks with antenatal fetal death, and it allowed for accelerating cure of pathological symptoms. Conclusion: PNH-clone was detected in 58% of patients with AA. Our data confirm the need for monitoring of PNH clone in patients with AA and for timely adequate therapy, including inhibitors of intravascular hemolysis, according to specific indications in each case. Disclosures Fominykh: Novartis Pharma: Honoraria; BMS: Honoraria.

Paroxysmal Nocturnal Hemoglobinuria in Patients with Aplastic Anemia: Challenges, Characteristics, and Analysis of Clinical Experience

“…Подобная ситуация является нередкой в клинической практике. Так, по данным различных авторов, трансформация в классическую ПНГ может наблюдаться у 10-18 % больных АА и отмечается, как правило, при становлении ремиссии за счет селекции клона в период восстановления гемопоэза [4,8,13]. Кумулятивная частота гемолитической ПНГ в течение 10 лет в данной группе больных АА/ПНГ достигает 29 %.…”

“…Размер клона менее 1 % обычно клинического значения не имеет и не сопровождается существенными отклонениями клиниколабораторных показателей. Первые клинические и лабораторные проявления заболевания, связанные с наличием ПНГ-клона и внутрисосудистым гемолизом, ПНГ у пациентов с апластической анемией выявляются, как правило, при его размере более 10 % от общего количества клеток крови [1,3,4]. Характерными клиническими проявлениями ПНГ являются гемолитическая анемия со внутрисосудистым гемолизом и тромбозы, обусловленные сложным патофизиологическим механизмом (сочетанием повышенной активации тромбоцитов и эндотелия, нарушением фибринолиза, вазоконстрикцией и др.)…”

“…Последний оценивается по уровню сывороточной лактатдегидрогеназы (ЛДГ). Такая динамика отмечается обычно при исходной величине клона более 10 % и положительных результатах иммуносупрессивной терапии АА с восстановлением костномозгового кроветворения [3,4,8,13]. В итоге возможна трансформация в классическую гемолитическую ПНГ.…”