Hematopoietic Stem Cell Transplantation following Reduced Intensity Conditioning for High Risk Patients with Paroxysmal Nocturnal Hemoglobinuria
Authors: Mikolajewska Agata , Al-Ali Haifa Kathrin , Basara Nadezda , Epner Elliot , Holler Ernst , Johnston Laura , Niederwieser Dietger , Lange Thoralf 
Published: April 2020

Abstract
Objectives: Paroxysmal nocturnal hemoglobinuria (PNH) is a non malignant acquired hematopoietic stem cell disorder that can cause severe complications such as arterial or venous thrombosis or deficient haematopoiesis. These patients have a high mortality rate and should be evaluated for allogeneic stem cell transplantation (SCT). However, conventional conditioning has been associated with high treatment related toxicity. We report here the extended follow up of 7 previously published and 4 additional patients with high risk PNH after allogeneic HCT with reduced intensity conditioning (RIC).
Patients: Eleven patients (3 males) with a median time from diagnosis to SCT of 16 (range 4 to 59) months were treated with red blood cell transfusions (n=9), anticoagulation (n=3), or immunosuppression (n=10): cyclosporine A (CSA, n=3), azathioprin (n=1), mycofenolate mofetil (MMF, n=1), antithymocyte globulin (n=1) or systemic steroids (n=9) until SCT. High risk PNH was characterized by venous thromboses: sinus veins (n=1), liver veins (n=3), vena portae (n=1), mesenterial veins (n=1) or thrombosis of lower extremity (n=1); bone marrow failure (n=6); recurrent life threatening haemolysis (n=8) or infections (n=5). Seven patients had more than one high risk feature. The median age at SCT was 34 (range 22 to 49) years. Conditioning regimen consisted of 2 Gy total body irradiation (TBI) at day 0 and fludarabine (30 mg/m2) at day-4 to -2 followed by treatment with MMF and CSA. The stem cell donors were related (n=2), allele matched unrelated (n=7) or mismatched (n=2).
Results: The median follow up was 43 (range 2–101) months after SCT. The median time until neutrophil recovery was 17 (range 0–29) days and 4/11 patients (36%) did not develop ANC&lt;500/l. All but one patient (91%) showed primary donor engraftment with a median T-cell chimerism of 59 (range 38.3–99.3) % in the bone marrow at day 28 after SCT. The patient with primary graft failure received a second transplant from an alternative donor after RIC with 3 Gy TBI and showed stable engraftment. Six out of 11 (55%) patients developed grade II or III acute graft-versus-host disease (GvHD), which was treated with systemic steroids in 5 patients. Extensive chronic GvHD occurred in 3/11 (27%) of the patients. Three patients (27%) died of complications (pancreatitis with subsequent multiorgan failure, pseudomonas sepsis and haemorrhage) following steroid treatment for acute (n=1) and extensive (n=2) chronic GvHD 2, 12.5 and 14 months after SCT. The remaining 8 patients are alive and without clinical and laboratory evidence of PNH after a median follow up 61.5 (range 10–101) months after SCT. All surviving patients show an ECOG of 0–1 and 4/8 patients (50%) are off all immunsuppression.
Conclusions: Allogeneic HCT with reduced intensity conditioning induces durable eradication of the PNH clone. The treatment related mortality even in high risk PNH with severe organ dysfunction was acceptable and due to complications after GVHD. All long term survivors have a good performance status and half of them are without any immunosuppression.