Eculizumab Treatment of Paroxysmal Nocturnal Hemoglobinuria (PNH). the Argentinian Experience
Authors: Brodsky Andres L. , Touliet Valeria Soledad , Rocaspana Adriana , Aldunate Ximena , Alzueta Abel Esteban , Barraza Teresa , Beguelin Raul , Campregher Gabriel , Colin Laura Beatriz , Dinardo Pablo , Gotta Daniel , Oliveira Natalia , Parodi Claudia , Perinotto Gabriela , Ramirez Mario , Rigada Guillermina , Ronzzetti Rosanna , Esther Rosenfeld , Blanca Rossi , Stivel Miriam , Zirone Sandra 
Published: October 2019

Abstract
INTRODUCTION: paroxysmal nocturnal hemoglobinuria (PNH) is a clonal, non malignant disease of hematopoiesis characterized by intravascular hemolysis, a variable depth of bone marrow failure and a marked thrombophilia. Classic therapeutic resources are supportive care and allogeneic hematopoietic stem cell transplantation. Eculizumab arrival to our country -in 2009- revolutionized PNH treatment. We report here our experience with a cohort of 33 patients treated with eculizumab.
AIMS: to evaluate indications of eculizumab, hematologic response, delays to initiate treatment, interruptions and its consequences, and mortality in our patients.
PATIENTS and METHODS: data of 33 patients with PNH who begun treatment with eculizumab between '01/09 and '12/14 were collected with a specific questionnaire. Qualitative data were analyzed as proportions. Quantitative data were evaluated as median (Md), range (R) and percentiles 25% and 75%, or mean (Mn) and 95% confidence interval (95% CI). Quantitative responses to treatment were evaluated with a non parametric test for paired data (Wilcoxon signed Rank test). A probability value <0.05 was used to define statistical significance.
RESULTS: cohort characteristics: Md age at diagnosis: 32 years old. R: 18 a 73. Eighteen were females and 15 males. Interval simptoms-PNH diagnosis Md: 284 days, R: 1 a 4,518. Granulocyte PNH clon size Md: 91%, R: 18 a 99%.
Symptoms prevalence: fatigue: 90.6%, dyspnea: 71.9%, abdominal pain 56.2%, dysphagia 25%, erectil dysfunction: 20% (of males). Complications frequency: thrombosis 27.3%, impaired renal function 21.2%, pulmonary hypertension 3.1%.
Severity criteria of PNH leading to eculizumab prescription: disabling symptoms 90.6%, steroid dependence 70%, transfusional requirement 54.5%, thrombosis 24.2%, impaired renal function 21.2%, severe dyspnea/ pulmonary hypertension 21.2%.
Delay of eculizumab treatment (from medical prescription to first infusion) in 28 patients: Md: 196 days, R: 37 to 592.
Hematologic responses to eculizumab: Mn LDH decline: 2,081 U/L (95% CI: 1,204 to 2,958) p=0.0003. Mn elevation of hemoglobin 1,5 g/dL (95% CI: 0.82 to 2.18) p=0.0005. Platelet counts increase in thrombocytopenic patients (<150,000 platelets/µL) Mn: 20,720/µL (95% CI: 712 to 40,730) p=0.042. There were no significant changes in neutrophil counts.
Eculizumab treatment interruptions were extremely frequent: 93.7% of patients suffered at least one or more treatment delay(s) ≥ 7 days. Only 2/33 patients did not have any treatment interruption. The mean cause of this treatment irregularities were delays in drug provision by the medical insurance (in 100% of affected patients). In only 10% of cases, lack of patient adherence was responsible for treatment interruptions. Even more, 25.8% of drug supplies were delayed for 7 days or more (99/384 provisions).
Results of treatment interruptions were: transfusional requirement in 41.4% of cases, severe anemia in 34.5%, hospital admission in 27.6%, acute renal impairment in 16.7%, Budd-Chiari syndrome progression in one case, and probable cause of death in another one.
Three patients died (9.1%). Causes were infection in 1, advanced colon cancer in 1, and multiorgan failure, probably related to visceral thrombosis, in the third case.
CONCLUSIONS: this argentinian cohort shows that disabling symptoms, corticosteroids dependence and transfusional requirements are the most frequents causes to start eculizumab treatment in our patients. Eculizumab was effective to block hemolysis, to improve anemia and thrombocytopenia and to prevent new thrombotic events. However, eculizumab achievements were hindered in our experience by the delay to initiate treatment and the frequent interruptions it suffered, as it is usual in Latin America. These treatment delays/interruptions, uncommon in the medical literature, led to multiple and severe complications.

Disclosures
Brodsky: Alexion Pharmaceuticals: Consultancy, Speakers Bureau. Touliet:Alexion Pharmaceuticals: Speakers Bureau. Dinardo:Alexion Pharmaceuticals: Speakers Bureau. Blanca:Alexion Pharmaceuticals: Speakers Bureau.