Page 64 - Haematologica May 2020

A. Tichelli et al.
that G-CSF has an impact on the outcome of severe aplastic anemia; nevertheless, very late events are common and eventually affect the prognosis of these patients, irrespectively of their age at the time of immunosuppres- sive therapy (NCT01163942).
Introduction
Acquired aplastic anemia is a rare disease defined by peripheral pancytopenia associated with hypocellularity of the bone marrow. The aim of treatment of aplastic anemia is to improve peripheral blood counts and obtain transfusion independency. First-line treatment for younger patients (≤40 year old) with a matched sibling donor is allogeneic stem cell transplantation (SCT). The standard of care for adult patients not eligible for SCT is immunosuppressive therapy (IST), including a combina- tion of horse antithymocyte globulin (ATG) and cyclosporine (CSA).1 In contrast to patients undergoing SCT, those treated with IST are not cured from their dis- ease and are at risk of late complications such as relapse and development of late clonal diseases, including parox- ysmal nocturnal hemoglobinuria (PNH), myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).2 Furthermore, the delayed recovery of peripheral blood counts exposes patients to infectious and hemorrhagic complications.3
Immunosuppression remains a suboptimal treatment, since about 30% of the patients fail to respond and even in responding patients, blood counts often remain sub- normal, possibly requiring maintenance IST with CSA. Efforts have been made for 40 years to improve the stan- dard horse ATG plus CSA treatment.1 Other immunosup- pressive combinations as well as the use of high-dose cyclophosphamide have been evaluated, without show- ing the expected breakthrough.4-7 Great hopes have been placed in the development of hematopoietic growth fac- tors. The role of granulocyte colony-stimulating factor (G-CSF) added to standard IST with ATG and CSA, test- ed in six small prospective randomized trials, was incon- clusive.8-13 Therefore, in 2001 a prospective randomized study was initiated to evaluate the short- and long-term effects of G-CSF added to standard IST. Patients with newly diagnosed severe aplastic anemia (SAA) were ran- domized to treatment with ATG and CSA, with or with- out G-CSF (NCT01163942). The study demonstrated that G-CSF added to ATG and CSA decreases the rate of early infectious episodes and days of hospitalization in patients with very SAA patients, but has no significant impact on overall survival (OS), event-free survival (EFS), relapse, or death rates.14 The role of G-CSF in triggering late clonal evolution to a hematologic malignancy has been debated for years.15-18 and we lacked follow-up in our previous study for a meaningful assessment of this risk.14
Early death occurs secondary to infection, bleeding, or complications of severe anemia. Limited data are avail- able on late malignant and non-malignant complications after IST. Today, 16 years after initiation, this random- ized controlled study is a unique opportunity to assess the long-term outcome of SAA patients treated with IST. We thus aimed to evaluate the durability of response to treatment, survival outcomes, and the risk of long-term complications of patients treated with ATG and CSA, with or without G-CSF.
Methods
Design
The design and methodology of the randomized study have been described previously.14 It was an open-label, multicenter randomized study conducted by the Severe Aplastic Anemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Disease severity was assessed with the use of standard criteria and categorized into SAA and very SAA. Patients of any age were included, but patients with congenital SAA, such as Fanconi anemia, as well as patients with hypoplas- tic MDS were excluded. A total of 192 patients with newly diag- nosed SAA, not eligible for SCT, were randomly assigned in a multicenter trial to receive horse ATG and CSA with (49.5%) or without G-CSF (50.5%). Patients randomized to receive G-CSF were given a dose of 150 mg/m2/day from day 8 through day 240 except for subjects who achieved complete remission before. Methylprednisolone (or prednisone) 1 mg/kg/day was adminis- tered on days 1-14. After 14 days, corticosteroids were tapered off over the subsequent 14 days. In the case of serum sickness, a longer tapering schedule, as clinically indicated, was allowed. Complete response was defined as transfusion independency with a hemoglobin level ≥110 g/L, a neutrophil count ≥1.5 x109/L and a platelet count ≥150 x109/L. Partial response was defined as no longer meeting the criterial of SAA and no transfusion dependence for platelets and/or red blood cells. Continuous transfusion dependency was classified as no response. Relapse was defined as a decrease in blood counts to values either requir- ing transfusions or needing re-treatment of the aplastic anemia with immunosuppression or SCT. For late complications, the par- ticipating centers were asked to report the date of first appear- ance of a clonal evolution to a hematologic malignancy (MDS or AML, whichever appeared first; or an isolated cytogenetic abnor- mality), solid cancer, clinical PNH, osteonecrosis and chronic kid- ney disease. The diagnosis of clinical PNH was retained in patients with a measurable PNH clone who developed either thromboembolic complications or active intravascular hemolysis. Chronic kidney disease was defined as persistence of abnormal creatinine or glomerulation filtration rates more than 1 year after randomization. The present analysis included all 192 randomized patients (Table 1). The study was approved by the ethics commit- tee of each center including patients in the study. All patients gave informed written consent to inclusion in the study.
Outcome measures
Given that at the time of first publication 44 of the original 192 patients had died, the follow-up was done for the remaining 148 patients. Endpoints of the present study were OS, EFS, causes of death, and probability of clonal evolution to a hematologic malignancy (including secondary MDS/AML and an isolated cytogenetic abnormality), solid cancer, clinical PNH, relapse, avascular osteonecrosis and chronic kidney disease by 15 years, comparing for each endpoint patients treated with or without G- CSF. Causes of deaths were classified as related to aplastic ane- mia (infection, bleeding, undefined), to secondary neoplasm (MDS, AML, solid cancer), transplantation related in patients who received SCT for treatment failure, unrelated to aplastic anemia, or of unknown cause. We analyzed the risk of osteonecrosis because of the use of steroids,19-21 and of chronic
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haematologica | 2020; 105(5)