Allogeneic stem cell transplantation for acquired pure red cell aplasia
Authors: Constantijn Halkes, Liesbeth C de Wreede, Cora Knol, Célestine Simand, Mahmoud Aljurf, Abdelghani Tbakhi, Lourdes Vazquez, Adrian Bloor, Eva Wagner‐Drouet, Filiz Vural, Ivana Bodova, Cecilia Isaksson, Miguel Ángel Diaz, Bernd Gruhn, John Snowden, Mutlu Arat, Ali Bazarbachi, Chloé Spilleboudt, Alexander Kulagin, Judith CW Marsh, Jakob Passweg, Antonio M. Risitano, Regis Peffault de Latour, Carlo Dufour
Journal: American Journal of Hematology (2019)

Pure red cell aplasia (PRCA) is a rare disease characterized by a normocytic anemia with reticulocytopenia.1 Acquired PRCA can be idiopathic or can occur in the context of other disorders. Idiopathic PRCA is supposed to be an autoimmune disorder and thus can be treated with immunosuppressive therapy (IST). Treatment with different immune suppressive drugs leads to transfusion independency in the majority of patients.1-3 Refractoriness to IST and relapse after successful IST are associated to a decreased overall survival.3 Allogeneic hematopoietic stem cell transplantation (alloHSCT) has been described as a successful treatment option for patients without lasting response after IST in several case reports.4 However there are no long-term cohort data on outcomes after alloHSCT. It is a given that patients with refractory PRCA can be managed as a chronic disease albeit with non-curative supportive care options. Thus individual clinical decision making in relation to alloHSCT should be a balance of safety and long-term outcomes. To help inform such decision making the Severe Aplastic Anemia Working Party (SAA-WP) of the European Society for Blood and Marrow Transplantation (EBMT) evaluated the outcome of alloHSCT in an EBMT-registry based cohort of adult patients with acquired PRCA. This retrospective multicentre study was coordinated by the EBMT Data Office in Leiden, the Netherlands (see Appendix S1 for supplemental methods). Patients who underwent a first alloHSCT between 2000 and 2015 for acquired PRCA after failure of previous IST were included. Patients in whom the diagnosis of PRCA was made before the age of 12 years were not included in this analysis, to formally exclude patients with a congenital PRCA. The database was closed in June 2017. Overall survivial (OS) was calculated from the date of alloHSCT to the date of last follow-up or to the date of death from any cause. Event-free survival (EFS) was calculated from the date of alloHSCT to the date of second transplant or death, with patients without an event censored at the last follow-up date. OS and EFS probabilities were estimated by the Kaplan-Meier method. From 2000 to 2015, 33 adult patients with acquired PRCA underwent HSCT. Median age at diagnosis was 34 years (range 12-54) and median age at time of alloHSCT was 37 years (range 18-66). Details on stem cell source, donor type and conditioning regimens are described in Table S1. Participating centers provided supplementary data on previous treatment for PRCA for 15 patients, who received a median number of 3 treatments before alloHSCT (range 1-7). Fourteen patients had been treated with cyclosporine A, nine patients had been treated with ATG and two patients had been treated with cyclophosphamide as immunosuppressive treatment for PRCA. After 1 and 5 years EFS in all 33 patients was 49% (95% confidence interval [CI] 31-67%), and 40% (95% CI 22-58%), respectively. Five patients needed a second transplantation after graft failure at one, two, four (two patients) and 39 months after he first alloHSCT. Of these five patients, two patients died (1 day and 3 months after the second transplantation, respectively). The OS of the total cohort was 55% (95%CI 37-73%) and 51% (95%CI 33-69%) at one and 5 years, respectively (Figure 1). During the follow-up period, 15 patients died. The causes of death were infection in eight patients (53%), GVHD in five patients (33%), multiple organ failure in one and unknown in one patient. A subgroup of eight patients was transplanted using an acquired aplastic anemia alloHSCT strategy. Bone marrow was a source of hematopoietic stem cells, and cyclophosphamide with in-vivo T cell depletion using ATG or alemtuzumab was the conditioning regimen). In this group five-year OS and EFS were 75% (95%CI 45-100%) and 47% (95%CI 10-83%), respectively. Our data confirm that alloHSCT is a potentially curative treatment option for patients with acquired PRCA who are refractory to IST. However, the five-year OS rate of 51% is disappointing, and should be balanced against possible outcomes of supportive care. This consists of red blood cell transfusions and effective chelation therapy, which are safer options, albeit non-curative, and with a considerable long term impact on quality of life. As only erythropoiesis is affected in PRCA, replacement of the hematopoietic system by an alloHSCT might have been expected to lead to more favorable outcomes as has been reported for alloHSCT in patients, with hemoglobinopaties sharing the multiple blood transfusions before transplantation as risk factor for graft failure.5 However, the supposed underlying auto-immune mechanism in idiopathic PRCA may have been a factor leading to an increased rate of graft failure. With a median age of 37 years at alloHSCT, the patients in our cohort represent a relatively young group of patients, as the mean age at diagnosis of patients with acquired PRCA is 60 years.3 In the light of this relatively young age, overall outcome with an EFS at 5 years of 40% is not very encouraging, although three of the five patients with graft failure were rescued by a second transplantation. The cause of death was an infection in eight patients, possibly explained by the fact that most of the patients had received several courses of immune suppressive treatment before alloHSCT. Another deleterious factor leading to the high non relapse mortality in this patient group could be the iron overload caused by multiple blood transfusions. We were not able to collect data on the number of blood transfusions or ferritin levels at time of the alloHSCT. However, all patients had refractory PRCA and the mean time between diagnosis and alloHSCT was 3.7 years, so it is reasonable to assume a heavy transfusion history. The cause of death in five patients was GVHD. There is no need for an immunological "graft versus malignancy" effect for patients with a non-malignant disease like PRCA. So, an important aim of the transplantation strategy should be to minimize GVHD by using in-vivo T cell depletion, graft manipulation or post transplantation interventions. Limited data were available about the safety or efficacy of these different strategies for PRCA in our analysis. The subgroup of PRCA patients receiving bone marrow derived stem cells, and as conditioning regimen cyclophosphamide with in-vivo T cell depletion (which is the preferred conditioning regimen in aplastic anemia patients6) had a 5 year OS of 75%. Despite a selection bias for this subgroup which can have played a role in the positive outcome, it is reasonable to use this conditioning regimen in young patients with PRCA. By strong immune suppression of the patient and the use of bone marrow stem cells, this conditioning regimen maximally aims to decrease the risk of graft failure and GVHD occurrence, and can be used in patients up to 40 to 50 years. These findings mirror current literature and recommendations for transplant technique for alloHSCT in acquired aplastic anemia (AA), which shares similar risk factors for graft failure, GVHD and NRM with acquired PRCA, such as transfusion history and preceding immune suppressive treatment. In conclusion, alloHSCT is a potentially curative treatment option for patients with acquired PRCA without enduring response to IST but has a considerable risk of graft failure and infectious complications which should be taken into account. Given that patients with refractory PRCA can be managed as a chronic disease with albeit non-curative supportive care options, clinical decision making in relation to alloHSCT should be a careful balance of safety and long-term outcomes. Recommendations for transplant technique for alloHSCT for AA patients could be considered in PRCA patients to minimize graft failure, GVHD and other complications. Further studies are clearly warranted to define the role and transplant techniques of alloHSCT in acquired PRCA. The rarity of acquired PRCA probably precludes prospective clinical trials, but retrospective or prospective studies using the EBMT or other large registry would be useful, especially if data from both transplanted and non-transplanted patients could be compared. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.