Refractory Cytopenia in Childhood Under Watch and Wait Strategy: Safe until Adulthood?
Authors: Drexler Beatrice , Schwarz-Furlan Stephan , Baumann Irith , Rudelius Martina , Noellke Peter , Lebrecht Dirk , Ramamoorthy Senthilkumar , Rotari Natalia , Karow Axel , Hirabayashi Shinsuke , Wlodarski Marcin , Beier Fabian , Behrens Yvonne Lisa , Göhring Gudrun , Kalb Reinhard , Strahm Brigitte , Erlacher Miriam , Niemeyer Charlotte Marie , Yoshimi Ayami 
Published: December 2024

Introduction: Refractory Cytopenia of Childhood (RCC) is a well-recognized type of bone marrow failure in pediatric patients. It is defined by persistent cytopenia, dysplastic changes in at least two hematopoietic lineages or in ≥ 10 % of cells in one lineage, and a characteristic histopathologic pattern with patchy distribution of hematopoiesis, predominance of erythropoiesis with left shift, and significantly reduced granulopoiesis and megakaryopoiesis. In some patients, the bone marrow harbors a truly MDS-defining clone, while in others, it represents a pre- or early malignant state, or is without proof of clonality. An underlying germline predisposition to myeloid neoplasia is recognized in approximately 20% of cases. The majority of patients with RCC undergo hematopoietic stem cell transplantation (HSCT) due to severe cytopenia and/or abnormal karyotype. Other patients are followed by a watch and wait strategy particularly in the absence of a germline predisposition. Here we study the clinical characteristics and long-term outcome of patients with RCC without a genetic predisposition or abnormal karyotype who were subjected to a watch and wait strategy.

Method: We analyzed 101 consecutive pediatric patients (&lt; 18 years) diagnosed with RCC, normal karyotype and absence of genetic predisposition who did neither receive HSCT nor immunosuppressive therapy within 2 years from diagnosis. All patients were enrolled in the German EWOG-MDS registries between 1998 and 2021 with informed consent from parental guardians. The research was approved by the University of Freiburg institutional ethics committee.

Results: The median age at diagnosis of the 55 males and 46 females was 10.1 years (1.4-17.3). The median white blood count was 3.4 G/L, and 12% and 30 % of patients had an absolute neutrophil count &lt; 0.5 G/L and ≥ 1.5 G/L, respectively. Anemia was frequent and the platelet count was &lt; 100 G/L in 74% of patients. The majority of patients (84%) had a hypocellular bone marrow. Patients were followed up till adulthood with a median follow up time of 7 years. Clonal evolution defined by an abnormal karyotype occurred in 3 patients, one of them had disease progression to MDS with excess blasts. In another 3 patients (3%), clinical paroxysmal nocturnal hemolysis (PNH) developed. Nine patients (9%) received allogeneic hematopoietic stem cell transplantation (HSCT) during the clinical course for clonal evolution (n=1), PNH (n=2) or cytopenia (n=6). All patients were alive at last follow up. Five and 10 years HSCT-free survival was 94% and 83%, respectively. Most of the patients had persistent cytopenia and/or elevated MCV over the course of disease. At last follow-up, in 15 patients without HSCT (16%) normal blood counts and a normal MCV was documented.

Conclusions: Our results indicate that in the absence of a known predisposition syndrome, pediatric patients with RCC and a normal karyotype can safely be managed by a watch and wait strategy unless transfusion dependency or severe neutropenia require HSCT. The persistence of cytopenia during the disease course in the vast majority of patients suggests that the RCC histopathology is the morphological phenotype of an intrinsic bone marrow defect. Furthermore, it emphasizes the need for a structured transition from pediatric to adult hematology to offer the affected patients long-term clinical surveillance.