Pediatric aplastic anemia and refractory cytopenia: A retrospective analysis assessing outcomes and histomorphologic predictors

Abstract

Pediatric acquired aplastic anemia (AA) is a bone marrow disorder that is difficult to distinguish from inherited bone marrow failure syndromes and hypocellular refractory cytopenia of childhood (RCC). Historically, patients with hypocellular RCC have been given the diagnosis of AA. To assess the clinical and histologic distinction between RCC and AA, we performed a retrospective analysis of 149 patients previously diagnosed with AA between 1976-2010. We evaluated event free survival (EFS), overall survival (OS), response rates to immunosuppressive therapy, treatment-related toxicities and clonal evolution. The 5-year EFS and OS were 50.8%±5.5% and 73.1%±4.7%, respectively. Patients with very severe AA had worse OS compared to patients with severe and moderately severe AA. Seventy-two patients had diagnostic pathology specimens available for review. Three pediatric hematopathologists reviewed and reclassified these specimens as AA, RCC or Other based on 2008 WHO Criteria. The concordance between pathologists in the diagnosis of AA or RCC was modest. RCC was associated with a trend towards improved OS and EFS and was not prognostic of immunosuppression therapy treatment failure. There was a low rate of clonal evolution exclusively associated with moderately severe AA. Our findings indicate that a diagnosis of RCC is difficult to establish with certainty and does not predict outcomes, calling into question the reproducibility and clinical significance of the RCC classification and warranting further studies.

Loss of B cells and their precursors is the most constant feature of GATA-2 deficiency in childhood myelodysplastic syndrome

“…31,32 Differences between the overlapping categories RCC and AA are a frequent subject of discussion, especially in patients with hypocellular BM and without adverse cytogenetics. The separation of patients into two categories seems to be less relevant because immunosuppressive therapy is indicated for both disease groups, [33][34][35] and there is no difference in prognosis nor in the probability of progression into advanced MDS. 35 We observed significant differences between RCC and AA in a limited number of parameters in BM (decreased in AA: CD34 pos , CD117 pos , granulocytes and erythroid precursors, increased in AA: CD19 pos and lymphocytes).…”

“…The separation of patients into two categories seems to be less relevant because immunosuppressive therapy is indicated for both disease groups, [33][34][35] and there is no difference in prognosis nor in the probability of progression into advanced MDS. 35 We observed significant differences between RCC and AA in a limited number of parameters in BM (decreased in AA: CD34 pos , CD117 pos , granulocytes and erythroid precursors, increased in AA: CD19 pos and lymphocytes). In summary, we found that the disturbances in the B-cell compartment were the strongest distinguishing biological feature of GATA-2 deficiency in childhood MDS, in contrast to other recently published factors, such as monocytopenia, which were less common and unspecific in our study.…”

Myelodysplasia and acute myeloid leukemia fifteen years after high-dose cyclophosphamide in a child with severe aplastic anemia

“…As in our case, most SAA patients lack a suitable donor and, in the absence of IST, mortality is 75% 8 . Currently, a response rate of 44–80% with a three- to five-year survival rate ranging from 81 to 93% for SAA patients immunosuppressed with ATG plus CsA and granulocyte-colony stimulating factor (G-CSF) has been reported 2 . AA patients, however, can have a partial response, fail to respond, relapse, or remain dependent of CsA.…”

“…Treatment with immunosuppressive therapy (IST) for patients who do not have an human leukocyte antigen (HLA)-compatible donor relies on the evidence that a deregulated immune system drives T lymphocytes to cytokine-mediated destruction of their own hematopoietic stem cells 1 . The majority of these patients respond well to up-front administration of IST, including anti-thymocyte globulin (ATG) and cyclosporine (CsA), which is successful in around 80% 2 . Unfortunately, ATG and CsA can lead to clonal disorders, in particular myelodysplastic syndrome (MDS) and paroxysmal nocturnal hemoglobinuria 3 .…”

The current perspective of low-grade myelodysplastic syndrome in children

“…Forester et al [22] performed retrospective analysis of children previously diagnosed with AA and found that histologic diagnosis of RCC did not predict IST failure or clonal evolution. Hama et al also argued that morphological classification (AA, RCC and RCMD) did not correlate with IST response or clonal evolution in the retrospective analysis.…”