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Editorials
tions either for ongoing analysis as their data set contin- ues to expand and mature or as hypotheses to be tested in prospective studies.
A practical outcome of this consortium analysis is a real-world assessment of the applicability of the modified Camitta criteria for AA diagnosis first described in 1976.3 These diagnostic criteria are still recommended by inter- national guidelines for assessment of AA severity.4 In these criteria, in addition to the depth of marrow hypocellularity and peripheral blood cytopenias, a reticu- locyte count is required both as a diagnostic criterion for AA and also to assist with severity classification. However, in a prior analysis by the NAPAAC, it was established that reticulocyte values substantially vary between institutions, making their inclusion in diagnostic criteria uncertain.2 To address this conundrum, Rogers et al. offer the interesting observation from their data set of a lack of correlation between hemoglobin and reticulo- cyte count in their pediatric cohort at the time of diagno- sis, and suggest that hemoglobin may be a more accurate and clinically relevant parameter on which to base man- agement decisions. Whilst the Camitta criteria have stood the test of time, and their use is a strong recommenda- tion, some of their elements are based on relatively low quality C level source data.4 The findings outlined in the Rogers et al. paper re-iterate the importance of ongoing review and modification of diagnostic criteria as new data sets, such as that collated by the NAPAAC, come to hand.
Similarly, collation and description by co-operative groups of current patterns of clinical practice and the degree of its adherence to consensus guideline is an important element of continued improvement in prac- tice, particularly for rare conditions where individual institutional experience may be limited. Currently, one of the most widely accepted management decisions in the treatment of young patients with AA is to offer HCT in patients aged under 40 years with an HLA matched sib- ling donor (MSD).4-7 For those without a MSD, IST with anti-thymocyte globulin (ATG), most commonly horse- derived, in combination with cyclosporine is used as ini- tial therapy with HCT from unrelated donors (UD) reserved for those who do not respond or who relapse after IST. Of the cohort outlined in the Rogers et al. analy- sis, the majority of HCT undertaken as second-line ther- apy utilized UD, indicating the lack of a MSD for upfront use, and in those who eventually received second-line HSCT from a MSD, it is unclear why this donor was not used in the upfront setting. This particular question may be answerable in future analyses by the NAPAAC.
The Rogers et al. analysis demonstrated a striking dif- ference in outcome following IST in pediatric patients compared to that in a historical cohort of adult patients. While complete response (CR) was only seen in 10% of adults treated with IST,8 the pediatric cohort showed CR rates of nearly 60%. Despite this excellent response rate, a pattern of continual events, including death, relapse or transformation to hematologic malignancy following IST, resulted in a disappointing 5-year event-free survival (EFS) of 62%, similar to the findings showing by Yoshida et al.6 The finding of a continued pattern of events even after apparent successful therapy with IST further rein-
forces the view that normalization of peripheral blood parameters and marrow cellularity after immunosuppres- sion does not imply normalization of hematopoietic clon- ality and/or immunological repertoire, and, as a conse- quence, the once-aplastic marrow remains at ongoing risk of recurrent aplasia, clonal evolution, and/or malignant transformation (Figure 1).
This description of the patterns of response and subse- quent relapse (or other event) in pediatric AA raises at least three important questions. Firstly, what is the most appropriate salvage therapy for those patients relapsing after initial IST? Secondly, given the high rate of relapse/events, should HCT from any matched donor be considered as front-line therapy in children? Thirdly, are there better biomarkers under development that might provide greater guidance in the choice between these treatment options? With regards to the first question, the Rogers et al. paper provides clear guidance. Re-treatment was required in 35%, and second-line therapy with an allogeneic HCT offered superior EFS to pursuing a second course of IST. These combined findings of unstable responses to IST, and the high rate of durable responses to HCT, contribute to the evolving debate as to whether HCT from any matched donor (related or unrelated) is preferable over IST as initial therapy for pediatric patients with proven AA. This question is clearly best answered in a randomized clinical trial, although such an undertaking would require a long-term commitment for feasible accrual and is only likely to succeed through consortia such as the NAPAAC. Lastly, biomarker development is critically required to more accurately determine the degree of clonal restriction (and therefore risk of clonal progression) and/or ongoing potential for immunological attack (and therefore post-IST relapse) to help determine whether IST or HCT should be offered as initial therapy. Clearly, in studies where restricted clonality is evident through genomic or cytogenetic analysis, poorer out- comes to IST are seen, indicating that with more sensitive techniques directed at assessment of the stem cell pool, more informed therapeutic decisions should follow.9 Again, it is likely that only through the co-ordinated efforts of consortia will sufficient biomarker samples be accumulated to begin to address this unmet need.
One clear determinant of clinical outcome from what- ever therapy is chosen is the certainty with which the diagnosis is made. Increasingly, there is an appreciation that occult constitutional bone marrow failure syndromes may underlie what is thought to be a presentation of idio- pathic AA, with significant implications for patient man- agement. Through the increasingly readily available tech- niques for telomere length assessment10 and next genera- tion sequencing for assessment of underlying germline lesions11 reclassification of many cases of AA is likely both during the prospective work up of new cases and retrospectively from archival diagnostic samples, which will further inform future treatment algorithms. As a greater clinical appreciation of the importance of diagnos- tic certainly has been met with greater diagnostic techni- cal capacity, consensus recommendations increasingly incorporate evaluation of constitutional syndromes by chromosomal fragility testing in all AA patients present- ing at younger than 50 years of age. Telomere length
haematologica | 2019; 104(10)
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