DISCUSSION
Given the morbidity associated with AIHA post-transplant and the absence of management guidelines for this rare complication, detailed review of the clinical characteristics, treatment, and outcomes of cases can be a helpful guide to clinical care. In a tertiary care pediatric transplant center, the incidence of AIHA after HSCT was 3.8%. There was a wide range of severity and treatment for the 33 cases identified. Although 3 required intensive care management, 13 patients were managed in the outpatient setting. In addition, this cohort was divided almost equally between patients who were able to be observed on their current therapy without the addition of new AIHA-directed therapy, while the other half required between 1-4 new AIHA-directed pharmacologic therapies added to their regimen.
The patients in the group that did not require new AIHA-directed therapy (17/33, 51.5%) seemed to have an overall milder course. Although many of these patients were still admitted at the time of AIHA diagnosis, it is notable that none of the patients in this group required a new admission or an ICU admission for treatment of AIHA. This group had several distinct characteristics compared with those patients who received AIHA-directed therapy: these patients were more often transplanted for malignant disease and were significantly older at the time of transplant. The onset of AIHA also occurred at an earlier timepoint after HSCT, and these patients tended to have a higher hemoglobin at the time of AIHA diagnosis. Notably, most of these patients were on immunosuppressants at the time of AIHA diagnosis, and these therapies may have protected them from development of more severe AIHA. Previously reported factors associated with the development of autoimmune cytopenias post-transplant include unrelated transplants and non-bone marrow cell sources.[4] In this cohort, most patients had bone marrow as the donor cell source and human leukocyte antigen (HLA) matching at 10 out of 10 alleles. Thus, although the incidence of AIHA was similar to previous reports, the milder course in a large number of patients may also correlate with the bone marrow source and HLA-matching in this cohort.
The patients who required new AIHA-directed pharmacologic therapy (16/33, 48.5%) generally experienced more morbidity. In this cohort, the patients who received second-line therapies or combination therapies were more often transplanted for non-malignant diagnoses, most often primary immune deficiencies. Of those who were not admitted at the onset of AIHA, most required a new admission for management of their AIHA. Although 6 patients were treated with corticosteroid monotherapy, many patients in this group received second-line (or higher) treatment. Other reports have shown efficacy with second-line treatment with rituximab, or third-line treatment with agents such as bortezomib and sirolimus or a second transplant. [1, 8, 12, 13] We saw variable responses to therapies in this cohort, although most patients (66.7%) were in either complete or partial remission at 6 months after AIHA diagnosis.
The immune landscape can be difficult to assess in the post-transplant period, and immune testing is not routinely obtained even in the setting of new autoimmune diagnoses. Lymphocyte subsets were only checked in a small number of cases and, therefore, subanalyses could not be completed. Most patients had whole blood chimerism checked within 1 month before or after diagnosis of AIHA and had full or high mixed chimerism. Given the small numbers but high chimerism, it is not clear whether chimerism status correlates with development of AIHA. This highlights the need for prospective studies in which chimerism, immunoglobulins and lymphocyte subsets are routinely collected to determine whether these findings help to identify features associated with the development of AIHA and direct treatment.
Limitations of the study include the small sample size as well as limited observational lab data given the retrospective nature of this study. This was a single center review of a rare post-transplant complication; multi-institutional cohorts would provide more robust data collection and statistical power. This study identified eligible patients through use of direct antiglobulin testing; patients were only included with a positive test. Up to 10% of patients with AIHA have a negative direct antiglobulin test and therefore the incidence is likely an underestimate.[16, 17] In addition, the diagnosis of AIHA is complex in the post-transplant period, at which time, the etiology for anemia can be multifactorial. Long-term follow up of outcomes after AIHA is challenging due to limited data due to patient death from other causes, second transplants, and other causes for anemia over time.
This cohort included 33 patients with AIHA post-HSCT over a sixteen-year time period at a single institution. Overall, the incidence of AIHA was 3.8% and was significantly higher in patients transplanted for non-malignant diagnoses (7%). The clinical course and management were highly variable and different clinical characteristics were noted in patients with a milder AIHA course. Future collaborative multi-institutional studies with prospective data collection would lead to a better understanding of the pathophysiology of this complication and effective directed treatments to limit exposing patients to unnecessary immunosuppressant medications.