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.