Case #4: A 56-year-old male patient was diagnosed with AITL. Standard chemotherapy was consolidated with auto HSCT. Five months after transplantation, enlarged pulmonary LN were noted on routine chest CT, and histopathologic examination showed granulomas consistent with pulmonary sarcoidosis. Oral GC therapy was initiated leading to a remission of pulmonary nodules and LN. After tapering of GC, an increase in size of mediastinal and infradiaphragmal LN was noted, and a repeat biopsy was performed leading to the diagnosis of a relapse of the AITL. An allo HSCT from a MRD with no known history of sarcoidosis was performed. Post allo HSCT, the patient suffered from GC-sensitive cutaneous and intestinal GvHD; no relapse of sarcoidosis was noted.
Overall, we observed symptomatic sarcoidosis in a total of 4 out of 1,065 and 957 patients, who had received allogeneic and autologous stem cell transplantations in the UMG transplantation program, respectively. The disease emerged within a median follow-up observation period of 22 months, resulting in an estimated incidence of 156/100,000 and 58/100,000 for patients at risk after allo and auto HSCT, respectively.
An additional 15 cases of sarcoidosis following HSCT have been reported in the literature, with 5 patients having received an auto HSCT, while 10 had received an allo HSCT. Together with our patients, this translates into a total number of 19 reported cases. Although the total populations of the previously published case reports are unknown, the overall low incidences in the allogeneic transplantation group appear consistent between our cohort and the published data. The patient characteristics are shown in Tables 1 and 2. At our center, we also identified 11 patients with a previous history of clinically apparent sarcoidosis prior to HSCT. None of these patients developed histologically proven symptomatic sarcoidosis following HSCT. Of note, only four patients with sarcoidosis prior to HSCT could be observed beyond the median time of disease emergence of 22 months, with a median post-transplantation observation period of 52 months.
The most frequently reported underlying disease leading to treatment with allo HSCT was lymphoma (n = 7) followed by leukemia (n = 4) and myelodysplastic syndrome (MDS)/myelofibrosis (MF) (n = 3). The reported underlying diseases leading to auto HSCT were breast or testicular cancer (n = 4), as well as polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes (POEMS) syndrome in one patient.
Of the 13 patients who received an allo HSCT, 6 patients were transplanted from a MUD, 6 from a MRD, and in 1 case, the donor status was not reported. Five patients received peripheral blood stem cell donations, five received bone marrow transplant donations, and in three patients, the mode of transplantation was not specified. None of the three donors of our cohort had a history of sarcoidosis, while this was the case in 3 of 10 donors in the cohort of published case studies.
The most frequently applied chemotherapeutic agents in the allo HSCT cohort were busulfan (BU) (n = 8), fludarabine (FLU) (n = 7), and cyclophosphamide (CYC) (n = 5). Two patients each also received alemtuzumab (ALM) or antithymocyte globulin (ATG) as part of the conditioning regimen, respectively. In five patients, chemotherapy had been combined with total body irradiation (TBI). In the autologous cohort carboplatin, etoposide, BEAM, and melphalan were the most frequently applied cytostatic drugs.
All patients had pulmonary sarcoidosis. Most patients showed changes on CT/chest radiographs (15/19; n = 3 unknown [UKN], n = 1 no changes). Involvement of extrapulmonary organs was present in 11/19 patients; the most common organ manifestation was skin followed by liver. Seven of the 13 allo HSCT also had evidence of GvHD; in two patients, the GvHD status was not reported. A response to GC was noted in all patients where they were given (12/19; 2 UKN, 4 asymptomatic, 1 resolution of symptoms after donor lymphocyte infusion [DLI]). No additional immunosuppressive therapies were used. The characteristics of the patients in both groups (allo vs. auto HSCT) are summarized in Table 3.
The HLA status was reported in eight cases. Four of these patients expressed the DRB1*03:01 HLA allele, already known for a strong association with sarcoidosis. Similarly, all other patients also exhibited HLA types known to be associated with sarcoidosis (Tables 1 and 2). Specifically, the allele frequencies of DRB1*03:01 and DQB1*02:01 were higher in our cohort compared to the respective allele frequency in the cohort of all reported patients with sarcoidosis following HSCT (our cohort and published case reports). The allele frequencies for the respective genotypes in this cohort were, in turn, higher than the allele frequency reported in a German and European reference population (Figure 2).
The median age of patients with sarcoidosis after HSCT was 50 years (range 25 to 69 years). The median time to onset of sarcoidosis post HSCT overall was 17 months (range 3 to 120 months), with patients developing sarcoidosis after allo HSCT at a median time of 20 months (range 3 to 30 months) and 7 months (range 3 to 120 months) after auto HSCT (p = 0.5422) (Figure 3A). In patients over 50 years of age, the median time to sarcoidosis after HSCT was 12 months, while it was 21 months in patients younger than 50 years (p = 0.1438) (Figure 3B). Overall, patients were more often female (11 vs. 8) and of Caucasian ethnicity. There were no statistically significant differences between groups. Furthermore, we analyzed the cumulative incidence of sarcoidosis depending on gender, donor status (MRD/MUD), solid vs. hematological neoplasia, and lymphoma vs. leukemia/MDS/MF (Figures 4A-E). Due to the low overall numbers, no statistically significant differences were detected.