Sarcoidosis following Hematopoietic Stem Cell Transplantation:  clinical characteristics and HLA associations

doi:10.21203/rs.3.rs-734177/v1

Purpose:

Extrinsic factors and genetic predisposition contribute to the etiology of sarcoidosis, converging in a phenotype of altered immune response associated with multisystemic inflammatory granulomatous tissue infiltration. Immunological reconstitution after hematopoietic stem cell transplantation (HSCT) may represent a unique window for the pathogenesis of the disease. We describe the incidence, clinicopathological features, and HLA associations of sarcoidosis after HSCT in a single-center cohort of patients, together with data from previously published cases.

Methods:

We retrospectively analyzed clinical characteristics and HLA haplotypes from allogeneic (allo) or autologous (auto) HSCT patients from January 2001 through May 2021 at the University Medicine Goettingen (UMG), and data from 15 previously published cases.

Results:

13 patients had received an allo HSCT, and six patients an auto HSCT, including four at our center (three allo HSCT, one auto HSCT). Sarcoidosis occurred after a median interval of 20 and 7 months, respectively. The predominant HLA allele associated with sarcoidosis was HLA DRB1*03:01. Sarcoidosis involved the respiratory tract in 15 patients (three unknown, one without pulmonary involvement), and it was associated with graft-versus-host disease in seven of 13 patients receiving allo HSCT. None of the donors or patients had a history of sarcoidosis before transplantation. Disease manifestations resolved by standard glucocorticoid treatment without long-term sequelae.

Conclusion:

Sarcoidosis may occur at low frequency during reconstitution of the immune system after HSCT. HLA allele associations reflect the associations observed in the general population, particularly with DRB1*03:01. Further insights into the interplay between T cell reconstitution and the development of sarcoidosis could also provide novel approaches to an improved understanding of the pathogenesis in sarcoidosis.

Hematology

Rheumatology

Sarcoidosis

hematopoietic stem cell transplantation

bone marrow transplantation

sarcoidosis

antigen HLA-DRB1

HLA

Sarcoidosis is a multisystemic inflammatory disease characterized by noncaseating granulomas, consisting of CD4⁺ T cells and macrophages surrounded by CD8⁺ T cells [1]. It frequently affects lungs and lymph nodes but may involve any organ [2]. Aberrant interactions of T-cells, monocytes, and macrophages after exposure to triggering factors, e. g. (in)organic particles or antigens from infectious agents may contribute to the pathogenic process [2, 3]. Genetic susceptibility for sarcoidosis was found associated with distinct human leukocyte antigen (HLA) types, as detected by genome-wide association studies [4, 5]. In particular, genetic variants in HLA-DRB1 located in the MHC class II region and the HLA class I antigens A1 and B8 have been implicated with an increased risk of disease [6–8].

While DRB1 alleles, such as *03:01 and *03:02, can confer protection against chronic disease [8, 9], HLA DRB1*14 and DRB1*15 are associated with chronic sarcoidosis [2]. HLA types implicated in the development of sarcoidosis depending on ethnicity are, among others, HLA-B51 [10], DQB1*02:01[11], DRB1*03:01 [12, 13], DRB1 *11:01 [13, 14], and DRB1*15:01 [12, 14]. An association between sarcoidosis and hematologic malignancies has been observed, documenting sarcoidosis occurring before, during, or after the diagnosis of lymphoma [15–17]. Sarcoidosis in the context of hematopoietic stem cell transplantation (HSCT) has been reported rarely [18].

In this study, we determined the incidence and characteristics of sarcoidosis following allogeneic (allo) and autologous (auto) HSCT in a cohort of consecutive patients in the context of findings with previously reported patient data, aiming at a comprehensive clinicopathological view at this rare condition.

Patient population and setting

We retrospectively searched our database for sarcoidosis disease following HSCT in all patients who underwent HSCT between January 2001 and May 2021, with a particular interest in the patients’ and donors’ HLA status and disease manifestations, chemotherapeutic regimens, sarcoidosis manifestations, and overall outcome. The ethics committee of the University Medical Center Göttingen (UMG) approved the study protocol (protocol number 30/6/21).

Review of the literature

Case reports and case series describing sarcoidosis following HSCT were searched using the MeSH terms “stem cell transplantation” and “sarcoidosis” in Medline/Pubmed. Gender, ethnicity, hematologic disease, prior history of sarcoidosis in the donor, remission status before HSCT, donor type, HLA status, conditioning regimen, interval to the onset of sarcoidosis after HSCT, imaging findings, pulmonary function tests (PFTs), involvement of non-pulmonary organs, evidence of graft-versus-host disease (GvHD), and response to glucocorticoids (GC) were extracted from the identified case reports or case series, when available.

HLA genotyping

High-resolution HLA typing was performed by sequence-based typing (SeCore SBT sequencing kits, One Lambda, West Hills, CA, USA) according to the standards for histocompatibility & immunogenetics testing of the European Federation for Immunogenetics (EFI) [19]. All ten HLA loci relevant for transplantation were characterized in the UMG cohort (HLA-A, -B, -C, - DRB1, -DQB1). Furthermore, HLA-DPB1 was characterized in two out of three UMG patients receiving a matched unrelated donor (MUD) transplantation. Phenotypes and genotypes are reported as recommended by the WHO Nomenclature Committee for Factors of the HLA System, using four digits in the UMG cohort. HLA phenotypes and genotypes of patients previously reported in the literature are reported as stated in the original publication.

Statistical analysis

Data collection and analysis was performed employing Microsoft Excel® (Version 16.48, Microsoft Corporation, Redmond, WA, USA) and Graphpad Prism® Version 9.1 (GraphPad Software, San Diego, CA, USA). Contingency tables and Fisher’s exact test as well as unpaired, two-tailed Student’s t-test were used for data analysis, as appropriate. P-values < 0.05 were considered significant, and p-values < 0.15 indicating trends worth reporting. Time to onset of disease (cumulative incidence) was calculated using Kaplan-Meier-Analysis (Log-rank test). The cut-off for age as criterion for the onset of sarcoidosis was calculated using the software X-tile (X-tile, New Haven, Connecticut, USA). Allele frequencies of HLA alleles were calculated via direct counting (number of observations for a given allele divided by the number of haplotypes (2 n, where n = sample size) and the HLA allele frequencies in Germany and Europe (Population 3,6,8) were stated as found in the classical allele frequency search [20]

Of a total number of 2022 patients who underwent HSCT from 2001 to 2021, four patients from our center and 15 patients reported in the literature were included for further analysis. The patient flow is depicted in Figure 1.

Sarcoidosis following HSCT in four patients

Case #1: A 35-year-old male patient without a history of sarcoidosis diagnosed with primary mediastinal B-cell lymphoma received an allo HSCT from a MUD (also without a history of sarcoidosis), leading to a complete remission (CR) without evidence of GvHD. Thirty months later enlarged pulmonary lymph nodes (LN) and ground glass opacities were noted on chest computed tomography (CT). A LN biopsy showed non-necrotizing granulomas, consistent with a diagnosis of sarcoidosis. Pulmonary function tests showed a reduced diffusion capacity for carbon monoxide (DLCO/SB) and forced vital capacity (FVC), compatible with a restrictive pattern. As the patient remained asymptomatic no specific treatment was initiated. A subsequent CT showed spontaneous regression of the pulmonary changes after six months.

Case #2: A 65-year-old male patient diagnosed with angioimmunoblastic T-cell lymphoma (AITL) received an allo HSCT from a MUD with no known history of sarcoidosis leading to a CR without evidence of GvHD. Eighteen months after HSCT the patient reported dyspnea and had a restrictive pattern on PFT. A chest CT showed basal consolidations and enlarged mediastinal LN. A bronchoalveolar lavage (BAL) showed non-specific inflammation without findings suggestive of sarcoidosis. Two months later, non-caseating granulomas consistent with sarcoidosis were histologically diagnosed after biopsy of a pulmonary lesion, and the patient was started on GC therapy with a tapering regimen, eliciting a good clinical response.

Case #3: A 56-year-old male patient diagnosed with acute myelogenous leukemia (M5) received an allo HSCT from a matched related donor (MRD) without a history of sarcoidosis. Subsequently, the patient suffered from cutaneous, hepatic, and intestinal GvHD. Twenty-four months after allo HSCT the patient complained of acute abdominal and thoracic pain, which was interpreted as post-herpetic neuralgia and side effects of gastrointestinal GvHD. A chest and abdominal CT showed bilateral hilar lymphadenopathy, intrapulmonary nodules, and prominent abdominal lymph nodes. Sarcoidosis was diagnosed following biopsy of a hilar LN, and, as the patient was asymptomatic, a watch-and-wait strategy was employed. However, in the following months the patient complained of arthralgias with shoulder pain, morning stiffness in the fingers and elbows as well as shortness of breath following moderate physical exertion. Therefore, a GC regimen with concomitant non-steroidal antirheumatic drugs was initiated with good clinical regression of symptoms.

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.

Patient characteristics

Overall, we observed symptomatic sarcoidosis in a total of four out of 1065 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 five patients having received an auto HSCT [18,21,22], while ten had received an allo HSCT [18,23–30]. 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 eleven 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.

Underlying disease in 19 patients who developed sarcoidosis after stem cell transplantation

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.

Donor status

Of the 13 patients who received an allo HSCT, six patients were transplanted from a MUD, six from a MRD, and in one 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 three of ten donors in the cohort of published case studies [23–25].

Types of chemotherapy

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.

Clinical characteristics

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.

HLA genotypes in association with sarcoidosis and HSCT

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 [20] (Figure 2).

Cumulative incidence of post-HSCT sarcoidosis

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 versus 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 versus hematological neoplasia, and lymphoma versus leukemia/MDS/MF (Figure 4A-E). Due to the low overall numbers, no statistically significant differences were detected.

Symptomatic sarcoidosis after hematopoietic stem cell transplantation represents a rare condition, and we here provide an estimate of incidences in the autologous and allogeneic transplantation setting and its clinical characteristics. Sarcoidosis post HSCT occurred in patients receiving both allogeneic and autologous stem cell transplantations at a ratio of 3:1, both in the UMG and the previously published patients. The increased frequency of sarcoidosis after allogeneic transplantation is compatible with the strong activation of the immune system upon engraftment in these patients. This observation suggests that a preformed immunological reaction may occur with increasing immunological competence of the T-cell repertoire and/or antigen presenting cells. This notion is further supported by the HLA allele associations observed for sarcoidosis post HSCT, which reiterates the associations described for sporadic sarcoidosis [2, 8–14] (Table 1). While the antigen(s) triggering sarcoidosis still remain elusive, our observations were best compatible with a minor self-antigen or a preexisting viral antigen, which is represented to the newly engrafted immune system in an HLA allele associated efficacy to elicit the sarcoidosis-type reaction in the post transplantation period (median time of 17 months, 20 months after allo HSCT, seven months after auto HSCT).

Seven of 13 patients with sarcoidosis post allogeneic HSCT also developed acute or chronic GvHD in the post-transplantation follow-up. Dependent on the precise transplantation setting, approximately 60% of patients develop GvHD after allo HSCT. Thus, our data do not support an association of sarcoidosis and GvHD, albeit this is limited by the small patient numbers.

Immunologically, granuloma formation is initiated by an interaction between CD4 + T cells and antigen presenting cells (APCs), such as macrophages or dendritic cells via HLA class II antigen-peptide complex leading to T cell activation, differentiation into Th1 cells, secretion of interleukin (IL)-2 and interferon (IFN)-g, and augmented macrophage tumor necrosis factor (TNF)-a production, resulting in immune response amplification [31–33]. After granuloma formation, there are two possible outcomes: Granuloma formation can either resolve, if the peptide antigens are presented by HLA-DR3 molecules on dendritic cells or macrophages and subsequently recognized by T cells leading to the release of a range of cytokines, or persistent granulomatous inflammation with subsequent tissue damage requiring immunosuppressive therapy [32]. The latter is thought to occur if the antigen recognition is inefficient and can be due to peptides displayed by molecules other than HLA-DRB1*03 (HLA-DR3) or T cells that are not capable of generating efficient T cell clones [34].

Two agents that interfere with both T cell and dendritic cell (DC) mediated immunity, which is necessary for the resolution of sarcoid granulomas, are ATG and ALM. Two of our allo HSCT patients received ATG, while its was not reported in any of the case reports. ATG, a polyclonal antibody, is used to prevent GvHD and suppress allograft rejection. Owing to its polyclonality, there are diverse effects of ATG on the immune system, among them T cell depletion, modulation of leukocyte/endothelial interactions, apoptosis in B cells, interference with DC function and the induction of regulatory T and natural killer (NK) T cells [35]. So far there have been no reported cases linking sarcoidosis to ATG treatment.

Alemtuzumab, however, has been associated with the development of sarcoidosis and there are several case reports describing the occurrence of sarcoidosis post ALM treatment in multiple sclerosis patients [36–38]. While the exact mechanism by which ALM triggers sarcoidosis is not yet known, a dysregulation in the Th1/Tc1 cell/IFN-γ network and the development of autoantibodies by dysregulated B cells has been postulated [39]. The immune dysregulatory effects of ATG and ALM could play a role in the development of sarcoidosis in the post HSCT setting, however, taking into account the heterogenous usage of ATG and ALM in the reported patients, no clear causal link can be inferred.

Different hypotheses have been proposed, aiming to explain the pathogenesis of sarcoidosis after malignancy: Firstly, it has been postulated that sarcoidosis develops as a reaction to the immunosuppressive effect of chemotherapies or to a specific chemotherapy agent, such as bleomycin, known to achieve high concentrations in LN, skin and lung tissue [40].

Secondly, Brincker et al. hypothesized that the appearance of sarcoidosis post malignancy may be driven by antigens derived from tumor cells leading to immunological events resulting in granuloma formation [41]. Thirdly, Kornacker et al. suggested that underlying immunologic disturbances associated with the primary malignancy may lead to the formation of epithelioid granulomas [42].

In three patients the occurrence of sarcoidosis has been reported after possible transmission from the donor [23–25]. The data from our patient cohort do not support an increased risk of transmission, as none of our patients was transplanted from a donor with a previous history of sarcoidosis, and vice-versa, none of the patients with sarcoidosis in their pre-transplant medical history experienced sarcoidosis recurrence.

The immunological environment post HSCT, similar to that present in sarcoidosis pathogenesis outside of the context of HSCT, could promote the development of sarcoidosis, especially in a genetically susceptible individual with a specific HLA allele. The reported disease pathogenesis and potentially triggering factors are summarized in Fig. 5: Before HSCT, the conditioning regimen as well as underlying disease damage of host tissues induce pro-inflammatory cytokines such as TNF-a, chemokines, and costimulatory molecules on host APCs. Following HSCT, donor T cells proliferate and differentiate in response to activated host APCs, then expressing IFN-g, IL-2 and TNF-a, leading to T cell expansion and differentiation into Th1 vs Th2 subtypes [43, 44]. This is followed by an increase in the number of suppressor/cytotoxic lymphocytes and then of helper-inducer phenotype T cells, thereby inverting CD4+/CD8 + ratios. A normalization of CD4+/CD8 + T cell ratios takes place around one to two years after HSCT [45, 46] with a longer time-span in older patients, whose thymic function is less pronounced.

During immune reconstitution higher levels of cytokines such as MCP-1, CCR1, CCR2, IL-8, and Rantes are present, leading to a tissue environment promoting the formation of non-necrotizing epithelioid granulomas [47–49].

All allogenously transplanted patients reported previously, including those in our cohort, developed sarcoidosis after complete donor engraftment of their bone marrow, suggesting that the development of sarcoidosis in these circumstances was initiated by the donor immune system. Interestingly, it has been shown that individuals with a HLA-B8/DR3 phenotype produce higher amounts of TNF-a compared to their IFN-g generation potential [50], making them susceptible to humoral hyperreactivity and anergy under an environmental stress.

The older age and shorter time to the onset of sarcoidosis post HSCT of the analyzed patients compared to the normal population might be explained with the progressive involution of thymic tissue during ageing with a decline in T cell output and T cell senescence with restricted T cell receptor repertoire diversity, leading to a slower immune reconstitution and impaired immune responses following transplantation [46]. However, a bias that patients with malignancies, especially lymphomas, are generally older must be considered.

The occurrence of extrapulmonary manifestations of sarcoidosis in patients with leukemia, MDS and MF compared to lymphoma patients has been linked to malignant antigens as a sarcoidosis trigger in leukemic diseases [41]. While the remission status prior to HSCT of most reported patients in the literature is unknown, sarcoidosis in our cohort patients occurred exclusively in patients with complete disease remissions, rendering a malignant antigenic trigger for sarcoidosis unlikely. Specific chemotherapeutic agents, such as bleomycin, have been hypothesized to trigger sarcoidosis. Interestingly, the majority of the allo HSCT patients received a regimen including BU, FLU, and CYC. There have been no reports implicating FLU and BU in the formation of sarcoidosis, CYC has been used previously in the treatment of severe cardiac or neurosarcoidosis [51]. TBI is known to lead to a delayed immune reconstitution [46].

Our study has several limitations. First, sarcoidosis post HSCT is a rarely reported event, although based on observations by Bhagat et al. [18] and the prevalence in our cohort of HSCT patients, the occurrence in HSCT might be higher than previously estimated. Also, the number of patients with accesible data for analysis was limited and the small number of cases may influence trends we observed in sub-groups during data analysis. Furthermore, multicentric analyses in additional cohorts may gain more granular insights into the prevalence, potential triggers, and the pathogenesis of sarcoidosis post HSCT. Nevertheless, our report has several strengths: To our knowledge, this report represents the most comprehensive analysis from a single center in comparison with previously published data. The strong HLA association reported and corroborated by our data suggest that sarcoidosis occurrence in this vulnerable population is influenced by a genetic predisposition requiring additional immunological events in the context of HSCT.

Based on the 2022 HSCT patients that have been treated at our institution over a 20-year span and 4 cases of sarcoidosis occurring therein, we estimate the incidence at 156 and 58 cases per 100,000 for allo and auto HSCT, respectively, which is higher than reported by Bhagat et al. [18] and higher than reported in the general German population [52]. Further insights into the interplay between T cell reconstitution and the formation of sarcoidosis may provide further insight into the overall pathogenesis of sarcoidosis.

Author contributions

RW-K and PK designed the study. Material preparation, data collection and analysis were performed by RW-K, JB, JK, NS, GW, and PK. JH and WJ treated patients and edited the manuscript. The figures were created by RW-K and PK. The first draft of the manuscript was written by RW-K, all authors edited the manuscript and approved the final version of the manuscript.

Conflicts of interest:

The authors report no conflicts of interest related to this paper.

Funding statement

No specific funding was obtained for this study.

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Table 1. Summary of sarcoidosis patient characteristics after allogenous HSCT.

Patient Number

PARAMETER

#1

#2

#3

#4

[23]

#5

[24]

#6

[25]

#7

[26]

#8

[18]

#9

[27]

#10

[27]

#11

[28]

#12

[29]

#13

[30]

Age*/Gender

39 M

69 M

59 M

34 M

38 F

37 F

55 F

52 F

46 F

52 M

48 M

65 F

58 F

Ethnicity

C

UKN

A

C

A

UKN

Diagnosis

PMBL

AITL

AML

NHL

LBL

CML

FL

CML

MDS

CMML

ATL

MF

History of Sarcoidosis in donor

N

Y

N

UKN

N

Remission status prior to HSCT

PR

CR

UKN

CR

Relapse

UKN

MR

UKN

Donor Type

MUD

MRD

MUD

UKN

MUD

MRD

MUD

MRD

HLA Status^#

A: 0201 B:

1501,4001 C:

0304

DR:

0301,

0901

DQ:

0201,0303

DP:

0401

A: 0101,0201 B:

4002,5101

C:

0202,1502 DR:

1101;

DQ:

0301

DP:

0401

A*: 01:01/.

B* 07:02/

08:01

C* 07:01/

07:02 DRB1* 03:01/

15:01 DQB1* 02:01/

06:02

A1, A2,

B8, B51, DR4, DR4

A(1,26); B(8,49); Bw(4,6); Cw (7,-); DRß1*03011; DRß1*1302

A-24(9) B-8 52(5) C-7 16; DR-17(3) 18(3) DQ-2 4

DP-

UKN

A*0101, A*2501, B*0801, B*1801, DRB1*0301, DRB1*1501, DQB1*0201, DQB1*0602

UKN

A*0301, B*0702, B*5501, C*0702, C*0304, DRB1* 1301, DRB1* 1501, DQB1*0602

Conditioning Regimen

FLU BU CYC

-ATG

FLU BU CYC

-ATG

FLU BU

UKN

TBI, Eto

TBI, CYC

TBI, FLU BU

TBI, CYC

FLU BU Alem

BU CP

TBI, FLU BU

UKN

Sarcoidosis Dx post HCT (months)

30

20

24

3

17

21

6

12

20

22

16

27

Chest CT/ rADIOGRAPHIC changes

Y

UKN

Y

N

Y

UKN

Abnormal PFT

Y

UKN

Y

UKN

Non-pulmonary organs involved

N

MSK

Liver

N

Bone marrow

N

Skin, Liver

Liver

Skin

Evidence of GVHD

N

Y

N

Y

UKN

Y

Response to GC

UKN

Y

Resolution after DLI

Asymp, nt

Y

Asymp, nt

UKN

Abbreviations: A, Asian; AA, African American; AITL, Angioimmunoblastic T-cell Lymphoma; Alem, alemtuzumab; AML, acute myelogenous leukemia; Asymp, asymptomatic; ATL, Adult T-cell leukemia; BU, busulfan; C, Caucasian; CML, chronic myelogenous leukemia; CMML, Chronic myelomonocytic leukemia; CYC, cyclophosphamide; DLCO, Diffusion Capacity for Carbon Monoxide; Dx, diagnosis; Eto, etoposide; F, female; FL, follicular lymphoma; FLU, fludarabine; GC, glucocorticoids; HLA, human leukocyte antigen; LBL, Large B-cell Lymphoma; M, male; MDS, myelodysplastic syndrome; MF, myelofibrosis; MR, minimal response; MRD, matched related donor; MSK, musculoskeletal system; MUD, matched unrelated donor; N, no/none; NHL, non-Hodgkin lymphoma; nt, no treatment; PFTs, pulmonary function tests; PMBL, Primary mediastinal B cell Lymphoma; TBI, total body irradiation; UKN, unknown; VC, vital capacity; Y, yes. *Age at diagnosis of sarcoidosis; ^#HLA status with known association to sarcoidosis reported in bold

Table 2. Summary of sarcoidosis patient characteristics after autologous HSCT.

	PATIENT NUMBER
*Parameter*	#1 (#4 of our cohort)	#2 [18]	#3 [18]	#4 [18]	#5 [21]	#6 [22]
*Age/Gender**	60 M	50 F	47 F	48 F	62 F	25 M
Ethnicity	C	AA	C	C	UK	UK
Diagnosis	AITL	Breast	Breast	Breast	POEMS	Testicular Cancer
Remission status prior to HSCT	PD	UKN	UKN	UKN	PD	PD
Conditioning Regimen	HD-BEAM	UKN	UKN	UKN	Melphalan	Carboplatin and etoposide
Sarcoidosis Dx post HCT (months)	5	8	3	120	6	60
Chest CT/RADIOGRAPHIC changes	Y	Y	Y	Y	Y	Y
Abnormal PFT	UKN	Y	UKN	UKN	UKN	UKN
EXTRApulmonary Organs involved	N	MSK	Skin	N	Yes, subdiaphragmatic LN	N
Response to GC	Y	Y	Y	Asym, nt	Asym, nt	Y

Abbreviations: AA, African American; AITL Angioimmunoblastic T-cell Lymphoma; C, Caucasian; F, female; GC, glucocorticoids; LN, lymph nodes; M, male; MSK, musculoskeletal system; N, no; POEMS, polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes syndrome; UKN, unknown; Y, yes. *Age at diagnosis of sarcoidosis

Sarcoidosis following Hematopoietic Stem Cell Transplantation: clinical characteristics and HLA associations

Status:

Version 1

Abstract

Purpose:

Methods:

Results:

Conclusion:

Figures

Introduction

Methods

Patient population and setting

Review of the literature

HLA genotyping

Statistical analysis

Results

Discussion

Conclusions

Declarations

References

Tables

Status:

Version 1