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JAAD Case Rep
JAAD Case Rep
JAAD Case Reports
2352-5126
Elsevier

S2352-5126(24)00238-8
10.1016/j.jdcr.2024.06.014
Case Report
Sclerotic chronic cutaneous graft-versus-host-disease following pseudoallogeneic chimeric antigen receptor T-cell therapy
Choi Esther BS ab
Nguyen Cuong V. MD cuong.nguyen@northwestern.edu
a∗
a Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
b Washington State University Elson S. Floyd College of Medicine, Spokane, Washington
∗ Correspondence to: Cuong V. Nguyen, MD, Department of Dermatology, Feinberg School of Medicine, Northwestern University, 676 N St Clair St, Ste 1600, Chicago, IL 60611-2941. cuong.nguyen@northwestern.edu
06 7 2024
10 2024
06 7 2024
52 4245
© 2024 by the American Academy of Dermatology, Inc. Published by Elsevier Inc.
2024
American Academy of Dermatology, Inc.
https://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Key words

allogeneic-hematologic stem cell transplant
chimeric antigen receptor T-cell
donor lymphocyte infusion
graft-versus-host disease
GVHD
ScGVHD
sclerotic cutaneous graft-versus-host disease
Abbreviations used

allo-HSCT allogeneic-hematologic stem cell transplant

DLI donor lymphocyte infusion

GVHD graft-versus-host disease

ScGVHD sclerotic chronic graft-versus-host disease
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pmcIntroduction

Chronic cutaneous graft-versus-host disease (GVHD) represents a common complication following allogeneic-hematologic stem cell transplant (allo-HSCT). Although GVHD has been well characterized in the context of allo-HSCT, autologous chimeric antigen receptor T-cell (CAR-T) therapy should, in theory, not exhibit self-reactivity because of thymic selection. However, it is important to note that patients may undergo CAR-T therapy after relapsing from allo-HSCT. Thus, the engineering of T cells procured from an allo-HSCT recipient with >95% donor chimerism is termed pseudoallogenic CAR-T therapy, given the likelihood of the engineered T cells originating from donor cell lines.1 Herein, we present a unique case of a patient who was diagnosed with sclerotic chronic GVHD (ScGVHD) 15 months following CAR-T therapy.

Case report

A 56-year-old woman presented with skin dyspigmentation, generalized erythema, and focal thickening of the upper portion of the back and upper portion of the arms. Her past medical history was significant for chronic lymphocytic leukemia with Richter transformation to diffuse large B-cell lymphoma. In addition to various chemotherapies, her treatment course included allo-HSCT with a matched sibling donor in 2016 followed by 2 donor lymphocyte infusions (DLIs) (dose 1 × 107 CD3+/kg) within 6 months of allo-HSCT for persistent disease. She experienced a recurrence of the disease and was treated with autologous CAR-T therapy with fludarabine and cyclophosphamide for lymphodepletion 44 months after HSCT. This was complicated by persistent transfusion-dependent pancytopenia, requiring DLI 1 month after CAR-T (dose 8 × 106 CD34+/kg), collected from her original HSCT donor. Restaging scans demonstrated progression, and the decision was made to repeat auto-CAR-T with dose reduced fludarabine and cyclophosphamide conditioning 4 months after her first CAR-T therapy. Her course was further complicated by immune-mediated myelotoxcity from CAR-T and hypogammaglobinemia requiring monthly intravenous immunoglobulin infusions. Until the current presentation, the patient had not exhibited cutaneous or systemic GVHD and she had not taken immunosuppression for GVHD prophylaxis since her allo-HSCT. See Fig 1 for the full timeline of the patient’s clinical presentation.Fig 1 Timeline of sclerotic chronic GVHD relative to time from allogeneic-hematologic stem cell transplant and time from chimeric antigen receptor T-cell therapy. CAR-T, Chimeric antigen receptor T-cell therapy; Derm, dermatology; DLI, donor lymphocyte infusion; GVHD, graft-versus-host disease; HSCT, hematologic stem cell transplant.

At the time of our initial evaluation, her leukemia was in remission, and she had achieved 100% donor chimerism for 2 years. Laboratory investigations revealed an elevated antinuclear antibody titer at 1:1280 but a negative reflexive panel. Subsequent visits demonstrated further sclerosis, forming curvy linear grooves on the trunk, upper and lower extremities, and progressive “salt-and-pepper” dyschromia, consistent with ScGVHD (Figs 2 and 3), as well as GVHD involving her joints causing stiffness. Skin biopsy from her initial visit exhibited a mild interface reaction with periadnexal involvement consistent with cutaneous GVHD (Fig 4). Treatments included topical steroids, ruxolitinib 10 to 20 mg, and 5 infusions of rituximab with subsequent moderate softening of her skin, but slow repigmentation.Fig 2 A and B, Progression of sclerotic chronic graft-versus-host disease with “salt-and-pepper” dyschromia on the lower extremities within 6 months.

Fig 3 Hypopigmented patches on the base of sclerotic skin, forming rippling, and linear grooves on the abdomen.

Fig 4 Vacuolar interface dermatitis with lymphocytes abutting the dermoepidermal junction and scattered necrotic keratinocytes consistent with grade II cutaneous graft-versus-host disease. (Hematoxylin-eosin stain; original magnification: ×130.)

Discussion

The safety and efficacy of pseudoallogeneic CAR-T therapy have been promising. However, the risk of GVHD development following therapy remains uncertain. This data paucity may be due, in part, to the limited sample sizes of CAR-T therapy studies, often with <50 patients in total. The incidence of acute and chronic GVHD of any organ type in this patient population has ranged from 0% to 50% with sparse information on skin disease presentation.1, 2, 3 Changes of ScGVHD, as in this case, have not been previously reported.

ScGVHD can mimic other sclerosing disorders, such as systemic sclerosis, morphea, and eosinophilic fasciitis, as well as macular hyperpigmentation disorders such as lichen planus pigmentosus or erythema dyschromicum perstans. Although all these conditions were considered, the lack of classic autoimmune connective disease features of Raynaud phenomenon, digital ulcerations, flexion contractures, coupled with the patient’s biopsy findings, ScGVHD was favored.

As most of these studies exclude patients with pre-existing GVHD, the effect of pseudoallogeneic CAR-T therapy on prior GVHD is also undefined. Interestingly, one report described a reversal of GVHD symptoms post-CAR-T therapy.4 The risk of GVHD development may be higher in settings where CAR-T is delivered within 10 months following allo-HSCT, particularly with the use of second-generation CAR-T.1,3 In line with prior studies, our patient received a second-generation CD19-directed CAR-T with a 4-1BB costimulatory domain, albeit this therapy was delivered 44 months after allo-HSCT.

In addition, the onset of ScGVHD occurs at a mean of 529 days after HSCT (range, 193-1001 days).5 First signs of skin changes developed in our patient approximately 450 days after the last CAR-T treatment and approximately 1900 days after her allo-HSCT. Her cutaneous symptoms may be more suggestive of a CAR-T complication, but the impact of DLIs following CAR-T therapy may have also played a clinical role in GVHD occurrence.

DLI is given with the intent of eliciting graft-versus-tumor effect after relapse from allo-HSCT. Unlike CAR-T where T cells are engineered to target malignant cells, the effects of DLI are less selective and have been associated with the induction of GVHD in 30% to 60% of patients.6 The onset of chronic GVHD after the initial infusion of DLI typically occurs at a median of 135 days (IQR, 89-237).7 Risk factors for GVHD after DLI include >60 years old, interval from HSCT to first infusion of DLI <184 days, and history of GVHD post-HSCT but pre-DLI.7 Our patient had no symptoms of cutaneous or systemic GVHD before her current ScGVHD development. Although our patient received her first DLI infusion approximately 150 days after HSCT, she exhibited first signs of cutaneous GVHD far beyond the typical IQR following DLI. Her ScGVHD symptoms developed just over 1740 days after her initial DLI infusion and approximately 450 days after her last DLI infusion. To our knowledge, only 1 other report has detailed the development of GVHD in patients who underwent CAR-T therapy following HSCT with or without DLI; of the 7 patients included, 2 developed new onset of GVHD post-CAR-T therapy, whereas none of these patients had a history of DLI. In contrast, 2 patients who received DLI following CAR-T therapy did not experience GVHD.8

As exemplified here, data concerning the incidence of GVHD and the role that CAR-T plays in its development require longer-term follow-up. GVHD is a complex, multifactorial process and the natural history and evolution of ScGVHD have yet to be elucidated. Although discerning the etiology of GVHD in patients with extensive pretreatment histories, such as ours, is challenging, we believe it is important to share the potential of this paradoxical phenomenon in patients with CAR-T therapy, given the anticipated expansion and utilization of this treatment modality against hematologic and solid organ tumors. We highlight the need for vigilant monitoring of patients undergoing CAR-T for the potential development of GVHD and other autoreactive cutaneous complications.

Conflicts of interest

None disclosed.

Funding sources: None.

Patient consent: The authors attest that they have obtained written consent from patient/s, their legal guardian/s or person/s with legal authority, for their photographs and medical information to be published in print and online and with the understanding that this information may be publicly available. Patient consent forms were not provided to the journal but are retained by the authors to be made available upon request.

IRB approval status: This case study was conducted in accordance with the Declaration of Helsinki. Ethics approval was not required for this study as this report is an observational study.

Data availability statement: Dr Nguyen had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
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