Graft-versus-host disease after radiation therapy in patients who have undergone allogeneic stem cell transplantation: two case reports
© The Author(s). 2016
Received: 27 October 2015
Accepted: 6 July 2016
Published: 28 July 2016
Patients who undergo allogeneic stem cell transplantation and subsequent radiation therapy uncommonly develop graft-versus-host disease within the irradiated area. We quantified the incidence of this complication, which is a novel contribution to the field. From 2010 to 2014, 1849 patients underwent allogeneic stem cell transplantation, and 41 (2 %) received radiation therapy afterward. Of these, two patients (5 %) developed graft-versus-host disease within the irradiated tissues during or immediately after radiation therapy.
The first patient is a 37-year-old white man who had Hodgkin lymphoma; he underwent allogeneic stem cell transplantation from a matched unrelated donor and received radiation therapy for an abdominal and pelvic nodal recurrence. After 28.8 Gy, he developed grade 4 gastrointestinal graft-versus-host disease, refractory to tacrolimus and steroids, but responsive to pentostatin and photopheresis. The other patient is a 24-year-old white man who had acute leukemia; he underwent allogeneic stem cell transplantation from a matched related donor and received craniospinal irradiation for a central nervous system relapse. After 24 cobalt Gy equivalent, he developed severe cutaneous graft-versus-host disease, sharply delineated within the radiation therapy field, which was responsive to tacrolimus and methylprednisolone.
We conclude that graft-versus-host disease within irradiated tissues is an uncommon but potentially serious complication that may follow radiation therapy in patients who have undergone allogeneic stem cell transplantation. Clinicians must be aware of this complication and prepared with strategies to mitigate risk. Patients who have undergone allogeneic stem cell transplantation represent a unique population that may offer novel insight into the pathways involved in radiation-related inflammation.
KeywordsGraft-versus-host disease GVHD Radiation therapy RT Allogeneic stem cell transplant
The management of hematologic malignancies is complex, often involving several types of therapies with toxicities that are heavily influenced by other treatments administered. Allogeneic stem cell transplantation (ASCT) is an important form of treatment for some hematologic cancers. A significant cause of morbidity and mortality after ASCT is graft-versus-host disease (GVHD), an immune response mounted by donor cells against recipient tissues. Several risk factors for GVHD have been identified [1, 2], among them radiation therapy (RT). Our group and others have reported rare cases of GVHD arising within irradiated tissues in patients who have undergone ASCT [3–5]. In this study, we aimed to assess the frequency of this complication.
With the approval of our institutional review board, we retrospectively reviewed records of patients who had undergone ASCT at our institution from 1 January 2010 to 31 December 2014. Those who had received at least one course of RT after ASCT comprised the study population. Disease characteristics, treatment details, and clinical outcomes were retrieved from electronic medical records. GVHD was defined and graded by treating physicians based on clinical and pathologic findings. The RT plans were reviewed to determine the dose that had been delivered to the affected organs.
Patient, disease, and treatment characteristics
Value or number of patients (%)
Age at allogeneic stem cell transplantation, years
32 (78 %)
9 (22 %)
26 (63 %)
10 (24 %)
5 (12 %)
Acute myeloid leukemia
9 (22 %)
Acute lymphocytic leukemia
7 (17 %)
Acute biphenotypic leukemia
1 (2 %)
Chronic myeloid leukemia
3 (7 %)
Chronic lymphoid leukemia
1 (2 %)
Mantle cell lymphoma
2 (5 %)
Classical Hodgkin lymphoma
7 (17 %)
6 (15 %)
Diffuse large B-cell lymphoma
4 (10 %)
Peripheral T-cell lymphoma
1 (2 %)
Matched unrelated donor
21 (51 %)
Matched related donor
18 (44 %)
2 (5 %)
11 (27 %)
5 (12 %)
1 (2 %)
13 (32 %)
1 (2 %)
1 (2 %)
1 (2 %)
2 (5 %)
1 (2 %)
4 (10 %)
Fludarabine/cyclophosphamide/2 Gy TBI
1 (2 %)
Time from ASCT to RT, days
RT dose, Gy
Number of RT fractions
In two patients (5 % of the cohort), GVHD developed during or immediately after RT within the irradiated tissues. In a third case, hemorrhagic esophagitis developed 7 days after completion of craniospinal irradiation (CSI). Although an esophageal biopsy was morphologically suggestive of GVHD, the clinical presentation was not consistent with this diagnosis, and the symptoms resolved with steroids alone. Therefore, the symptoms were attributed to RT-induced inflammation, and this case was not included. The two cases of GVHD following RT are described below.
An otherwise healthy 37-year-old white man had chemorefractory classic Hodgkin lymphoma, treated with the following regimens: (1) doxorubicin, bleomycin, vinblastine, and dacarbazine; (2) ifosfamide, carboplatin, and etoposide; (3) brentuximab; (4) gemcitabine and vinorelbine; (5) bendamustine; (6) everolimus; (7) sirolimus and vorinostat; (8) lenalidomide; and (9) dexamethasone, cytarabine, and cisplatin. He then underwent an ASCT from a 10/10 matched unrelated donor, with a fludarabine and melphalan conditioning regimen.
As previously reported , an otherwise healthy 24-year-old white man with relapsed Philadelphia-positive B-cell acute lymphocytic leukemia was treated initially with cyclophosphamide, vincristine, doxorubicin, dexamethasone, cytarabine, and methotrexate (hyper-CVAD) with dasatinib. Disease relapse in his central nervous system (CNS) and bone marrow during maintenance therapy was salvaged with augmented hyper-CVAD and dasatinib, followed by a 10/10 human leukocyte antigen (HLA)-matched related ASCT from his sister, with a busulfan and clofarabine conditioning regimen.
On day 82 after the ASCT, he presented with a headache; he was diagnosed as having an isolated CNS relapse and was treated with rituximab, asparaginase, dasatinib, high-dose methotrexate, and intrathecal cytarabine, followed by consolidative CSI. The CSI was with proton therapy, to a total dose of 24 cobalt Gy equivalent (CGE) in 12 fractions. His brain was treated with right and left posterior oblique beams, and his spine was treated with three posterior-anterior beams. The CSI was begun on day 197 after the ASCT, and no evidence of GVHD was present at that time. The tacrolimus dose was reduced during RT.
One month after completing CSI, he developed severe dermatitis within the RT portals and conjunctivitis, keratopathy, and conjunctival ulceration. The dose delivered to his skin had been 22 CGE . A skin biopsy showed inflammatory cell-poor interface dermatitis with vacuolar alterations of the basal keratinocytes and dyskeratotic cells, consistent with grade 2 to 3 GVHD. Treatment with tacrolimus and methylprednisolone (2 mg/kg/day) resulted in resolution of his cutaneous GVHD; however, keratoconjunctivitis sicca persisted despite prednisolone ophthalmic drops. His cutaneous GVHD returned several months later, both within and outside the RT field. This extensive chronic GVHD progressed despite steroids, tacrolimus, and photopheresis, manifesting as ulcerations, scleroderma-like changes, and chronic osteomyelitis that necessitated bilateral above-the-knee amputations. He died of aspiration pneumonia and respiratory failure 4.5 years after the ASCT, with no evidence of leukemia.
GVHD is a potentially serious complication that may follow RT in patients who have undergone ASCT. Cases have been reported [4–6]; however, the incidence of this complication was unknown previously. We identified 41 sequential patients who received RT after ASCT, two (5 %) of whom developed clinically significant GVHD within the irradiated tissues during or immediately after RT, despite delivery of relatively low doses to the affected organs. Radiation-induced inflammation was an alternative diagnosis that was considered; however, both the clinical and pathological findings were consistent with GVHD. We conclude that GVHD following RT is uncommon; however, this diagnosis should be considered in patients who have undergone ASCT and who develop RT-related side effects that are more severe than expected.
Given the study design, conclusive demonstration of a causal relationship between RT and GVHD is not possible. However, GVHD developed within the irradiated tissues during or immediately following RT, in patients who were without evidence of GVHD previously. Furthermore, in Case 2, cutaneous GVHD was strictly demarcated within the irradiated area . These findings strongly suggest a causal relationship.
The small number of events in this study precludes the identification of factors that might modify the risk of GVHD. It is notable, however, that the doses of immunosuppressive agents were tapered around the time of RT in both cases. This observation suggests that immunosuppressive therapy should not be reduced during this period, even if patients are free of clinically apparent GVHD at the time of RT.
Theoretically, RT can trigger GVHD via local cellular damage and induction of pro-inflammatory pathways. Multiple inflammatory mediators are activated, upregulated, or released in response to ionizing radiation, such as NF-kB, TNF-α, TGF-β, GM-CSF, COX-2, ICAM-1, IL-1, IL-6, IL-8, IFN, c-Fos, c-Myc, c-Jun, and extracellular nucleotides [6–11]. The resulting chemotactic signals lead to rapid recruitment of diverse leukocyte subgroups into the irradiated area [12–14]. RT also upregulates expression of major histocompatibility complex (MHC) class I/II antigens by cancer cells, rendering them more sensitive to T cell recognition through antigen presentation by dendritic cells [13, 15, 16]. RT may well have similar effects on normal tissues. For patients who have had an ASCT, this immune stimulation may cause dendritic cells to present host antigens to donor T cells, predisposing to the development of GVHD.
The immune response induced by ionizing radiation is an area of fervent study, both in the laboratory and in the clinic. Patients who have undergone ASCT represent a unique population that may offer additional insight into the pathways involved in radiation-related inflammation. Furthermore, clearer understanding of the mechanisms by which RT induces GVHD may enable the development of therapeutic interventions. RT is a highly effective form of treatment for hematologic malignancies, but clinicians must be able to recognize risk factors for toxicity, including GVHD, and strive to develop strategies to mitigate morbidity.
ASCT, allogeneic stem cell transplantation; CGE, cobalt Gray equivalent; CNS, central nervous system; CSI, craniospinal irradiation; GVHD, graft-versus-host disease; HLA, human leukocyte antigen; hyper-CVAD, cyclophosphamide, vincristine, doxorubicin, dexamethasone, cytarabine, and methotrexate; MHC, major histocompatibility complex; RT, radiation therapy
The authors would like to thank Dr Valerie Reed for her thoughtful review of the manuscript.
There was no source of funding for this research.
Availability of data and materials
The datasets upon which the conclusions of the manuscript are based have been made available at zenodo.org (doi:https://doi.org/10.5281/zenodo.53915).
SAM drafted the manuscript. All authors revised it critically, gave approval of the final version to be published, and agree to be accountable for all aspects of the work.
The authors declare that they have no competing interests.
Consent for publication
Written informed consent was obtained from the patient (Case 1) for publication of the case and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Written informed consent was obtained from the patient’s next of kin (Case 2) for publication of the case. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Ethics approval and consent to participate
Approval was obtained from our institutional review board to conduct this study (MDACC protocol ID #PA13-0947).
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Flowers ME, Inamoto Y, Carpenter PA, Lee SJ, Kiem HP, Petersdorf EW, et al. Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria. Blood. 2011;117(11):3214–9. doi:https://doi.org/10.1182/blood-2010-08-302109.View ArticlePubMedPubMed CentralGoogle Scholar
- Jagasia M, Arora M, Flowers ME, Chao NJ, McCarthy PL, Cutler CS, et al. Risk factors for acute GVHD and survival after hematopoietic cell transplantation. Blood. 2012;119(1):296–307. doi:https://doi.org/10.1182/blood-2011-06-364265.View ArticlePubMedPubMed CentralGoogle Scholar
- Okamoto S, Takahashi S, Inoue T, Tojo A, Tani K, Kikuchi A, et al. Cutaneous chronic graft-versus-host disease localized to the field of total lymphoid irradiation. Bone Marrow Transplant. 1996;17(1):111–3.PubMedGoogle Scholar
- Sharp H, Grosshans D, Kadia T, Dabaja BS. Cutaneous graft-versus-host disease after proton-based craniospinal irradiation for recurrent Philadelphia-positive acute lymphoblastic leukaemia. BMJ Case Reports. 2012;2012. doi:https://doi.org/10.1136/bcr.02.2012.5742.
- Socie G, Gluckman E, Cosset JM, Devergie A, Girinski T, Esperou H, et al. Unusual localization of cutaneous chronic graft-versus-host disease in the radiation fields in four cases. Bone Marrow Transplant. 1989;4(1):133–5.PubMedGoogle Scholar
- Hong JH, Chiang CS, Sun JR, Withers HR, McBride WH. Induction of c-fos and junB mRNA following in vivo brain irradiation. Brain Res Mol Brain Res. 1997;48(2):223–8.View ArticlePubMedGoogle Scholar
- Akashi M, Hachiya M, Koeffler HP, Suzuki G. Irradiation increases levels of GM-CSF through RNA stabilization which requires an AU-rich region in cancer cells. Biochem Biophys Res Commun. 1992;189(2):986–93.View ArticlePubMedGoogle Scholar
- Steinauer KK, Gibbs I, Ning S, French JN, Armstrong J, Knox SJ. Radiation induces upregulation of cyclooxygenase-2 (COX-2) protein in PC-3 cells. Int J Radiat Oncol Biol Phys. 2000;48(2):325–8.View ArticlePubMedGoogle Scholar
- Son EW, Rhee DK, Pyo S. Gamma-irradiation-induced intercellular adhesion molecule-1 (ICAM-1) expression is associated with catalase: activation of Ap-1 and JNK. J Toxicol Environ Health A. 2006;69(24):2137–55. doi:https://doi.org/10.1080/15287390600747759.View ArticlePubMedGoogle Scholar
- Pasi F, Facoetti A, Nano R. IL-8 and IL-6 bystander signalling in human glioblastoma cells exposed to gamma radiation. Anticancer Res. 2010;30(7):2769–72.PubMedGoogle Scholar
- Zhang JS, Nakatsugawa S, Niwa O, Ju GZ, Liu SZ. Ionizing radiation-induced IL-1 alpha, IL-6 and GM-CSF production by human lung cancer cells. Chin Med J (Engl). 1994;107(9):653–7.Google Scholar
- Shiao SL, Coussens LM. The tumor-immune microenvironment and response to radiation therapy. J Mammary Gland Biol Neoplasia. 2010;15(4):411–21. doi:https://doi.org/10.1007/s10911-010-9194-9.View ArticlePubMedPubMed CentralGoogle Scholar
- Gupta A, Probst HC, Vuong V, Landshammer A, Muth S, Yagita H, et al. Radiotherapy promotes tumor-specific effector CD8+ T cells via dendritic cell activation. J Immunol. 2012;189(2):558–66. doi:https://doi.org/10.4049/jimmunol.1200563.View ArticlePubMedGoogle Scholar
- Burnette BC, Liang H, Lee Y, Chlewicki L, Khodarev NN, Weichselbaum RR, et al. The efficacy of radiotherapy relies upon induction of type i interferon-dependent innate and adaptive immunity. Cancer Res. 2011;71(7):2488–96. doi:https://doi.org/10.1158/0008-5472.CAN-10-2820.View ArticlePubMedPubMed CentralGoogle Scholar
- Abdel-Wahab Z, Dar MM, Hester D, Vervaert C, Gangavalli R, Barber J, et al. Effect of irradiation on cytokine production, MHC antigen expression, and vaccine potential of interleukin-2 and interferon-gamma gene-modified melanoma cells. Cell Immunol. 1996;171(2):246–54. doi:https://doi.org/10.1006/cimm.1996.0200.View ArticlePubMedGoogle Scholar
- Ciernik IF, Romero P, Berzofsky JA, Carbone DP. Ionizing radiation enhances immunogenicity of cells expressing a tumor-specific T-cell epitope. Int J Radiat Oncol Biol Phys. 1999;45(3):735–41.View ArticlePubMedGoogle Scholar