Upper GI Involvement in the Acute and Chronic GVHD Setting; Dysphagia and Esophageal Eosinophilic Infiltration and Ulceration
Presentation
A 68-year-old female patient with a history of polycythemia vera had disease progression to myeloproliferative neoplasm(MPN)/myelofibrosis, which was positive for mutations with ASXL1, JAK2, SRSF2 and TET2. For her initial treatment, she received 6 cycles of azacitidine combined with ruxolitinib.
A human leukocyte antigen (HLA)-matched, ABO/Rh-mismatched unrelated female donor was identified. The patient underwent an allogeneic stem cell transplant (SCT) using a conditioning regimen of fludarabine and busulfan. GvHD prophylaxis consisted of post-transplant cyclophosphamide on days +3/+4 and tacrolimus starting day +5. Her post-transplant course was complicated by expected pancytopenia that was treated with transfusion support and filgrastim.
After approximately 45 days post-transplant, the patient developed dysphagia and xerostomia, making it difficult to swallow.
Workup
She was given a swallow study around day +60 which revealed delayed throat clearing and esophageal stasis.
The patient had an esophagogastroduodenoscopy (EGD) on day +65, which revealed erosive gastropathy and esophageal stenosis. She was seen to have duodenitis and reactive gastropathy. Clinically, at that time she had no diarrhea but did have persistent dysphagia and persistent nausea and anorexia.
Treatment and Follow-up
At that time, pantoprazole was changed to twice daily and tacrolimus was continued at therapeutic dosing. The patient was given budesonide and beclomethasone as well, which are topical therapies often used in the treatment of upper and lower gastrointestinal (GI) GVHD, with limited systemic absorption. Dysphagia improved with these measures.
The patient continued with improvement until tacrolimus was weaned off between 4 and 6 months post-transplant. Approximately 10 months after the transplant, the patient developed persistent dysphagia and was referred to the GI team for another EGD. She underwent EGD at 11 months post-transplant and was found to have esophagitis with bleeding in the entire esophagus. Diffuse mildly erythematous mucosa was also found in the stomach. Biopsies were taken and revealed acute inflammatory cells with intra-epithelial lymphocytosis and scattered apoptotic keratinocytes in the esophagus, suggestive of GVHD of the esophagus. The biopsy of stomach was normal.
On examination, the patient had no involvement of the skin, eyes, mouth, or joints. However, given the biopsy results and the patient’s worsening dysphagia, she was given a trial of prednisone at 1 mg/kg, which quickly improved her symptoms. This was tapered quickly down to approximately 0.3 mg/kg (20 mg) and then to every other day, but she developed trouble swallowing again.
The patient also noted weight gain and improved response while on prednisone. After approximately 20 months post-transplant, the patient was started on sirolimus but that was stopped approximately 4 weeks later due to poor tolerance.
She was then given ruxolitinib for approximately 10 weeks without improvement in dysphagia and required the continuation of prednisone. Approximately 25 months post-transplant, she was found to have osteoporosis and unfortunately had a vertebral compression fracture. This motivated the patient and clinician to consider additional options to reduce prednisone exposure over time.
She was started on ibrutinib with improvement in her symptoms and an EGD was repeated at this time, which revealed no ulcerations or esophagitis but did reveal stricture, which was able to be dilated at that time.
The patient has remained on ibrutinib with continued resolution of her symptoms and has been able to wean completely off prednisone. She has continued to have close follow-up with the GI team regarding her esophageal strictures, which occasionally require dilation, but she has remained stable without flare of her chronic esophageal involvement of GVHD. Ibrutinib has been tapered to lower doses, but she hasn’t successfully been able to discontinue. Her myelofibrosis/MPN has remained in remission, and she has remained full donor chimerism since the time of transplant.
Discussion
The incidence of upper GI acute GVHD is approximately 30% of hematopoietic stem cell transplant recipients who develop acute GVHD.1 At the time of her initial involvement, according to the Mount Sinai Acute GvHD Consortium (also known as the MAGIC criteria), the patient would be classified as stage I upper involvement of GVHD and stage I lower GI involvement, making her overall grade II acute GvHD with stage I upper and lower GVHD of the gut.2 She was treated successfully with topical therapies (budesonide and beclomethasone) and did not require systemic steroids at that time.
According to the National Institutes of Health (NIH) Consensus Criteria, in the chronic upper GVHD presentation, the patient had a score of 2 for symptoms associated with mild to moderate weight loss of 5%-15% but met a score of 3 for the GI tract for requiring esophageal dilation.
At the height of her symptoms, this classified her on the NIH global severity scale as having severe chronic GvHD with at least one organ with a score of 3.3 She required high-dose steroids and eventually was well controlled on ibrutinib as per above. With treatment, her score improved to an overall severity of mild chronic GvHD, with no more than a score of 1 (dysphagia without significant weight loss).
Per the 2014 NIH criteria, the diagnosis of chronic GVHD requires at least one diagnostic manifestation or one distinctive manifestation confirmed by biopsy or testing of the same or other involved organ. Diagnostic manifestations sufficient by themselves to establish the diagnosis of chronic GVHD may be found in the skin, mouth, GI tract, lung, fascia, and genitalia (for example, lichen planus or lichen sclerosis, poikiloderma, sclerosis, or esophageal webs).4 The patient had esophageal stenosis and erosive esophagitis on EGD, so she met the criteria for the diagnosis of GvHD even though she did not have other systemic or organ manifestations.
As of November 2022, there are three U.S. Food and Drug Administration (FDA)-approved drugs on the market for use in chronic GVHD: ibrutinib, ruxolitinib, and belumosidil. A recent report in the journal Blood described the mechanisms of action of each of these medications and the studies that led to their approval.5 Ibrutinib inhibits Bruton’s tyrosine kinase (BTK), a mechanism that helps block the activation of B cells. Ibrutinib also blocks IL-2 and inducible tyrosine kinase (ITK), which helps avoid the T cell activation and cytokine release from the T-cell pathway. Ruxolitinib inhibits JAK1 and JAK2, which mediate the downstream effects of multiple cytokines. Ruxolitinib treatment results in increased Treg numbers and lower levels of collagen deposition. Belumosidil inhibits rho-associated coiled-coil–containing protein kinase-2 (ROCK2) which helps to decrease the proinflammatory cytokines IL-21 and IL-17 and decreases antibody presence and fibrosis.5 Both ibrutinib and ruxolitinib are FDA-approved after the failure of one other systemic treatment, while belumosidil is approved after the failure of two prior lines of therapy.
If our patient who failed ruxolitinib and is stable on a low dose of ibrutinib needs an additional treatment, we could consider belumosidil in the future.
References
- Harris AC, Young R, Devine S, et al. International, Multicenter Standardization of Acute Graft-versus-Host Disease Clinical Data Collection: A Report from the Mount Sinai Acute GVHD International Consortium.Biol Blood Marrow Transplant. 2016;22(1):4-10. doi:10.1016/j.bbmt.2015.09.001
- Nikiforow S, Wang T, Hemmer M, et al. Upper gastrointestinal acute graft-versus-host disease adds minimal prognostic value in isolation or with other graft-versus-host disease symptoms as currently diagnosed and treated.Haematologica. 2018;103(10):1708-1719. doi:10.3324/haematol.2017.182550
- Jagasia MH, Greinix HT, Arora M, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group Report. Biol Blood Marrow Transplant. 2015;21(3):389-401.e1. doi:10.1016/j.bbmt.2014.12.001
- Lee SJ. Classification systems for chronic graft-versus-host disease.Blood. 2017;129(1):30-37. doi:10.1182/blood-2016-07-686642
- Zeiser R, Lee SJ. Three US Food and Drug Administration-approved therapies for chronic GVHD.Blood. 2022;139(11):1642-1645. doi:10.1182/blood.2021014448