Vulvovaginal Chronic GVHD Following Allogeneic Stem Cell Transplant

Presentation

A 36-year-old female has transferred into the area requesting follow-up approximately 18 months after her allogeneic hematopoietic stem cell transplant (allo-HSCT).

She reports a prior history of acute myeloid leukemia (AML) that was positive for inversion 16 (CBFB MYH 11) and was initially treated with induction with traditional 7+3 using cytarabine and daunorubicin. Following induction chemotherapy the patient was found to have evidence of minimal residual disease (MRD) by CBFB-MYH 11 polymerase chain reaction (PCR) at 0.6%. The patient was consolidated with HIDAC (high-dose Ara-C) and following induction, was again found to have MRD positivity.

The decision was made to undergo allo-HSCT. Fortunately the patient had a matched related sibling donor (sister). She had busulfan and cyclophosphamide (Bu/Cy) conditioning chemotherapy, and transplant was followed by GvHD prophylaxis with tacrolimus and low-dose methotrexate. Her post-transplant course was complicated by infectious diarrhea, gastrointestinal toxicity, and skin toxicity secondary to busulfan. She has a history of prolonged dysuria with JC (John Cunningham) virus and BK virus, both previously positive. Following transplant, the patient developed chronic GVHD.

Her chronic GVHD manifestations are primarily ocular, oral, and vulvovaginal in nature. Her ocular symptoms include sensitivity to light in her eyes, extremely dry eye with pain, and blurry vision. She has oral pain when she eats spicy and acidic foods, along with limited ability to open her mouth fully. The patient also experiences also vulvovaginal pain, sexual dysfunction, and dysuria.

Workup

On physical exam, the patient has erythema of the conjunctiva, photophobia on exam, oral mucosal erythema with ulceration, and lichenoid changes. In the BMT clinic, the patient declines vulvovaginal exam but agrees to specialist referral.

Her BK virus and JC virus PCR test from the urine and the blood are both negative. Her complete blood count (CBC) is relatively normal with a white blood count (WBC) in the 4.5 range, hemoglobin ranging from 10.5 to 11.3, and platelets in the 110K range. PCR for CBFB MYH 11 post-transplant has remained MRD negative.

Treatment

Prior to her arrival to the region, the patient reports that she was treated for her chronic GvHD symptoms with tacrolimus and ruxolitinib, and reports these were both discontinued recently prior to her move as they were ineffective to manage her symptoms. She has been on steroids in the past and is currently on approximately 0.5 mg/kg/day with the inability to taper further without progression of symptoms. The patient also expresses an unwillingness to be on higher doses due to inability to tolerate the side effects of high-dose steroids. She is offered to temporarily increase her prednisone dose, but adamantly declines another trial of high-dose steroids.

Because the patient has failed at least two prior lines of therapy for her chronic GVHD, she is started on systemic oral belumosudil¹ and simultaneously given topical therapies for her oral and vaginal symptoms (dexamethasone swish and spit, miracle mouthwash, clobetasol topical ointment, and estradiol cream).

The patient is referred to both ophthalmology and a subspecialist who specializes in dermatologic vulvovaginal disorders. The specialist reports significant erythema, inflammation, and friability, with adhesions and agglutination of the vaginal canal and inability to visualize the urethral opening. Following her visit to the specialist, the patient’s dysuria worsens, and she begins to have urine retention and bladder distension requiring referral to the emergency department. The patient is referred urgently to the surgery clinic, and they perform surgical opening of the urethra and vaginal opening. Upon recovery from surgery, the patient is recommended to be on topical steroids and use a series of vaginal dilators in order to keep the area from developing additional adhesions following surgical intervention. She continues with belumosudil, prednisone, and topical therapies with significant improvement of her pain and urination.

Scoring

This patient’s vulvovaginal involvement is scored as severe. Scoring of female genital involvement of GVHD as per the NIH consensus guidelines⁴ is as follows:

Female genitalia: Severity of signs

• Mild (any of the following): Erythema on vulvar mucosal surfaces, vulvar lichen-planus, or vulvar lichen-sclerosis
• Moderate (any of the following): Erosive inflammatory changes of the vulvar mucosa, and fissures in vulvar folds
• Severe (any of the following): Labial fusion, clitoral hood agglutination, fibrinous vaginal adhesions, circumferential fibrous vaginal banding, vaginal shortening, synechia, dense sclerotic changes, and complete vaginal stenosis⁴

Discussion

Vulvovaginal chronic GVHD, unfortunately often overlooked and underreported, is commonly associated with other mucosal involvement, as well as oral or ocular and often skin chronic GVHD.² It is strongly recommended that gynecologic evaluation be standard for all female patients at approximately 1 year, or earlier for those with other signs or symptoms of mucosal involvement of GVHD. Female patients post allo-HSCT should be monitored for signs and symptoms of genital involvement closely and started early on treatment in order to avoid progression of disease, which unfortunately may be irreversible without surgical intervention. In addition, female patients post allo-HSCT are at higher risk of secondary malignancies and should be monitored for cervical dysplasia or condylomas, as these are more common in these patients.² Treatment of vulvovaginal chronic GvHD includes topical steroids, dilator use, and topical estrogens.³ Advanced practitioners should also monitor for familial or personal history of breast cancer as this is a contraindication for estrogen use. Additional potential treatment options for this patient would be adding rituximab, ibrutinib, or extracorporeal photopheresis.

References

1. Cutler C, Lee SJ, Arai S, et al. Belumosudil for chronic graft-versus-host disease after 2 or more prior lines of therapy: The ROCKstar Study [published correction appears in Blood. 2022 Mar 17;139(11):1772]. Blood. 2021;138(22):2278-2289. doi:10.1182/blood.2021012021
2. Kornik RI, Rustagi AS. Vulvovaginal graft-versus-host disease. Obstet Gynecol Clin North Am. 2017;44(3):475-492. doi:10.1016/j.ogc.2017.05.007
3. Jacobson M, Wong J, Li A, Wolfman WL. Vulvovaginal graft-versus-host disease: A review. Climacteric. 2019;22(6):603-609. doi:10.1080/13697137.2019.1635580
4. 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