Critical Role of Sustained Monitoring for Post-Transplant Chronic GVHD Symptoms

Clinical Pearl: Establishing an effective ongoing chronic GVHD assessment protocol at the time that patients transfer away from the transplant center is essential as timely identification and intervention can significantly improve long-term outcomes. Managing adolescent and young adult (AYA) patients during this transitional period post-transplant can be particularly challenging, as they often try to exert their independence and may lack full awareness of the long-term risks associated with chronic GVHD.

JB is a 28-year-old male who was diagnosed with high-risk acute lymphocytic leukemia when traveling to see his parents for a visit. To have caregiver support, he moved back to his hometown where he received his care. His treatment consisted of an aggressive pediatric protocol, but he had residual disease after treatment and was thus transitioned to blinatumomab bridging therapy and subsequently underwent a matched unrelated peripheral blood stem cell transplant. The conditioning regimen included cyclophosphamide and total body irradiation.

His post-transplant course was complicated with two separate incidences of acute GVHD of the skin. The first was on day +40 post-transplant, he presented with a flat confluent rash that encompassed >80% of his body surface area. He had hidden the rash from his parents and did not report the symptom until his scheduled follow-up; no other sites of acute GVHD were observed or reported. He responded to topical and oral steroids at 1 mg/kg that were tapered off quickly over 1 month. 

His second incidence was at day +89 and was reported much earlier by his mother who called immediately for assessment. This was a macular popular rash encompassing only 32% of his body surface area. He was reinitiated on prednisone 1 mg/kg again with a short 1-month taper.

After tapering off his immunosuppressive agents at a delayed time point of day +180 when he finally established a solid ongoing minimal residual disease–negative remission, he moved back to his pre-disease residence almost 1000 miles away from the transplant center. His follow-up was not consistent when he transitioned away from the transplant center. He came back for a visit 2 years later and his mother suggested he re-establish treatment at the original transplant center. At this point he was diagnosed with extensive skin presentation of chronic GVHD with deep sclerosis in the upper arms, lower legs, abdomen, back, and the sides of the chest, amounting to more than 50% of his body surface area. His GVHD skin score was a 3 due to the deep sclerotic features.

Treatment was initiated with steroids, but over time he became steroid dependent given that any time the dose dropped below 0.25 mg/kg, he had a flare. He also started UVA-1 phototherapy. He continued to travel back and forth to the transplant center with sporadic follow-up when not at the transplant center. Because of his steroid dependence, ruxolitinib was initiated with topical treatments.

He achieved improvement in the upper arms and lower legs to the point that he could straighten his arms at the elbows and completely dorsiflex. After 12 months of treatment, he had no additional benefit to the abdomen and chest/sides, so extracorporeal photopheresis (ECP) was added to optimize outcomes, which required moving back to the transplant center area to complete the weekly/biweekly and then monthly treatments of ECP. He continued to have stable skin disease on the arms and legs and mild improvement of the sclerotic features on the abdomen and sides with the ruxolitinib, ECP, and topical treatments. 

Fourteen months later, his abdomen, chest, and back were beginning to appear hidebound and were concerning for fibrotic changes. All other sites remained quiescent and at best response. Because of the progression of the chronic GVHD in the abdomen, chest, and back, ECP was discontinued and belumosudil was added.

He has since been able to taper off of steroids and ruxolitinib. He has maintained belumosudil treatment with ongoing close evaluation, including staying in the care of the transplant program.

Multifaceted Presentation of Chronic GVHD Leading to Multiple Lines of Therapy Use

Clinical Pearl: Effective management of chronic GVHD requires ongoing assessment of symptom control, organ involvement, and functional impact. Escalation or transition of therapy should be considered when there is progression despite treatment, lack of improvement after an appropriate trial period, intolerable side effects, or emergence of new organ involvement. Timely adjustments can help reduce complications and improve quality of life for allogeneic stem cell transplant recipients.

MR is a 33-year-old female who was diagnosed with myelodysplastic syndrome with excess blasts (MDS-EB-2). At baseline, her weight was 245 lb. She was categorized as high risk with a Revised International Prognostic Scoring System score of 5. Next-generation sequencing showed mutations of significance in WT1 and SAMD9. She was treated initially with decitabine/cedazuridine and venetoclax, resulting in a first hematologic complete remission.

She went on to receive a matched unrelated stem cell transplant from a 25-year-old male cytomegalovirus-negative donor. The blood type of both donor and recipient were O+. Conditioning preparation was myeloablative with a fludarabine, busulfan, and antithymocyte globulin regimen.

Her post-transplant course was complicated by deep vein thrombosis, pulmonary embolism, and prolonged cytopenias. Her counts finally stabilized about 60 days post-transplant. She tapered off of immunosuppression at 6 months post-transplant with no initial GVHD or other symptoms.

Eight months post-transplant, she was noted to have fallen donor chimerisms with concern of losing graft/disease progression. To manage the falling chimerisms, a planned donor lymphocyte infusion with 1 x 10⁷ CD3+ cells was given. The low CD3 chimerism persisted, so an additional donor lymphocyte infusion was planned with 3 x 10⁷ CD3+ cells and this resulted in full 100% CD3 and CD33 chimerisms. 

Four months after the last donor lymphocyte infusion, she presented with dry, gritty eyes and was diagnosed with ocular GVHD. Treatment included ocular-derived treatment (no systemic immunosuppression).

Two months later, she complained of cough and fluctuating shortness of breath. Serial pulmonary function tests noted worsening function and oxygen dependency 24 hours per day:

Initiated 1 mg/kg of prednisone and fluticasone, azithromycin, and montelukast therapy due to concern for bronchiolitis obliterans based on pulmonary imaging, and ultimately a bronchoscopy. Steroids were tapered and she was reinitiated on tacrolimus and mycophenolate mofetil. 

Over the next 4 months, she had multiple hospitalizations for acute onset shortness of breath and chest tightness. At this point, steroids were reinitiated and she was transitioned from tacrolimus and mycophenolate mofetil to belumosudil for concern of fibrosis; ruxolitinib was also added to offer additional suppression of the inflammatory process based on a differing mechanism of action. These treatments did offer stability of pulmonary function that lasted for 6 months but did not significantly enhance her clinical benefit as she had to remain on oxygen and was not able to walk more than 2 to 3 minutes on the treadmill. She remained on 0.5 mg/kg of prednisone as any further tapering induced a flare of her pulmonary symptoms.

Given her age, ongoing disease remission status, and the likely irreversible damage to her lungs, she was referred to a thoracic surgeon for consideration of a lung transplant. The thoracic transplant surgeon identified that she met the lung function criteria for a lung transplant. However, with her weight gain to 296 lb from the steroids and reduced endurance, she was deemed ineligible. She was told she needed to lose 80 lb before a transplant could be considered.

Given her ongoing pulmonary compromise, the decision was made to add extracorporeal photopheresis to add a treatment with limited added immunosuppression, but this offered minimal benefit. She was hospitalized again for worsening lung function. She was then referred to another transplant physician specializing in GVHD who recommended starting the newly approved treatment axatilimab, which has a unique mechanism of action targeting the colony stimulating factor-1 (CSF1) receptor.

After six doses of axatilimab, she is off oxygen during the day and able to get on a treadmill for 18 minutes a day (up from 0 minutes prior to starting the medicine) and has already lost 20 pounds.