Patient With History of Acute Steroid-Dependent Skin GVHD Develops Chronic GVHD: Part 2

Presentation

A 67-year-old male has a prior history of myelofibrosis that transformed into acute myeloid leukemia. Following induction with liposomal daunorubicin and cytarabine, along with a bone marrow biopsy that revealed remission, he underwent allogeneic stem cell transplantation with a haplo-identical donor. His transplant conditioning regimen consisted of fludarabine, cyclophosphamide, and total-body irradiation and post-transplant cyclophosphamide on days 3 and 4 post-transplant. Mycophenolate mofetil was added on days 5 through 35 and tacrolimus started on day 5 and continued for graft-versus-host disease (GVHD) prophylaxis. His immediate post-transplant course was complicated by grade 2 GI toxicity with diarrhea and nausea, which improved upon engraftment, and a transient rash that resolved without interventions prior to hospital discharge.

Following transplant, the patient was treated for steroid dependent acute skin GVHD requiring steroids, ruxolitinib, and eventually ibrutinib 280 mg daily (see Part 1 of this case study). All immunosuppressive therapy was tapered over time and ibrutinib was successfully discontinued at 8 months post-transplant.

The patient did well without evidence of GVHD or infection until unfortunately, at approximately 11 months post-transplant, the patient developed pulmonary infiltrates, hypoxia requiring supplemental oxygen, diarrhea, and rising liver function tests (LFTs). Hospital admission was indicated, and the workup revealed the following:

A chest CT with IV contrast revealed scattered multifocal ground-glass opacity throughout bilateral lungs, in the peripheral distribution. Extensive infectious disease workup was negative. Bronchoscopy was performed and revealed bilateral infiltrates. Bronchoalveolar lavage was performed. Transbronchial biopsies revealed organizing pneumonia with diffuse interstitial mononuclear inflammation.

Following a negative infectious workup, the patient was diagnosed with chronic GVHD of the lungs with bronchiolitis obliterans organizing pneumonia (BOOP) and possible liver and GI involvement.

Treatment

The patient was subsequently restarted on high-dose steroids (initially methylprednisolone and then prednisone 1 mg/kg daily), as well as ursodiol and inhaled steroids (fluticasone), azithromycin, and montelukast (called FAM therapy and commonly used to treat BOOP in patients with pulmonary involvement of GVHD).¹ The patient’s symptoms improved significantly, and oxygen was successfully weaned. He was discharged from the hospital approximately 1 month after admission, around the 1-year mark.

Steroids were tapered by 10 mg every 2 weeks in the outpatient setting until 1 month later, the patient unfortunately developed septic shock and was admitted to the hospital approximately 13.5 months post-transplant. While admitted for sepsis, steroids were continued at approximately 0.5 mg/kg. The patient developed a flare of liver and GI GVHD, and the patient was restarted on ibrutinib at 280 mg. Due to worsening oxygenation and further decline, he required ICU admission, intubation, pressor support, and continuous renal replacement therapy (CRRT). Ibrutinib was held on intubation and  resumed at 140 mg following extubation. He was found to have Legionella and coagulase-negative staph infection and was treated with broad-spectrum antibiotics (including meropenem). The patient required a short course of hemodialysis secondary to renal failure associated with septic shock but thankfully kidney function recovered.

Due to improvement in his symptoms and LFTs, a liver biopsy was not performed. His lung symptoms continued to improve. Prednisone continued to be tapered over the course of 3 months and discontinued successfully at 17 months post-transplant.

Following 5 months of ibrutinib treatment, at approximately 20 months post-transplant, the patient was found to have a right lower pleural effusion; ibrutinib was discontinued. The pleural effusion resolved. The patient’s breathing, lung symptoms, and LFTs remained stable and without worsening. Frequent loose stools returned approximately 1 month following the discontinuation of the ibrutinib. The patient was then started on budesonide 3 mg orally three times daily, with resolution of the loose stools.

In patients with GI involvement of GVHD, budesonide can be used as a topical agent for lower GI symptoms such as abdominal cramping and diarrhea. In patients with upper GI involvement who have symptoms of persistent nausea and vomiting, compounded beclomethasone solution can be used. These agents act to calm the inflammation of the gastric and intestinal mucosa, much like topical steroid creams are used for skin GVHD.

The patient was tapered off budesonide slowly over a few months, but each time it was discontinued, the loose stools recurred. He remained stable on budesonide 3 mg daily with no other signs or symptoms of chronic GVHD.

This patient’s repeat pulmonary function tests revealed a normal forced expiratory volume (FEV1), normal forced vital capacity (FVC), and mildly reduced diffusion capacity of the lungs for carbon monoxide (DLCO), at 64% of predicted (stable and not worse from prior). Residual volume (RV) is only 68% of predicted. In GVHD, especially BOOP, residual volume (which represents the amount of air left in the lungs after a patient exhales fully) is often higher than expected because of the obstruction caused by the lack of elasticity of the small airways and alveoli.²

Discussion

This case report highlights the complexity of the GVHD patient and the many organ systems that can be involved, as well as the various infectious complications patients may experience while on immunosuppressant therapies. 

Patients with a history of BOOP who have successfully tapered off steroids can continue with FAM therapy. Azithromycin has some reports of malignancy risk among patients with chronic lung GVHD,³ so it is physician’s choice as to whether patients continue on long-acting inhalers (fluticasone-salmeterol) and montelukast without long-term azithromycin. Where possible, topicals such as budesonide and inhaled steroids can be helpful while minimizing systemic immunosuppression. 

In addition, patients with chronic GVHD are at higher risk for sepsis and septic shock due to their prolonged immunocompromised state. 

References

1. Williams KM, Cheng GS, Pusic I, et al. Fluticasone, azithromycin, and montelukast treatment for new-onset bronchiolitis obliterans syndrome after hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2016;22(4):710-716. doi:10.1016/j.bbmt.2015.10.009
2. Hildebrandt GC, Fazekas T, Lawitschka A, et al. Diagnosis and treatment of pulmonary chronic GVHD: report from the consensus conference on clinical practice in chronic GVHD. Bone Marrow Transplant. 2011;46:1283-1295.
3. Cheng GS, Bondeelle L, Gooley T, et al. Azithromycin use and increased cancer risk among patients with bronchiolitis obliterans after hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2020;26:392-400.