How I treat refractory chronic graft-versus-host disease

Abstract

Approximately 35% to 50% of patients otherwise cured of hematologic malignancies after allogeneic hematopoietic stem cell transplantation will develop the pleomorphic autoimmune-like syndrome known as chronic graft-versus-host disease (cGVHD). Since in 2005, National Institutes of Health (NIH) consensus panels have proposed definitions and classifications of disease to standardize treatment trials. Recently, the first agent was approved by the US Food and Drug Administration for steroid-refractory cGVHD. Despite these advances, most individuals do not achieve durable resolution of disease activity with initial treatment. Moreover, standardized recommendations on how to best implement existing and novel immunomodulatory agents and taper salvage agents are often lacking. Given the potential life-threatening nature of cGVHD, we employ in our practice patient assessment templates at each clinic visit to elucidate known prognostic indicators and red flags. We find NIH scoring templates practical for ongoing assessments of these complex patient cases and determination of when changes in immunosuppressive therapy are warranted. Patients not eligible or suitable for clinical trials have systemic and organ-directed adjunctive treatments crafted in a multidisciplinary clinic. Herein, we review these treatment options and offer a management and monitoring scaffold for representative patients with cGVHD not responding to initial therapy.

Figure 1.

NIH global severity assessments to determine need for intervention in patients with ongoing cGVHD.^, Our approach to patients seen in our multidisciplinary clinic for ongoing refractory cGVHD entails assessment of global severity score as well as assessment of treatment response measures per consensus publications (yellow box, top left). Patients without treatment response and/or worsening disease require addition of immunosuppressive therapy (IST) and may also require modification of IST. The group of patients with stable or fixed disease (gray box, bottom left) may have unacceptable toxicity from steroids or may have what has been deemed steroid intolerance. For patients with unresponsive cGVHD or fixed organ damage, tapering steroids is typically recommended (to avoid further steroid toxicity) while maintaining other agents that may be keeping disease in a stable state. *After ≤2 weeks if lung or liver or moderate to severe disease; otherwise, after 4 weeks if no life-sustaining organs are involved. †NIH cGVHD consensus definitions: steroid refractory, steroid dependent, steroid intolerant.^, LFT, liver function tests; PFT, pulmonary function tests.

Figure 2.

Assessment of worsening cGVHD reflective of cGVHD pathophysiology that requires urgent attention. (A) Decrease in FEV1 may reflect pathology of bronchiolitis obliterans found in cGVHD. High lung symptom score carries a high risk of death. Pulmonary function test abnormalities, specifically evidence of obstruction (FEV1/FVC <0.7) and decreases in FEV1, should raise strong suspicion for development of lung cGVHD, because FEV1 decrease without evidence of restrictive disease may reflect underlying small airway occlusion related to extracellular matrix deposited within or around the airways in cGVHD. Because a drop of FEV1 alone is an indicator of impaired lung function and could be also due to restrictive lung disease, FEV1 is a useful indicator of obstruction only when FEV1/FVC is <0.7 (consistent with obstructive lung disease). (B) Abnormal liver tests may reflect liver pathology in cGVHD that is associated with increased mortality. cGVHD of the liver can be diagnosed and tracked in patients using total bilirubin and alkaline phosphatase per NIH consensus criteria. An increase in total bilirubin occurs when conjugated bilirubin is not excreted, either because of inflammation or loss of the ducts. When the ducts are not functioning properly, alkaline phosphatase rises. Dysfunctional bile ducts can be due to bile duct dropout, presumably a result of cellular damage and preceding inflammation or (more rarely) fibrosis. Infectious or drug-induced causes, in some cases, should be ruled out via biopsy. (C) Significant weight loss with or without diarrhea warrants further investigation because of its association with increased mortality.^, The etiology of weight loss may be multifactorial and, importantly, may be reversible (eg, decreased calorie intake related to oral cGVHD, esophageal stricture, or intestinal malabsorption). (D) Abnormalities found on the complete blood count are known prognostic factors,^,,, including in newly diagnosed cGVHD.^, CMV, cytomegalovirus; EBV, Epstein-Barr virus; HSV, herpes simplex virus; PCR, polymerase chain reaction.