How I treat refractory chronic graft-versus-host disease

Stefanie Sarantopoulos, Adela R. Cardones and Keith M. Sullivan

Data supplements

Article Figures & Data


  • Figure 1.

    NIH global severity assessments to determine need for intervention in patients with ongoing cGVHD.24,25 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.24,25 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.102 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.103 cGVHD of the liver can be diagnosed and tracked in patients using total bilirubin and alkaline phosphatase per NIH consensus criteria.25 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.94,104 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,9,79,101,105 including in newly diagnosed cGVHD.81,105 CMV, cytomegalovirus; EBV, Epstein-Barr virus; HSV, herpes simplex virus; PCR, polymerase chain reaction.


  • Table 1.

    Adverse reactions of commonly used therapies in refractory chronic GVHD14

    AgentPotential major adverse effects (with major study citations)Common (>10%) generally less severe adverse effects
    BortezomibPeripheral neuropathy, thrombocytopenia, malignancy relapse106Herpes virus reactivation
    ECPVascular access complications107Thrombocytopenia
    FAMNew FDA MedWatch warning; warning only applies to azithromycin use in prophylactic (not treatment) setting108,109
    Ibrutinib (Imbruvica R)Pneumonia,29 impaired platelet functionFatigue, muscle pain, peripheral edema
    ImatinibPeripheral edema
    Interleukin-2Injection site induration, infections36Constitutional flu-like symptoms
    MMF (Cellcept)Viral reactivation, hypertension, pneumonia, posttransplantation lymphoproliferative disease110GI toxicity, neutropenia, leukopenia
    PamolidomideTremor, muscle cramps, peripheral neuropathy111Skin rash
    Rituximab (Rituxan R)Infection, late neutropenia38,39,112B lymphopenia
    Ruxolitinib (Jakafi R)Viral reactivation/infection, bacterial infections35Cytopenias
    Sirolimus (Rapamune)TAM when used in combination with calcineurin inhibitors, renal insufficiency,113 proteinuriaPeripheral edema, hyperlipidemia, cytopenias
    • This list of agents represents a fraction of agents being actively evaluated. Preferred use of any agent still requires validation via larger clinical trials.

    • ECP, extracorporeal photopheresis; FAM, fluticasone, azithromycin, and montelukast; FDA, US Food and Drug Administration; GI, gastrointestinal; MMF, mycophenolate mofetil; TAM, transplantation-associated microangiopathy.