Bone Marrow Transplantation (2017) 52, 337–340 © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved 0268-3369/17 www.nature.com/bmt LETTER TO THE EDITOR A proposed biology- and biomarker-based algorithm for management of acute GvHD Bone Marrow Transplantation (2017) 52, 337–340; doi:10.1038/ manifestation (Figure 1), along with the accurate stratification of bmt.2016.289; published online 21 November 2016 these patients (Figure 2). Secondly, novel therapeutic targets are desperately needed as no treatment to date added to upfront steroids has proven beneficial. Acute GvHD remains a major cause of hematopoietic cell We propose that layering detailed information regarding the transplant (HCT)-related mortality. aGvHD represents the primary risk factors of advanced and refractory aGvHD, biological and limitation to more widespread use of allogeneic HCT as a biomarker profile, endoscopic and histological findings over potentially curative modality for patients with malignant and descriptive classical organ staging will provide a more accurate non-malignant diseases. Two main approaches may improve the risk stratification of patients with aGvHD. A more precise outcomes of patients with aGvHD: the ability to diagnose the prediction of the outcomes will lead to application of the disease in a timely manner, or even predict aGvHD prior to clinical treatment principle ‘to each according to his need’ and Diagnosis Symptoms of aGvHD Diarrhea ± abdominal Skin rash Liver injury Satiety, anorexia, pain nausea and vomiting after day Yes 20 even in the absence of diarrhea, gut or liver manifestations Cholestatic Hepatitic especially with risk High pretest probability 1 factors for CMV of GvHD, skin GvHD is No present, low risk of Typical and no competing CMV1, and screening diagnosis Evidence of gut and/or After day 100 2 panel of gut infection is 6 EGD with biopsies skin GvHD and on minimal negative (Rate of false-negative immunosuppres No Yes histology is high) sion or after No Yes No 10 Yes DLI Extensive: Stage III or IV No Yes Risk for GvHD related mortality: Biopsy4 No risk of viral deep jaundice>3-4, diarrhea>>1L, 7 Yes infection, SOS Clinical extensive skin rash, albumin 8 3 Yes or DILI diagnosis drop>0.5 or albumin <1.6 g/dL No Yes No No Skin biopsy5 Skin biopsy Clinical diagnosis is 11 can be sufficient9 Liver biopsy Biopsy can be deferred deferred Check biological profile12 Serum albumin and total bilirubin Serum biomarkers: TNFR1, ST2, REG3a Fecal calprotectin & Fecal α-1 antitrypsin Absolute lymphocyte count (ALC) Endothelial markers: angiopoietin-2, circulating angiogenic factors (EGF, VEGF-A, FS, and PlGF) C-reactive protein Cytokine profile Figure 1. For caption see next page. Letter to the Editor 338 Figure 1. 1. Risk factors for CMV: seropositive recipient, mismatched or unrelated donor, T-cell depletion, alemtuzumab administration. 2. The rate of false-negative histology in upper-gut GvHD is significant. Discordance between symptoms, endoscopic findings and ‘negative’ mucosal histology for GvHD is common. When the burden of evidence favors a diagnosis of GvHD, treatment should be started.1 3. A decrease in serum albumin ⩾ 0.5 g/ dL is a useful marker of impending lower-gut GvHD.2 4. Terminal ileum should be inspected whenever possible (small bowel shows grade 4 involvement more frequently than the colon).1 Colonoscopy including inspection of terminal ileum has the highest diagnostic yield, which is not increased by additional upper EGD. The combination of recto-sigmoidoscopy and EGD including histology of the duodenum may be equivalent. 5. Skin biopsy may be dispensable because of the characteristic clinical features of aGvHD and inability to assure distinct discrimination between aGvHD and other diagnosis. Skin biopsy should be performed based on the stage (extensive rash), the clinical course of aGvHD, in cases of atypical clinical features, or attempting to exclude other diagnosis.3 Further systematic investigations of the indications and the appropriate point of time for the biopsy are required. 6. Rare cases of acute liver GvHD in the absence of skin and gut GvHD must be distinguished from drug-induced liver injury (DILI), cholangitis lenta and biliary obstruction. 7. Risk for sinusoidal obstruction syndrome: preexisting liver disease, choice of conditioningtherapy (higher doses of RT given as single dose, cyclophosphamide, busulfan, cytarabine, azathioprine, carmustine, mitomycin, dacarbazine), patient age, poor baseline performance status. 8. Risk for DILI: medications used for myeloablative conditioning (for example, cyclophosphamide, busulfan), other chemotherapy agents (for example, cytarabine, carmustine, mitomycin, 6-mercaptopurine, dacarbazine), drugs for GvHD prophylaxis (for example, cyclosporine, methotrexate) and antimicrobials (for example, amphotericin and azole antifungal agents, trimethoprim-sulfamethoxazole, ribavirin). Given the number of medications used and their sometimes unpredictable effect on liver function, it is often difficult to define the contribution of any single drug. 9. In a patient with skin and gut GvHD who is not at risk for viral infection or DILI but who develops cholestatic liver injury, a clinical diagnosis can suffice. 10. Acute hepatitis with marked elevation of serum alanine aminotransferase, usually after day 100, is most commonly seen in allograft recipients on minimal immunosuppression or after donor lymphocyte infusion (DLI).4 Immunosuppressants are usually discontinued and donor lymphocytes are infused upon relapse of leukemia, in attempt to achieve a GvL effect. Severe GvHD that develops after DLIs can lead to rapidly progressive mucosal and hepatocellular necrosis, jaundice and multi-organ failure. The prognosis is usually dismal in these cases and both GvHD and leukemia relapse will lead to death. 11. Liver biopsy is not useful for diagnosis of IL-6-caused cholestasis but may be essential when there are competing or simultaneous causes of liver injury (sinusoidal obstruction syndrome: viral hepatitis or DILI). 12. The key mechanistic and biological insights that are emerging from pre-clinical studies provide a fertile ground for translational studies. There is now an abundance of viable strategies that can be derived from these new insights not only to improve the diagnosis and risk stratification (serum albumin,2 endothelial markers,5 serum biomarkers,6,7 and absolute lymphocyte count8,9) of aGvHD, but also to provide new and effective therapeutics (cytokine inhibitors10). Grading and risk stratification Standard-risk High-risk 1 organ (stage 1-3 skin or stage 1-2 GI) or 2 organs Refined (stage 1-3 skin + stage 1 GI or stage 1-3 skin + stage MacMillan13 1-4 liver)14 Classical Grade II Grade I Grade III-IV Glucksberg or IBMTR Biomarker- Low-score Moderate-score High-score based15 (TNFR1, ST2, REG3α) Other risk factors to consider when deciding low vs high dose: mismatched unrelated16, diarrhea volume, high total bili at onset, abrupt fall in albumin≥ 0.5 g/dL, extevsive skin GvHD , ulceration & sloughing, and histology. Therapy17 Well-designed Optimize CI Methylprednisolone or prednisone 1 Methylprednisolone 2 Well-designed phase II or III Levels. mg/kg/d (0.5 may be also acceptable)20 mg/kg/d or prednisone at 2- phase II or III trials that test Maximize Optimize CI Levels. 2.5 mg/kg/d. trials that test less intensive topical agents19 Maximize topical agents. Optimize CI Levels. novel, and Nonabsorbable steroids for GI 8- Maximize topical agents. intensified, or immunosuppr 9mg/day21 Nonabsorbable steroids for combined essive Adjunctive therapy: UDCA GI 8-9 mg/day. therapies with therapies18 Adjunctive therapy: UDCA standardized endpoints18 Figure 2. For caption see next page. Bone Marrow Transplantation (2017) 337 – 340 © 2017 Macmillan Publishers Limited, part of Springer Nature. Letter to the Editor 339 Figure 2. 13. MacMillan refined score uses standard GvHD organ staging categories, with ‘high-risk GvHD (HR-GvHD)’ differentiated from ‘standard-risk GvHD: SR-GvHD’ by number of organs involved and severity of symptoms. Failure to achieve a complete response to prednisone after initial therapy for 28 days was seen in 73% and 52% of patients with high-risk GvHD and standard-risk GvHD, respectively. This suggests that a significant number of patients classified as standard risk had their risk treatment failure at 28 days underestimated, and buried in the classification ‘high-risk’ are patients who are incurable by any means.11 A free web-based program to easily determine the GvHD risk group for a given patient using this refined risk score is available at: http://z.umn.edu/MNAcuteGVHDRiskScore. Incorporating biomarkers into the available clinical scores may improve the predictive and risk-stratification power of these scores. 14. 1% of patients present with stage 1-4 liver disease alone and should be deemed as HR-GvHD as their outcomes are universally poor. However, 3% of patients who present with stage 1-3 skin plus stage 1-4 liver have favorable outcomes and should be considered standard-risk GVHD. This discrepancy cannot be fully explained.11 15. Incorporating the clinical characteristics and risk factors with biomarker scores (such as Ann Arbor score) will improve the predictive power of these scores and their treatment algorithms.6,7 16. Patients who receive a graft from a HLA-matched or mismatched URD are less likely to respond than those who received either a related donor or an umbilical cord blood graft. 17. There are few reports of randomized controlled