This patient’s clinical presentation most strongly suggests acute GVHD, possibly complicated by CMV reactivation.  44% of respondents favored concurrent treatment for CMV and GVHD, while 29% would treat only for CMV and 24% would treat only for GVHD at this point.  Given the new skin/gut/liver findings, the diagnosis of GVHD is clinically established, and treatment should not await biopsy documentation. Prompt initiation of steroids is warranted even when a patient has low stage multiorgan GVHD (skin stage 2, gut 1, liver 1; Clinical grade II or grade B using Consensus or IBMTR grading schemas). 

In addition, effective anti-viral therapy should be started in a patient with low level viremia, particularly if steroids are started for GVHD. I favor treatment with ganciclovir over foscarnet or cidofovir, especially in a patient with mildly compromised renal function receiving tacrolimus.

With undetectable CMV, persistence of the GVHD symptoms after 8 days is a usual indication for added therapy.  I would also review the patient’s medications and workup thus far (review/repeat earlier biopsies; consider liver biopsy) and consider alternate diagnoses that could explain why the patient is not responding to GVHD treatment. For example, I would consider other diagnoses such as a drug rash, C. difficile, withdrawal of constipating drugs like opiates, drug-induced diarrhea from antacids, magnesium, or stool softeners or drug-induced cholestasis from fluconazole, voriconazole, or TMP-sulfa could be confounding or exaggerating the signs of GVHD

Second choice therapy for steroid-resistant acute GVHD is not standardized, and the poll reflects the uncertainty in the field. Only prednisone (for those 34% not giving it initially) or MMF (chosen by 26%) received substantial enthusiasm. A few chose ATG, sirolimus, etanercept or other therapy.  For uncertain reasons, nearly 9% of respondents did not add additional therapy despite clear persistence of GVHD after 8 days of high dose steroids. I would not recommend this approach as early recognition of steroid-resistant GVHD and addition of a second agent is most likely to result in control of GVHD, even if the optimal therapy is still undefined. In the absence of an appropriate clinical trial, addition of any of these agents is reasonable.

References

Weisdorf D, Haake R, Blazar B, et al. Treatment of moderate/severe acute graft-versus-host disease after allogeneic bone marrow transplantation: an analysis of clinical risk features and outcome. Blood, 1990;75:1024-1030.

Martin PJ, Schoch G, Fisher L, Byers V, Anasetti C, Appelbaum FR, et al. A retrospective analysis of therapy for acute graft-versus-host disease: initial treatment. Blood, 1990;76:1464-1472.

Hings IM, Severson R, Filipovich AH, et al. Treatment of moderate and severe acute GVHD after allogeneic bone marrow transplantation. Transplantation, 1994;58:437-442.

MacMillan ML, Weisdorf DJ, Wagner JE, DeFor TE, Burns LJ, Ramsay NK, Davies SM, Blazar BR.  Response of 443 Patients to Steroids as Primary Therapy for Acute Graft-versus-Host Disease:  Comparison of Grading Systems.  Biol Blood Marrow Transplant, 2002;8(7):387-394.

MacMillan ML, Weisdorf DJ, Davies SM, DeFor TE, Burns LJ, Ramsay NK, et al. Early antithymocyte globulin therapy improves survival in patients with steroid-resistant acute graft-versus-host disease. Biol Blood Marrow Transplant, 2002;8:40-46.

Lee SJ, Zahrieh D, Agura E, MacMillan ML, Maziarz RT, McCarthy PL, et al. Effect of up-front daclizumab when combined with steroids for the treatment of acute graft-vs.-host disease: results of a randomized trial. Blood, 2004;104:1559-1564.

Nash RA, Furlong T, Storb R, Anasetti C, Appelbaum FR, Deeg HJ, et al. Mycophenolate mofetil (MMF) as salvage treatment for graft-versus-host-disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT): safety analysis. Blood, 1997;90 (Suppl. 1):105a.

Bolanos-Meade J, Jacobsohn DA, Margolis J, Ogden A, Guillaume Wientjes M, Byrd JC, et al. Pentostatin in steroid refractory acute graft versus host disease. J Clin Oncol, 2005:23:2661-2668.

Couriel D, Saliba R, Hicks K, Ippoliti C, Marcos de Lima, Hosing C, et al. Tumor necrosis factor alpha blockade for the treatment of acute GVHD. Blood, 2004;104:649-654.