Year: 2008
Type: article
Abstract: A 38-year-old man received a myeloablative conditioning regimen and peripheral blood stem cell transplant (PBSCT) from his HLA identical sister for acute myelogenous leukemia (AML) in an early second relapse. The patient developed grade II acute graft-versus-host disease (aGVHD) on day 40 after transplantation, which responded promptly to steroids at 2 mg/kg/day. A steroid taper was begun. When his steroid dose reached 0.25 mg/kg/day, a new raised rash with plaque-like lesions involving 36% of his body surface area and mouth sores developed. Liver function tests were 5 times normal and a platelet count was 40,000. Steroids were increased to 1 mg/kg/day for the diagnosis of chronic GVHD (cGVHD), and tacrolimus was continued. Unfortunately, when seen 2 weeks later his skin rash was almost confluent, oral examination showed an extensive lichen planus-like eruption, liver function tests were now 10 times normal, and his platelet count was 20,000. The patient is quite symptomatic, and reports that he lost 20 pounds and is unable to accomplish his normal activities.What therapy would you recommend?•Continue current therapy—the patient has had an inadequate steroid trial to evaluate his response•Add PUVA (Psoralen and UVA light)•Add mycophenolate mofetil (MMF)•Add rituximab•Add sirolimus A 38-year-old man received a myeloablative conditioning regimen and peripheral blood stem cell transplant (PBSCT) from his HLA identical sister for acute myelogenous leukemia (AML) in an early second relapse. The patient developed grade II acute graft-versus-host disease (aGVHD) on day 40 after transplantation, which responded promptly to steroids at 2 mg/kg/day. A steroid taper was begun. When his steroid dose reached 0.25 mg/kg/day, a new raised rash with plaque-like lesions involving 36% of his body surface area and mouth sores developed. Liver function tests were 5 times normal and a platelet count was 40,000. Steroids were increased to 1 mg/kg/day for the diagnosis of chronic GVHD (cGVHD), and tacrolimus was continued. Unfortunately, when seen 2 weeks later his skin rash was almost confluent, oral examination showed an extensive lichen planus-like eruption, liver function tests were now 10 times normal, and his platelet count was 20,000. The patient is quite symptomatic, and reports that he lost 20 pounds and is unable to accomplish his normal activities. What therapy would you recommend?•Continue current therapy—the patient has had an inadequate steroid trial to evaluate his response•Add PUVA (Psoralen and UVA light)•Add mycophenolate mofetil (MMF)•Add rituximab•Add sirolimus In a recent issue of the ASBMT eNEWS, readers were presented with the above Clinical Challenge and invited to use an online poll to recommend a course of treatment. The reader recommendations for therapy were:•54% Add mycophenolate mofetil•17% Add PUVA (Psoralen and UVA light)•15% Add sirolimus•10% Add rituximab•5% Continue current therapy—the patient has had an inadequate steroid trial to evaluate his response This patient has very high-risk, steroid-refractory chronic graft-versus-host disease (cGVHD), because he has progressed despite appropriate doses of steroids administered for at least 2 weeks [1Martin P.J. Weisdorf D. Przepiorka D. et al.National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: VI. Design of Clinical Trials Working Group report.Biol Blood Marrow Transplant. 2006; 12: 491-505Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar]. Therefore, continuing current therapy would not be a desirable therapeutic option in this patient. Some manifestations in our patient are reminiscent of acute GVHD (aGVHD) and such late presentations of aGVHD manifestations are associated with worse survival in cGVHD studies [2Jagasia M. Giglia J. Chinratanalab W. et al.Incidence and outcome of chronic graft-versus-host disease using National Institutes of Health Consensus Criteria.Biol Blood Marrow Transplant. 2007; 13: 1207-1215Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar]. Unfortunately, the prognosis for this patient is grim, and the best therapy is not known [3Shlomchik W.D. Lee S.J. Couriel D. Pavletic S.Z. Transplantation's greatest challenges: advances in chronic graft-versus-host disease.Biol Blood Marrow Transplant. 2007; 13: 2-10Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar]. If a clinical trial is available, we would strongly recommend enrolling this patient to help us determine the best treatment for patients with multiple high-risk features not responding to primary steroid-based therapy. The options listed are not optimal. In this poll 17% of respondents recommended PUVA. PUVA therapy has been shown to be helpful in patients with skin (lichen planus-like) disease only, but not systemic disease as seen in this patient [4Vogelsang G.B. Wolff D. Altomonte V. et al.Treatment of chronic graft-versus-host disease with ultraviolet irradiation and psoralen (PUVA).Bone Marrow Transplant. 1996; 17: 1061-1067PubMed Google Scholar]. Phototherapy (not given as an option in this poll) is more commonly delivered in the form of extracorporeal photopheresis (ECP) and could be considered as it may control systemic GVHD, whereas theoretically maintaining the desired graft-versus-leukemia (GVL) effect. But the rapid progression of the patient's symptoms is concerning because ECP therapy often requires several weeks to see improvement. Likewise, he would require careful management with his degree of thrombocytopenia through the line placement and the procedure. At least in 1 trial patients with thrombocytopenia also had a lower rate of response to ECP [5Couriel D. Hosing C. Saliba R. et al.Extracorporeal photopheresis for acute and chronic graft-versus-host disease: does it work?.Biol Blood Marrow Transplant. 2006; 12: 37-40Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar]. Fifty-four percent of respondents recommended mycophenolate mofetil (MMF). MMF has been used in steroid-refractory cGVHD and is the most commonly used second-line agent. There have been a number of small phase II trials reported using MMF, with response rates in steroid refractory disease ranging from 45% to 75% [6Cutler C. Antin J.H. Chronic graft-versus-host disease.Curr Opin Oncol. 2006; 18: 126-131Crossref PubMed Scopus (43) Google Scholar]. Although the drug is well tolerated in general, in our experience it would be difficult to administer in this patient given his mouth sores, weight loss, and thrombocytopenia. Mycophenolic acid (MPA) drug levels may prove useful in ensuring he is receiving an adequate trial. Rituximab (10% of responders) is also appealing given its low toxicity, positive effects in immune thrombocytopenia, and unique mechanism of action. However, rituximab may be less effective for visceral disease, such as the rapidly progressive hepatic involvement seen in this patient [7Cutler C. Miklos D. Kim H.T. et al.Rituximab for steroid-refractory chronic graft-versus-host disease.Blood. 2006; 108: 756-762Crossref PubMed Scopus (372) Google Scholar]. Sirolimus (15% of responders) has been studied also in phase II trials of cGVHD [8Couriel D.R. Saliba R. Escalon M.P. et al.Sirolimus in combination with tacrolimus and corticosteroids for the treatment of resistant chronic graft-versus-host disease.Br J Haematol. 2005; 130: 409-417Crossref PubMed Scopus (156) Google Scholar]. When combined with tacrolimus and steroids, response rates of more than 60% have been reported. The major toxicity seen with this combination was renal. Again, obtaining blood levels may help to minimize toxicities and ensure an adequate trial of treatments. We would encourage the patient to enroll in a clinical trial, if one is available. If the patient is unable to participate in a trial, then of the potential treatments listed above, we would first try sirolimus because of its mechanism of action and encouraging results reported so far. However, both MMF and rituximab are also reasonable choices. Because this patient is showing some worrisome features of aGVHD, it would be reasonable concurrently with starting the new therapy also to administer a 3- to 7-day course of prednisone at 2 mg/kg/day or a 4-day pulse of intravenous methylprednisolone at 10 mg/kg/day for more rapid disease control and then go back immediately to previous dose of prednisone [9Akpek G. Lee S.M. Anders V. Vogelsang G.B. A high-dose pulse steroid regimen for controlling active chronic graft-versus-host disease.Biol Blood Marrow Transplant. 2001; 7: 495-502Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar]. As stated above, the best therapy is not known, and it is unfortunately a matter of trial and error based on toxicity profiles, past experience, and patient choice. cGVHD remains a great challenge, and major community efforts will need to continue to better address this late effect of transplantation.
Authors: Steven Pavletic, Georgia B. Vogelsand
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,650
OpenAlex ID: W2032199366