Bone Marrow Transplantation (2003) 32, 165–170 & 2003 Nature Publishing Group All rights reserved 0268-3369/03 $25.00 www.nature.com/bmt Graft-Versus-Host Disease Thalidomide after allogeneic haematopoietic stem cell transplantation: activity in chronic but not in acute graft-versus-host disease S Kulkarni, R Powles, B Sirohi, J Treleaven, R Saso, C Horton, A Atra, M Ortin, C Rudin, S Goyal, S Sankpal, S Meller, CR Pinkerton, J Mehta1 and S Singhal1 Leukaemia and Myeloma Units, Royal Marsden Hospital, Surrey, UK Summary: of morbidity and mortality after allogeneic haematopoietic stem cell transplantation, and is directly or indirectly Thalidomide was used to treat acute (n ¼ 21) or chronic responsible for death in over half of the patients who (n ¼ 59) graft-vs-host disease (GVHD) in 80 haemato- experience treatment-related mortality. Patients with acute poietic stem cell allograft recipients after failure to leukaemia who are alive and well 2 years after an allograft respond to the combination of cyclosporine and corticos- have a significantly higher risk of continued treatment- teroids with or without other agents. The median time to related mortality, and poorer survival in the presence of onset of acute GVHD was 11 days, and thalidomide was chronic GVHD requiring immunosuppressive therapy.6 started at a median of 48 days post transplant. In addition This results from a number of factors including infections to corticosteroids and cyclosporine, 13 patients had also and secondary malignancies.7,8 received other agents before thalidomide. None of the The treatment of chronic GVHD is difficult. Cyclospor- patients responded and all died of acute GVHD. For ine, prednisone, and azathioprine have been the main chronic GVHD (limited in 13, extensive in 46), thalido- agents used with variable success rates. The combination of mide was started at a median of 385 days post transplant. cyclosporine and prednisone used for high-risk chronic In addition to corticosteroids and cyclosporine, 34 patients GVHD results in a response rate of 30–40%.9 The addition received azathioprine concomitantly. In all patients, of azathioprine in standard-risk patients has been asso- thalidomide was added to the ongoing immunosuppressive ciated with adverse outcome.10 While none of the newer regimen. The median duration of therapy with thalidomide drugs has activity that is consistently superior to cyclo- was 60 days (range, 11–1210; o2 weeks in 11). In total, sporine-prednisone, alternative drugs have been found to 13 patients (22%) had complete response, eight (14%) be useful in certain situations.11 partial response and 38 (64%) no response. Response Thalidomide was developed as a sedative–hypnotic drug, rates were comparable for limited (39%) and extensive but the development of severe foetal malformation led to (33%) chronic GVHD. At a median of 53 months, 19 withdrawal of its use from clinical practice.12 Its diverse patients are alive, 13 without evidence of chronic GVHD. effects on the immune system and the cytokine cascade Survival was significantly better in patients who responded resulted in continued exploration of the drug in various to thalidomide. The principal causes of death were disorders.12 Initial murine data showed that the drug was progressive chronic GVHD (n ¼ 29) and relapsed leukae- active in acute GVHD,13 and subsequent human data mia (n ¼ 7). In conclusion, thalidomide has no activity in showed it to be active in acute14 as well as chronic acute GVHD, but has some activity in chronic GVHD in GVHD.15–17 While questions have been raised about its combination with other agents. activity in chronic GVHD in a recent blinded, placebo- Bone Marrow Transplantation (2003) 32, 165–170. controlled study,18 most phase II reports show that the doi:10.1038/sj.bmt.1704033 drug does possess some activity in GVHD.19–23 Keywords: Thalidomide; transplantation; GVHD Our preliminary impression of thalidomide was that it controlled chronic GVHD in a proportion of patients with haematological malignancies without increasing relapse24— perhaps in some way secondary to its antimalignancy Acute graft-versus-host disease (GVHD) is seen in 20–80% activity.12,25 We have now undertaken a formal retro- of marrow- or blood-derived haematopoietic stem cell spective analysis of our data to see if this impression is allograft recipients, and chronic GVHD in 30–60% of accurate. those surviving beyond day 100.1–5 GVHD is a major cause Patients and methods Correspondence: Professor R Powles, Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, UK. 26 1Current address: Division of Hematology/Oncology, Northwestern Comprehensive, prospectively gathered data on 80 University Medical School, Chicago, IL, USA allograft recipients treated with thalidomide for acute Received 8 May 2002; accepted 17 October 2002 (n ¼ 21) or chronic (n ¼ 59) GVHD at the Royal Marsden Thalidomide after allo-HSCT S Kulkarni et al 166 Table 1 Patient characteristics preceded by acute GVHD, progressive if it evolved from acute GVHD, and quiescent if there was a period without Parameter Acute Chronic GVHD GVHD GVHD between acute and chronic GVHD. Total 2159 Sex Treatment of GVHD Male 14 39 Female 7 20 Patients with acute GVHD were initially treated with high- Median age 24.5 y 31.5 y dose intravenous methylprednisolone (10–20 mg/kg/day) (Range) (4–51) (2–52) for at least 3 days. Further therapy was continued Diagnosis according to the clinical response. All patients also Acute leukaemia 15 34 Chronic myeloid leukaemia 5 13 continued cyclosporine during the therapy of acute GVHD. Other malignancies 112 Patients developing chronic GVHD after stopping Donor cyclosporine were recommenced on the drug. All patients HLA-matched sibling 20 47 were initially also treated with oral prednisone (1–5 mg/kg/ Matched unrelated 112 day). Other drugs such as azathioprine, tacrolimus (sub- Conditioning TBI-based 14 51 stituted for cyclosporine) and mycophenolate mofetil were Chemotherapy 7 8 added if there was no improvement. GVHD prophylaxis Cyclosporine 15 12 Cyclosporine–methotrexate 6 47 Thalidomide therapy Stem cell source Marrow 18 50 Thalidomide was started at a dose of 50–100 mg thrice a Blood 3 9 day. The dose was gradually increased to reduce the severity of the side effects with the aim of administering a total daily dose of 600–1200 mg. The dose was adjusted Hospital were reviewed. Patient characteristics are shown according to patient tolerance, and clinical signs and in Table 1. Conditioning regimens used were standard and symptoms of GVHD. Patients continued all the immuno- varied with the disease. All patients and donors provided suppressive agents they were already receiving. Four informed consent for the procedure, and all research patients with severe pulmonary involvement were treated protocols were approved by the institutional review board. with the combination of thalidomide, tacrolimus, predni- sone and azathioprine (four-drug therapy) as first-line therapy. GVHD prophylaxis Cyclosporine was started at a dose of 3 mg/kg/day Response evaluation intravenously on day À1and was switched to the oral Standard response criteria28,30 were used to evaluate route when mucositis resolved. Oral cyclosporine was response. Complete response (CR) was defined as complete started at a dose of 12.5 mg/kg/day in two divided doses. resolution of clinical signs, no new organ involvement, and The dose was gradually tapered after day 50 at the rate of normal performance status. Partial response (PR) was 5%/week with the aim of stopping the drug on day +180. defined as improvement in the performance status of at Methotrexate, when used, was given at a dose of 15 mg/m2 least two orders and at least 50% resolution of signs and on day +1and 10mg/m 2 on days +3, +6, and +11. symptoms of disease. No response (NR) was defined as lack Unless there was significant liver or kidney dysfunction, of improvement within 3 months or progression of disease methotrexate doses were not modified or omitted. on therapy. Supportive care Statistical methods All patients were nursed in positive-pressure HEPA-filtered The probabilities of survival and mortality were determined single rooms. Patients received oral nonabsorbable anti- using the Kaplan–Meier life-table method. The percentage biotics. Prophylactic growth factors were not administered of patients responding to thalidomide was compared using routinely. Neutropenic fever was treated with broad- the Wilcoxon rank-sum test. spectrum antimicrobial agents according to the prevalent institutional guidelines. All blood products were irradiated to 2500 cGy. All patients received Pneumocystis prophy- Results laxis with oral trimethoprim-sulphamethoxazole or inhaled pentamidine. Patients with chronic GVHD received peni- Acute GVHD cillin V for pneumococcal prophylaxis.7 The median time to development of acute GVHD was 11 Grading and staging of GVHD days (range 9–40). Skin was involved in all, liver in 13 and gut in 19. In addition to high-dose methylprednisolone and Acute27 and chronic28,29 GVHD were graded and staged cyclosporine, patients also received a murine anti-IL2 according to standard previously published criteria. receptor antibody (n ¼ 5), azathioprine (n ¼ 2), Campath- Chronic GVHD was considered de novo if it was not 1G(n ¼ 2), methotrexate (n ¼ 2), total-lymphoid irradiation Bone Marrow Transplantation Thalidomide after allo-HSCT S Kulkarni et al 167 Chronic GVHD N=59 CR PR NR N=13 N=8 N=38 12 alive 1 dead 2 alive 6 dead 5 alive 33 dead 25 chronic GVHD 3 on Second 2 on 4 chronic GVHD 2 on 5 relapsed immunosupression immunosupression 2 Relapsed leukaemia malignancy leukaemia immunosupression 3 other 1 on 1 on thalidomide 0 on thalidomide thalidomide Figure 1 Thalidomide in chronic graft-versus-host disease – patient flow. (n ¼ 1) and antithymocyte globulin (n ¼ 1). All patients had Table 2 Organ involvement in 59 patients with chronic GVHD progressive GVHD, with no response to the first- or Organ n % second-line therapy.