Randomized clinical trial of thalidomide, cyclosporine, and prednisone versus cyclosporine and prednisone as initial therapy for chronic graft-versus-host disease.

Chronic graft-versus-host disease (CGVHD) is a major cause of morbidity following allogeneic bone marrow transplantation. Thalidomide is active in salvage therapy for high-risk or resistant CGVHD. In a prospective randomized trial, we tested initial therapy with thalidomide. Patients with extensive CGVHD were randomized to receive either cyclosporine and alternate-day prednisone (n = 27, no-thalidomide [no-thal] group) or cyclosporine, prednisone, and thalidomide (200-800 mg/day; n = 27, thal group). Although most patients responded, initial therapy with thalidomide did not improve control of CGVHD. Response rates were 83% versus 89% at 2 months (P = .7), 88% versus 84% at 6 months (P > .8) and 85% versus 73% at 1 year (P = .5) in the thal and no-thal groups, respectively. Multivariate analysis revealed related donor transplant (odds ratio [OR] = 11.3; P =.03) and de novo or quiescent onset of CGVHD (OR = 7.7; P =.04) to be significant predictors of good early response, whereas a platelet count of > or =100,000/microL was a significant predictor of good response (OR = 10.4; P =.04) at 1 year. Survival for the thal and no-thal groups was similar at 1 year (66% versus 74%) and 2 years (66% versus 54%, P = .85). Multivariate analysis revealed progressive onset CGVHD (relative risk [RR] = 4.2; P =.01), unrelated donor (RR = 5.7; P < .01), sex mismatch (RR = 7.9; P < .01), and platelet counts of <100,000/microL (RR = 3.8; P = .01) as significant predictors of poorer survival. These data suggest that despite a high response rate (79% response and 53% complete response) and encouraging survival rates (70% at 1 year and 60% at 2 years), thalidomide offers no clinical benefit when incorporated into initial therapy for CGVHD. The value of thalidomide as salvage therapy requires further study.     

Dasatinib as salvage therapy for steroid refractory and imatinib resistant or intolerant sclerotic chronic graft-versus-host disease

Sclerotic chronic graft-versus-host disease (scGVHD) is a severe form of this disease that resembles systemic sclerosis and has limited and disappointing treatment options. Tyrosine kinase inhibitors (TKI) targeting up-regulated profibrotic pathways, such as imatinib mesylate, have been proposed as a potential therapeutic approach for patients with scGVHD. Dasatinib, a second-generation TKI with a well-established safety and efficacy profile in chronic myeloid leukemia patients, who are refractory or intolerant to imatinib, has also shown potent antifibrotic effects. We present here the first direct clinical evidence, from 3 patients treated in a small single-center series, suggesting that dasatinib can be a therapeutic option for patients with severe scGVHD resistant or intolerant to imatinib. All patients achieved partial response, with improvement in scGHVD target organs severity, joint mobility, lung impairment, and deep fibrotic lesions. This clinical response has remained stable or continued to improve after a median of 22 months (20-25) on dasatinib treatment, with very good tolerance. In addition, corticosteroids could be discontinued or significantly reduced in all patients. This clinical evidence suggests that dasatinib could be a safe and effective alternative for scGVHD patients refractory to corticosteroids and resistant or intolerant to imatinib. Based on these preliminary findings, and in order to address appropriate patient selection, time of intervention, and choice of drug, future larger studies should more formally establish the efficacy and safety of second-generation TKI for the treatment of scGVHD.     

Sirolimus as part of immunosuppressive therapy for refractory chronic graft-versus-host disease.

Many patients receiving allogeneic stem cells develop chronic graft-versus-host disease (cGVHD), which remains as the main cause of morbidity and mortality. Although the first line of therapy is generally with steroids, it is not well known how to manage refractory cases. Those patients are usually treated with alternative experimental agents. Sirolimus (Rapamycin), a new immunosuppressive agent, inhibits signal transduction and cell cycle progression after binding to FKBP12. We report a retrospective analysis with sirolimus in transplant recipients with cGVHD refractory to previous immunosuppressive therapy. Forty-seven patients with refractory or relapsed cGVHD were treated with the combination of sirolimus and calcineurin inhibitors (n = 33), mycophenolate (n = 9), or prednisone (n = 5). Thirty-eight of 47 (81%) patients had clinical responses (complete = 18, partial = 20). The main toxicity was mild renal failure, particularly at the start of therapy. Four patients who presented thrombotic microangiopathy were managed with plasmapheresis and the discontinuation of sirolimus and calcineurin inhibitors. Statistical analysis showed the type of cGVHD onset and presirolimus clinical status as the main variables influencing the response to treatment. The Kaplan-Meier estimate of survival was 57.4% at 3 years. The current study shows the efficacy and safety of sirolimus in refractory cGVHD patients. Further investigation is warranted to elucidate the role of sirolimus in cGVHD, and find the best combination (sirolimus + calcineurin inhibitors versus others) for therapeutic use.     

Bisphosphonate therapy for reduced bone mineral density in children with chronic graft-versus-host disease.

Reduced bone mineral density (BMD) occurs frequently in children after hematopoietic cell transplantation (HCT), but therapy for this complication is undefined. To determine the impact of bisphosphonate therapy on reduced BMD after HCT, we compared baseline and follow-up dual energy X-ray absorptiometry (DEXA) scans of 48 patients (controls) who received calcium and vitamin D to 18 patients who also received bisphosphonate therapy. Among the controls, median annualized increase in standardized BMD (sBMD) was 10% (range, -26% to +41%), but the deviation of sBMD from normal, as indicated by the Z-score, did not improve from baseline, -2.46 (range: -5.15 to -1.16) compared to follow-up, -2.79 (range: -5.76 to +0.07). For the bisphosphonate-treated patients, the median annualized increase in sBMD was 33% (range 3% to 147%, P = .0002) and the median Z-score improved from -3.57 (range: -5.13 to -0.86) at baseline, to -1.80 (-4.89 to +0.47) at follow-up (P = .06). The annualized median change in BMD Z-scores per year was +0.12 (-2.28 to +4.24) among the controls and +1.43 (-0.29 to +3.72) for the bisphosphonate group (P = .0002). The greatest improvement in BMD was observed in children who received therapy with bisphosphonates.     

Thalidomide for the treatment of chronic graft-versus-host disease.

BACKGROUND. Allogeneic bone marrow transplantation is an accepted therapy for hematologic cancer, aplastic anemia, and inherited immunodeficiencies. Chronic graft-versus-host disease (GVHD) is the principal complication in patients surviving more than 100 days. Thalidomide has been shown experimentally to be effective in treating GVHD. METHODS. We treated 23 patients with chronic GVHD refractory to conventional treatment and 21 patients with "high-risk" chronic GVHD (identified as having at least two of the following three risk factors: chronic GVHD that has evolved from acute GVHD, lichenoid skin or mucous-membrane changes, and hepatic dysfunction. Such patients have a high mortality rate.) with thalidomide in a dose that produced a plasma level of 5 micrograms per milliliter two hours after administration. Therapy was continued for three months after a complete response or for six months after a partial response. RESULTS. The overall actuarial survival of all enrolled patients was 64 percent. Survival was 76 percent among the patients receiving salvage therapy for refractory GVHD and 48 percent among those with high-risk GVHD. A complete response was observed in 14 patients, a partial response in 12 patients, and no response in 18. Side effects were minor, most notably sedation in almost all patients. CONCLUSIONS. In this preliminary trial, thalidomide appeared to be safe and effective for the treatment of chronic GVHD. A trial comparing thalidomide with prednisone in patients with newly diagnosed chronic GVHD will be required to demonstrate its relative efficacy.     

Halofuginone to treat fibrosis in chronic graft-versus-host disease and scleroderma.

Chronic graft-versus-host disease (cGvHD) and systemic sclerosis (scleroderma [SSc]) share clinical characteristics, including skin and internal organ fibrosis. Fibrosis, regardless of the cause, is characterized by extracellular matrix deposition, of which collagen type I is the major constituent. The progressive accumulation of connective tissue results in destruction of normal tissue architecture and internal organ failure. In both SSc and cGvHD, the severity of skin and internal organ fibrosis correlates with the clinical course of the disease. Thus, there is an unmet need for well-tolerated antifibrotic therapy. Halofuginone is an inhibitor of collagen type I synthesis in cells derived from various tissues and species and in animal models of fibrosis in which excess collagen is the hallmark of the disease. Halofuginone decreased collagen synthesis in the tight skin mouse (Tsk) and murine cGvHD, the 2 experimental systems that show many features resembling those of human GvHD. Inhibition of collagen synthesis by halofuginone is achieved by inhibiting transforming growth factor beta-dependent Smad3 phosphorylation. Dermal application of halofuginone caused a decrease in collagen content at the treated site of a cGvHD patient, and reduction in skin scores was observed in a pilot study with SSc patients. The results of the human studies provide basis for using halofuginone treatment for dermal fibrosis. As a first step toward future treatment of internal organ involvement, an oral administration study was performed in which halofuginone was well tolerated and plasma levels surpassed the predicted therapeutic exposure.     

Autoimmunity in chronic graft-versus-host disease

F₁ mice with chronic GVH disease were studied to investigate the hypothesis that non-specific stimulation of helper T cells, such as might be seen in graft-versus-host (GVH) disease, results in autoantibody production. Antinuclear antibody (ANA) was detected significantly more frequently in F₁ mice with GVH disease than in control animals. The antigenic specificities of the ANA indicate that it is of host origin and, since it reacts with syngeneic nuclei, it can be considered a true autoantibody. The pattern of development, intensity, prevalence and sex distribution of ANA reactions differed notably in experiments with A × CBA F₁s compared to those with C57B1/6 × BALB/c F₁s suggesting that these parameters of ANA formation are influenced significantly by the genotype of the animal with GVH disease.     

De novo chronic graft-versus-host disease in marrow graft recipients given methotrexate and cyclosporine: risk factors and survival.

A retrospective study was performed to determine risk factors for the development of de novo chronic graft-versus-host disease (GVHD) in patients given marrow grafts from HLA-identical sibling donors (85%), HLA-nonidentical family members (3%), or HLA-matched unrelated donors (12%) and for postgrafting immunosuppression with methotrexate and cyclosporine. We also examined the impact of chronic GVHD on survival and identified patients at low risk for chronic GVHD in whom immunosuppression might be stopped safely early after transplantation. Among 489 patients with either grade 0 or I acute GVHD, 33% developed chronic GVHD. Overall survival was 70%, and relapse-free survival was 63% at 8 years. Risk factors for chronic GVHD were found to include donor buffy coat infusions among patients given transplants for aplastic anemia (relative risk [RR] = 2.9, P = .05), patient-donor sex/parity combination (likelihood ratio test, P < .001), grade I acute GVHD (RR = 1.6, P = .003), and active cytomegalovirus infection (RR = 1.5, P = .05) before day 60. Among 45 patients aged <19 years who had male donors, only 1 developed chronic GVHD. This group had an overall survival rate of 65% and a relapse-free survival rate of 54% at 8 years post-transplantation-a result not better than that among the entire cohort. The lack of improvement in survival in the low-risk group was related to a high rate of relapse of the underlying diseases. Therefore, the development of de novo chronic GVHD does not have a negative impact on patient survival; the adverse effect from increased transplantation-related complications is offset by a lower relapse rate, the result of an allogeneic graft-versus-tumor effect.     

Humoral immunity to cytomegalovirus and chronic graft-versus-host disease

Abstract Human cytomegalovirus (HCMV) is an important cause of morbidity and mortality in patients with chronic graft-versus-host disease (cGVHD), but the underlying mechanisms are not understood. The aim of this investigation was to determine whether humoral immune responses to the HCMV antigens were quantitatively different in hematopoietic cell transplant (HCT) recipients who developed cGVHD from those who did not. Antibodies to HCMV and its proteins UL94 and UL70 were quantitated in 79 cGVHD and 30 non-cGVHD patients by enzyme-linked immunosorbent assays (ELISAs). Mean levels of antibodies to the whole HCMV and to its protein UL94 were not significantly different between the cGVHD and the non-cGVHD subjects. However, the levels of antibodies to HCMV UL70 were significantly higher in non-cGVHD subjects than in those with cGVHD (20.91±15.63 versus 15.00±10.35?ng/mL; p=0.03). This suggests that anti-UL70 antibodies might play a protective role in the development of cGVHD.     

Rapamycin (sirolimus) for treatment of chronic graft-versus-host disease.

We conducted a phase II trial in 19 chronic graft-versus-host disease (cGVHD) patients with rapamycin, calcineurin inhibitors, and prednisone with the goals of controlling cGVHD, reducing prednisone use, and defining the safety of this regimen. Rapamycin was begun as second-line (n = 9) or more than second-line (n = 10) therapy. With a median follow-up of 42 months, 16 patients were evaluable for response. Nine patients discontinued rapamycin because of poor compliance/patient request (n = 2) or an adverse event (n = 7), 3 of whom were not evaluable because of withdrawal at < or =1 month or noncompliance. The adverse events included serum creatinine > or =2.4 mg/dL (n = 4), hemolytic uremic syndrome (n = 2), and relapse of malignancy (n = 1). Fifteen of 16 evaluable patients had a clinical response. Five of the 16 discontinued the drug, and 1 died of relapsed leukemia. Of the 10 patients who continued rapamycin, 2 discontinued and 1 successfully tapered all systemic immunosuppression. Three of the 10 developed progressive cGVHD with tapering immunosuppression; all responded to resumption of prior medications. Four of the 10 patients required alternate therapy for persistent or progressive cGVHD while receiving rapamycin; prednisone was discontinued (n = 2) or tapered at the time of progressive disease (n = 2). Seventeen of 19 original patients were alive. One death was due to relapsed malignancy, and 1 was due to congestive heart failure. In this report of rapamycin as cGVHD therapy, there is evidence of rapamycin's efficacy. Given the significant toxicities described, investigation of altered administration of rapamycin and calcineurin inhibitors should be pursued in future cGVHD trials.     

Response of 443 patients to steroids as primary therapy for acute graft-versus-host disease: comparison of grading systems.

Acute GVHD remains a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). In a retrospective analysis, the response of 443 HSCT patients who received prednisone, 60 mg/m2, for 14 days followed by an 8-week taper, as initial therapy for acute GVHD from 1990 through 1999 at a single institution was examined. Median patient age was 29.0 years (range, 0.3-60.3 years), with 40% of patients <20 years old. Patients received HSCT from 201 related (189 matched sibling/12 partially matched) and 242 unrelated (130 HLA-A, B, DRB1 matched/112 partially matched) donors. GVHD score was measured and outcomes compared using the Minnesota, Consensus, and International Bone Marrow Transplant Registry (IBMTR) grading systems. Prior to initiation of steroid therapy, severe (grades III-IV) acute GVHD was observed in 57 (13%) patients (Minnesota or Consensus grading) and in 192 (43%) patients (IBMTR grading). At day 28 of treatment, overall improvement was observed in 55% of patients, with durable (> or = 28 days) complete response observed in 35% and partial response observed in 20% of patients. Patients with acute lower gastrointestinal GVHD (+/- other organ involvement) had lower response rates. In multivariate logistic regression analysis, recipients of related donor grafts and recipients of GVHD prophylaxis other than methotrexate alone had the highest likelihood of overall response. Initial Minnesota GVHD grade or Consensus GVHD grade was not associated with significant differences in overall response, whereas patients with an initial IBMTR grade of B or C had a higher likelihood of response. Chronic GVHD developed in 42% of patients by 1 year after HSCT. The probability of survival at 1 year after initiation of steroid therapy was 53% (95% confidence interval, 48%-58%). In Cox regression analysis, factors associated with better survival included patients' youth, receipt of related or HLA-matched unrelated grafts, and administration of GVHD prophylaxis other than T-cell depletion in all 3 grading systems. Lower initial GVHD grade (I-II or A-B) led to better survival. These data suggest that steroids provide an active but inadequate therapy for acute GVHD, especially with higher grade GVHD. More effective prophylaxis and therapy for acute GVHD is needed for mismatched unrelated donor recipients and for those with severe GVHD.     

他克莫司转换为环孢素A改善肾移植后新发糖尿病

背景：肾移植后糖尿病的发生原因目前尚不明确,一般认为与患者种族、年龄、体质量、家族史、丙肝病毒感染及免疫抑制剂方案有关 目的：探讨将他克莫司转换为环孢素A改善移植后新发糖尿病的有效性和安全性。 方法：将42例符合入组标准的肾移植受者随机分为转换组(n=20)和对照组(n=22);转换组将他克莫司转换为环孢素A,对照组不转换。从对照组确诊为新发糖尿病、转换组他克莫司转换为环孢素A的时间开始随访1年,动态监测患者的血糖状况,同时监测患者体质量指数、血清肌酐、尿素氮、尿酸、肝功能、血脂、免疫抑制剂用量及浓度范围、尿微量白蛋白、急性排斥反应发生率、感染发生率、丙肝感染率、人/肾存活率等直至随访终点。 结果与结论：随着时间的增长,转换组的空腹血糖及糖化血红蛋白逐渐改善,需要接受降糖治疗的患者例数逐渐减少,转换1年后,有11例(55%)新发糖尿病完全缓解,不需接受降糖药物治疗;而对照组,需要接受降糖药物治疗的患者例数逐渐增多,1年后所有患者均需接受治疗,而且空腹血糖及糖化血红蛋白控制情况均不如转换组。同时,转换组与对照组相比,血清肌酐、谷丙转氨酶、三酰甘油、胆固醇、尿酸等均无明显差异,而尿微量白蛋白在转换后6个月开始则明显少于对照组;两组的急性排斥反应发生率、感染发生率及人/肾存活率均无明显差异。将他克莫司转换为环孢素A,短期内(1年内)改善肾移植后新发糖尿病是安全而有效的。 中国组织工程研究杂志出版内容重点：肾移植;肝移植;移植;心脏移植;组织移植;皮肤移植;皮瓣移植;血管移植;器官移植;组织工程全文链接：     

Sirolimus and tacrolimus without methotrexate as graft-versus-host disease prophylaxis after matched related donor peripheral blood stem cell transplantation.

Methotrexate in combination with a calcineurin inhibitor is a standard graft-versus-host disease (GVHD) prophylactic regimen in allogeneic stem cell transplantation. However, methotrexate is associated with delayed engraftment, mucositis, idiopathic pneumonia syndrome, and other transplant-related complications. Sirolimus, a novel immunosuppressant without methotrexate's toxicities, has been used successfully in solid organ transplantation. We hypothesized that replacing methotrexate with sirolimus would preserve effective prophylaxis of GVHD while minimizing transplant-related toxicity after allogeneic peripheral blood stem cell transplantation. We enrolled 30 patients in a phase II study to test the efficacy of tacrolimus in combination with sirolimus in lieu of methotrexate in preventing GVHD after allogeneic peripheral blood stem cell transplantation from HLA-matched related donors. Grade II GVHD occurred in 3 patients (10%), and no patient developed grade III or IV GVHD. Neutrophil and platelet engraftment were prompt, occurring on days 14 and 13, respectively. All patients survived to hospital discharge (median, 18 days), and peritransplantation toxicity was mild. Four patients developed thrombotic microangiopathy, and 3 patients developed hepatic veno-occlusive disease. Chronic GVHD occurred in 11 patients. Relapse-free and overall survival at 100 days were 93% and 97%, respectively, and were 71% and 67% at 1 year. Causes of death included relapse (n = 6), veno-occlusive disease (n = 1), and late pulmonary toxicity (n = 1). Sirolimus in combination with tacrolimus is a promising alternative to methotrexate-based regimens for GVHD prophylaxis after matched related donor peripheral blood stem cell transplantation. Mucositis was modest, engraftment was prompt, and transplant-related toxicity was modest. Methotrexate-free, sirolimus-based GVHD prophylactic regimens should be tested in randomized trials against the current standard of care.     

A high-dose pulse steroid regimen for controlling active chronic graft-versus-host disease.

Corticosteroids remain essential for controlling active chronic graft-versus-host disease (cGVHD). However, the optimum dose and administration schedule is unknown. We have reviewed our results in 61 patients with severe refractory cGVHD who were treated with a high-dose pulse steroid regimen (PS) consisting of methylprednisolone at 10 mg/kg per day for 4 consecutive days, with subsequent tapering doses. After 4 days, all patients received a course of additional immunosuppressive therapy. The median age of the 56 patients who were evaluable for response was 32 years (range, 0.2-57 years). Patients had failed a median of 2 (range, 1-5) treatments prior to the PS. The median follow-up for 45 surviving patients after PS was 1.5 years. The probability of survival at 1 year and 2 years after PS was 88% (95% confidence interval [CI], 76%-95%) and 81% (95% CI, 65%-91%), respectively. Twenty-seven patients (48%) showed a major response to PS with substantial improvement of cGVHD manifestations, including softening of the skin, increased range of motion, and improved performance status; 15 patients (27%) showed a minor response, defined as improvement in some but not all symptoms of cGVHD. Of the 42 responders, 21 (50%) had progression of their cGVHD afterwards. The median time to progression was 1.9 years. The probability of progression at 1 and 2 years after PS was 36% (95% CI, 23%-53%) and 54% (95% CI, 38%-71%), respectively. The probability of progression at 1 year was 25% (95% CI, 12%-47%) and 55% (95% CI, 32%-81%) for patients who had major and minor response, respectively (hazard ratio, 2.13). Ten of the 42 responders (24%) were able to discontinue all systemic immunosuppressive treatments. The probability of discontinuation at 1 and 2 years after PS was 9% (95% CI, 3%-25%) and 27% (95% CI, 15%-48%), respectively. The treatment was well tolerated with no serious adverse events. Our results suggest that PS is a well-tolerated regimen for achieving rapid clinical response in the majority of patients with cGVHD who failed on multiple previous therapies. Further studies are warranted to maintain the efficacy of this regimen by combining with new active agents in cGVHD.     

Psoralen and ultraviolet A irradiation (PUVA) as therapy for steroid-resistant cutaneous acute graft-versus-host disease.

Psoralen plus ultraviolet A irradiation (PUVA) has immunomodulatory effects and is used to treat a variety of immune-mediated dermatologic diseases. We administered PUVA to 103 patients for treatment of steroid-resistant acute graft-versus-host disease (GVHD) of the skin. Twenty-nine patients had related donors (12 HLA-mismatched) and 74 had unrelated donors (23 HLA-mismatched). The median onset of GVHD was day 13 after transplantation, and the median onset of PUVA treatment was day 46. PUVA was administered as secondary therapy for 86 patients and tertiary therapy or greater for 17 patients. The median number of treatments was 16, and the mean cumulative exposure was 41 J/cm2. PUVA was generally well tolerated with 8 patients discontinuing therapy because of toxicity. At the start of PUVA treatment, 48 patients had rash affecting >50% of their body surface area (BSA), and 91 had rash involving >25% BSA. Of 65 patients who were evaluated after 6 weeks of PUVA treatment, 11 still had rash involving >50% BSA, 24 had rash involving >25% BSA, and 24 had no rash. The mean daily dose of prednisone at the start of PUVA therapy was 1.6 mg/kg compared to 0.7 mg/kg after 6 weeks of therapy. Fifty-nine patients (57%) did not require additional therapy for skin GVHD after starting PUVA. Ninety-two percent of patients developed chronic GVHD. Fifty-three patients (51%) remain alive at 129-1883 days after transplantation. These results suggest that PUVA can be an effective therapy for steroid-resistant acute GVHD of the skin.     

Outcome of renal transplantation after tacrolimus switch to cyclosporine

Calcineurin inhibitors play the key role in current immunosuppressive therapy in transplantation medicine. We present our experience with tacrolimus as immunosuppressive therapy and the reasons for replacing tacrolimus with cyclosporine in some patients. We monitored graft function, serum lipid levels, and blood glucose concentration before and after immunosuppressant switch. The most common reason for change of immunosuppressive therapy was insulin dependent hyperglycemia; calcineurin inhibitor nephrotoxicity was the reason for switching immunosuppressive therapy in a small number of patients; and in one patient, the reason for immunosuppressive therapy switching was BK virus infection. Blood glucose normalized soon after the introduction of cyclosporine in the treatment. Monitoring of laboratory tests before and after immunosuppressive therapy switching showed the graft function to have remained unchanged.