2254 Poster Board II-231 Chronic graft-versus-host disease (cGVHD) remains a major cause of morbidity and mortality in hematopoietic transplant recipients. The mammalian target of rapamycin inhibitors (mTOR-I) sirolimus and everolimus are immunosuppressants that have activity in the prevention and treatment of acute GVHD. Sirolimus in combination with calcineurininhibitors (CNI) has also been shown to have activity in chronic GVHD, however at the cost of considerable toxicity. Since mTOR-I exert their action by blocking interleukin 2 receptor signaling and thus arresting the cells at G1 phase they are promising candidates for tolerance induction. In addition, they also have antiangiogenic and antiproliferative activity. We hypothesized that treatment of cGVHD with mTOR-I and without CNI would be more effective in inducing tolerance than the combination of both and would have a lower toxicity profile. In this retrospective analysis we report 31 consecutive patients (pts) with severe cGVHD according to the NIH consensus, in whom treatment with mTOR-I (everolimus n=20; sirolimus n=11) was initiated between 2004 and 2006, with a median follow-up after initiation of mTOR-I therapy for surviving pts of 46.5 months. Three pts terminated treatment prematurely (within 3 months after starting therapy) because of adverse events (1xsevere cough; 1xhypertriglyceridemia; 1xmouth ulcers) and they were excluded from further analysis. Of the remaining, 12 pts had de novo or quiescent cGVHD, 5 progressive cGVHD developing from acute GVHD and 11 had cGVHD following donor lymphocyte transfusions. Organ involvement included skin (scleroderma) in 21, lungs in 12, mucous membranes in 9, liver in 6, gut in 2 and eyes in 4 pts. Eighteen pts received mTOR-I in combination with steroids, three received a monotherapy and 7 pts received additional immunomodulatory drugs, no CNI however. To further reduce the risk of adverse events drug trough levels were monitored and the dosing was adjusted to low therapeutical levels (3-8 ng/ml). Eleven pts each had a complete and partial response, respectively, with an overall response rate of 78%. At the time of analysis 6 of the 15 surviving pts were complete off immunosuppression and steroids could be tapered and stopped in 5 additional pts. Best responses were seen in pts with de novo or quiescent cGvHD. Thirteen pts have died. Causes of death were: progressive cGvHD (n=5) relapse of the underlying disease (n=4), infections (n=2), secondary malignancy (n=1), unknown (n=1). No difference was observed in everolimus- and sirolimus-treated pts. With a median treatment time of 24 months (range 3 – 54 mo) the major adverse events possibly related to mTOR-I were hyperlipidaemia and impaired wound healing, especially in pts with ulcerative lesions of skin or mucous membranes. Only one of the pts developed thrombotic microangiopathy (TMA) and infectious complications were rare. In pts treated in combination with steroids frequently a shortened prothrombin time has been observed, suggesting an increased risk for thomboembolic events. Controlled trials comparing this approach with alternative strategies are warranted. Disclosures: Off Label Use:Everolimus and Sirolimus for the treatment of chronic GVHD. Jedlickova:Wyeth: Research Funding.
Allogeneic bone marrow transplantation (BMT) remains a curative treatment option for patients with CML. Unrelated donor (URD)-BMT is a realistic treatment option for a large group of patients (pts) in need. To ensure engraftment and to reduce the incidence of acute and chronic GVHD antithymocyte globulin (ATG) has been incorporated into the preparative regimen by many centers. However, little is known if the various preparations available yield comparable results. This analysis reports a single center experience on URD-BMT in chronic phase CML pts with special emphasis on the different ATG preparations used (immunization of rabbits with human thymus, ATG Merieux/Sangstat/Genzyme (ATG-M) or with the leukemic cell line Jurkat, ATG Fresenius (ATG-F)). Since 1995 61 pts (40 male; 21 female) with CML received an URD-BMT. Three pts (1 male, 2 female) from the ATG-F group were excluded because they also received ATG-M after early graft failures, which possibly were attributable to dose adjustments for obesity, to HHV6 infection, and prior use of Imatinib mesylate. Median patient age was 38 years (16–61). 46 pts were transplanted in first chronic phase and 12 in accelerated or second chronic phase and 76% received a fully matched (HLA-A, B, DRB1) transplant. 13 pts received a 1 antigen and 1 patient a 2 antigen mismatched transplant. All pts received in vivo T-cell depletion with ATG during conditioning. 46 pts received ATG-M and 12 pts ATG-F. As analyzed by July 2004 after a median follow-up of 3.3 years for surviving pts. the estimated probability for overall survival is 61%. For eventfree survival, despite the low number and short follow-up of pts who received ATG- F, there was a strong trend (p=0.0611; Log-Rank) in favor of ATG-F as compared to ATG-M, which reached significance in a matched pair analysis (p=0.03). In multivariate cox regression analysis for pretransplant risk assessment for overall survival a time interval of more than a year from diagnosis to transplant (RR 2.5, 1.0–6.3) and a CMV-IgG negative donor for a CMV-IgG positive patient (RR 2.9, 1.1–7.7) and for eventfree survival again the time interval from diagnosis to transplant (RR 2.3, 0.9–5.7) and the use of ATG-M (RR 4.7, 0.6–35.2) were independent negative predictors. The incidence of acute GVHD grade III - IV was higher in the ATG-M group (17% vs. 8%) as was the rate of extensive chronic GVHD (29% vs. 0%). This also translated into a higher risk of death without relapse (35% vs. 8%). However, these observations may be biased to some extent, since most patients who were receiving ATG-F received a conditioning regimen based on intravenous busulfan, whereas most patients who were receiving ATG-M received conditioning regimens mainly based on oral untargeted busulfan, although the type of conditioning was no independent risk factor in the Cox regression model used. Nevertheless, our data indicate that the results of URD-BMT in chronic phase CML patients can further be improved by reducing the rate of acute and chronic GVHD. A promising approach seems to be a conditioning regimen based on intravenous busulfan incorporating ATG-Fresenius.
4573 Patients with acute myeloid leukemia (AML) with FLT-3 mutations have an extremely high risk of relapse after conventional chemotherapy. The role of allogeneic stem cell transplantation (SCT) for this patient cohort has been discussed controversially in recent years. This retrospective analysis reports our cumulative experience in a cohort of 42 consecutive patients (age 17–70, median 51 years) allografted for FLT-3 positive AML in a single centre. In more than 80% a FLAMSA-RIC based conditioning regimen was used, in 5% BCNU/Melphalan/Fludarabine, and in 14% conventional radiation- or Busulfan- based regimens. Most patients received mobilized peripheral blood stem cells as graft and 10 patients had a sibling and 32 an unrelated donor (MUD), respectively. Half of the patients were allografted in complete remission and twenty with active, mostly refractory disease. With a median follow-up for surviving patients of nearly 2 years (range 64 – 1746 days) the Kaplan-Meyer procedure estimates a 48% probability of survival at 2 y after transplantation. Interestingly, there is no difference what so ever in survival if patients had an identical sibling donor or a MUD. Similarly, neither patient age below or above the median, nor the applied conditioning regimen did affect the outcome. The only significant variable for improved survival was being in complete remission at transplantation with a 2-year overall survival probability of 60% as compared to 30% for patients with active disease. Thirteen patients (31%) relapsed after allografting, which is substantially lower as to what is reported after conventional chemotherapy. Three of these patients could be salvaged by a second transplant, whereas 10 patients finally died from leukaemia. Non relapse mortality was 24% with 2 patients dying from acute GVHD, 7 from infections and 1 from suicide, despite being well physically. In conclusion, our data support the notion that allogeneic SCT is a highly effective treatment option for patients with AML and FLT-3 mutations and that, if the patient is eligible, it should be undertaken whenever possible in 1. complete remission. However, even patients with primary induction failure have a reasonable chance to be salvaged by allogeneic SCT. Disclosures: No relevant conflicts of interest to declare.
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