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We retrospectively analysed 111 consecutive patients (pts) with HR AML who received a first allogeneic SCT in our center between January 2000 and December 2009. HR AML was defined by (1) unfavorable cytogenetics (Mrozek and Bloomfield, Blood 2006), (2) AML secondary to myelodysplastic syndromes or prior radio/chemotherapy, (3) delayed response to induction chemotherapy, i.e. inadequate blast clearance on day 15 or persistent AML after the first course and/or (4) AML relapse.Sixty pts who had achieved first (n=49), second (n=10) or third (n=1) complete remission (CR) at the time a donor with no or not more than one HLA mismatch was available were treated with a classical total body irradiation (TBI 12 or 8 Gy)-based (n=47) or intravenous busulfan (BU 16×0.8 mg/kg or 8×0.8mg/kg)-based (n=13) conditioning regimen (CC cohort). In contrast, 51 pts with active AML at the time of SCT received sequential treatment with intensive chemotherapy and reduced-intensity conditioning (RIC) as a fast-transplant strategy (FTx). The FLAMSA-RIC regimen (fludarabine (FLU), cytarabine, amsacrine from day -12 to -9, TBI 4 Gy on day - 5 (pts ≤ 60 yrs) or 4×0.8 mg/kg intravenous BU on day - 5 and -4 (pts > 60 yrs), and cyclophosphamide 40–60 mg/kg on day -3 and -2; Schmid C, Blood 2006) was applied to 26 pts. Twenty-five pts were treated with another course of intensive chemotherapy followed by FLU 30 mg/m2 from day -6 to -2 and melphalan 150 mg/m2 on day -3 given in aplasia (FLU/MEL; Platzbecker U, Leukemia 2006).Patient's age ranged from 18 to 70 years and was significantly higher in the FTx than in the CC cohort (52 vs. 46 years; p=0.017). Of the leukemia-specific risk factors, the percentages of unfavorable cytogenetics did not differ between AML patients in the FTx and CC cohort (31 vs. 40%). Both groups were comparable with respect to the interval from first diagnosis of AML to SCT (median 244 vs. 247 days, range 17–2019 days), the use of unrelated donors (57 vs. 65%) and peripheral blood stem cells (93 vs. 88%). Graft versus host disease prophylaxis consisted of rabbit antithymocyte globulin which was equally balanced between the FTx and CC groups (47 vs. 53%), and cyclosporin A plus mycophenolate mofetil or methotrexate. In the FTx group, the median follow-up of surviving patients was significantly shorter than in the CC group (3.0 vs. 4.6 years, p=0.017).Estimated median overall survival (OS) of the entire cohort was 5.7 years (95% CI, 4.8–6.6 years). Patients treated with CC showed significantly superior OS rates of 82%, 72% and 67% at 1, 2 and 4 years after SCT compared to 64%, 50% and 33% in the FTx group (p=0.001), due primarily to a significantly lower incidence of non-relapse mortality (10 vs. 25%, p=0.043). In contrast, the incidences of relapses after SCT were not different in both groups (23 vs. 35%).Among the 51 patients of the FTx cohort, those transplanted with inaedequate blast clearance or persistent AML after the first induction course (n=27) had a better outcome than the more heavily pretreated patients with AML relapse (n=24). Median estimated OS in these groups was 4.0 vs.1.7 years and OS rates of 56 vs. 33% at 2 years (p=0.02). These groups did not differ significantly in terms of age, HCT-CI score (median 2.7) and bone marrow blast count at transplantation.The fast transplant approach yields encouraging long-term survival in high-risk AML refractory to induction therapy, nearly approaching the results of patients transplanted in CR using classical conditioning. Among patients of the FTx cohort, relapsed AML with more extensive pretreatment had a significantly inferior outcome.No relevant conflicts of interest to declare.

From 2000 to 2009 (F) and from 2005 to 2009 (H) a total number of 72 (F: n=39; H: n=33) consecutive patients who had undergone first-line salvage treatment of histologically proven severe steroid-refractory aGvHD of the GI-tract with pentostatin were retrospectively analyzed. Steroid-refractory aGvHD was defined as progression or no improvement of diarrhea despite a treatment with prednisolone (≥2mg/kg/d) for ≥ 3 days. In steroid-refractory aGvHD pentostatin was infused at a dose of 1mg/m2 for 3 consecutive days. Patients received 1–4 cycles. Response after therapy with pentostatin was classified as complete (CR, no ongoing symptoms of GvHD), very good partial (VGPR, residual symptoms only) or no response (NR). 31 females and 41 males with a median age of 48 (range: 20–68) years were included. The underlying diseases were AML (n=43), ALL (n=10), CML (n=1), lymphoma (n=7), MDS (n=6), and multiple myeloma (n=5). The conditioning regimen was myeloablative in 25 patients and reduced intensity in 47 patients. Patients were transplanted with peripheral blood stem cells (except one bone marrow transplantation) from matched siblings (n=26), matched unrelated (n=27) or mismatched donors (n=19). All patients suffered from severe steroid-refractory intestinal aGvHD overall grade III (n=39) or IV (n=33).39 patients (54%) responded to pentostatin. 30 patients (42%) achieved CR, 9 patients (12%) VGPR. Clinical improvement occurred within a median of 13 (range: 5–58) days after the first infusion of pentostatin. 33 patients (46%) did not respond. After a median follow up of 27 (range 10 to 108) months 23 patients (32%) are alive. 49 patients (68%) died (53% therapy related, 15% due to relapse of the malignant disease). 59% of the 39 responding patients versus 0% of the non-responders survived. 10 patients without response to pentostatin received further salvage therapies including alemtuzumab, infliximab, rituximab, tacrolimus, etanercept or mesenchymal stem cells (MSC). All these patients died without response. 26 patients (36%) achieved CR or VGPR after one cycle of pentostatin. 24 patients without CR or VGPR after one cycle were treated with 1–3 further cycles. The probability of survival was significantly higher for patients who responded after one cycle in comparison with patients without response and further pentostatin treatment (73% versus 13%, p<0.01). Thus, further immunosuppressive therapy beyond one cycle of pentostatin has almost no positive impact on survival. Except one patient who died 4 years after pentostatin due to relapse of lymphoma all one-year-survivors stayed alive.In the critical clinical situation of severe steroid-refractory intestinal aGvHD pentostatin conferred encouraging rates of response and overall survival. In comparison with other treatment options such as MSC or immunosuppressive monoclonal antibodies pentostatin has some favorable characteristics: Its effect is sustainable; the majority of responding patients survived. Costs for pentostatin are relatively low and toxicity is moderate. However, despite therapy with pentostatin mortality in steroid-refractory aGvHD is still unacceptably high. Since response rates and survival after other therapies are even less convincing we suggest using pentostatin as salvage therapy in severe steroid-refractory intestinal aGvHD.Klein: Hospira: Honoraria.

Abstract 1336

Abstract 1274

Respiratory syncytial viruses (RSV) frequently cause severe respiratory disease in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Within the first post-transplant month, progression of upper respiratory tract infection to life-threatening bronchiolitis and pneumonia is common and mortality rates of up to 80% have been reported if left untreated. Aerosolized ribavirin plus/minus immunoglobulins is considered the treatment of choice for RSV pneumonia. With this regimen, the 30-day all cause mortality is still 40% in immunosuppressed HSCT patients. In addition, nebulizing ribavirin may induce toxic side effects on patients and staff.Concurrent with an outbreak in the community, RSV infection was diagnosed in 10 out of 29 patients (34%) undergoing allogeneic HSCT in the winter season 2008. Diagnosis was based on RSV-specific PCR of routinely collected throat swaps. Intravenous ribavirin was dosed according to Schleuning et al., 2003 (day 1: 33 mg/kg, day 2-5: 4×16 mg/kg, day 6-10: 3×8 mg/kg) for 8-10 days, followed by oral ribavirin (1800 mg per day) until recovery from symptoms. Airflow obstruction (AFO) was defined as a FEV1/FVC ratio <0.7 or a drop in FEV1 >20% from baseline. All RSV-infected patients (median age 60 years) had undergone reduced-intensity conditioning HSCT for high-risk acute myeloid leukemia (1st CR: n=2; subsequent CR: n=3; untreated or refractory relapse: n=5). GvHD prophylaxis consisted of cyclosporine A and mycophenolate mofetil with (n=8) or without (n=2) antithymocyte globulin. Donors were HLA-idential siblings (n=1), matched (n=8) or mismatched unrelated donors (n=1).Median time from HSCT to detection of RSV was 15 (range, 1-40) days. In 7 out of 10 patients, RSV infection was diagnosed pre-engraftment during neutropenia. Four patients had bronchiolitis or pneumonia and 6 patients suffered from tracheobronchitis. High-dose intravenous ribavirin was administered to all patients with pneumonia and/or diagnosis of RSV infection within 7 days after transplantation (n=5). These patients had hypoxia and required oxygen supplementation. Treatment with oral ribavirin was initiated in the other five patients with tracheobronchitis diagnosed on days 12-40 after HSCT. With a median follow up of 6 months, 9 out of 10 patients are alive and in complete remission of their AML. All 9 patients became RSV-negative in throat swabs after a median time of 22 days from start of therapy. Severe AFO caused by RSV pneumonia occurred in 2 patients and improved after treatment. Despite severe lymphopenia, no patient treated for tracheobronchitis progressed to RSV pneumonia. Neutrophil recovery was delayed in the three patients diagnosed with RSV pneumonia pre-engraftment until days 26, 28+ and 111 after HSCT, due to high-dose intravenous ribavirin and/or RSV infection itself. One of these patients died of septic shock associated with pseudomonas aeruginosa-induced pneumonia on day 28 after HSCT in prolonged neutropenia. No other ribavirin-associated toxicity such as hepatotoxicity or clinically relevant hemolysis was observed. Three patients developed acute intestinal GvHD, 2 of them recovering upon steroid treatment and one proceeding to chronic disease despite salvage therapy. One additional patient had steroid-responsive acute GvHD of the skin.High-dose intravenous or oral ribavirin therapy appears to be safe and effective even if administered to neutropenic allogeneic HSCT recipients. None of these patients with RSV infection in the early post-transplant period developed bronchiolitis obliterans or persistent AFO. Based on our favourable results, further studies are required. Meanwhile, we suggest to treat all patients with symptomatic RSV infections in the early post-transplant phase with oral or intravenous ribavirin.Off Label Use: Ribavirin is approved for inhalative treatment of RSV infections but not for systemic therapy..

Abstract 1163

Steroid refractory intestinal acute Graft versus Host Disease (aGvHD) is a mayor complication after allogeneic hematopoietic cell transplantation. Survival rate of severe intestinal aGvHD is low. No therapy has been proven to increase the survival rate in steroid refractory aGvHD so far. A promising strategy is the use of pentostatin, a purine nucleotide analogue and inhibitor of adenosine deaminase, which is known to decrease function and number of lymphocytes. Here we report the six year follow-up of a pilot study on salvage therapy of aGvHD by pentostatin. We treated 18 patients with steroid refractory intestinal aGvHD stage III or IV with Pentostatin (8 female and 10 male patients). The mean age was 45 (range: 25–61 years). The underlying diseases were ALL (4), AML (10), Multiple Myeloma (2), Hodgkin’s Disease (1) and CML (1). Eight patients were allografted with HLA-identical sibling donors, three with related donors with a single HLA class I mismatch, seven with matched unrelated donors. All patients were allografted with peripheral blood stem cells. As GvHD prophylaxis ciclosporine A in combination with mycophenolate mofetil or methotrexate were used. Eleven patients had aGvHD stage III, seven stage IV. All patients had a severe gastrointestinal-tract involvement (grade III or IV). After failure of steroid treatment (prednisolone >2 mg/kg for at least 3 days) pentostatin was applied as a salvage therapy (1 mg/m2 for three consecutive days). Eight patients received between one and three further courses of pentostatin every three to four weeks. Therapy was well tolerated. No severe neutropenia was observed. Except one case of hemolytic uremic syndrome (HUS) no impairment of renal function was observed. Eleven patients achieved a complete, five a partial remission of aGvHD. Time until a clinical improvement could be observed was 12–14 days. Two patients died before day 12 without improvement of GvHD symptoms. Seven patients (39%) are alive (510–2060 days post first cycle of pentostatin), two with extensive chronic GvHD. All one-year-survivors stayed alive. Eleven patients died (two due to relapse of leukemia, nine transplant related [1 x interstitial pneumonitis, 1 x pneumonia, 1 x chronic GvHD, 4 x aGvHD and multiple organ failure (MOF), 1 x parvo B19 infection and MOF, 1 x HUS and MOF]). In conclusion, in this pilot study pentostatin has been demonstrated to be a highly effective and well tolerated drug for salvage therapy of steroid refractory acute GvHD with intestinal involvement. Moreover, compared with earlier studies on steroid refractory aGvHD a high rate of long term survivors could be observed. By a multicenter prospective randomised study we are currently investigating whether pentostatin can improve the outcome in steroid refractory intestinal aGvHD.

Steroid refractory intestinal acute Graft versus Host Disease (aGvHD) is a mayor complication after allogeneic hematopoietic cell transplantation. Survival rate of severe intestinal aGvHD is low. No therapy has been proven to increase the survival rate in steroid refractory aGvHD so far. A promising strategy is the use of pentostatin, a purine nucleotide analogue and inhibitor of adenosine deaminase, which is known to decrease function and number of lymphocytes. Here we report the six year follow-up of a pilot study on salvage therapy of aGvHD by pentostatin. We treated 18 patients with steroid refractory intestinal aGvHD stage III or IV with Pentostatin (8 female and 10 male patients). The mean age was 45 (range: 25–61 years). The underlying diseases were ALL (4), AML (10), Multiple Myeloma (2), Hodgkin's Disease (1) and CML (1). Eight patients were allografted with HLA-identical sibling donors, three with related donors with a single HLA class I mismatch, seven with matched unrelated donors. All patients were allografted with peripheral blood stem cells. As GvHD prophylaxis ciclosporine A in combination with mycophenolate mofetil or methotrexate were used. Eleven patients had aGvHD stage III, seven stage IV. All patients had a severe gastrointestinal-tract involvement (grade III or IV). After failure of steroid treatment (prednisolone >2 mg/kg for at least 3 days) pentostatin was applied as a salvage therapy (1 mg/m2for three consecutive days). Eight patients received between one and three further courses of pentostatin every three to four weeks. Therapy was well tolerated. No severe neutropenia was observed. Except one case of hemolytic uremic syndrome (HUS) no impairment of renal function was observed. Eleven patients achieved a complete, five a partial remission of aGvHD. Time until a clinical improvement could be observed was 12–14 days. Two patients died before day 12 without improvement of GvHD symptoms. Seven patients (39%) are alive (510–2060 days post first cycle of pentostatin), two with extensive chronic GvHD. All one-year-survivors stayed alive. Eleven patients died (two due to relapse of leukemia, nine transplant related [1 x interstitial pneumonitis, 1 x pneumonia, 1 x chronic GvHD, 4 x aGvHD and multiple organ failure (MOF), 1 x parvo B19 infection and MOF, 1 x HUS and MOF]). In conclusion, in this pilot study pentostatin has been demonstrated to be a highly effective and well tolerated drug for salvage therapy of steroid refractory acute GvHD with intestinal involvement. Moreover, compared with earlier studies on steroid refractory aGvHD a high rate of long term survivors could be observed. By a multicenter prospective randomised study we are currently investigating whether pentostatin can improve the outcome in steroid refractory intestinal aGvHD.