ALBERT

Description: Abstract 1163 Poster Board I-185 Introduction 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. Patients and treatment 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 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). Results 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. Conclusions 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. Disclosures Off Label Use: Ribavirin is approved for inhalative treatment of RSV infections but not for systemic therapy..

Description: Abstract 1336 Despite improvements in stem cell transplant (SCT) procedures and supportive care, treatment of high risk (HR) AML patients remains a major challenge. In recent years, there have been few reports showing promising results of fast transplant (FTx) strategies applied to patients with uncontrolled AML. Aim of this retrospective analysis was to compare the FTx strategy to the well established approach of allogeneic SCT in complete remission (classical conditioning, CC) in high risk AML patients. Secondly, the impact of more extensive pretreatment in patients with uncontrolled AML was investigated. Methods: 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). Results: 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. Summary: 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. Disclosures: No relevant conflicts of interest to declare.

Description: Inhibitors of class I/II histone deacetylases (HDACi) possess anti-leukemic activity and have been reported to modulate the function of immune effector cells. Thus, they could provide specific clinical benefit in the allogeneic hematopoietic stem cell transplantation (HSCT) setting. Panobinostat (PAN) is a potent, orally available pan-HDACi reported to either suppress or stimulate regulatory T cells (T reg), depending on the administered dose (Shen L & Pili R, OncoImmunology 1;7:948, 2012). The feasibility and efficacy of PAN treatment following HSCT for patients (pts) with high risk acute myeloid leukemia (AML) has not been established. We report clinical and translational results of the dose-escalation phase of the PANOBEST study with PAN as post-HSCT maintenance. Primary objectives were, based on dose-limiting toxicity (DLT), determining the maximum tolerated dose (MTD) and/or the recommended phase 2 dose (RP2D) of PAN in patients with high risk AML or myelodysplastic syndromes (MDS) in complete remission (CR) after reduced-intensity conditioning HSCT. Secondary objectives were the evaluation of safety, tolerability and immunoregulatory properties of PAN, and overall (OS) and disease-free survival (DFS) of treated patients. PAN was started at 10 mg p.o. three times a week (TIW) and escalated to 20 and 30 mg TIW using a 3+3 design. Treatment was initiated 60-150 days after HSCT and continued for up to one year. Eligibility criteria included: recovery of peripheral blood counts, adequate organ function and no severe graft versus host disease (GvHD). All pts gave written informed consent. DLT was defined as prolonged grade 4 hematologic or grade 3/4 non-hematologic toxicity within 28 days of the first PAN dose. Immunophenoytyping of lymphocyte subsets was performed pre-treatment and on days 3, 8, 30, 90, 180 and 360. 12 pts (11 AML, 1 MDS), median age of 52 years (21-62) were enrolled. PAN was started within a median of 73 days (60-126) after HSCT, which was performed with active disease (n=11) or in CR2 (n=1). The RP2D was determined to be 20 mg TIW based on one DLT (fatigue grade 3) at 20 mg and two DLTs (nausea/emesis and colitis grade 3 each) at 30 mg. Grade 2-4 adverse events (AEs) were reported in 10 out of the 12 pts (83%). Grade 3/4 AEs included hematologic toxicity (50% of pts), laboratory alterations (33%), gastrointestinal symptoms (25%), fatigue, pulmonary infection (17% each), sepsis, herpes stomatitis, diabetes, syncope, deep vein thrombosis and pulmonary embolism (8% each). Toxicity was reversible and required at least one PAN dose reduction in 3 pts. Acute GvHD grade 2 (1 pt) and 3 (2 pts) was responsive to steroids in 2 pts or salvage therapy in 1 pt. Four pts developed mild (n=3) or moderate (n=1) chronic GvHD. To date, 5 pts have completed one year of PAN and 2 pts remain on treatment (days 238, 290). Five pts discontinued treatment prematurely after 10-217 days due to grade 3 toxicities (n=4) or AML relapse (n=1). With a median follow up of 579 days (129-911), 11/12 pts are alive and 10/12 in continuous CR after HSCT. Seven pts received prophylactic donor lymphocyte infusions (DLIs, 1-5 doses of 0.1-20x106 CD3+ cells/kg). Immunophenotyping revealed no impact of PAN on absolute T reg numbers (9 pts), but a significantly reduced proportion of CD4+CD25++CD127dim/- T reg to CD3+CD4+ T helper (Th) cells by day 8 after 3 doses of PAN (mean±SEM: 14.6±2.6 vs. 9.6±1.2%, p value of t test =0.03). While Treg/Th proportion continuously decreased in pts with ongoing CR, it again increased after PAN discontinuation or remained stable under PAN treatment in both relapsing patients. Outcome of the study population was compared with a historical cohort of 29 consecutive pts with active AML transplanted in Frankfurt in 2000-2009. Both cohorts were similar in age, gender, disease stage or BM blasts at time of HSCT, donor type and use of DLIs. In a landmark analysis including all pts who were in CR and without severe GvHD on day 73 after HSCT, probabilities for DFS and OS at 18 months after HSCT were 83±11% vs. 55±9% (p=0.145, log-rank test) and 92±8% vs.66±9% (p=0.085) in the PANOBEST vs. historical cohort (Fig 1). PAN is well tolerated after HSCT at a RP2D of 20 mg TIW. Comparison with a historical control cohort of pts transplanted with active AML shows a low relapse rate, which appears to be associated with a PAN-induced modulation of the T reg/Th proportion. Disclosures: Bug: Novartis: Honoraria, Travel grants, support for the clinical study Other. Ottmann:Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau.