ALBERT

Description: Pulmonary complications, both infectious and non-infectious, significantly contribute to mortality following allogeneic bone marrow transplantation (BMT). In the acute setting, a diffuse non-infectious process termed Idiopathic Pneumonia Syndrome (IPS) may occur. Clinically, IPS is associated with a rapid progression to respiratory failure and mortality rates of 50 – 70%. Historically, we have noted a 9.0% incidence of IPS at our center, with a median survival of only 14 days following its onset. Etanercept, a soluble tumor necrosis factor (TNF) receptor, consists of two soluble p75 TNF receptors fused to the Fc portion of a human IgG1. A trial examining etanercept in the treatment of IPS following allogeneic BMT was undertaken. Fifteen patients (median 18 yrs, range 1 – 60 yrs), each meeting the diagnostic criteria for IPS were enrolled. Broncho-alveolar lavage (BAL) specimen were obtained pre and post therapy, undergoing analysis for both infectious pathogens (viral, bacterial, fungal, PCP, AFB) and for a panel of inflammatory cytokine markers, including TNFa and TNFR1. Patients in whom the pre-therapy BAL was positive for a potential pathogen (by specific stain or culture) were ineligible for therapy. Etanercept was administered subcutaneously at a dose of 0.4 mg/kg (maximum dose 25 mg) twice weekly, for a maximum of 8 doses. All patients required supplemental oxygen at therapy onset, with seven patients requiring mechanical ventilation. Etanercept therapy was initiated a median of 17 days (range 11–87 days) post transplant. All patients received corticosteroids (2 mgkg/day) x 7 days, which were then tapered as clinically indicated. RESULTS: Nine of 15 patients had a complete response, defined as the ability to completely withdraw from supplemental oxygen support within 28 days of initiation of etanercept therapy. In responders, the median time to complete response was 7 days (range 3–18 days). The median survival was extended from 14 days (historical controls) to 67 days (range 3–822) in treated patients. Survival at day 28 and day 56 (following the first etanercept dose) was 73% and 60% respectively. The duration of mechanical ventilation required prior to therapy onset had a significant impact on survival. Patients requiring 〈 48 hours of mechanical ventilation prior to study entry had a median survival of 150 days (range 46 – 822), compared to 17 days (range 3–148) for those requiring mechanical ventilation 〉 48 hours prior to study entry. Overall, therapy was well tolerated. Two episodes of bacteremia, without sepsis, were noted during therapy, . No infectious pulmonary complications were noted. Three patients died while on therapy, from progressive pulmonary or organ dysfunction. Post therapy BAL fluid analysis noted significant reductions in all inflammatory cytokines tested, including TNFa, TNFR1, sCD14, LBP and MCP-1, when compared to pre-therapy BAL values. CONCLUSION: The addition of etanercept to corticosteroids for the treatment of IPS post allogeneic BMT may improve survival, with minimal toxicity. Moreover, the timing of such intervention may have a significant impact on overall outcome. A phase III trial, investigating the efficacy of etanercept in treating IPS is now being considered. IPS therapy n day 28 day 56 Group A: etanercept + corticosteroids 15 73% 60% Group B: corticosteroids (historical controls with IPS) 49 33% 26%

Description: In murine BMT systems, the administration of palifermin reduces small bowel damage and serum systemic inflammatory mediators resulting in less clinical aGVHD while preserving graft-vs-leukemia and improving leukemia free survival. We initiated a phase I schedule escalation trial of palifermin plus standard aGVHD prophylaxis (tacrolimus and 5 mg/m2 methotrexate on days 1, 3, 6, and 11) in patients with an unrelated or HLA mismatched donor who are at high risk for developing aGVHD. All study patients (n=35) had high risk hematologic malignancies and received a fully myeloablative conditioning regimen. Palifermin (60 mcg/kg/day intravenously) was administered for 3 consecutive days prior to the conditioning regimen, and then for 3 consecutive days each week starting Day 0, escalating by 6 doses per cohort, to a maximum of 36 doses. There were 6 cohorts, and each cohort had at least 2 patients. Dose schedules were escalated to the next cohort as long as the dose limiting toxicity (DLT) rate for the current cohort was less than 20% as determined by statistical analysis using a modified form of the continual reassessment method. A DLT was defined as any grade 3 or 4 nonhematologic toxicity that was possibly, probably, or definitely related to palifermin occurring within 14 days of receiving the final dose of palifermin. Nine DLTs were observed (table), and all patients were fully evaluable for aGVHD. In 20 patients, palifermin was not administered through engraftment—three patients completed palifermin prior to engraftment by protocol design (early cohorts), eight patients were removed from study due to DLTs, and nine patients discontinued palifermin by preference of either patient or physician. In this group of 20, 7 (35%) developed grade 3–4 aGVHD. In the other group of 15 patients, palifermin was administered through the time of neutrophil engraftment and only 3 (20%) developed grade 3–4 aGVHD. Mortality at 100 days for subjects who did not receive palifermin through engraftment was 30±10% compared to14±9% for patients who received palifermin through engraftment (p=NS). When adjusted for the interaction of palifermin administration with the number of methotrexate doses given (1–2 vs. 3–4), administration of palifermin through the time of engraftment was associated with improved survival (p = 0.02). Disease status at time of transplant (advanced vs non-advanced) and degree of HLA disparity (5/6 vs 6/6) did not alter the association. These preliminary data suggest that the administration of palifermin through the time of engraftment possibly has a survival benefit in patients at high risk for acute GVHD, perhaps mediated through an interaction with methotrexate. Dose Limiting Toxicities Toxicity # of patients # of palifermin doses Rash (gd 3) 4 2, 6, 6, 6 Hand-foot reaction (gd 3) 2 7, 9 Elevated amylase (gd 4) 1 3 Dyspnea (gd 3) 1 15 Hypoxia (gd 3) 1 15