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Ricardo Spielberger - One of the best experts on this subject based on the ideXlab platform.
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long term safety outcomes in patients with hematological malignancies undergoing autologous hematopoietic stem cell transplantation treated with Palifermin to prevent oral mucositis
Biology of Blood and Marrow Transplantation, 2016Co-Authors: Patrick J Stiff, Mattias Rudebeck, Torbjorn Kullenberg, Mika Leinonen, Maarten De Chateau, Ricardo SpielbergerAbstract:Abstract The purpose of our study was to compare long-term safety outcomes (overall survival, disease progression, and incidence of secondary malignancies) between Palifermin and placebo in the prevention of oral mucositis in patients with hematological malignancies undergoing autologous hematopoietic stem cell transplantation (HSCT). Patients were enrolled between 1997 and 2005 into 4 phase I to III studies (3 double-blind placebo-controlled and 1 open-label) conducted at 31 sites in Australia, Europe, and the United States. Survival outcomes (overall survival, progression-free survival) were compared using hazard ratios (HRs) estimated with a Cox model that included treatment group, baseline age, disease type, Eastern Cooperative Oncology Group performance status, country, and presence of prior radiotherapy as covariates. The incidence of secondary malignancies was compared with a chi-square test. A total of 672 patients were randomized into the studies (428 Palifermin and 244 placebo). The median follow-up time for subjects alive at last visit was 7.9 years (range, .1 to 14.9) for Palifermin and 8.8 years (range, .1 to 14.8) for placebo. Palifermin-treated patients had overall survival (HR, 1.01; 95% confidence interval [CI], .78 to 1.31; P = .921) and progression-free survival times (HR, 1.04; 95% CI, .83 to 1.31; P = .733) that were comparable with placebo-treated patients. Secondary malignancies were reported by 13% of Palifermin-treated patients versus 11% of placebo patients (P = .477). Breakdown into secondary hematological malignancies (7% versus 6%) or solid tumors (6% versus 6%) did not suggest any differences between the treatment groups. After a follow-up of up to 15 years, comparable long-term safety outcomes (overall survival, progression-free survival, and incidence of secondary malignancies) were observed for Palifermin- and placebo-treated patients undergoing autologous HSCT.
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Palifermin for prevention of oral mucositis in allogeneic hematopoietic stem cell transplantation a single institution retrospective evaluation
Supportive Care in Cancer, 2015Co-Authors: Diana T Nguyen, Sepideh Shayani, Joycelynne Palmer, Andrew Dagis, Stephen J Forman, Joel B Epstein, Ricardo SpielbergerAbstract:The purpose of this study is to assess the impact of Palifermin on oral mucositis (OM) and its sequelae in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) who were conditioned with fractionated total body irradiation (FTBI) and etoposide. This retrospective chart review study compared the effect of Palifermin on the development of OM in patients who received this agent during an allo-HSCT (n = 99) to those who did not (n = 30). The primary end points were severity and duration of OM. Secondary end points included requirements for opioids, total parenteral nutrition (TPN), and intensive oral care; incidence of infection; length of hospital stay; and overall survival. There was no significant difference in the incidence of all grades of OM, but incidence of severe OM was decreased in Palifermin-exposed patients (34 vs 80 %, p < 0.0001). In patients who developed OM (all grades), the median duration of OM was shorter in Palifermin-exposed patients (13 vs 18 days, p = 0.0001); there was no difference in the median duration of severe OM. Patients who received Palifermin used less opioids and required a shorter duration of intensive oral care. There was no difference in duration of TPN, incidence of infection, length of hospital stay, and overall survival. Our findings demonstrated a significant benefit with the use of Palifermin for allo-HSCT recipients who were conditioned with FTBI and etoposide. Palifermin can potentially improve quality of life for this patient population and reduce complications and resources used during the transplant process. A randomized clinical trial is required to confirm these results.
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Palifermin for prevention of oral mucositis has no negative effect on long term outcome in patients with hematological malignancies undergoing hsct long term follow up to 15 years
Blood, 2013Co-Authors: Patrick J Stiff, Ricardo SpielbergerAbstract:Background Palifermin has been shown to reduce the incidence and duration of severe oral mucositis in hematological stem cell transplantation (HSCT) recipients. A follow-up study was performed to rule out a potential long-term safety risk of Palifermin use. Objectives to compare long-term disease outcome (overall survival, disease progression and incidence of secondary malignancies) between Palifermin and placebo. Methods This is a long-term follow-up study of patients with hematological malignancies undergoing HSCT and treated with Palifermin or placebo to prevent oral mucositis. The aim of the study was to detail any potential late complications due to Palifermin exposure. Patients were enrolled between 1997-2003 into four randomized, placebo-controlled phase II/III studies conducted at 31 sites in Australia, Europe and the US. The survival outcomes were compared using hazard ratios (HRs) estimated with Cox model including the treatment group, baseline age, disease type (Hodgkin lymphoma, non-Hodgkin lymphoma, multiple myeloma, leukemia), ECOG performance status, country and presence of prior radiotherapy as covariates. The incidence of secondary malignancies was compared with chi-squared test. Results A total of 672 patients were randomized to the parent studies (429 Palifermin, 243 placebo) and 543 (345, 198) were enrolled to the long-term follow-up. The median follow-up time for subjects alive was 7.9 years (range 0.1-14.9) for Palifermin and 8.8 (0.1-14.8) for placebo. No significant differences were seen for either overall survival (HR = 1.01; 95% confidence interval (CI) 0.78-1.31; p=0.921) or progression-free survival (HR=1.04; 95% CI 0.83-1.31; p=0.733). Secondary malignancies were reported by 13% (Palifermin) vs. 11% (placebo) of the patients (p=0.477). The most common secondary malignancies were acute myeloid leukemia/myelodysplastic syndrome (5% vs. 5%) and skin cancers (2% vs. 2%). Conclusion The overall survival, progression-free survival, and the incidence of secondary malignancies were comparable between Palifermin and placebo in patients undergoing HSCT. After a follow-up of up to 15 years, no negative effect of Palifermin on long-term outcomes was observed. Disclosures: No relevant conflicts of interest to declare.
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no difference in survival or long term disease outcomes in Palifermin treated patients with hematologic malignancies undergoing hematopoietic stem cell transplantation
Blood, 2007Co-Authors: Ricardo Spielberger, Mary C Territo, Simon Durrant, Stephen D Nimer, John M Mccarty, David D Hurd, Dietmar Berger, Jeff Aycock, Mongy Chen, Patrick J StiffAbstract:Abstract Background: Oral mucositis is an adverse effect of myeloablative therapy which has serious clinical and economic consequences as well as a negative impact upon quality of life. The duration and severity of oral mucositis can be reduced by administering Palifermin to patients with hematological malignancies receiving myeloablative therapy and undergoing hematopoietic stem cell transplantation (HSCT). However, we still require additional data on the long-term disease outcomes of patients treated with Palifermin. Therefore we present here the long-term, safety data for Palifermin-treated HSCT patients followed up for approximately 60 months after the last Palifermin dose. Methods: The long-term safety data were collected during the follow-up phase of 4 parent trials where patients had received at least one dose of Palifermin or placebo. Study assessments included overall survival (OS), progression-free survival (PFS), and secondary malignancies. Assessments were made at 6-month intervals during year 1 and annually thereafter until death or loss to follow-up. Kaplan-Meier curves for overall survival and PFS were calculated and the treatment groups were compared using stratified log-rank test. Results: Altogether 662 patients were randomized to treatment and received either Palifermin or placebo (421 Palifermin, 241 placebo); 538 patients entered the follow-up study (342 Palifermin, 196 placebo). The median follow-up time for patients alive at last visit was 49.8 months (Palifermin N=290) and 49.5 months (placebo N=169). There were 131 (32%) and 72 (30%) deaths in the Palifermin and placebo groups, respectively. The overall survival curves were similar for both groups (p=0.717). Disease progression occurred in 167 (41%) Palifermin- and 87 (36%) placebo-treated patients; the difference in PFS between the two groups was non-significant (p=0.280). Secondary malignancies were observed in 8% of patients in both groups: the incidence of secondary hematologic malignancies was 4% (Palifermin: 14/342) versus 5% (placebo: 10/196) while the incidence of solid tumors was 2% in both groups. Conclusion: The results of this 60-month follow-up study indicate that long-term disease outcomes are not affected by administering Palifermin to patients with hematological malignancies who are receiving myeloablative therapy and undergoing HS. There was no difference in OS and PFS between the Palifermin and placebo groups. Furthermore there was no difference in the incidence of secondary malignancies between the two patient groups. The incidence of secondary hematologic malignancies and solid tumors was low, comparable between groups, and within the expected range for this patient population.
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economic impact of Palifermin on the costs of hospitalization for autologous hematopoietic stem cell transplant analysis of phase 3 trial results
Biology of Blood and Marrow Transplantation, 2007Co-Authors: Linda S Elting, Ricardo Spielberger, Patrick J Stiff, William I Bensinger, Ya Chen Tina Shih, Scott B Cantor, Catherine D Cooksley, Christos EmmanoulidesAbstract:Abstract A double-blind, randomized trial showed that, compared with placebo, Palifermin (recombinant human keratinocyte growth factor) reduced the frequency and duration of oral mucositis in patients with hematologic malignancies undergoing high-dose chemotherapy and total-body irradiation with autologous stem-cell support. This previously published study also showed a significant reduction in the incidence of adverse subsequent outcomes. The objective of this study was to estimate the impact of Palifermin prophylaxis on hospital costs of transplantation in the trial. This was a retrospective, economic analysis of estimated costs for a previously published clinical trial. Costs were not collected during the trial. Therefore, we estimated the direct medical costs of hospitalization using hospital charges from similar patients' hospitalization charges selected from the National Inpatient Sample, a population-based, nationally representative sample of hospital claims. Costs were estimated from charges using Medicare's state-specific cost-to-charge ratios. These cost estimates were applied to the outcome data (incidence of febrile neutropenia, bacteremia/fungemia, or pneumonia, and use of total parenteral nutrition) from the clinical trial. Patients were those with hematologic malignancies who received high-dose chemotherapy and total-body irradiation with autologous stem cell transplant. We compared the estimated total hospital costs (in 2005 United States dollars) incurred by patients who received Palifermin in the clinical trial with those incurred by patients who received placebo. Costs were analyzed from the provider's perspective. The mean cost of a hospital day in this population varied between $2,834, when no adverse outcomes occurred, and $4,663, when all 4 outcomes occurred. Reductions in adverse outcomes and their associated hospital stay offset the acquisition price of Palifermin. A nonsignificant mean savings of $3,595 per patient (95% confidence interval: $2,090-$5,103) was observed. In sensitivity analyses, this observation was robust to all plausible values of per diem hospital costs and hypothetic per diem outpatient costs. In addition to its previously demonstrated clinical benefit, Palifermin prophylaxis offers a favorable economic profile among patients with hematologic malignancies who receive total body irradiation and autologous stem cell support.
Saroj Vadhanraj - One of the best experts on this subject based on the ideXlab platform.
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clinical applications of Palifermin amelioration of oral mucositis and other potential indications
Journal of Cellular and Molecular Medicine, 2013Co-Authors: Saroj Vadhanraj, Dietmar Berger, Jenna D Goldberg, Miguelangel Perales, Marcel R M Van Den BrinkAbstract:Mucositis is one of the most significant toxicities in cancer patients undergoing cytotoxic treatment. It can have a negative impact on both quality of life and health economics. Severe oral mucositis can contribute to hospitalization, need for narcotic analgesics, total parentral nutrition, suboptimal delivery of anti-neoplastic treatment, and morbidity and mortality. Palifermin, a recombinant derivative of human keratinocyte growth factor, is the first active agent approved by the FDA for the prevention of severe oral mucositis in patients undergoing haematopoietic stem cell transplantation (HSCT). Several studies have also shown significant reduction in the incidence, severity and/or duration of oral mucositis in other high-risk settings such as concurrent chemoradiotherapy (CT/RT) for patients with head and neck cancer, and use of mucotoxic chemotherapeutic agents such as doxorubicin in sarcoma and fluorouracil for the treatment of colorectal cancer. The reduction in mucositis has translated into amelioration of symptoms and improvement in daily functioning as measured by patient-reported outcome in multiple studies. The clinical response to Palifermin appears to be related in part to epithelial proliferation and mucosal thickening. Palifermin also has other potential clinical applications including the acceleration of immune reconstitution and inhibition of graft-versus-host disease in patients undergoing HSCT, and mitigation of dysphagia in lung cancer patients treated with concurrent CT/RT. Palifermin is generally well tolerated with mild-to-moderate skin and oral adverse events. Future studies may expand the use of Palifermin into other areas that would benefit from its cytoprotective and regenerative effects.
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single dose Palifermin prevents severe oral mucositis during multicycle chemotherapy in patients with cancer a randomized trial
Annals of Internal Medicine, 2010Co-Authors: Saroj Vadhanraj, Marcella M Johnson, Shana Sherril Oroark, Dejka M Araujo, Joseph A Ludwig, Ann M. Gillenwater, Jonathan C Trent, Shreyaskumar Patel, Xiao Zhou, Carlos E BuesoramosAbstract:Results: A median of 6 blinded cycles (range, 1 to 6) were completed by the Palifermin group and 2 (range, 1 to 6) by the placebo group. Compared with placebo, Palifermin reduced the cumulative incidence of moderate to severe (grade 2 or higher) mucositis (44% vs. 88%; P 0.001; difference, 44 percentage points [95% CI, 71 to 16 percentage points) and severe (grade 3 or 4) mucositis (13% vs. 51%; P 0.002; difference, 38 percentage points [CI, 67 to 9 percentage points]). The main adverse effects were thickening of oral mucosa (72% in the Palifermin group vs. 31% in the placebo group; P 0.007) and altered taste. Seven of the 8 patients who had severe mucositis in the placebo group received open-label Palifermin. None of these patients had severe mucositis in the subsequent cycles (a total of 17) with open-label Palifermin.
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single dose Palifermin prevents severe oral mucositis during multicycle chemotherapy in patients with cancer a randomized trial
Annals of Internal Medicine, 2010Co-Authors: Saroj Vadhanraj, Marcella M Johnson, Shana Sherril Oroark, Dejka M Araujo, Joseph A Ludwig, Ann M. Gillenwater, Jonathan C Trent, Shreyaskumar Patel, Xiao Zhou, Carlos E BuesoramosAbstract:BACKGROUND Mucositis can be a serious complication of cancer treatment. Palifermin reduces mucositis when given in multiple doses to patients undergoing hematopoietic stem-cell transplantation. OBJECTIVE To evaluate the efficacy of Palifermin given as a single dose before each cycle in patients receiving multicycle chemotherapy. DESIGN Randomized, double-blind, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00267046) SETTING The University of Texas M.D. Anderson Cancer Center, Houston, Texas. PATIENTS 48 patients with sarcoma were randomly assigned in a 2:1 ratio to receive Palifermin or placebo. All patients received doxorubicin-based chemotherapy (90 mg per m(2) of body surface area over 3 days, by infusion). INTERVENTION Palifermin (180 µg per kg of body weight) or placebo was administered intravenously as a single dose 3 days before each chemotherapy cycle (maximum, 6 cycles). Patients who had severe mucositis received open-label Palifermin in subsequent cycles. MEASUREMENTS Oral assessment of mucositis by using World Health Organization (WHO) oral toxicity scale (grades 0 to 4), with moderate to severe mucositis (grades 2 to 4) as the main outcomes; patient-reported outcome questionnaire; and daily symptom record diary. RESULTS A median of 6 blinded cycles (range, 1 to 6) were completed by the Palifermin group and 2 (range, 1 to 6) by the placebo group. Compared with placebo, Palifermin reduced the cumulative incidence of moderate to severe (grade 2 or higher) mucositis (44% vs. 88%; P < 0.001; difference, -44 percentage points [95% CI, -71 to -16 percentage points) and severe (grade 3 or 4) mucositis (13% vs. 51%; P = 0.002; difference, -38 percentage points [CI, -67 to -9 percentage points]). The main adverse effects were thickening of oral mucosa (72% in the Palifermin group vs. 31% in the placebo group; P = 0.007) and altered taste. Seven of the 8 patients who had severe mucositis in the placebo group received open-label Palifermin. None of these patients had severe mucositis in the subsequent cycles (a total of 17) with open-label Palifermin. LIMITATIONS Study limitations include smaller sample size for the control group, inclusion of only patients with sarcoma, and perceived unblinding of the treatment because of notable differences between the biologic effects of Palifermin and placebo. CONCLUSION A single dose of Palifermin before each cycle reduced the incidence and severity of mucositis. The drug was generally well tolerated, but most patients experienced thickening of oral mucosa. Further investigation is needed to determine whether Palifermin use will facilitate greater adherence to chemotherapy regimens by reducing mucositis.
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single dose Palifermin prevents severe oral mucositis during multicycle chemotherapy in patients with cancer
Annals of Internal Medicine, 2010Co-Authors: Saroj Vadhanraj, Marcella M Johnson, Shana Sherril Oroark, Dejka M Araujo, Joseph A Ludwig, Ann M. Gillenwater, Jonathan C Trent, Shreyaskumar Patel, Xiao Zhou, Carlos E BuesoramosAbstract:Mucositis is a serious complication of cancer treatment that sometimes limits the dose and duration of chemotherapy. This small, randomized, placebo-controlled trial found that Palifermin, a ketino...
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randomized double blind placebo controlled study of Palifermin for the prevention of mucositis in patients receiving doxorubicin based chemotherapy
Journal of Clinical Oncology, 2008Co-Authors: Saroj Vadhanraj, Dejka M Araujo, Joseph A Ludwig, Ann M. Gillenwater, J C Trent, S R Patel, D Bailey, Xian Zhou, El A Naggar, Robert S. BenjaminAbstract:9547 Background: Mucositis is a common complication in patients (pts) receiving chemotherapy (CT). Palifermin, a recombinant keratinocyte growth factor, has been shown to reduce mucositis when give...
John G Gartner - One of the best experts on this subject based on the ideXlab platform.
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immunomodulatory effects of Palifermin recombinant human keratinocyte growth factor in an sle like model of chronic graft versus host disease
Scandinavian Journal of Immunology, 2012Co-Authors: Cynthia A Ellison, Ionela Gheorghiu, Yuriy Lissitsyn, John G GartnerAbstract:Keratinocyte growth factor (KGF) promotes epithelial cell proliferation and survival. Recombinant human KGF, also known as Palifermin, protects epithelial cells from injury induced by chemicals, irradiation and acute murine graft-versus-host disease (GVHD). Findings from our studies and others have shown that Palifermin also has immunomodulatory properties. In a model of acute GVHD, we showed that it shifts the immune response from one in which Th1 cytokines dominate to mixed Th1 and Th2 cytokine profile. Using the DBA/2→(C57BL/6 × DBA/2)F(1)-hybrid model of chronic, systemic lupus erythematosus-like GVHD, we showed that Palifermin treatment is associated with higher levels of Th2 cytokines, the production of anti-nuclear antibodies, cryoglobulinemia and the development of more severe pathological changes in the kidney. The aim of our current study was to gain a better understanding of the immunobiology of KGF by further characterizing the Palifermin-mediated effects in this model of chronic GVHD. Because the pathological changes we observed resemble those seen in thymic stromal lymphopoietin (TSLP) transgenic mice, we had originally hypothesized that Palifermin might augment TSLP levels. Surprisingly, we did not observe an increase in thymic TSLP mRNA expression in Palifermin-treated recipients. We did, however, observe some differences in the percentages of CD4(+) CD25(+) Foxp3(+) regulatory T cells in the spleen at some time points in Palifermin-treated recipients. Most importantly, we found that TGFβ levels were higher in Palifermin-treated recipients early in the GVH reaction, raising the possibility that KGF might indirectly induce the development of fibrosis and glomerulonephritis through a pathway involving TGFβ.
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role of thymic stromal lymphopoietin tslp in Palifermin mediated immune modulation and protection from acute murine graft versus host disease
Journal of Clinical Immunology, 2011Co-Authors: Cynthia A Ellison, Yuriy Lissitsyn, Juliet A Packiasamy, Warren J Leonard, John G GartnerAbstract:Using the C57BL/6→(C57BL/6 x DBA/2)F1-hybrid model of acute graft-versus-host disease (GVHD), we previously showed that treating the donor mice with Palifermin provides protection from morbidity and a shift from Th1 to Th2 cytokine production. To determine whether thymic stromal lymphopoietin (TSLP) is involved in Palifermin-mediated immune modulation, we used donors from the following groups: (1) untreated wild-type donors, (2) Palifermin-treated wild-type donors, (3) untreated TSLPR−/− donors, and (4) Palifermin-treated TSLPR−/− donors. Survival in the recipients was 0%, 100%, 31%, and 0%, for groups 1–4, respectively, indicating that TSLP responsiveness is required for Palifermin-mediated protection from GVHD. We also found that the increases in Th2 cytokine levels that are induced by Palifermin treatment are obviated in TSLPR−/− donors, and that protection from GVHD (group 2) is associated with a higher percentage of CD4+CD25+Foxp3+ cells in the graft. Collectively, our findings show that when Palifermin and TSLP act in concert, the predominant effect is protection in this model.
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Palifermin mediates immunoregulatory effects in addition to its cytoprotective effects in mice with acute graft versus host disease
Journal of Clinical Immunology, 2008Co-Authors: Cynthia A Ellison, Bryce M Makar, Jacqie M M Wiseman, Ionela Gheorghiu, Masaru Taniguchi, John G GartnerAbstract:Treating recipient mice with Palifermin (recombinant human keratinocyte growth factor) prevents the development of acute, lethal, graft-versus-host disease (GVHD). This is due, at least in part, to the ability of Palifermin to protect epithelial cells from injury. Using the C57BL/6→(C57BL/6 × DBA/2)F1-hybrid model, we previously showed that the protective effect of Palifermin was also associated with redirection of the cytokine profile from Th1 to Th2. To study this immunoregulatory effect more directly, we induced acute GVH reactions in which we treated the donors rather than the recipients with Palifermin. The recipient mice were protected from GVHD-associated morbidity, and their cytokine profile was predominantly Th2. The Palifermin-treated donor mice alone showed a similar Th2 cytokine profile, and we observed elevated levels of thymic stromal lymphopoietin mRNA in the thymus. We further demonstrated that treating the donor mice with Palifermin protects against GVHD-associated morbidity, even if the donors are deficient in Vα14i natural killer T cells. Our findings clearly show that Palifermin mediates immunoregulatory effects in addition to its cytoprotective effects and that both are likely to be involved in the mechanism through which Palifermin provides protection from acute murine GVHD.
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effect of Palifermin in a murine model of graft versus host disease gvhd associated with th2 cytokine production autoantibody production and glomerulonephritis
Journal of Clinical Immunology, 2006Co-Authors: Cynthia A Ellison, Ian W Gibson, Kent T Hayglass, John G GartnerAbstract:Palifermin (recombinant human keratinocyte growth factor) prevents the development of acute, lethal graft-versus-host disease (GVHD). It does so, at least in part, by protecting cells from injury. Another property of Palifermin is immune regulation. How the latter influences the evolution of GVHD remains uncertain. We explored the effect of Palifermin on GVHD in the DBA/2 --> ((DBA/2)x(C57BL/6))F(1)-hybrid strain combination, a model associated with autoantibody production and glomerulonephritis. Untreated recipients survived until at least day 150 post-induction. Palifermin-treated recipients succumbed between days 50 and 90 with levels of proteinuria of up to 20 g/L, ascites, and rapidly progressive, crescentic glomerulonephritis that was most severe in mice with the greatest levels of proteinuria. Kidney sections from both Palifermin-treated and untreated recipients showed the presence of granular deposits of IgG, IgM, IgA, and C3 in the mesangium and the glomerular basement membrane. Electron microscopy confirmed the extensive glomerular immune complex deposition. Antinuclear and anti-dsDNA antibodies were present in sera from both treated and untreated recipients; however, those in the latter were only detectable if the serum was kept at 37 degrees C, indicating that they were cryoglobulins. IL-4 was detectable only in cultures from Palifermin-treated recipients and the levels of IL-5 and IL-13 were significantly higher in the Palifermin-treated group than in untreated GVHD mice. IFN-gamma was only detectable in untreated GVHD mice. These data suggest that although Palifermin can protect mice with acute GVHD, it exacerbates GVHD in a model associated with autoantibody production and a preponderance of Th2 cytokines.
Patrick J Stiff - One of the best experts on this subject based on the ideXlab platform.
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long term safety outcomes in patients with hematological malignancies undergoing autologous hematopoietic stem cell transplantation treated with Palifermin to prevent oral mucositis
Biology of Blood and Marrow Transplantation, 2016Co-Authors: Patrick J Stiff, Mattias Rudebeck, Torbjorn Kullenberg, Mika Leinonen, Maarten De Chateau, Ricardo SpielbergerAbstract:Abstract The purpose of our study was to compare long-term safety outcomes (overall survival, disease progression, and incidence of secondary malignancies) between Palifermin and placebo in the prevention of oral mucositis in patients with hematological malignancies undergoing autologous hematopoietic stem cell transplantation (HSCT). Patients were enrolled between 1997 and 2005 into 4 phase I to III studies (3 double-blind placebo-controlled and 1 open-label) conducted at 31 sites in Australia, Europe, and the United States. Survival outcomes (overall survival, progression-free survival) were compared using hazard ratios (HRs) estimated with a Cox model that included treatment group, baseline age, disease type, Eastern Cooperative Oncology Group performance status, country, and presence of prior radiotherapy as covariates. The incidence of secondary malignancies was compared with a chi-square test. A total of 672 patients were randomized into the studies (428 Palifermin and 244 placebo). The median follow-up time for subjects alive at last visit was 7.9 years (range, .1 to 14.9) for Palifermin and 8.8 years (range, .1 to 14.8) for placebo. Palifermin-treated patients had overall survival (HR, 1.01; 95% confidence interval [CI], .78 to 1.31; P = .921) and progression-free survival times (HR, 1.04; 95% CI, .83 to 1.31; P = .733) that were comparable with placebo-treated patients. Secondary malignancies were reported by 13% of Palifermin-treated patients versus 11% of placebo patients (P = .477). Breakdown into secondary hematological malignancies (7% versus 6%) or solid tumors (6% versus 6%) did not suggest any differences between the treatment groups. After a follow-up of up to 15 years, comparable long-term safety outcomes (overall survival, progression-free survival, and incidence of secondary malignancies) were observed for Palifermin- and placebo-treated patients undergoing autologous HSCT.
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Palifermin for prevention of oral mucositis has no negative effect on long term outcome in patients with hematological malignancies undergoing hsct long term follow up to 15 years
Blood, 2013Co-Authors: Patrick J Stiff, Ricardo SpielbergerAbstract:Background Palifermin has been shown to reduce the incidence and duration of severe oral mucositis in hematological stem cell transplantation (HSCT) recipients. A follow-up study was performed to rule out a potential long-term safety risk of Palifermin use. Objectives to compare long-term disease outcome (overall survival, disease progression and incidence of secondary malignancies) between Palifermin and placebo. Methods This is a long-term follow-up study of patients with hematological malignancies undergoing HSCT and treated with Palifermin or placebo to prevent oral mucositis. The aim of the study was to detail any potential late complications due to Palifermin exposure. Patients were enrolled between 1997-2003 into four randomized, placebo-controlled phase II/III studies conducted at 31 sites in Australia, Europe and the US. The survival outcomes were compared using hazard ratios (HRs) estimated with Cox model including the treatment group, baseline age, disease type (Hodgkin lymphoma, non-Hodgkin lymphoma, multiple myeloma, leukemia), ECOG performance status, country and presence of prior radiotherapy as covariates. The incidence of secondary malignancies was compared with chi-squared test. Results A total of 672 patients were randomized to the parent studies (429 Palifermin, 243 placebo) and 543 (345, 198) were enrolled to the long-term follow-up. The median follow-up time for subjects alive was 7.9 years (range 0.1-14.9) for Palifermin and 8.8 (0.1-14.8) for placebo. No significant differences were seen for either overall survival (HR = 1.01; 95% confidence interval (CI) 0.78-1.31; p=0.921) or progression-free survival (HR=1.04; 95% CI 0.83-1.31; p=0.733). Secondary malignancies were reported by 13% (Palifermin) vs. 11% (placebo) of the patients (p=0.477). The most common secondary malignancies were acute myeloid leukemia/myelodysplastic syndrome (5% vs. 5%) and skin cancers (2% vs. 2%). Conclusion The overall survival, progression-free survival, and the incidence of secondary malignancies were comparable between Palifermin and placebo in patients undergoing HSCT. After a follow-up of up to 15 years, no negative effect of Palifermin on long-term outcomes was observed. Disclosures: No relevant conflicts of interest to declare.
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no difference in survival or long term disease outcomes in Palifermin treated patients with hematologic malignancies undergoing hematopoietic stem cell transplantation
Blood, 2007Co-Authors: Ricardo Spielberger, Mary C Territo, Simon Durrant, Stephen D Nimer, John M Mccarty, David D Hurd, Dietmar Berger, Jeff Aycock, Mongy Chen, Patrick J StiffAbstract:Abstract Background: Oral mucositis is an adverse effect of myeloablative therapy which has serious clinical and economic consequences as well as a negative impact upon quality of life. The duration and severity of oral mucositis can be reduced by administering Palifermin to patients with hematological malignancies receiving myeloablative therapy and undergoing hematopoietic stem cell transplantation (HSCT). However, we still require additional data on the long-term disease outcomes of patients treated with Palifermin. Therefore we present here the long-term, safety data for Palifermin-treated HSCT patients followed up for approximately 60 months after the last Palifermin dose. Methods: The long-term safety data were collected during the follow-up phase of 4 parent trials where patients had received at least one dose of Palifermin or placebo. Study assessments included overall survival (OS), progression-free survival (PFS), and secondary malignancies. Assessments were made at 6-month intervals during year 1 and annually thereafter until death or loss to follow-up. Kaplan-Meier curves for overall survival and PFS were calculated and the treatment groups were compared using stratified log-rank test. Results: Altogether 662 patients were randomized to treatment and received either Palifermin or placebo (421 Palifermin, 241 placebo); 538 patients entered the follow-up study (342 Palifermin, 196 placebo). The median follow-up time for patients alive at last visit was 49.8 months (Palifermin N=290) and 49.5 months (placebo N=169). There were 131 (32%) and 72 (30%) deaths in the Palifermin and placebo groups, respectively. The overall survival curves were similar for both groups (p=0.717). Disease progression occurred in 167 (41%) Palifermin- and 87 (36%) placebo-treated patients; the difference in PFS between the two groups was non-significant (p=0.280). Secondary malignancies were observed in 8% of patients in both groups: the incidence of secondary hematologic malignancies was 4% (Palifermin: 14/342) versus 5% (placebo: 10/196) while the incidence of solid tumors was 2% in both groups. Conclusion: The results of this 60-month follow-up study indicate that long-term disease outcomes are not affected by administering Palifermin to patients with hematological malignancies who are receiving myeloablative therapy and undergoing HS. There was no difference in OS and PFS between the Palifermin and placebo groups. Furthermore there was no difference in the incidence of secondary malignancies between the two patient groups. The incidence of secondary hematologic malignancies and solid tumors was low, comparable between groups, and within the expected range for this patient population.
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economic impact of Palifermin on the costs of hospitalization for autologous hematopoietic stem cell transplant analysis of phase 3 trial results
Biology of Blood and Marrow Transplantation, 2007Co-Authors: Linda S Elting, Ricardo Spielberger, Patrick J Stiff, William I Bensinger, Ya Chen Tina Shih, Scott B Cantor, Catherine D Cooksley, Christos EmmanoulidesAbstract:Abstract A double-blind, randomized trial showed that, compared with placebo, Palifermin (recombinant human keratinocyte growth factor) reduced the frequency and duration of oral mucositis in patients with hematologic malignancies undergoing high-dose chemotherapy and total-body irradiation with autologous stem-cell support. This previously published study also showed a significant reduction in the incidence of adverse subsequent outcomes. The objective of this study was to estimate the impact of Palifermin prophylaxis on hospital costs of transplantation in the trial. This was a retrospective, economic analysis of estimated costs for a previously published clinical trial. Costs were not collected during the trial. Therefore, we estimated the direct medical costs of hospitalization using hospital charges from similar patients' hospitalization charges selected from the National Inpatient Sample, a population-based, nationally representative sample of hospital claims. Costs were estimated from charges using Medicare's state-specific cost-to-charge ratios. These cost estimates were applied to the outcome data (incidence of febrile neutropenia, bacteremia/fungemia, or pneumonia, and use of total parenteral nutrition) from the clinical trial. Patients were those with hematologic malignancies who received high-dose chemotherapy and total-body irradiation with autologous stem cell transplant. We compared the estimated total hospital costs (in 2005 United States dollars) incurred by patients who received Palifermin in the clinical trial with those incurred by patients who received placebo. Costs were analyzed from the provider's perspective. The mean cost of a hospital day in this population varied between $2,834, when no adverse outcomes occurred, and $4,663, when all 4 outcomes occurred. Reductions in adverse outcomes and their associated hospital stay offset the acquisition price of Palifermin. A nonsignificant mean savings of $3,595 per patient (95% confidence interval: $2,090-$5,103) was observed. In sensitivity analyses, this observation was robust to all plausible values of per diem hospital costs and hypothetic per diem outpatient costs. In addition to its previously demonstrated clinical benefit, Palifermin prophylaxis offers a favorable economic profile among patients with hematologic malignancies who receive total body irradiation and autologous stem cell support.
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Palifermin reduces patient reported mouth and throat soreness and improves patient functioning in the hematopoietic stem cell transplantation setting
Journal of Clinical Oncology, 2006Co-Authors: Patrick J Stiff, Alessandra Cesano, Christos Emmanouilides, William I Bensinger, Bruce R Blazar, Teresa Gentile, Thomas C Shea, John Isitt, Ricardo SpielbergerAbstract:Purpose To describe patient-reported outcomes of mouth and throat soreness (MTS) and related sequelae on daily activities from a phase III study of Palifermin in the autologous hematopoietic stem-cell transplantation (HSCT) setting and to compare patient self-evaluations with clinicians’ assessments of oral mucositis using objective scales. Patients and Methods Patients (n 212) received Palifermin (60 g/kg/d) or placebo for 3 days before total-body irradiation (12 Gy), etoposide 60 mg/kg, and cyclophosphamide 100 mg/kg, and 3 days after HSCT. Patients completed a daily questionnaire (Oral Mucositis Daily Questionnaire [OMDQ]) evaluating MTS severity and its effects on daily functional activities. Patients’ self-assessment data were compared with clinicians’ assessments of oral mucositis using the objective scales. Results Palifermin reduced the incidence and duration of severe oral mucositis, as assessed by both clinicians and patients. Comparisons between patient and clinician assessments demonstrated that the average daily scores between mucositis grade and subjective (MTS) instruments were similar, although patients reported MTS onset, peak, and resolution earlier (1 to 3 days) than clinicians’ assessments. Patients receiving Palifermin reported statistically significant improvements (P .001) in daily functioning activities (swallowing, drinking, eating, talking, sleeping) and required significantly less narcotic opioids (P .001); improvement in the patient’s overall physical and functional well-being was also reported. This was confirmed by the results of the Functional Assessment of Cancer Treatment questionnaire. Conclusion These results support the clinical benefit of Palifermin in the HSCT setting, providing evidence that a patient’s self-assessment instrument (OMDQ) may serve as an alternative tool to assess oral mucositis severity in clinical trials.
Nicole M A Blijlevens - One of the best experts on this subject based on the ideXlab platform.
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in a high dose melphalan setting Palifermin compared with placebo had no effect on oral mucositis or related patient s burden
Bone Marrow Transplantation, 2013Co-Authors: Nicole M A Blijlevens, Werner Rabitsch, Gergely Krivan, Arpad Szomor, Robert Pytlik, Hans Erik Johnsen, M De Château, A Lissmats, T De Witte, Hermann EinseleAbstract:This randomized-controlled trial studied the efficacy of Palifermin in a chemotherapy-only, high-dose Melphalan (HDM) transplant setting, to reduce oral mucositis (OM) and its sequelae measured by patient-reported outcomes (PRO) and medical resource use. Palifermin, relative to placebo was given either pre-/post-HDM or pre-HDM in patients with multiple myeloma (MM) undergoing auto-SCT at 39 European centers. Oral cavity assessment (WHO) and PRO questionnaires (oral mucositis daily questionnaire (OMDQ) and EQ 5D) were used in 281 patients (mean age 56, ± s.d.=8 years). 57 patients received placebo. One hundred and fifteen subjects were randomized to pre-/post-HDM receiving Palifermin on 3 consecutive days before HDM and after auto-SCT and 109 patients were randomized to pre-HDM, receiving Palifermin (60 μg/kg/day) i.v. for 3 consecutive days before HDM. There was no statistically significant difference in maximum OM severity. Severe OM occurred in 37% (placebo), 38% (pre-/post-HDM) and 24% (pre-HDM) of patients. No significant difference was observed with respect to PRO assessments or medical resource use, but more infections and fever during neutropenia were reported in pre-/post-HDM vs placebo (for example, 51 and 26%). To conclude, Palifermin was unable to reduce OM or OM-related patient's burden in MM transplant patients.
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randomized controlled trial of two different dosing regimens of Palifermin to prevent mucositis in multiple myeloma patients receiving one day administration of high dose melphalan
Blood, 2010Co-Authors: Nicole M A Blijlevens, Agneta Lissmats, Werner Rabitsch, Maarten E De Chateau, Gergely Krivan, Arpad Szomor, Robert Pytlik, Hans Erik Johnsen, Tapani Ruutu, Hermann EinseleAbstract:Abstract 904 Palifermin administered pre and post radiochemotherapy conditioning has previously been shown to significantly reduce the incidence and duration of severe oral mucositis (OM) in patients undergoing autologous stem cell transplantation (ASCT). This randomized clinical trial (RCT) aimed to study the efficacy and safety of Palifermin when administered in two different dosing regimens in a chemotherapy-only conditioning setting. The efficacy of Palifermin relative to placebo was investigated with Palifermin given either pre/post high-dose melphalan (HDM) or pre HDM only in patients with multiple myeloma (MM) undergoing ASCT. Assessment of oral mucositis was primarily based on WHO grades (0/1, 2, 3 or 4) and safety primarily on adverse event (AE) reporting. 281 patients (mean age 56 ± 8 years) were enrolled at 39 centers; 224 patients were randomized to receive Palifermin and 57 patients to receive placebo. In the Palifermin group, 109 patients were randomized to the pre-only arm, receiving Palifermin (60 μg/kg/day) iv for 3 consecutive days before HDM and 115 subjects were randomized to the pre/post arm receiving Palifermin on 3 consecutive days before HDM and again on 3 consecutive days after ASCT. The number of subjects actually receiving study drug in the these two arms was 109 and 111, respectively. Assessments of OM and safety were made daily until 32 days post transplant or hospital discharge. There was no difference in maximum severity of OM between placebo and Palifermin administered pre/post HDM (odds ratio: 0.7 [CI: 0.4, 1.3]) or pre HDM (odds ratio: 1.2 [CI: 0.6, 2.4]). Severe OM (WHO grade 3 and 4) occurred in 37% (placebo), 38% (pre/post-HDM) and 24% (pre-HDM) of the patients. A total of 275 patients (99.3%) experienced at least 1 AE during the study. There were more serious AEs and AEs reported as treatment related by the investigators for patients in the pre/post HDM arm, and less in the pre-HDM arm but still more than in the placebo arm. Overall, no statistically significant differences were observed between placebo and either the Palifermin pre-post HDM arm or pre-only HDM arm for maximum severity of OM in this clinical setting with a chemotherapy conditioning regimen of short duration and a comparably low incidence of severe oral mucositis. The pre-only group, however, showed a numerically better result than placebo for the primary and most of the secondary efficacy endpoints. Patients treated with Palifermin in the pre HDM arm experienced a more favorable safety profile than the pre/post HDM arm. Possible explanations for the apparent discrepancy compared to previously published trials might be differences in high dose chemotherapy and/or the shorter time interval between the pre and post doses in this study. The impact of the timing of the Palifermin post-dose in relation to the pre-dose and in relation to the onset of manifest OM and pathogenesis thus needs to be further explored. Disclosures: Blijlevens: Biovitrum: Consultancy. de Chateau: Biovitrum : Employment. Lissmats: Biovitrum: Employment. Niederwieser: Biovitrum: Consultancy.
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Palifermin in allogeneic hsct many questions remain
Bone Marrow Transplantation, 2009Co-Authors: W J F M Van Der Velden, A H E Herbers, Nicole M A BlijlevensAbstract:Mucositis has become the dose-limiting complication of high-dose chemotherapy. Therefore, recombinant keratinocyte growth factor (KGF)-1, Palifermin, seems a major breakthrough in the management of patients receiving intensive treatment for solid tumours and haematological malignancies.1 Palifermin reduces the incidence and severity of oral mucositis and its clinical consequences.1 The side effects of treatment are generally mild and transient, and are confined to skin rashes, pruritus, mouth and tongue disorders and altered taste.1 This led the Food and Drug Administration (FDA) to approve Palifermin for the prevention of oral mucositis of patients with haematological malignancies and boosted the development of other mucosa-protective growth factors, such as repifermin (KGF-2) and velafermin (fibroblast growth factor-20).
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Palifermin induced flexural hyperpigmentation a clinical and histological study of five cases
British Journal of Dermatology, 2008Co-Authors: L A G Sibelt, Nicole M A Blijlevens, N Aboosy, W J F M Van Der Velden, Willeke A M Blokx, M M B SeygerAbstract:Palifermin is a human keratinocyte growth factor that is efficacious in reducing duration and severity of oral mucositis during autologous haematopoietic stem-cell transplantation for haematological cancer as well as chemotherapy for colorectal cancers. We report the clinical and histological characteristics of a series of five patients who developed flexural hyperpigmentation after treatment with Palifermin. All patients showed ill-defined symmetrical hyperpigmented papillomatous plaques with slight erythema in the skin folds, especially affecting axillary and inguinal areas. The most striking histological finding was the thickened granular layer in all patients. We demonstrate that filaggrin, an essential component in the terminal differentiation of the epidermis, was upregulated in these cases. Palifermin-induced flexural hyperpigmentation is a newly defined clinical and histological entity. The possible aetiology is discussed.
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Palifermin recombinant keratinocyte growth factor 1 a pleiotropic growth factor with multiple biological activities in preventing chemotherapy and radiotherapy induced mucositis
Annals of Oncology, 2007Co-Authors: Nicole M A Blijlevens, Stephen T SonisAbstract:Oral and intestinal mucositis are among the most significant dose-limiting toxic effects of intensive cancer treatment and are associated with adverse clinical and economic outcomes. Palifermin (Kepivancetrade mark), an N-truncated recombinant human keratinocyte growth factor-1, is the first agent to be approved for prevention of oral mucositis. Keratinocyte growth factor, a potent epithelial mitogen, appears to play a major role in the healing process. Palifermin has multiple biological activities that appear to protect the mucosal epithelium and promote its early regeneration after irradiation- and chemotherapy-induced injury. These include inhibition of epithelial cell apoptosis and DNA damage, up-regulation of detoxifying enzymes and down-regulation of pro-inflammatory cytokines, as well as enhanced migration, proliferation and differentiation of epithelial cells. Palifermin reduces the incidence, severity and duration of oral mucositis in patients with haematological malignancies undergoing myelotoxic conditioning therapy and haematopoietic stem-cell transplantation. Clinical sequelae, including febrile neutropenia and resource use (opioid analgesia and parenteral feeding), are concomitantly reduced. Other potential applications being explored include use in the solid tumour setting, reduction of intestinal mucositis and reduction of GVHD in allogenic transplantation. Thus, the development of Palifermin and other potential new agents for preventing chemotherapy- and radiotherapy-induced mucositis represents an important breakthrough in oncological supportive care.