scholarly journals A Phase III, Randomized, Double-Blind Trial to Evaluate Efficacy and Safety of Isavuconazole Versus Voriconazole in Patients with Invasive Mold Disease (SECURE): Outcomes in Hematopoietic Stem Cell Transplant Patients with Invasive Aspergillosis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1133-1133 ◽  
Author(s):  
Werner J Heinz ◽  
Oliver A Cornely ◽  
Billy Franks ◽  
Fei Shi ◽  
Nkechi Azie ◽  
...  
Keyword(s):  
Stem Cell ◽  
Confidence Interval ◽  
Hematopoietic Stem Cell Transplant ◽  
Stem Cell Transplant ◽  
Phase Iii ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Double Blind ◽  
Hematopoietic Stem ◽  
All Cause Mortality

Abstract Background: Isavuconazole (ISA) is a novel, water-soluble, triazole agent, with broad-spectrum antifungal activity. The SECURE trial (NCT00412893), a Phase III, randomized, double-blind study, investigated the efficacy and safety of ISA vs. voriconazole (VRC) in patients with invasive fungal disease caused by Aspergillus spp. or other filamentous fungi. Patients undergoing hematopoietic stem cell transplant (HSCT) are at particular risk of developing invasive aspergillosis (IA), which is associated with a high mortality in this population. The outcomes in HSCT patients with IA enrolled in SECURE are presented here. Methods: Patients with proven/probable/possible invasive mold disease were randomized 1:1 to receive ISA or VRC. Patients in the ISA arm received ISA 200mg IV TID for 2 days, followed by 200mg QD (IV or PO) thereafter. Patients in the VRC arm received VRC6mg/kg IV BID on Day 1; 4mg/kg IV BID on Day 2; then either 4mg/kg IV BID or 200mg PO BID. Antifungal therapy was given up to 84 days. The primary endpoint was all-cause mortality on Day 42. Overall treatment success (clinical, mycological, and radiological) at end-of-treatment (EOT), safety, and tolerability were also analyzed in HSCT patients with proven or probable IA who received at least one dose of the study drug (mycological intent-to-treat population [myITT]). All outcomes were assessed by an independent data review committee. Results: Of the 527 patients randomized for the SECURE trial, 67 patients with proven or probable IA had a history of HSCT (ISA: n=38; VRC: n=29). Fifty four (80.6%) patients had received an allogeneic stem cell transplant, 32 (47.8%) were neutropenic, and 26 (38.8%) had graft-vs-host disease (GVHD). Mortality was higher in patients with neutropenia (37.5%) compared with those without neutropenia (14.3%; adjusted difference: 17.8; 95% confidence interval: –0.09, 35.6); and, was higher in patients without GVHD (32.6%) compared with those with GVHD (15.4%; adjusted difference; –13.2; 95% confidence interval: –35.3, 8.9). The highest mortality was observed in HSCT patients with neutropenia (Table 1). Treatment-emergent adverse events (TEAEs) were reported in 94.7% (ISA) and 100% (VRC) of patients, and drug-related TEAEs in 36.8% (ISA) and 62.1% (VRC) of patients (P=0.051). The percentages of TEAEs in most System Organ Classes were lower in the ISA arm, although the difference between arms only reached statistical significance for cardiac disorders (ISA 15.8% vs. VRC 41.4%; difference –0.256, asymptotic 95% confidence interval: –0.47, –0.04; P=0.027). Conclusion: In this large, prospective, randomized study, IA was shown to adversely affect the outcomes of HSCT patients. Patients with neutropenia at the time of diagnosis had the highest rate of mortality. ISA was demonstrated to be efficacious for the primary treatment of IA in HSCT patients. The analyses of adverse events suggest a safety advantage of ISA compared with VRC. Abstract 1133. Table 1. Efficacy outcomes (myITT population) Outcome ISA arm VRC arm Adjusted difference % (95% CI) Total (ISA+VRC) N Event (%) N Event (%) Event/N (%) All-cause mortality at Day 42 a All HSCT patients 38 8 (21.1) 29 9 (31.0) –7.5 (–25.8, 10.8) 17/67 (25.4) Allogeneic HSCT 32 7 (21.9) 22 6 (27.3) –2.1 (–22.8, 18.6) 13/54 (24.1) Non-allogeneic HSCT 6 1 (16.7) 7 3 (42.9) –38.5 (–72.2, –4.7) 4/13 (30.8) With neutropenia 21 6 (28.6) 11 6 (54.5) –26.0 (–69.6, 17.6) 12/32 (37.5) With GVHD 13 2 (15.4) 13 2 (15.4) 0.4 (–23.4, 24.2) 4/26 (15.4) Without GVHD 26 7 (26.9) 17 7 (41.2) –15.9 (–43.4, 11.5) 14/43 (32.6) Overall success at EOTb 38 10 (26.3) 29 9 (31.0) 4.5 (–13.5, 22.5) 19/67 (28.4) Clinical response at EOT 34 19 (55.9) 28 13 (46.4) –5.8 (–27.1, 15.5) 32/62 (51.6) Mycological response at EOT 38 11 (28.9) 29 9 (31.0) 2.5 (–15.5, 20.4) 20/67 (29.9) Radiological response at EOT 38 8 (21.1) 29 8 (27.6) 8.0 (–9.4, 25.5) 16/67 (23.9) a Adjusted treatment difference calculated for ISA−VRC b Adjusted treatment difference calculated for VRC−ISA Disclosures Heinz: Astellas, Gilead Science, Janssen-Cilag, MSD Sharp & Dohme/Merck, Pfizer : Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: Isavuconazole for the treatment of aspergillosis (Marketing Authorization Application has been submitted by Astellas (FDA ) and Basilea (EMA)).. Cornely:Astellas: Consultancy, Honoraria, Research Funding, Speakers Bureau. Franks:Astellas: Employment. Shi:Astellas: Employment. Azie:Astellas: Employment. Maertens:Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Allogeneic Hematopoietic Stem Cell Transplant in Advanced Multiple Myeloma: Experience from a Single Center

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5536-5536
Author(s):  
Yizel Elena Paz Nuñez ◽  
Beatriz Aguado Bueno ◽  
Isabel vicuña Andrés ◽  
Ángela Figuera Álvarez ◽  
Miriam González-Pardo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Board Of Directors ◽  
Hematopoietic Stem Cell ◽  
Hematopoietic Stem Cell Transplant ◽  
Stem Cell Transplant ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Hematopoietic Stem

Abstract Introduction The prognosis of patients with multiple myeloma (MM) has improved in the last years due to the important advances in the knowledge of the biology of the disease, the implementation of new drugs and the incorporation of autologous hematopoietic stem cell transplant (autoHSCT). The allogenic hematopoietic stem cell transplant (alloHSCT) continues to be controversial: it offers a curative potential but with the cost of high toxicity, limiting the procedure to those young patients with a high-risk disease. This procedure shall be performed in expert centers and, whenever possible, in the context of a clinical trial. In the following we describe the experience of our center with alloHSCT in advance multiple myeloma patients. Patients and methods A total of 18 patients were diagnosed with multiple myeloma received an alloHSCT during a 13 year period (1996-2013), with a median age of 46 ± 5.9 years. All of our patients received an allogenic HLA matched sibling donor with reduced-intensity conditioning. The majority of patients were transplanted because of advanced disease, relapse after an autologous transplant or as part of a sequential transplant in patient with a high risk disease. One patient received, in two occasions, an alloHSCT. Around 70% of patients had received more than 3 previous lines of treatment including, in nearly 95%, an autoHSCT. Patient's characteristics can be found on table 1, characteristics of the procedure can be found in table 2.Table 1.Patient«s CharacteristicsN (%)GenderMale Female10 (55,5%) 9 (44,4%)Secreted ProteinIgGκ IgG λ IgA κ BJ Plasmocitoma8 (44,4%) 4 (22,2%) 2 (11,1%) 3 (16,7%) 1 (5,6%)Debut DS stageII-A II-B III-A III-B Plasmocitoma5 (27,8%) 1 (5,6%) 8 (44,4%) 3 (16,7%) 1 (5,6%)Cytogentics at diagnosisMissing Unfavorable Favorable10 (55,5%) 6 (33,3%) 2 (11,1%)Previous lines of treatment²2 3-4 ³56 (33,3%) 10 (55,5%) 2 (11,1%)Previous autoHSCTYes No17 (94,5%) 1 (5,6%)Previous radiotherapyYes No8 (44,4%) 10 (55,6%)Disease status at transplantComplete remission Partial remission Relapse9 (50,0%) 3 (16,7%) 6 (33,3%)Table 2.Treatment characteristicsN (%)Conditioning regimenMyeloablative Reduced-intensity6 (33,3%) 12 (66.7%)Stem cell sourceBone marrow Peripheral blood4 (22.2%) 14 (77.8%)GVHD prophylaxisCsA+MTXCsA+CSCsA+MMF10 (55.6%) 3 (16.7%) 5 (27.8%)InfectionsYes No16 (88.9%) 2 (11.1%)MucositisYes No12 (66.7%) 6 (33.3%)Acute GVHDYes II-IV III-IV No4 (22.3%) 3 (16.7%) 1 (5.6%) 14 (77.8%)Chronic GVHDNo Limited Extensive8 (44.3%) 5 (27.8%) 5 (27.8%) Results: Transplant related mortality (TRM) before day 100th was one case due to a thromboembolic event. Global TRM was 16.6% (3 cases). The incidence of acute graft versus host disease (aGVHD) was 22%, controlled on most cases when corticosteroids were initiated. More than half of the patients developed chronic graft versus host disease (cGVHD), with an equal distribution on either presentation as limited or extensive. (Table 2) The total number of patients eligible for analysis was 17 (one patient was lost on follow-up). With a median follow up of 11 years, the overall survival (OS) was of 8.06 years [IC 95% 4,33-11,78] (figure 1.) and the estimated progression free survival (PFS) was of 25.83 months [IC 95% 8.87-42.79](figure 2). A total of 5 (29,4%) patients are still alive and 2 (11,7%) of them are in complete remission, of these 1 patient did not have a previous autoHSCT with a follow up of almost 15 years. Conclusions: Our results are similar to those reflected on the literature1-2. However we have to point out that our population is homogenous with advanced MM with more than 3 previous lines of treatment including in most cases auto-HSCT. In spite of this, morbility and mortality in our cohort was acceptable with the limitation of a high rate of cGVHD. There is a need of more studies including more patients to evaluate the role of alloHSCT in the era of new drugs for MM. References 1. Rosi-ol L et al. Allogeneic hematopoietic SCT in multiple myeloma: long-term results from a single institution. Bone Marrow Transplant. 2015. 2. Beaussant Y et al. Hematopoietic Stem Cell Transplantation in Multiple Myeloma: A Retrospective Study of the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC). Biol Blood Marrow Transplant. 2015 Disclosures Alegre: Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees.

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