Excellent Clinical and Pharmacokinetic Real-World Experience after Switching to Rurioctocog ALFA Pegol

Background:Prophylactic treatment with standard half-life coagulation factors (SHL) requires 3-4 weekly periodic infusions. Extended half-life (EHL) factor VIII (FVIII) provides improvements in half-life (t1/2) and area under the curve (AUC) of 1.3 and 1.25 times compared to standard half-life (SHL) products. Rurioctocog alfa pegol is an extended half-life (EHL) rFVIII (rFVIII-EHL) treatment that could be a more convenient and cost-effective therapeutic alternative than SHL, since it would reduce the number of weekly infusions (NWI). Aims:The aim of this study is to analyze pharmacokinetic (PK) parameters and compare NWI and bleeding rates after switching from SHL to this EHL in hemophilia A (HA) patients. Methods:In a prospective study, the number of weekly infusions (NWI), annualized bleeding rate (ABR), annualized joint bleeding rate (AJBR), and PK parameters were compared between previous treatment with FVIII-SHL vs rFVIII-EHL (Rurioctocog alfa pegol). The assessment of the PK parameters: volume of distribution (Vd (dL/kg)), clearance (Cl (dL/h/kg)) and half-life time (t½ (h)) was performed by using the pharmacokinetic poblacional software online myPKFiT®. Results:Nineteen patients from 2 Spanish hospitals (n=12 Vall d'Hebron Hospital, n=7 Hospital Regional Universitario de Málaga) were recruited. Median age was 30 years (range, 12-54), with five pediatric patients, and 18 had severe HA (one moderate HA). Sixteen patients were under prophylactic treatment with Advate® and 1 with Kovaltry®. Two patients were switched from on-demand treatment to prophylaxis. The median use of rFVIII-EHL was 15.63 month. The PK parameters after the switch to the rFVIII-EHL in entire cohort and pediatric cohort are shown in Table 1. The t ½ of rFVIII-EHL was positively correlated to preinfusion plasma levels of von Willebrand factor antigen (vWF:Ag) (Figure 1). ABR and AJBR were reduced, as well as weekly infusion frequency (33.3%, IQR:0-50%) (Table 2). Of note, 57.9% of patients presented zero joint bleeding events after switchingtorFVIII-EHL. Conclusions:In this prospective analysis rFVIII- EHL presents as a therapeutic alternative that allows reducing ABR and AJBR as well as weekly infusion frequency according to PK patient parameters. Disclosures Bosch: Roche:Honoraria;Celgene:Honoraria;Jansen:Honoraria;Abbvie:Honoraria;Novartis:Honoraria;Astra Zeneca:Honoraria;Takeda:Honoraria.Gironella Mesa:Bristol Myers Squibb:Honoraria, Speakers Bureau;Janssen:Consultancy, Honoraria.

Cross-Sectional Comparative Study of PK-Guided Switch between Standard Half-Life and Extended Half-Life Factor VIII Products

Background The high inter-individual variability in pharmacokinetics (PK) of factor VIII (FVIII) justifies the use of PK-guided prophylaxis, especially in switching between different products. A proposed definition of extended half-life (EHL) FVIII requires improvements of at least 1.3 times in half-life (t1/2) and 1.25 times the area under the curve (AUC) compared to standard half-life (SHL) products (Mahlangu et al. Haemophilia. 2018;24(3):348-358). The objective of this multicenter study was to analyze the results of a PK-guided switch from SHL to EHL in patients with hemophilia A (HA). Methods Multicenter comparative, cross-sectional, prospective study in HA severe/moderate patients in prophylaxis analyzing PK differences after switch from SHL to EHL (efmoroctocog alfa [rFVIII-Fc] and rurioctocog alfa pegol [PEG-rFVIII]). WAPPS-Hemo® was used to analyze PK parameters with 2-3 samples: t1/2; AUC, peak level (PL); trough level at 24, 48 and 72 h (TL24, TL48, TL72); and time to reach FVIII levels of 1, 2, 5% (T1%, T2%, T5%). We have also compared the ratio of t1/2 and AUC, the number of weekly doses and the dose/kg/week before and after the switch. Wilcoxon and Kruskal-Wallis tests (SPSS®) were used to compare the PK parameters. Results are expressed with the median and interquartile range (IQR) or range, and mean and standard deviation (SD). Results Eighty-one patients from 8 Spanish hospitals were analyzed (61 rFVIII-Fc; 20 PEG-rFVIII), 78 had severe HA and 3 moderate HA. Mean age was 30 years (range=3-64) and no differences in weight were observed between both periods [70 (range=12-116) vs 70 (13.7-116) kg; p=0,141]. Dose/kg/week and weekly infusion frequency were reduced after the switch to EHL, and significant improvements were observed in all PK parameters after the change from SHL to EHL (Table 1). These results were similar in adult and pediatric patients switching to rFVIII-Fc. The median ratios of t1/2 and AUC were 1.3 (IQR:1.2-1.6) and 1.5 (IQR:1.3-2.3) in the entire cohort. These results were reproduced in the subset of patients with ≥12 years treated with rFVIII-Fc and PEG-rFVIII (ratio t1/2: 1.4 [IQR:1.3-1.6]; ratio AUC: 1.6 [IQR:1.3-2.3]), and were slightly in the cohort of 15 patients <12 years treated with rFVIII-Fc (ratio t1/2: 1.3 [IQR:0.9-1.3]; ratio AUC: 1.3 [IQR:1.1-1.9]), the only EHL approved in Europe for children. After the switch to EHL, weekly dose frequency (median 23.3%, IQR:0-33.3%) and dose/kg/week (median 16%, IQR:5.3-30%) were reduced. In a small subset of 17 patients the dose/kg/week increased a median of 31.4%, and this subset was younger than the patients with dose/kg/week reduction or no changes (median age 18 [IQR:8-22] vs. 33 [IQR:16.5-42.5]). No differences were observed in any of the PK parameters and median ratios of t1/2 and AUC in patients aged ≥12 years treated with rFVIII-Fc vs. PEG-rFVIII (46 rFVIII-Fc; 20 PEG-rFVIII; Table 2). Conclusions EHL FVIII have shown significant PK improvements in clinical real practice, allowing to reduce weekly infusion number and dose/kg/week, especially in adult patients. Outside the clinical trial setting, we have observed an increase in t1/2 and AUC ratios accordingly to EHL definition. Comparisons regarding clinical outcomes (bleeding rate after switch) will be performed after a follow-up of 1 year with EHL for the full cohort. WAPPS-Hemo PK-guided switch easily facilitates individualization of prophylaxis with a potential reduction in the cost of treatment and patient perceived outcomes. Disclosures Megias: Baxalta US INC.: Research Funding; Grifols: Research Funding. Bonanad Boix:Baxalta US INC.: Research Funding. Berrueco:NovoNordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SOBI: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL-Bering: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mingot-Castellano:Sobi: Consultancy; Bayer: Consultancy; Amgen: Consultancy; Roche: Consultancy; Novartis: Consultancy; Novonordisk: Consultancy; Takeda: Consultancy; CSL Behring: Consultancy. Cid:Shire, a Takeda company: Honoraria; Novo Nordisk: Honoraria. Sanz:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer-Ingelheim: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Helsinn Healthcare: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen - Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onconova: Membership on an entity's Board of Directors or advisory committees, Research Funding; Hoffman - La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

The Combination of Weekly Infusion of Rituximab and Bortezomib Is Effective in Relapsed or Refractory Indolent and Mantle Cell Lymphoma: Long-Term Results of Phase II BRIL06 Study of the Fondazione Italiana Linfomi (FIL)

Background. Bortezomib, an inhibitor of the proteasome, is effective in relapsed mantle cell lymphoma (MCL) and indolent lymphomas and it is synergistic with Rituximab to enhance apoptosis and NFkB depletion. On these basis, the FIL conducted a phase II multicenter study aimed to evaluate safety and efficacy of Bortezomib in association with Rituximab in relapsed/refractory non-follicular Lymphoma (Linfocytic, LL and Marginal Zone Lymphoma, MZL) and MCL, not eligible to high dose chemotherapy with stem cell transplantation. Patients and methods. The study was a prospective single arm phase II trial, designed on Simon two-stage Optimal Design. Primary end-point was to obtain an Overall Response Rate (ORR) > 40%. The aim of this analysis is to evaluate long term follow-up of Bortezomib and Rituximab combination. A central histological revision was planned in all the patients at the enrollment. Inclusion criteria were: 18-75 years, relapsed/refractory LL, MZL, MCL after 1-4 lines. Treatment schedule was: one course of 1.6 mg/sqm Bortezomib weekly in combination with standard 375 mg/sqm Rituximab on days 1, 8, 15, 22 followed by two courses of four weekly intravenous bolus of Bortezomib alone; patients with complete (CR), partial remission and stable disease at the intermediate evaluation were planned to be given three further courses with the same schedule. Results. From September 2006 to March 2008, 55 patients were enrolled and six were excluded at central histological revision. Clinical characteristics were: median age 68 (50-74); 16 (33%) LL, 8 (16%) MZL, 25 (51%) MCL; 42 (86%) stage III/IV; 33 (67%) bone marrow involvement. Median number of previous treatments was 2 (range 1-7); 34 (69%) were Rituximab pretreated; 21 (43%) had refractory disease. Thirty (61%) patients completed the treatment and 233 courses were delivered (median: 4.7 courses/patient); 19 (39%) patients did not because of no response in 13, adverse events in five, with only one toxic death due to interstitial pneumonia. ORR was 53% (CR 26.5%); no response was seen in 43% and 4% were not evaluable for response. ORRs by clinical subgroup were: LL 37%, MZL 50%, MCL 64%; Rituximab pretreated 62%, Rituximab naïve 33%; relapsed 64% and refractory 38%. With a median follow-up of 85 months, median Overall Survival (OS) was 61.5 months (95%CI: 35.0-81.5), with 5-years OS 51% (95% CI: 36-65) and median Progression Free Survival (PFS) was 8.9 months (95%CI: 5.3-18.3), with 5-years PFS 16% (95% CI: 7-28%). Five-years PFS by histology was: 12% (95% CI: 2-31) for LL, 17% (95% CI: 5-34) for MCL and 19% (95% CI: 11-53) for MZL. PFS rates were not different between Rituximab pretreated versus naïve nor international prognostic index 1-2 versus 3-4-5 nor refractory versus relapsed. By number of previous therapies, 5-years PFS for 1 previous therapy versus 2 versus 3 or more was: 24%, 14% and 13%, respectively, p=0.36. Conclusions. Weekly infusion of Bortezomib in combination with Rituximab is effective in relapsed/refractory indolent and MCL and represents a treatment option in this setting of patients. Disclosures No relevant conflicts of interest to declare.

Bortezomib, Melphalan, Prednisone and Thalidomide Followed by Maintenance with Bortezomib and Thalidomide (VMPT-VT) for Initial Treatment of Elderly Multiple Myeloma Patients: Updated Follow-up and Impact of Prognostic Factors

Abstract 620 Background. The combination of bortezomib-melphalan-prednisone (VMP) is a new standard of care for elderly newly diagnosed multiple myeloma. This phase 3 study compared the 4 drug combination bortezomib-melphalan-prednisone-thalidomide followed by maintenance bortezomib-thalidomide (VMPT-VT) with VMP alone. Methods. Patients (N=511) older than 65 years were randomized to receive nine 6-week cycles of VMPT-VT (N=254; induction: bortezomib 1.3 mg/m2, d 1, 4, 8, 11, 22, 25, 29, 32, cycles 1–4, d 1, 8, 22, 29, cycles 5–9; melphalan 9 mg/m2 d 1–4, prednisone 60 mg/m2, d 1–4, thalidomide 50 mg d 1–42; maintenance: bortezomib 1.3 mg/m2 every 14 days and thalidomide 50 mg/day) or VMP (N=257) alone. In March 2007, the protocol was amended: both VMPT-VT and VMP induction schedules were changed to nine 5-week cycles and bortezomib schedule was modified to weekly administration (1.3 mg/m2 d 1,8,15,22, all cycles). The primary end point was progression-free survival (PFS). Results. All patients have been evaluated in intention-to-treat. Patient characteristics were similar in both groups, median age was 71 years. The response rates were superior in the VMPT-VT group with a complete remission (CR) rate of 38% vs 24% (p=0.0008). After a median follow-up of 26.1 months, the 3-year PFS were 55% in patients receiving VMPT-VT and 38% in those receiving VMP (HR 0.65, 95% CI 0.49–0.85, P=0.002, Table). The 3-year time-to-next-therapy were 69% with VMPT-VT and 55% with VMP (HR 0.60, 95% CI 0.42–0.85, P=0.004). The 3-year overall survival was 86% with VMPT-VT and 84% with VMP (HR 0.88, 95% CI 0.53–1.45, P=0.62). The achievement of CR was a strong predictive factor of longer PFS in both groups (P=0.0001): in VMPT-VT arm, 3-year PFS was 66% in patients who obtained CR and 47% in those achieving PR; in VMP arm, it was 70% and 30%, respectively. The PFS benefit of VMPT-VT was seen consistently across different subgroups defined by creatinine clearance, LDH and bortezomib schedule; by contrast, in patients older than 75 years (HR 0.87; 95% CI 0.54–1.43, P=0.59) and in those at increased risk of disease progression, defined as presence of cytogenetic abnormalities [t(4;14) or t(14;16) or del17p] and ISS 3 (HR 1.35; 95% CI 0.45–4.06, P=0.60), VMPT-VT seemed not to add any significant PFS advantage to VMP. Grade 3–4 neutropenia (38% vs. 28%, p=0.02), cardiological events (10% vs. 5%, p=0.04) and thromboembolic events (5% vs. 2%, p=0.08) were more frequent among patients assigned to the VMPT-VT group; treatment-related deaths were 4% with VMPT-VT and 3% with VMP. In both groups, the once-weekly infusion of bortezomib significantly reduced the incidence of severe sensory peripheral neuropathy from 16% to 3% (p<0.0001). One hundred and forty-nine VMPT-VT patients were assessable for maintenance treatment. After a median duration of maintenance of 14.4 months, the PR rate was 90%, including 45% CR. The 1-year landmark analysis of PFS in patients completing the 9 induction cycles, showed a 2-year PFS of 63% in the VMPT-VT group and 40% in the VMP group, demonstrating that maintenance with VT reduced the risk of disease progression of 51% (HR 0.49, 95% CI 0.33–0.72, p=0.0003, Figure). This advantage was less evident in patients older than 75 years (HR 0.97, 95% CI 0.52–1.78, P=0.91) and in those with high-risk of disease progression, defined as presence of cytogenetic abnormalities and ISS 3 (HR 1.31, 95% CI 0.22–7.85, p=0.77). Continuous therapy with VT had favourable safety profile: 3% of patients experienced grade 3–4 hematological toxicity, 5% grade 3–4 peripheral neuropathy and 7% discontinued due to adverse events. Conclusion. In summary the current results indicate that: 1. VMPT-VT prolonged PFS with an unprecedented 3-year PFS of 55% in elderly patients; 2. once-weekly infusion of bortezomib improved safety without affecting outcome; 3. higher dose-intensity regimens seemed to be less effective in frail patients (≥ 75 years) and 4. maintenance therapy with VT further improved PFS with a good safety profile. Disclosures: Palumbo: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bringhen:Celgene: Honoraria; Janssen-Cilag: Honoraria. Patriarca:Celgene: Honoraria; Janssen Cilag: Honoraria; Roche: Honoraria; Merck: Membership on an entity's Board of Directors or advisory committees. Guglielmelli:Celgene: Honoraria; Janssen Cilag: Honoraria. Petrucci:Celgene: Honoraria; Janssen Cilag: Honoraria. Musto:Celgene: Honoraria; Janssen Cilag: Honoraria. Boccadoro:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.