LB001EFFICACY AND SAFETY OF BELIMUMAB IN PATIENTS WITH ACTIVE LUPUS NEPHRITIS: A PHASE 3, RANDOMISED, PLACEBO-CONTROLLED TRIAL

Abstract Background and Aims Belimumab (BEL), an anti-B-cell-activating factor (BAFF) monoclonal antibody, is approved in patients (pts) ≥5 years of age with active systemic lupus erythematosus (SLE). Post hoc analyses of pooled renal outcomes data from two Phase 3 SLE studies showed favourable trends of greater reduction in proteinuria, haematuria, pyuria and lower renal flare rates in BEL-treated pts vs placebo (PBO).1 This is the largest study in acute lupus nephritis (LN) to date that evaluated efficacy and safety of intravenous (IV) BEL plus standard therapy (ST) in pts with active LN. Method BLISS-LN is a Phase 3, randomised, double-blind, placebo-controlled, 104-week study (GSK study BEL114054, NCT01639339); eligible pts (≥18 years) with autoantibody-positive SLE and active, biopsy-proven LN (classes III, IV and/or V) were randomised (1:1) to monthly BEL 10 mg/kg IV or PBO, plus ST. Randomisation was stratified by induction regimen: high dose corticosteroids [HDCS] plus either cyclophosphamide (CyC), followed by azathioprine + low dose corticosteroids (LDCS), or mycophenolate mofetil (MMF), followed by MMF + LDCS. Primary endpoint: primary efficacy renal response (PERR; defined as urine protein creatinine ratio [uPCR] ≤0.7; estimated glomerular filtration rate [eGFR] no more than 20% below pre-flare value or ≥60 ml/min/1.73m2; no rescue therapy) at Week (Wk) 104. Key secondary endpoints: complete renal response (CRR; defined as uPCR <0.5; eGFR no more than 10% below pre-flare value or ≥90 ml/min/1.73m2; no rescue therapy) at Wk 104; PERR at Wk 52; risk of renal-related event (defined as end-stage renal disease/doubling of serum creatinine/renal worsening/renal disease-related treatment failure) or death at any time up to Wk 104. Other endpoints: PERR and CRR at Wk 104 by induction regimen; proportions of pts with baseline uPCR ≥0.5 with uPCR shift to <0.5 while on study. Results Overall, 448 pts were randomised (efficacy: 223/treatment group; safety: 224/treatment group); 118 pts received CyC induction and 328 MMF induction; 278 (62.3%) completed the treatment. At Wk 104, 43.0% BEL and 32.3% PBO pts achieved PERR (OR [95% CI] vs PBO 1.55 [1.04, 2.32], p=0.0311); 30.0% BEL and 19.7% PBO pts achieved CRR (OR [95% CI] vs PBO 1.74 [1.11, 2.74], p=0.0167). Over 104 weeks, more BEL than PBO pts achieved CRR at each visit (Figure 1A). PERR at Wk 52 was achieved by 46.6% BEL and 35.4% PBO pts (OR [95% CI] vs PBO 1.59 [1.06, 2.38], p=0.0245). The risk of a renal-related event or death was 49% lower with BEL than PBO (HR [95%CI] 0.51 [0.34, 0.77]; p=0.0014) at any time point during the study. Overall, 15.7% of BEL and 28.3% of PBO pts experienced a renal-related event or death. When analysed by induction regimen, PERR at Wk 104 was achieved by 33.9% BEL and 27.1% PBO CyC-induced pts (OR [95% CI] vs PBO 1.52 [0.66, 3.49], p=0.3272), and by 46.3% BEL and 34.1% PBO MMF-induced pts (OR [95% CI] vs PBO 1.58 [1.00, 2.51], p=0.0501). CRR at Wk 104 was achieved by 18.6% BEL and 18.6% PBO CyC-induced pts (OR [95% CI] vs PBO 1.07 [0.41, 2.78], p=0.8843), and by 34.1% BEL and 20.1% PBO MMF-induced pts (OR [95% CI] vs PBO 2.01 [1.19, 3.38], p=0.0085). Proportions of pts with uPCR shift from ≥0.5 at baseline to <0.5 while on study (calculated post hoc) are presented in the Figure 1B. Overall, 95.5% BEL and 94.2% PBO pts had ≥1 adverse event (AE); 25.9% BEL and 29.9% PBO pts had ≥1 serious AE; 13.8% BEL and 17.0% PBO pts had serious infections; 12.9% pts in each group had ≥1 AE resulting in study treatment discontinuation; on-treatment fatal AEs were reported in 1.8% BEL and 1.3% PBO pts. Conclusion BEL demonstrated improved renal responses vs PBO in pts with active LN, with a safety profile consistent with previous BEL trials.

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FC 035VOCLOSPORIN INCREASES RENAL RESPONSE AT COMMONLY USED UPCR THRESHOLDS IN PATIENTS WITH LUPUS NEPHRITIS

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab121.004 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Maria Dall'Era ◽

Paola Mina-Osorio ◽

Vanessa Birardi ◽

Simrat Randhawa

Keyword(s):

Lupus Nephritis ◽

Primary Endpoint ◽

Low Dose ◽

Therapeutic Drug ◽

Phase 3 ◽

Renal Response ◽

Dose Concentration ◽

Dose Oral ◽

One Year ◽

Post Hoc

Abstract Background and Aims Voclosporin is a novel calcineurin inhibitor with a favorable metabolic profile and a consistent dose-concentration relationship, potentially eliminating the need for therapeutic drug monitoring. We have previously reported the primary endpoint of the Phase 3 AURORA trial showing the addition of voclosporin to mycophenolate mofetil (MMF) and a low-dose glucocorticoid regimen results in significantly higher renal response (RR) rates at one year of treatment compared to MMF and low-dose glucocorticoids alone in patients with lupus nephritis (LN). For the primary endpoint, RR was defined as ≤0.5 mg/mg UPCR with stable renal function in the presence of low-dose glucocorticoids and no use of rescue medication. Several studies have demonstrated that proteinuria represents the best single predictor for long-term renal outcomes.1,2 Given the efficacy of voclosporin in terms of proteinuria reduction, we conducted a sensitivity analysis evaluating RR with additional UPCR targets. Method A total of 179 participants in the voclosporin (23.7 mg BID) arm and 178 participants in the control arm from the AURORA trial were included in this analysis. All participants received MMF (target 1 g BID) and low-dose oral glucocorticoids (initiated at 20-25 mg/day and tapered to 2.5 mg/day at 16 weeks). For this post hoc analysis, the UPCR component of RR was revised to include UPCR targets at 0.2 mg/mg intervals above and below the original ≤0.5 target used for the primary endpoint in AURORA (i.e., ≤0.7 mg/mg or ≤0.3 mg/mg, respectively). Odds ratios for RR at six months and one year of treatment were analyzed using a logistic regression model with terms for treatment, baseline UPCR, biopsy class, and MMF use at baseline and region. Results RR with UPCR ≤0.7 mg/mg was achieved by 46.9% of participants in the voclosporin arm vs 32.0% of participants in the control arm at one year of treatment (OR 2.07, p<0.0014) and 39.1% of participants in the voclosporin arm vs 24.7% of participants in the control arm at six months of treatment (OR 2.10, p=0.0020). RR with UPCR ≤0.3 mg/mg was achieved by 28.5% of participants in the voclosporin arm vs 15.7% of participants in the control arm at one year (OR 2.27, p=0.0023 and 22.9% of participants in the voclosporin arm vs 14.0% of participants in the control arm at six months of treatment (OR 1.90, p=0.0238; Table 1). Conclusion Participants treated with voclosporin in addition to MMF and low-dose glucocorticoids achieved statistically significantly increased renal response rates regardless of the level of UPCR used, including at an even more stringent ≤0.3 mg/mg target. This analysis further supports the efficacy observed with voclosporin in the Phase 3 AURORA and the prior Phase 2 AURA-LV global trials.

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Pengaruh Pemberian Cuka Apel 'A' terhadap Kadar MDA Hepar Tikus Wistar Jantan yang Diinduksi Parasetamol Dosis Toksik

Pustaka Kesehatan ◽

10.19184/pk.v6i2.7667 ◽

2018 ◽

Vol 6 (2) ◽

pp. 272

Author(s):

Niki Niki Rahmawati ◽

Sugiyanta Sugiyanta ◽

Elly Nurus Sakinah

Keyword(s):

Treatment Group ◽

Normal Control ◽

Negative Control Group ◽

Negative Control ◽

Control Group ◽

High Dose ◽

Toxic Dose ◽

Group A ◽

Post Hoc ◽

Cytochrome P 450

High dose of paracetamol is metabolized by cytochrome P-450 become free radical N-acetyl-p-benzoquinoneimine (NAPQI) but liver Glutathione (GSH) is not adequate to change it become nonreactive metabolite so that NAPQI bind to unsaturated fatty acid of cell membrane, causing lipid peroxidation and increase liver Malondialdehyde (MDA). 'A' apple vinegar contains anthocyanin with an antioxidant effect by electron donor to NAPQI and acetic acid to improve liver GSH level. The aim of research was to investigate the effect of 'A' apple vinegar on the rat liver MDA induced by toxic dose of paracetamol. Research groups consist of normal control (CMC Na 1% 1 ml for 14 days), negative control (CMC Na 1% 1ml for 14 days + paracetamol 291.6 mg/200gBW on the day 12nd,13rd,14th), and treatment group ('A' apple vinegar 0.4 ml/150gBW for 14 days + paracetamol 291.6 mg/200gBW on the day 12nd,13rd,14th). Liver MDA was measured on the day 15th with competitive ELISA. The average of normal control group was 21.58 ng/ml, negative control group was 70,71 ng/ml, treatment group was 37,67 ng/ml. One way ANOVA and Post hoc LSD test showed significantly differences between all groups (p<0,05). It can be concluded that 'A' apple vinegar had an effect on the liver MDA induced by toxic dose of paracetamol. Keywords: Paracetamol, NAPQI, MDA, 'A' apple vinegar, antioxidant

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High Dose Melphalan and Autologous Stem Cell Transplantation In Light Chain and Light and Heavy Chain Deposition Disease: Hematologic and Renal Outcomes.

Blood ◽

10.1182/blood.v116.21.4597.4597 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4597-4597

Author(s):

David Telio ◽

John Shepherd ◽

Donna L. Forrest ◽

Michael J. Barnett ◽

Thomas J. Nevill ◽

...

Keyword(s):

Stem Cell ◽

Renal Disease ◽

Light Chain ◽

High Dose ◽

Al Amyloidosis ◽

Renal Response ◽

Deposition Disease ◽

Stage Renal Disease ◽

High Dose Melphalan

Abstract Abstract 4597 Introduction: Light chain deposition disease (LCDD) and light and heavy chain deposition disease (LHCDD) are plasma cell disorders characterized by pathologic aggregation and deposition of immunoglobulin components in tissues leading to organ dysfunction. Reported outcomes with conventional chemotherapy include high rates of end stage renal disease and death. High dose melphalan followed by autologous stem cell transplantation (ASCT) has been employed in an attempt to improve outcomes, but few published data are available to support this practice. Methods: We conducted a retrospective review of all patients within our institutional database treated with ASCT for LCDD or LHCDD. Diagnosis was based in all cases upon renal biopsy. Associated multiple myeloma (MM) was diagnosed if bone marrow plasma cells were > 10% with concomitant anemia, hypercalcemia or lytic bone disease. Filgrastim was used for peripheral blood stem cell mobilization. All patients received melphalan conditioning at a reduced dose of 140 mg/m2 (due to renal dysfunction) with the exception of one patient who received melphalan 200 mg/m2. Response to treatment was adapted from the International Consensus Criteria (Gertz et al. 2005) designed for use in AL amyloidosis except that bone marrow biopsies were not performed to confirm complete hematologic remission. A renal response was considered to have been reached if proteinura decreased from 50% of baseline with stable creatinine or if creatinine decreased by 50% from its peak value. Results: We identified eight patients (7 LCDD, 1 LHCDD) treated with ASCT between August 2006 and November 2009. The median age at diagnosis was 48 years (range 40–62). Two patients had associated MM. All patients had come to medical attention as a consequence of renal dysfunction. The median serum creatinine at presentation was 192 μ mol/L (119-444) with two patients meeting criteria for nephrotic syndrome and a third having anasarca with nephritic syndrome. No patients were found to have associated AL amyloidosis, myeloma cast nephropathy, or extrarenal LCDD. Left ventricular ejection fraction was normal in all patients and none had evidence of cardiac infiltration. Kappa light chain restriction was present in seven patients with lambda light chain restriction in the eighth. Median kappa FLC level at diagnosis was 528 mg/L (range 42–1290, normal 3.3–19.4). Induction therapy consisted of dexamethasone in five patients and dexamethasone with bortezomib in two patients; one patient proceeded directly to ASCT without induction therapy. At the time of ASCT, the median serum creatinine was 183 μ mol/L (122-298). Stem cell mobilization was uncomplicated and ASCT was tolerated with no treatment related deaths or requirement for ICU admission. Significant toxicities included engraftment syndrome requiring steroids (2), bacteremia (2), sepsis with hypotension (1), pneumonia (1), grade 3 mucositis (1) and edema requiring ultrafiltration (1). One patient with a pre-ASCT creatinine of 298 μ mol/L went on to develop end stage renal disease and dialysis dependence two months after ASCT. Hematologic response was CR in two, PR in four, and not assessable in two patients due to insufficiently elevated baseline M-protein quantity for response determination. Seven patients had a renal response. After a median follow up from ASCT of 18 months (1-39 months), only one patient had experienced disease progression with increasing kappa FLC level. With the exception of the one dialysis dependent patient, no patients had symptoms related to renal disease at last follow up. Conclusion: In selected patients with LCDD and LHCDD, high dose melphalan with ASCT produced a high rate of hematologic and renal response with acceptable toxicity. Longer follow up is needed to assess the durability of response. Disclosures: No relevant conflicts of interest to declare.

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Durability of Initial Platelet Count Response in Patients Treated with Avatrombopag for Immune Thrombocytopenia (ITP): Post-Hoc Results from a Phase 3 Clinical Study

Blood ◽

10.1182/blood-2020-142764 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 22-23

Author(s):

Shivi Jain ◽

Matthew Wojdyla ◽

Michael Vredenburg ◽

Brian Jamieson ◽

Terry B. Gernsheimer

Keyword(s):

Research Funding ◽

Rescue Medication ◽

Rescue Therapy ◽

Initial Response ◽

Median Number ◽

Boxed Warning ◽

Phase 3 ◽

Response Level ◽

Loss Of Response ◽

Post Hoc

Background: The clinical management of ITP has been evolving. Thrombopoietin receptor agonists (TPO-RAs) have become widely utilized as subsequent treatments, and the 2019 ASH guidelines recommend their use over rituximab to achieve a durable response. TPO-RAs eltrombopag (ELT) and romiplostim (ROMI) have been FDA approved for over a decade with a well demonstrated efficacy profile. ELT, an oral medication, must be administered two hours prior to or four hours after meals containing polyvalent cations such as calcium or magnesium to mitigate clinically relevant effects on the pharmacokinetic profile (ELT prescribing information). Additionally, ELT carries a boxed warning for hepatoxicity that requires monitoring. ROMI, an injectable, is typically administered in a health care practitioner's office weekly which may be challenging for some patients (Pts). Avatrombopag (AVA) is an oral TPO-RA approved in 2019 for Pts with ITP. In clinical trials, AVA rapidly increased platelet count (PC) (5 days) and maintained it in the target range (50 to 150×109/L) with chronic dosing. Further, it has an exposure-adjusted safety profile generally comparable to placebo with no boxed warning for hepatotoxicity. AVA does not chelate polyvalent cations; therefore, it is administered with food and without restrictions regarding meal composition. A high proportion of Pts (~90%) respond to AVA; but limited information is available regarding the durability of response over time utilizing clinically relevant loss of response definitions. Aims: To understand the duration of initial response with AVA and the overall percent of treatment days a response level PC was achieved in responding Pts. Methods: A 6-month, multicenter, randomized, double-blind, Phase 3 study enrolled 32 AVA and 17 placebo-treated Pts with ITP. The study design included a 6-week study drug titration period, 12-week concomitant ITP medication reduction period, and an 8-week maintenance period. The primary endpoint was the median number of cumulative weeks of PC response (PC ≥50,000/µL) over the course of the study without rescue medication. Pts receiving rescue medication during the study were deemed to be non-responders for the remainder of the study. For this post-hoc analysis, we analyzed how many days it took for responding AVA Pts (n=29) to experience their first loss of response (LOR) or reach core study conclusion. After the initial PC ≥50,000/µL was noted, we also examined the percentage of remaining treatment time that initial response was maintained. Response was defined as the first time achieving a PC ≥50,000/µL. LOR was defined as a Pt experiencing a PC <30,000/µL for 4 consecutive weeks (LOR-4wk), or in a more conservative manner, Pts experiencing a PC <30,000/µL on 2 consecutive scheduled visits (LOR-2vis) [visits were weekly or biweekly depending on the phase of the study with 21 visits occurring over 26 weeks]. When a LOR was observed, the date of the first PC <30,000/µL was used for subsequent calculations with a return of response defined as a PC exceeding ≥30,000/µL again. Pts who required rescue therapy (n=6) were included in the analyses and the first date of administration was used for the LOR date. Pts requiring either corticosteroids (n=4) or IVIg (n=1) as rescue therapy were considered non-responders for a minimum of 8 weeks and Pts receiving a platelet transfusion (n=1) for a minimum of 1 week. Results: 72.4% (21/29) and 55.2% (16/29) of AVA responsive Pts never experienced a LOR-4wk or LOR-2vis, respectively. The median number of days until responding Pts experienced their first LOR-4wk, discontinued treatment, or completed the 6-month study was 170 (mean 134.7) and 146 (mean 119.1) for the LOR-2vis analysis. Pts maintained their initial response on average for 87.7% (median 100%) of their remaining time in the study for LOR-4wk and 84.5% (median 100%) for LOR-2vis analyses, with Pts often losing response only briefly when noted. Pts requiring rescue therapy often returned to a response level PC and remained in the 6-month study for approximately 5 months following their initial response. Conclusions: These data suggest that the initial response to AVA is stable and durable with up to 72.4% of Pts never experiencing a LOR, even with the planned objective of reducing the use of baseline concomitant ITP medications during the study. In those pts experiencing a LOR, many ended up achieving response level PCs again without a subsequent LOR. Disclosures Wojdyla: Dova Pharmaceuticals: Current Employment. Vredenburg:Dova Pharmaceuticals: Current Employment. Jamieson:Dova Pharmaceuticals: Current Employment. Gernsheimer:Amgen Corporation: Consultancy, Honoraria; Novartis: Consultancy; Cellphire: Consultancy; Rigel Corporation: Consultancy, Research Funding; Principia: Research Funding; Sanofi: Consultancy; Vertex: Consultancy; Dova Pharmaceuticals: Consultancy.

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FC 034SAFETY AND EFFICACY OF INTRAVENOUS BELIMUMAB IN PATIENTS WITH LUPUS NEPHRITIS: A 6-MONTH OPEN-LABEL EXTENSION

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab121.003 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Brad Rovin ◽

Richard Furie ◽

Frédéric A Houssiau ◽

Gabriel Contreras ◽

Y K O Teng ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Nephritis ◽

Lupus Erythematosus ◽

Rescue Therapy ◽

Systemic Lupus ◽

Open Label ◽

Appreciable Change ◽

Sledai Score ◽

Renal Response ◽

Number Of Patients

Abstract Background and Aims Lupus nephritis (LN) is the most common severe manifestation of systemic lupus erythematosus (SLE), occurring in up to 40% of patients (pts) with SLE over their disease course, and resulting in 10–20% of pts progressing to end-stage kidney disease.1-3 The BLISS-LN (GSK Study BEL114054; NCT01639339) study demonstrated that the addition of intravenous (IV) belimumab (BEL) to standard therapy (ST) in pts with active LN significantly improved renal responses over 2 years compared with ST alone.4 Here we present additional safety and efficacy data from the 6-month open-label (OL) extension phase of BLISS-LN. Method In this OL phase, eligible completers of the Phase 3 BLISS-LN study (those who received BEL or placebo [PBO] through Week 100 and completed Week 104 assessments) received BEL 10 mg/kg IV plus ST every 28 days for 24 weeks. Endpoints at OL Week 28 included: safety; Primary Efficacy Renal Response (PERR; defined as urine protein:creatinine ratio [uPCR] ≤0.7; eGFR no more than 20% below OL baseline value or ≥60 ml/min/1.73m2; no rescue therapy); Complete Renal Response (CRR; defined as uPCR <0.5; eGFR no more than 10% below OL baseline value or ≥90 ml/min/1.73m2; no rescue therapy); uPCR; eGFR; the proportion of pts with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score <4; Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI); and corticosteroid use. Analyses were based on observed data and summarised relative to the OL baseline (last available value measured prior to dosing on or before the date of the first OL treatment dose). Results Of 257 pts (57.4 % of pts in BLISS-LN double-blind [DB] study) screened and enrolled, 255 pts were treated (safety population: 123 pts switched from PBO to BEL; 132 pts remained on BEL). In total, 254 pts were included in the efficacy analyses (PBO to BEL: 122 pts; BEL to BEL: 132 pts). Mean (standard deviation) age was 35.9 (10.3) years. In total, 3.5% of pts withdrew from the OL phase, mainly due to adverse events (AE; 2.0%). Overall, 168/255 (65.9%) pts experienced ≥1 AE (76/123 [61.8%] PBO to BEL pts; 92/132 [69.7%] BEL to BEL pts); 49/255 (19.2%) pts had ≥1 treatment-related AE (25/123 [20.3%] PBO to BEL pts; 24/132 [18.2% ] BEL to BEL pts); 15/255 (5.9%) pts had ≥1 serious AE (5/123 [4.1%] PBO to BEL pts; 10/132 [7.6%] BEL to BEL pts); and 1 death was reported in the PBO to BEL group. The proportion of patients achieving PERR and CRR increased from OL baseline to OL Week 28 in both groups (Table). The median (interquartile range [IQR]) for uPCR and eGFR were maintained from OL baseline through to OL Week 28 (Table). The proportion of SLEDAI score <4 responders in BEL to BEL group tended to increase from OL baseline to OL Week 28, and decrease in the PBO to BEL group (Table). SDI worsening (change >0) was experienced by 7 (2.9%) pts (4 [3.3%] PBO to BEL; 3 [2.5%] BEL to BEL) compared with OL baseline. There was no appreciable change in the number of patients receiving average daily prednisone-equivalent doses of ≤5 mg or ≤7.5 mg from OL baseline to OL Week 28 (Table). Conclusion BEL was well tolerated as an add-on to ST, with no new safety signals. Efficacy among pts with LN randomised to BEL during the DB phase was maintained during the OL phase. Study funding GSK. Editorial assistance (GSK-funded): Olga Conn, PhD, Fishawack Indicia Ltd., part of Fishawack Health, UK.

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A Randomized Comparison of Induction Therapy for Untreated Acute Myeloid Leukemia (AML) in Patients < 60 Years Using P-Glycoprotein (Pgp) Modulation with Valspodar (PSC833): Preliminary Results of Cancer and Leukemia Group B Study 19808.

Blood ◽

10.1182/blood.v106.11.407.407 ◽

2005 ◽

Vol 106 (11) ◽

pp. 407-407 ◽

Cited By ~ 15

Author(s):

Jonathan E. Kolitz ◽

Stephen L. George ◽

Guido Marcucci ◽

Ravi Vij ◽

Bayard L. Powell ◽

...

Keyword(s):

Interleukin 2 ◽

Hepatic Clearance ◽

Risk Groups ◽

Left Ventricular ◽

Comparable Efficacy ◽

High Dose ◽

Phase 3 ◽

Induction Regimen ◽

Intent To Treat ◽

Group B

Abstract In order to assess whether Pgp modulation with PSC833 improves disease-free (DFS) and overall (OS) survival in untreated patients (pts) with AML < 60 years, a phase 3 trial (CALGB 19808) was undertaken comparing two induction regimens: Ara-C (A), Daunorubicin (D), and Etoposide (E), with (ADEP) or without (ADE) PSC833. All pts received A 100 mg/m2 by CIV daily for 7 days. In ADE, D 90 mg/m2 and E 100 mg/m2 were each given daily by short IV infusion on days 1–3; the corresponding doses in ADEP were D 40 mg/m2 and E 40 mg/m2. PSC833 10 mg/m2 was given by CIV over 72 hrs after a loading dose of 2.8 mg/kg IV over 2 hrs. These doses were based on findings from parallel phase I trials that showed comparable efficacy and toxicity for the 2 regimens (JCO2004; 22:4290). Pts in complete remission (CR) received consolidation therapy according to cytogenetic risk (ASH2001, 688a) and were then randomized to a phase 3 immunotherapy sequence comparing interleukin-2 with observation. The Pgp modulation portion of the trial ended when PSC833 became unavailable after 302 of a planned 600 pts had been randomized. Prior myelodysplasia or therapy-related AML were exclusion criteria. The median age was 45 years; the arms were comparable with respect to cytogenetic risk groups (Core-Binding Factor (CBF) leukemia vs. others). Response by intent-to-treat on the part of 296 evaluable pts and toxicity data are tabulated below. The median follow-up is 2.2 years. None of the differences in CR rate, OS, or DFS are statistically significant. ADE (n=149) ADEP (n=147) CR 77% 78% CR - CBF AML 100% (21/21) 100% (25/25) CR With One Induction Course 89% 88% Induction Mortality 7% 7% Median OS (months) 21 20 Median DFS (months) 19 15 Median OS -pts ≤ 45 yrs (months) 29 Not Reached Median DFS pts ≤ 45 yrs (months) Not Reached 13 Grade 3 and 4 Toxicities Dysphagia/Esophagitis 6% 17% Stomatitis 9% 24% Bilirubin 6% 25% Rash 1% 10% Left Ventricular Function 2% 1% The high dose daunorubicin regimen was given safely, without excess induction mortality or cardiotoxicity. Hepatotoxicity due to ADEP consisted of generally reversible hyperbilirubinemia. PSC833 did not cause significant neurotoxicity. Compared with the induction regimen used in the previous group study in this pt population in which 474 pts received D 45 mg/m2 x 3 days and A 200 mg/m2 x 7 days without E or PSC833, (CALGB 9222, Blood2005; 105:3420), the CR rates in this study were higher (78% vs 72%), the number of pts achieving CR with 1 induction higher (89% vs. 77%), and the induction mortality comparable (7% vs 9%). These preliminary findings suggest that similar outcomes occur following an induction regimen using 2.25-fold higher D and 2.5-fold higher E doses (ADE) relative to a regimen employing a Pgp modulator (ADEP). PSC833 is known to delay the hepatic clearance of D and E. These data cannot distinguish between the possibilities that PSC833 augments the anti-leukemia activity of the lower dose ADE regimen or whether there is, in fact, no clinically meaningful dose-response relationship with D and E within the evaluated dose ranges. The findings of this trial to date suggest that Pgp-mediated drug efflux may not be the major or sole mechanism of drug resistance in AML or that PSC833 is an inadequate inhibitor of Pgp activity or both.

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