- Email: [email protected]
Adherence To The Ibrutinib 420 mg Dose Administered To Patients With Previously Treated CLL
Abstracts analysis. Results: Trisomy12 (38-80% of cells) and NOTCH1 mutation (53-100% of cells) was detected in all patients. All patients had two or more cell populations defined by NOTCH1 mutation, Trisomy12 or both (major clone in 2/5 cases). Two patients demonstrated further intra-clonal diversity through either convergent or parallel evolution of two different or identical NOTCH1 mutations in Trisomy12 sub-clones, respectively. Conclusions: Trisomy12-NOTCH1 evolution is more complex than previously thought and may provide insight into progression and transformation. Grant Acknowledgements: Wessex Medical Research Innovation award, Kay Kendal Leukaemia Fund. Keywords: Singlecell, Genetics, CLL, Cancer.
302 Adherence To The Ibrutinib 420 mg Dose Administered To Patients With Previously Treated CLL Jan A. Burger, MD, PhD,1 Paul M. Barr, MD,2 Jennifer R. Brown, MD, PhD,3 Peter Hillmen, MB ChB, PhD,4 Susan O’Brien, MD,1 Jacqueline C. Barrientos, MD,5 Nishitha M. Reddy, MBBS, MScl,6 Steven Coutre, MD,7 Stephen P. Mulligan, MBBS, MD, FRACP, FRCPA,8 Ulrich Jaeger, MD,9 Richard R. Furman, MD,10 Florence Cymbalista, MD,11 Marco Montillo, MD,12 Claire Dearden, MD,13 Tadeusz Robak, MD, PhD,14 Carol Moreno, MD,15 John Pagel, MD, PhD,16 Samuel Suzuki, MS, MBA,17 Juthamas Sukbuntherng, PhD,17 George Cole, MD,17 Danelle F. James, MD, MAS,17 John C. Byrd, MD18 1
University of Texas MD Anderson Cancer Center, Houston, TX; Wilmot Cancer Institute, University of Rochester, NY; 3Dana-Farber
2
Signal transducer and activator of transcription (STAT)-3 is a double edged sword in CLL cells
Nashville, TN; 7Stanford University School of Medicine, Stanford, CA; 8
1
5
James Institute of Oncology, Leeds, UK; North Shore-LIJ Cancer Institute, Lake Success, NY; 6Vanderbilt-Ingram Cancer Center, Royal North Shore Hospital, Sydney, Australia; 9Medical University of
Vienna, Vienna, Austria;
10
Weill Cornell Medical College/New York
Presbyterian Hospital, New York, NY; 11Hôpital Avicenne, Paris, France; 12Niguarda Ca’ Granda Hospital, Milan, Italy; 13Royal Marsden Hospital, London, UK; Poland;
14
Medical University of Lodz, Lodz,
15
Hospital de la Santa Creu Sant Pau, Barcelona, Spain;
16
Swedish Cancer Institute, Seattle, WA;
Abbvie Company, Sunnyvale, CA;
17
Pharmacyclics LLC, an
18
The Ohio State University Med-
ical Center, Columbus, OH
Context: Ibrutinib is a first-in-class, once-daily, oral, covalent inhibitor of Bruton’s tyrosine kinase (BTK). BTK active site occupancy (median 90%) is achieved at 4 and maintained at 24 hours with ibrutinib 420 mg once-daily (Lancet Oncology 2013). Using simulated 140 or 280 mg doses, fewer patients attained complete BTK occupancy (Poggesi, AACR 2014). Objective: To evaluate ibrutinib dose adherence parameters on IRC-assessed progression-free survival (PFS), in accordance with iwCLL criteria, in patients with previously
-
303
Uri Rozovski,1 David M. Harris,2 Ping Li,2 Zhiming Liu,2 Srdana Grgurevic,2 Alessandra Ferrajoli,2 William G. Wierda,2 Srdan Verstovsek,2 Michael Keating,2 Zeev Estrov2
Cancer Institute, Boston, MA; 4The Leeds Teaching Hospitals, St.
S24
treated CLL. Design: Phase 3, randomized, open-label multicenter study of ibrutinib versus ofatumumab (RESONATE). Patients/ Intervention: Analysis included patients (1 prior treatment for CLL/SLL) who received ibrutinib 420 mg once-daily dose. Main Outcome Measures: Overall mean dose intensity (DI) defined as the proportion of administered vs. planned doses of 420 mg, and in first 8 weeks to avoid confounding (8-week mean dose intensity); PFS beyond 8 weeks; steady-state AUC/Cmax estimated using week 1 and 4 timepoints; missed doses 8 consecutive days with ibrutinib restarting after missed dose. Results: Overall mean DI was 95% (median 100%) with median 8.6 months of ibrutinib treatment (N¼195). 8-week mean DI was 96%. 73 of 79 patients (92%) with dose holds restarted at 420 mg. 3.6% of patients had dose reduction to 280 mg and 0.5% dose reduction to 140 mg. Fewer progression events occurred with overall mean DI above vs. below mean (12% vs. 33%). PFS was longer with 8-week mean DI above vs. below mean (median not reached vs. 6.9 months, P¼0.0127), and shorter in patients missing 8 (n¼57) vs. <8 (n¼136) consecutive days of ibrutinib (median 10.9 months vs. not reached). Higher mean DI was associated with fewer PFS events regardless of del17p, or TP53 mutation. No difference was seen in median PFS with lower vs. higher ibrutinib exposure (AUC or Cmax) in patients receiving ibrutinib 420 mg with pharmacokinetic assessment (n¼179) at weeks 1 and 4. Conclusions: Higher mean ibrutinib DI is associated with improved PFS, with patients missing 8 consecutive days experiencing more PFS events. These results support the clinical importance of sustained adherence to continuous once-daily 420 mg ibrutinib dosing in patients with previously treated CLL.
Clinical Lymphoma, Myeloma & Leukemia September 2015
Institute of Hematology, Davidoff Cancer Center, Beilinson Hospital,
Sackler School of Medicine, Tel-Aviv University, Israel; 2The University of Texas MD Anderson Cancer Center
In CLL STAT3 is constitutively phosphorylated on serine 727 residues and activates anti-apoptotic genes. Therefore, we hypothesized that STAT3 levels and rate of spontaneous apoptosis would be inversely correlated. To test levels of STAT3 we used quantitative western immunoblotting and found that levels were significantly higher in patients with high (N ¼ 32) compared to low (N ¼ 32) WBC counts (P ¼ 0.007). To test the rate of spontaneous apoptosis we stained the cells of 19 CLL patients with Annexin V and PI and found that apoptosis rates were highly correlated with white blood cell (WBC) counts (rp¼0.88, P< 0.0001). Accordingly, levels of cleaved PARP were 3 times higher in patients with high (N ¼ 32) compared to low (N ¼ 32) WBC counts (P ¼ 0.007). Hence, contrary to our hypothesis in high-count CLLs levels of STAT3 and rate of spontaneous apoptosis are both increased. Intrigued by these
302 Adherence To The Ibrutinib 420 mg Dose Administered To Patients With Previously Treated CLL Jan A. Burger, MD, PhD,1 Paul M. Barr, MD,2 Jennifer R. Brown, MD, PhD,3 Peter Hillmen, MB ChB, PhD,4 Susan O’Brien, MD,1 Jacqueline C. Barrientos, MD,5 Nishitha M. Reddy, MBBS, MScl,6 Steven Coutre, MD,7 Stephen P. Mulligan, MBBS, MD, FRACP, FRCPA,8 Ulrich Jaeger, MD,9 Richard R. Furman, MD,10 Florence Cymbalista, MD,11 Marco Montillo, MD,12 Claire Dearden, MD,13 Tadeusz Robak, MD, PhD,14 Carol Moreno, MD,15 John Pagel, MD, PhD,16 Samuel Suzuki, MS, MBA,17 Juthamas Sukbuntherng, PhD,17 George Cole, MD,17 Danelle F. James, MD, MAS,17 John C. Byrd, MD18 1
University of Texas MD Anderson Cancer Center, Houston, TX; Wilmot Cancer Institute, University of Rochester, NY; 3Dana-Farber
2
Signal transducer and activator of transcription (STAT)-3 is a double edged sword in CLL cells
Nashville, TN; 7Stanford University School of Medicine, Stanford, CA; 8
1
5
James Institute of Oncology, Leeds, UK; North Shore-LIJ Cancer Institute, Lake Success, NY; 6Vanderbilt-Ingram Cancer Center, Royal North Shore Hospital, Sydney, Australia; 9Medical University of
Vienna, Vienna, Austria;
10
Weill Cornell Medical College/New York
Presbyterian Hospital, New York, NY; 11Hôpital Avicenne, Paris, France; 12Niguarda Ca’ Granda Hospital, Milan, Italy; 13Royal Marsden Hospital, London, UK; Poland;
14
Medical University of Lodz, Lodz,
15
Hospital de la Santa Creu Sant Pau, Barcelona, Spain;
16
Swedish Cancer Institute, Seattle, WA;
Abbvie Company, Sunnyvale, CA;
17
Pharmacyclics LLC, an
18
The Ohio State University Med-
ical Center, Columbus, OH
Context: Ibrutinib is a first-in-class, once-daily, oral, covalent inhibitor of Bruton’s tyrosine kinase (BTK). BTK active site occupancy (median 90%) is achieved at 4 and maintained at 24 hours with ibrutinib 420 mg once-daily (Lancet Oncology 2013). Using simulated 140 or 280 mg doses, fewer patients attained complete BTK occupancy (Poggesi, AACR 2014). Objective: To evaluate ibrutinib dose adherence parameters on IRC-assessed progression-free survival (PFS), in accordance with iwCLL criteria, in patients with previously
-
303
Uri Rozovski,1 David M. Harris,2 Ping Li,2 Zhiming Liu,2 Srdana Grgurevic,2 Alessandra Ferrajoli,2 William G. Wierda,2 Srdan Verstovsek,2 Michael Keating,2 Zeev Estrov2
Cancer Institute, Boston, MA; 4The Leeds Teaching Hospitals, St.
S24
treated CLL. Design: Phase 3, randomized, open-label multicenter study of ibrutinib versus ofatumumab (RESONATE). Patients/ Intervention: Analysis included patients (1 prior treatment for CLL/SLL) who received ibrutinib 420 mg once-daily dose. Main Outcome Measures: Overall mean dose intensity (DI) defined as the proportion of administered vs. planned doses of 420 mg, and in first 8 weeks to avoid confounding (8-week mean dose intensity); PFS beyond 8 weeks; steady-state AUC/Cmax estimated using week 1 and 4 timepoints; missed doses 8 consecutive days with ibrutinib restarting after missed dose. Results: Overall mean DI was 95% (median 100%) with median 8.6 months of ibrutinib treatment (N¼195). 8-week mean DI was 96%. 73 of 79 patients (92%) with dose holds restarted at 420 mg. 3.6% of patients had dose reduction to 280 mg and 0.5% dose reduction to 140 mg. Fewer progression events occurred with overall mean DI above vs. below mean (12% vs. 33%). PFS was longer with 8-week mean DI above vs. below mean (median not reached vs. 6.9 months, P¼0.0127), and shorter in patients missing 8 (n¼57) vs. <8 (n¼136) consecutive days of ibrutinib (median 10.9 months vs. not reached). Higher mean DI was associated with fewer PFS events regardless of del17p, or TP53 mutation. No difference was seen in median PFS with lower vs. higher ibrutinib exposure (AUC or Cmax) in patients receiving ibrutinib 420 mg with pharmacokinetic assessment (n¼179) at weeks 1 and 4. Conclusions: Higher mean ibrutinib DI is associated with improved PFS, with patients missing 8 consecutive days experiencing more PFS events. These results support the clinical importance of sustained adherence to continuous once-daily 420 mg ibrutinib dosing in patients with previously treated CLL.
Clinical Lymphoma, Myeloma & Leukemia September 2015
Institute of Hematology, Davidoff Cancer Center, Beilinson Hospital,
Sackler School of Medicine, Tel-Aviv University, Israel; 2The University of Texas MD Anderson Cancer Center
In CLL STAT3 is constitutively phosphorylated on serine 727 residues and activates anti-apoptotic genes. Therefore, we hypothesized that STAT3 levels and rate of spontaneous apoptosis would be inversely correlated. To test levels of STAT3 we used quantitative western immunoblotting and found that levels were significantly higher in patients with high (N ¼ 32) compared to low (N ¼ 32) WBC counts (P ¼ 0.007). To test the rate of spontaneous apoptosis we stained the cells of 19 CLL patients with Annexin V and PI and found that apoptosis rates were highly correlated with white blood cell (WBC) counts (rp¼0.88, P< 0.0001). Accordingly, levels of cleaved PARP were 3 times higher in patients with high (N ¼ 32) compared to low (N ¼ 32) WBC counts (P ¼ 0.007). Hence, contrary to our hypothesis in high-count CLLs levels of STAT3 and rate of spontaneous apoptosis are both increased. Intrigued by these