Ponatinib In Heavily Pretreated Patients With Chronic Phase Chronic Myeloid Leukemia (CP-CML): Management Of Adverse Events (AEs)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1496-1496 ◽  
Author(s):  
Philipp D. Le Coutre ◽  
Dong-Wook Kim ◽  
Javier Pinilla-Ibarz ◽  
Ronald Paquette ◽  
Charles Chuah ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Stock Options ◽  
Research Funding ◽  
Peripheral Vascular ◽  
Vascular Events ◽  
Advisory Committees ◽  
Dose Modification ◽  
Advisory Boards ◽  
Initial Onset ◽  
Grade 3

Abstract Background Ponatinib is a potent oral pan–BCR-ABL tyrosine kinase inhibitor (TKI) with activity against native and mutant BCR-ABL. The efficacy and safety of ponatinib (45 mg once daily) in pts with CP-CML were evaluated in the phase 2 PACE trial. Objectives To review the management of treatment-related AEs (TRAEs) that emerged during therapy with ponatinib in the PACE trial. Methods A total of 270 CP-CML pts (267 in efficacy population) resistant or intolerant to dasatinib or nilotinib or with the T315I mutation were enrolled in this ongoing, phase 2, international, open-label clinical trial. The primary endpoint was major cytogenetic response (MCyR) at any time within 12 mos. Safety monitoring included collection of AEs, and the following variables were evaluated: incidence, severity, time to onset, duration, and management. Select TRAEs are discussed. Data as of 01 Apr 2013 are reported, with a median follow-up of 20 (0.1–28) mos. Minimum follow-up for pts remaining on study was 18 mos. Results Median age was 60 (18-94) yrs; median time from diagnosis to first dose was 7 (0.5-27) yrs; 93% had ≥2 prior TKIs, 60% ≥3. Ponatinib demonstrated significant activity in CP-CML pts: 56% MCyR, 46% CCyR, and 36% MMR. At the time of analysis, 60% of pts remained on study. The most frequent reasons for discontinuation were AEs (14%) and progression (8%). The most common hematologic TRAE was thrombocytopenia (41% any grade, 32% grade 3/4). The incidence by time to initial onset is shown below (Figure). Pts experienced thrombocytopenia for a median total duration of 166 days (64% of whom had >1 event) and typically required dose modification: 13% drug withdrawn, 40% dose reduced, 29% dose interrupted only, 17% no dose modification. Among pts with thrombocytopenia, 27% required a platelet transfusion. Thirteen percent of CP-CML pts experienced treatment-related neutropenia and thrombocytopenia. The most common nonhematologic TRAE was rash (39% any grade, 4% grade 3/4), which includes erythematous, macular, and papular rash. Pts experienced rash for a median total duration of 65 days (46% of whom had >1 event) and most did not require dose modification: 0% drug withdrawn, 15% dose reduced, 11% dose interrupted only, 73% no dose modification. One additional pt discontinued due to grade 2 treatment-related exfoliative rash. Pancreatitis was observed (7% any grade, 6% grade 3/4). Median duration was 5 days. Pts were typically managed with dose modification: 5% drug withdrawn, 58% dose reduced, 32% dose interrupted only, 5% no dose modification. Treatment-emergent cardiovascular events were observed in 8% of pts and treatment-emergent cerebrovascular or peripheral vascular events in 11%. Cardiovascular events were considered treatment-related in 4%; cerebrovascular or peripheral vascular events were also considered treatment-related in 4%. The median time to initial onset was 9 mos for cardiovascular and 11 mos for cerebrovascular or peripheral vascular events. The median duration was 6 and 97 days, respectively. Management of pts with cardiovascular AEs: 20% drug withdrawn, 10% dose reduced, 40% dose interrupted only, 30% no dose modification. Management of pts with cerebrovascular or peripheral vascular AEs: 8% drug withdrawn; 8% dose reduced; 17% dose interrupted only; 67% no dose modification. Conclusions Ponatinib has robust antileukemic activity in heavily pretreated CP-CML pts (93% of whom received ≥2 prior TKIs). Treatment-related thrombocytopenia and pancreatitis generally occurred early in therapy and were manageable with dose modification. Treatment-related rash generally occurred early in therapy, was mild-to-moderate in severity, managed without the need for dose modification, and rarely led to discontinuation. Management of treatment-related arterial thrombotic events varied; pts with predisposing cardiovascular risk factors should be monitored closely and managed accordingly. ClinicalTrials.gov ID: NCT01207440 aIncidence = (number of pts with initial onset during time interval) / (number of pts dosed during time interval [N] excluding those who previously experienced the event) X 100 Disclosures: Le Coutre: Novartis: Research Funding; Novartis, BMS, Pfizer: Honoraria. Kim:BMS, Novartis, IL-Yang: Consultancy; BMS, Novartis, Pfizer, ARIAD, IL-Yang: Research Funding; BMS, Novartis, Pfizer, IL-Yang: Honoraria; BMS, Novartis, Pfizer: Speakers Bureau; BMS, Pfizer: Membership on an entity’s Board of Directors or advisory committees. Pinilla-Ibarz:Novartis, Ariad: Research Funding; Novartis, Ariad, BMS and Pfizer: Speakers Bureau. Paquette:Ariad, BMS, Novartis: Consultancy; Ariad, BMS, Novartis: Honoraria; Ariad, BMS, Novartis: Speakers Bureau. Chuah:Novartis, BMS: Honoraria. Nicolini:Novartis, ARIAD, Teva: Consultancy; Novartis, BMS: Research Funding; Novartis, BMS, Teva, Pfizer, ARIAD: Honoraria; Novartis, BMS, TEva: Speakers Bureau; Novartis, ARIAD, Teva, Pfizer: Membership on an entity’s Board of Directors or advisory committees. Apperley:Novartis: Research Funding; Ariad, Bristol Myers Squibb, Novartis, Pfizer, Teva: Honoraria. Talpaz:Ariad, BMS, Sanofi, INCYTE: Research Funding; Ariad, Novartis: Speakers Bureau; Ariad, Sanofi, Novartis: Membership on an entity’s Board of Directors or advisory committees. DeAngelo:Ariad, Novartis, BMS: Consultancy. Abruzzese:BMS, Novartis: Consultancy. Rea:BMS, Novartis, Pfizer, Ariad, Teva: Honoraria. Baccarani:ARIAD, Novartis, BMS: Consultancy; ARIAD, Novartis, BMS, Pfizer, Teva: Honoraria; ARIAD, Novartis, BMS, Pfizer, Teva: Speakers Bureau. Muller:Novartis, BMS, ARIAD: Consultancy; Novartis, BMS: Research Funding; Novartis, BMS, ARIAD: Honoraria. Gambacorti-Passerini:Pfizer: Research Funding; Pfizer, BMS: Honoraria. Lustgarten:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Yanase:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc. Other, Employment. Turner:ARIAD: Employment. Haluska:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Deininger:BMS, ARIAD, NOVARTIS: Consultancy; BMS, NOVARTIS, CELGENE, GILEAD: Research Funding; ARIAD, NOVARTIS: Advisory Boards, Advisory Boards Other. Hochhaus:Ariad, Novartis, BMS, MSD, Pfizer: Research Funding; Novartis, BMS, Pfizer: Honoraria. Hughes:Novartis, BMS, ARIAD: Honoraria, Research Funding. Goldman:ARIAD: Honoraria. Shah:Ariad, Bristol-Myers Squibb: Consultancy, Research Funding. Kantarjian:ARIAD, Novartis, BMS, Phizer: Research Funding. Cortes:Ariad, Pfizer, Teva: Consultancy; Ariad, BMS, Novartis, Pfizer, Teva: Research Funding.

Efficacy and Safety Of Ponatinib Following Failure Of Dasatinib In Patients (pts) With Chronic Phase Chronic Myeloid Leukemia (CP-CML) In The PACE Trial

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1498-1498 ◽  
Author(s):  
Andreas Hochhaus ◽  
Jorge E. Cortes ◽  
Dong-Wook Kim ◽  
Javier Pinilla-Ibarz ◽  
Philipp D le Coutre ◽  
...  
Keyword(s):  
Pleural Effusion ◽  
Board Of Directors ◽  
Stock Options ◽  
Research Funding ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Advisory Boards ◽  
Group I ◽  
Grade 3 ◽  
Group D

Abstract Background The efficacy and safety of subsequent TKIs in pts who have experienced failure of dasatinib is not fully known. Ponatinib, a pan-BCR-ABL inhibitor, was evaluated in a phase 2, international, open-label clinical trial (PACE). This post-hoc analysis explored the efficacy and safety of ponatinib following failure of dasatinib in CP-CML pts in the PACE trial. Methods The PACE trial enrolled 449 pts, including 270 with CP-CML. Pts had to be resistant or intolerant to dasatinib or nilotinib, or they had to have the T315I mutation at baseline. The primary endpoint in CP-CML was major cytogenetic response (MCyR) at any time within 12 months after treatment initiation. The trial is ongoing. Data as of 1 April 2013 are reported, with a minimum follow-up of 18 months for pts remaining on study. The efficacy and safety of ponatinib (45 mg QD) in 107 CP-CML pts following failure of dasatinib as the most recent prior therapy, irrespective of other TKI therapy, is presented (Group D). Eighteen pts who experienced failure of dasatinib but received ≥1 anticancer therapy, other than hydroxyurea or anagrelide, prior to ponatinib treatment were excluded from the analyses. Data are also presented for 2 subsets of Group D: 52 pts whose only TKI therapy was imatinib followed by dasatinib (Group I-D), and 46 pts whose only TKI therapy was imatinib, then nilotinib, and then dasatinib (Group I-N-D). An analysis of cross-intolerance was also conducted in 69 pts with prior dasatinib treatment at any time who discontinued dasatinib due to intolerance. Results Baseline characteristics are shown in the table. Group I-D tended to be younger, with less time since diagnosis versus Group I-N-D. At the time of analysis, 60%, 65%, and 54% of pts in Groups D, I-D, and I-N-D remained on study. The most common reasons for discontinuation were adverse events (AEs; 16%, 15%, 17%) and progressive disease (9%, 6%, 11%) in Groups D, I-D, and I-N-D. Efficacy end points are shown in the table. In Group D, MCyR was seen in pts with the following dasatinib-resistant mutations at baseline: V299L, 3/4 (75%); T315I, 17/23 (74%); F317L, 3/10 (30%). The most common treatment-related AEs were thrombocytopenia (44%, 37%, 57%), rash (39%, 39%, 39%), and dry skin (39%, 29%, 52%) in Groups D, I-D, and I-N-D. Serious cardiovascular, cerebrovascular, and peripheral vascular AEs occurred in 6%, 3%, and 3% of pts in Group D (treatment-related: 3%, 1%, 0%). Seventy-three of 217 pts receiving prior dasatinib at any time discontinued dasatinib due to intolerance. Of these 73 pts, 27 experienced the same AE(s) with ponatinib that led to dasatinib intolerance; 12 pts had grade 3/4 thrombocytopenia, 6 pts had other grade 3/4 AEs (3 with neutropenia, 1 each with pleural effusion, dyspnea, pulmonary hypertension), 8 pts had grade 1/2 AEs. Six of these 27 pts discontinued ponatinib due to the same AE that led to dasatinib intolerance. Thrombocytopenia was the primary AE involved in cross-intolerance (4 pts); congestive cardiac failure (grade 5) and pleural effusion each occurred once. Conclusions Ponatinib has substantial activity in pts with CP-CML following failure of dasatinib, with a safety profile reflective of this heavily pretreated population. Cross-intolerance between dasatinib and ponatinib was infrequent. Disclosures: Hochhaus: Ariad, Novartis, BMS, MSD, Pfizer: Research Funding; Novartis, BMS, Pfizer: Honoraria. Cortes:Ariad, Pfizer, Teva: Consultancy; Ariad, BMS, Novartis, Pfizer, Teva: Research Funding. Kim:BMS, Novartis,IL-Yang: Consultancy; BMS, Novartis, Pfizer,ARIAD,IL-Yang: Research Funding; BMS, Novartis,Pfizer,IL-Yang: Honoraria; BMS, Novartis,Pfizer: Speakers Bureau; BMS, Pfizer: Membership on an entity’s Board of Directors or advisory committees. Pinilla-Ibarz:Novartis, Ariad: Research Funding; Novartis, Ariad, BMS and Pfizer: Speakers Bureau. le Coutre:Novartis: Research Funding; Novatis, BMS, Pfizer: Honoraria. Paquette:ARIAD, BMS, Novartis: Consultancy, Honoraria, Speakers Bureau. Chuah:Novartis, Bristol-Myers Squibb: Honoraria. Nicolini:Novartis, Ariad and Teva: Consultancy; Novartis & Bristol Myers Squibb: Research Funding; Novartis, BMS, Teva, Pfizer, Ariad: Honoraria; Novartis, BMS, Teva: Speakers Bureau; Novartis, Ariad, Teva, Pfizer: Membership on an entity’s Board of Directors or advisory committees. Apperley:Novartis: Research Funding; Ariad, Bristol Myers Squibb, Novartis, Pfizer, Teva: Honoraria. Talpaz:Ariad, BMS, Sanofi, INCYTE: Research Funding; Ariad, Novartis: Speakers Bureau; Ariad, Sanofi, Novartis: Membership on an entity’s Board of Directors or advisory committees. DeAngelo:Araid, Novartis, BMS: Consultancy. Abruzzese:BMS, Novartis: Consultancy. Rea:BMS, Novartis, Pfizer, Ariad, Teva: Honoraria. Baccarani:Ariad, Novartis, BMS: Consultancy; Ariad, Novartis, BMS, Pfizer, Teva: Honoraria, Speakers Bureau. Müller:Novartis, BMS, Ariad: Consultancy, Honoraria; Novartis, BMS: Research Funding. Gambacorti-Passerini:Pfizer: Research Funding; Pfizer, BMS: Honoraria. Lustgarten:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Rivera:ARIAD: Employment. Clackson:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Turner:ARIAD: Employment. Haluska:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Deininger:BMS, ARIAD, NOVARTIS: Consultancy; BMS, NOVARTIS, CELGENE, GILEAD: Research Funding; ARIAD, NOVARTIS: Advisory Boards, Advisory Boards Other. Hughes:Novartis, BMS, ARIAD: Honoraria, Research Funding. Goldman:Ariad: Honoraria. Shah:Ariad, Bristol-Myers Squibb: Consultancy, Research Funding. Kantarjian:RIAD, Novartis, BMS, Pfizer: Research Funding.

scholarly journals Updated Results of a Phase II Randomized Study (ROMULUS) of Polatuzumab Vedotin or Pinatuzumab Vedotin Plus Rituximab in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4457-4457 ◽  
Author(s):  
Franck Morschhauser ◽  
Ian Flinn ◽  
Ranjana H Advani ◽  
Catherine S. Diefenbach ◽  
Kathryn Kolibaba ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Clinical Activity ◽  
Advisory Committees ◽  
Advisory Boards ◽  
Grade 5 ◽  
Grade 3

Abstract Background: Previously reported results from an ongoing study of polatuzumab vedotin (PoV) and pinatuzumab vedotin (PiV), antibody drug conjugates (ADC) containing the anti-mitotic MMAE targeting CD79b (PoV) and CD22 (PiV), showed clinical activity in combination with rituximab (R) in relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). Here we report updated results of ADC + R at the RP2D of 2.4 mg/kg and initial results of PoV + R in r/r FL at the PoV dose of 1.8 mg/kg. Methods: Pts were randomized to receive PoV or PiV + R (ADC 2.4 mg/kg + R 375 mg/m2). In a separate non-randomized cohort (Cohort C), r/r FL pts were treated with PoV (1.8 mg/kg) + R. ADC + R was given every 21 days. Tumor assessments were performed every 3 months. Results: As of 21 February 2014, 59 pts received PoV + R (39 DLBCL; 20 FL), 63 PiV + R (42 DLBCL; 21 FL); 20 r/r FL pts were treated in Cohort C. Median time of follow-up was 10 mo. for PoV + R, 9 mo. for PiV + R, and 5 mo. for Cohort C. Median prior therapies [DLBCL, 3 (1-10); FL, 2 (1-8)] were balanced among the randomized treatment (tx) arms, median prior therapies in Cohort C was 2 (1-13); overall 44% were R refractory. Median tx cycles in DLBCL: 6 PoV (range 1-16) and 7 PiV (1-15); FL: 10 PoV (3-17), 7 PiV (1-14), and 6 Cohort C (2-10). Overall safety profiles of both regimens in the randomized arms receiving 2.4 mg/kg ADC were similar. The most common tx-emergent adverse events (AE) ≥25%: fatigue (55%), diarrhea (43%), nausea (37%), peripheral neuropathy (PN) (39%), neutropenia (27%), constipation (26%), sensory PN (25%), and decreased appetite (25%). Grade ≥ 3 AE >3%: neutropenia (24%), diarrhea (6%), dyspnea (5%), febrile neutropenia (4%), hyperglycemia (4%), fatigue (3%), and thrombocytopenia (3%). Serious AEs were reported in 43% and 36% of PiV and PoV treated pts, respectively. Discontinuation of study treatment for AE was reported in 49% and 41% of PiV and PoV treated pts, respectively. Thirty-five pts discontinued treatment due to PN with a median time to discontinuation of 5.6 mo. PN reversibility was observed following treatment interruptions and ADC dose modifications. Two of 9 Grade 5 AEs (sepsis, urosepsis) were attributed to CD22 ADC; no Grade 5 AEs were attributed to CD79b ADC. In Cohort C the most common tx-emergent AE ≥ 25%: fatigue (55%), nausea (45%), neutropenia (40%), sensory PN (30%), diarrhea (25%), constipation (25%) and pyrexia (25%). Grade ≥ 3 neutropenia was reported in 7 pts; no other Grade ≥ 3 AE was reported in >1 pt. Serious AE were reported in 5 pts. Two pts discontinued study treatment for AE. No Grade 5 AEs were reported. Overall response rate (ORR), complete (CR) and partial (PR) response rates, n (%) [95% CI], and median PFS in DLBCL (95% CI) are shown in the table. Median PFS in the FL cohorts are not reported due to insufficient follow-up duration. Table PoV (CD79b) + R PiV (CD22) + R PoV [1.8 mg/kg] + R (Cohort C) R/R DLBCL ORR CR PR mPFS (mo.) N=39 22 (56%) [41, 71] 6 (15%) [7, 30] 16 (41%) [26, 58] 5.4 (2.8-8.4) N=42 24 (57%) [41, 72] 10 (24%) [12, 39] 14 (33%) [20, 48] 5.2 (4.1-NR) N/A R/R FL ORR CR PR N=20 14 (70%) [47, 86] 8 (40%) [21, 64] 6 (30%) [14, 53] N=21 13 (62%) [40, 80] 2 (10%) [2, 30] 11 (52%) [30, 72] N=16 7 (44%) [20, 70] 0 7 (44%) [20, 70] Pharmacokinetic profiles were similar for both ADCs across DLBCL and FL with no free MMAE accumulation. Pts receiving PoV at 1.8 mg/kg had proportionately lower exposure of antibody conjugated MMAE compared to pts treated at the 2.4 mg/kg dose level. Conclusions: PoV and PiV + R were generally well-tolerated with similar toxicity profiles. Neutropenia, PN, and diarrhea were the principal toxicities. Similar efficacy was observed with both ADCs in heavily pretreated pts with DLBCL. The higher CR rate with PoV + R compared to PiV + R suggests greater clinical activity in r/r FL. Lower overall response rates were observed in r/r FL pts treated with a lower dose of PoV. Results based on longer follow-up to further assess differences in safety and tolerability between the two PoV doses in r/r FL will be presented. Additional data of pts who received crossover ADC + R treatment following documented disease progression on initial ADC + R treatment will also be presented. Combination studies of PoV + R with chemotherapy and with ADC schedules to reduce PN are ongoing or in planning. Disclosures Morschhauser: Genentech/roche: Honoraria, travel grants Other; Celgene: advisory boards, advisory boards Other, Honoraria. Off Label Use: obinutuzumab and lenlidomide in relapsed follicular lymphoma. Flinn:Genentech, inc.: Research Funding. Advani:Genentech, inc.: Research Funding. Diefenbach:Genentech, inc.: Research Funding. Press:Genentech, inc.: Research Funding. Chen:Genentech, inc.: Membership on an entity's Board of Directors or advisory committees. Salles:Genentech, inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Tilly:Genentech, inc.: Research Funding. Cheson:Celgene: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. Assouline:Roche: Honoraria, Research Funding. Dreyling:Roche: Honoraria, Research Funding. Hagenbeek:millenium: Membership on an entity's Board of Directors or advisory committees. Zinzani:Genentech, inc.: Membership on an entity's Board of Directors or advisory committees. Yalamanchili:Genentech, inc.: Employment. Lu:Genentech, inc.: Employment. Jones:Genentech, inc.: Employment. Jones:Genentech, inc.: Employment. Chu:Genentech, inc.: Employment. Sharman:Gen: Research Funding.

Impact Of Baseline (BL) Mutations, Including Low-Level and Compound Mutations, On Ponatinib Response and End Of Treatment (EOT) Mutation Analysis In Patients (Pts) With Chronic Phase Chronic Myeloid Leukemia (CP-CML)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 652-652 ◽  
Author(s):  
Michael W. Deininger ◽  
Neil P. Shah ◽  
Jorge E. Cortes ◽  
Dong-Wook Kim ◽  
Franck E. Nicolini ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Stock Options ◽  
Research Funding ◽  
Single Mutation ◽  
Advisory Committees ◽  
Mutation Status ◽  
Low Level ◽  
Advisory Boards ◽  
Equity Ownership

Abstract Background In CML, the presence of BCR-ABL kinase domain (KD) mutations, including low-level mutations, can predict clinical responses to 2nd line BCR-ABL tyrosine kinase inhibitors (TKIs). In addition, sequential treatment with TKIs can lead to development of compound mutations (≥2 mutations in the same BCR-ABL allele) that can be highly TKI-resistant. Ponatinib is a potent BCR-ABL TKI that, preclinically, has demonstrated activity against all BCR-ABL mutations tested and suppresses the emergence of any single mutation at clinically achievable concentrations (40 nM with ≥30 mg/d). In vitro, higher ponatinib concentrations were required to suppress emergence of certain compound mutations on a background of T315I or E255V single mutations. We evaluated the impact of single, low-level, and compound mutations at BL on responses to ponatinib and EOT mutations in CP-CML pts in the phase 2 PACE trial. Methods Pts with CP-CML (93% received ≥2 prior TKIs, 60% ≥3) resistant or intolerant to dasatinib and/or nilotinib (N=203) or with T315I confirmed at BL (N=64) were enrolled. The primary endpt was major cytogenetic response (MCyR) by 12 mos. Median follow-up at analysis (1 Apr 2013) was 20 (0.1-28) mos, with a minimum follow-up of 18 mos for pts remaining on study. Next generation sequencing (NGS) and Sanger sequencing (SS) were done at a central laboratory. NGS was conducted on all BL samples (N=267) with the Ion Torrent PGM using chemistry that enabled read lengths up to 400 bp for detection of compound mutations; mutations observed at a frequency ≥1% are reported. SS was conducted on both BL and EOT samples. Results By NGS at BL, 267 mutations (amino acid substitutions in the ABL KD [M237-E507]) were detected among 163 (61%) pts; 106 (40%) mutations were low level mutations not detected by SS. 75 unique single mutations were observed: 27 were detected by SS and NGS, all 27 have been associated with resistance to TKIs other than ponatinib; 48 were low level mutations detected only by NGS, 5 have been associated with resistance to TKIs other than ponatinib. 12% of pts had only low level mutations. Overall, no mutations were detected in 39% of pts, 1 mutation in 37%, and ≥2 mutations in 24%. Compound mutations were detected in 65% of pts who had ≥2 mutations, representing 15% of pts overall (10% with 1, 5% with 2 to 4 compound mutations). 48 unique compound mutations were observed; T315I, F317L, and F359C/I/V were the most commonly observed mutations within compound mutations. Responses were seen in pts with each of the 20 unique single mutations present in >1 pt at BL by NGS, including Y253H, E255V/K, T315I, M351T, F359V. Responses were observed regardless of overall NGS BL mutation status (table). The high response rates and durability of response in pts with compound mutations suggest that, in general, the presence of compound mutations at BL did not adversely affect the activity of ponatinib. Of the 109 pts who discontinued, 84 had successful mutation assessments by SS at or near the EOT visit. 4 pts had mutations at EOT that were not detected by NGS at BL; all 4 involved compound mutations (T315I/F359V [100%/90%], T315I/M351T [100%/40%], Y253H/F359V [100%/100%; n=2]), with one or both of the involved mutations detected individually at BL or by history. Overall, 12 pts lost MCyR (none with T315I at BL); 6 of the 12 discontinued and had EOT mutations assessed, no changes from BL were observed. Conclusions Responses to ponatinib were observed regardless of BL mutation status. Interestingly, responses tended to be lower in pts without mutations, suggesting that BCR-ABL independent mechanisms may be involved. No single mutation conferring resistance to ponatinib in CP-CML has been observed to date. In general, ponatinib activity was not adversely affected by the presence of compound mutations at BL. Rarely, the development of compound mutations was observed at EOT in pts with one of the involved mutations at BL or by history. Early introduction of ponatinib may suppress the emergence of single BCR-ABL mutations, and, as a result, the development of compound mutations. NCT01207440 Disclosures: Deininger: BMS, ARIAD, NOVARTIS: Consultancy; BMS, NOVARTIS, CELGENE, GILEAD: Research Funding; ARIAD, NOVARTIS: Advisory Boards, Advisory Boards Other. Shah:Ariad, Bristol-Myers Squibb: Consultancy, Research Funding. Cortes:Ariad, Pfizer, Teva: Consultancy; Ariad, BMS, Novartis, Pfizer, Teva: Research Funding. Kim:BMS, Novartis, IL-Yang: Consultancy; BMS, Novartis, Pfizer, ARIAD, IL-Yang: Research Funding; BMS, Novartis, Pfizer, IL-Yang: Honoraria; BMS, Novartis, Pfizer: Speakers Bureau; BMS, Pfizer: Membership on an entity’s Board of Directors or advisory committees. Nicolini:Novartis, ARIAD, Teva: Consultancy; Novartis, BMS: Research Funding; Novartis, BMS, Teva, Pfizer, ARIAD: Honoraria; Novartis, BMS, TEva: Speakers Bureau; Novartis, ARIAD, Teva, Pfizer: Membership on an entity’s Board of Directors or advisory committees. Talpaz:Ariad, BMS, Sanofi, INCYTE: Research Funding; Ariad, Novartis: Speakers Bureau; Ariad, Sanofi, Novartis: Membership on an entity’s Board of Directors or advisory committees. Baccarani:ARIAD, Novartis, BMS: Consultancy; ARIAD, Novartis, BMS, Pfizer, Teva: Honoraria; ARIAD, Novartis, BMS, Pfizer, Teva: Speakers Bureau. Muller:Novartis, BMS, ARIAD: Consultancy; Novartis, BMS: Research Funding; Novartis, BMS, ARIAD: Honoraria. Lustgarten:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Clackson:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Turner:ARIAD: Employment. Haluska:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Hodgson:ARIAD: Employment, Equity Ownership. Rivera:ARIAD: Employment, Equity Ownership. Goldman:ARIAD: Honoraria. Kantarjian:ARIAD, Novartis, BMS, Phizer: Research Funding. Soverini:Novartis, BMS, ARIAD: Consultancy. Hochhaus:Ariad, Novartis, BMS, MSD, Pfizer: Research Funding; Novartis, BMS, Pfizer: Honoraria. Hughes:Novartis, BMS, ARIAD: Honoraria, Research Funding. Branford:Novartis, BMS, ARIAD: Research Funding; Novartis, BMS, ARIAD: Honoraria.

Ponatinib In Patients (pts) With Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL) Resistant Or Intolerant To Dasatinib Or Nilotinib, Or With The T315I BCR-ABL Mutation: 2-Year Follow-Up Of The PACE Trial

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 650-650 ◽  
Author(s):  
Jorge E. Cortes ◽  
Dong-Wook Kim ◽  
Javier Pinilla-Ibarz ◽  
Philipp D le Coutre ◽  
Ronald Paquette ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Stock Options ◽  
Research Funding ◽  
Response Rates ◽  
Advisory Committees ◽  
Advisory Boards ◽  
Common Drug ◽  
Heavily Pretreated ◽  
History Of

Abstract Background Ponatinib is a potent, oral, pan-BCR-ABL inhibitor with activity against native and mutant forms of BCR-ABL, including the tyrosine kinase inhibitor (TKI)-resistant T315I mutant. The efficacy and safety of ponatinib (45 mg orally QD) were evaluated in the phase 2, international, open-label clinical trial (PACE) in pts with CML or Ph+ ALL. Methods 449 pts resistant or intolerant (R/I) to dasatinib or nilotinib or with the T315I mutation confirmed at entry were enrolled. Five pts (3 CP-CML, 2 AP-CML) without confirmed T315I and not R/I to dasatinib or nilotinib were treated, but not assigned to a cohort; they were included in safety analyses only. The primary endpoint was major cytogenetic response (MCyR) at any time within 12 mos for CP-CML, major hematologic response (MaHR) at any time within 6 mos for advanced Ph+ leukemia. Data are as of 1 April 2013, with a median follow-up of 19 (0.1-30) mos, and 18 mos minimum follow-up for pts remaining on study. Results Median age was 59 (18-94) yrs; 53% were male. Median time from diagnosis to ponatinib was 6 (0.3-28) yrs. Pts were heavily pretreated: 96% received prior imatinib, 84% dasatinib, 65% nilotinib, 7% bosutinib; 58% received ≥3 TKIs. In pts previously treated with dasatinib or nilotinib (N=427), 88% had a history of resistance, 12% were purely intolerant to dasatinib or nilotinib. Best prior response to most recent dasatinib or nilotinib was 26% MCyR or better in CP-CML, 23% MaHR or better in advanced Ph+ leukemia. The most common BCR-ABL mutations at baseline were 29% T315I, 8% F317L, 4% E255K, 4% F359V, 3% G250E. No mutations were detected in 44% of pts (Sanger sequencing). At the time of analysis, 46% of pts remained on study (60% CP-CML). The most common reasons for discontinuation: progressive disease (20%), adverse events (AEs; 13%; most common was thrombocytopenia, 4%). Response rates are shown in the table. Response rates were higher in CP-CML T315I vs R/I cohorts, however, a post-hoc multivariate analysis previously showed that T315I was not an independent predictor of MCyR. Other features, especially higher dose intensity and younger age in T315I pts, may explain the higher response rates. In CP-CML, responses were deep and durable; 91%, 91%, and 75% of pts with MCyR, CCyR, or MMR, respectively, were estimated to remain in response at 12 mos; progression-free survival (PFS) and overall survival (OS) were estimated to be 80% (median 27 mos) and 94% at 12 mos, respectively; progression to AP/BP occurred in 3 CP-CML pts , 2 other pts with a history of AP re-entered AP. 49% of AP-CML pts with MaHR were estimated to remain in response at 12 mos (median 12 mos); PFS and OS were estimated to be 56% (median 14 mos) and 84% at 12 mos. 36% of BP-CML pts with MaHR were estimated to remain in response at 12 mos (median 5 mos); PFS and OS were estimated to be 18% (median 4 mos) and 30% (median 7 mos) at 12 mos. 8% of Ph+ ALL pts with MaHR were estimated to remain in MaHR at 12 mos (median 3 mos); PFS and OS were estimated to be 7% (median 3 mos) and 39% (median 8 mos) at 12 mos. The most common drug-related AEs (>30%) were thrombocytopenia (37%), rash (34%), and dry skin (32%). Pancreatitis was the most common drug-related serious AE (5%); it occurred early and was primarily managed with dose modification, 1 pt discontinued. Serious cardiovascular, cerebrovascular, and peripheral vascular AEs occurred in 6%, 3%, and 2% of pts (drug-related: 2%, 1%, 1%). Conclusions Ponatinib has substantial activity in these heavily pretreated Ph+ leukemia pts who have limited available treatment options, with a safety profile reflective of the population. Updated data with a minimum follow-up of 2 yrs will be presented. Disclosures: Cortes: Ariad, Pfizer, Teva: Consultancy; Ariad, BMS, Novartis, Pfizer, Teva: Research Funding. Kim:BMS, Novartis, IL-Yang: Consultancy; BMS, Novartis, Pfizer, ARIAD, IL-Yang: Research Funding; BMS, Novartis, Pfizer, IL-Yang: Honoraria; BMS, Novartis, Pfizer: Speakers Bureau; BMS, Pfizer: Membership on an entity’s Board of Directors or advisory committees. Pinilla-Ibarz:Novartis, Ariad: Research Funding; Novartis, Ariad, BMS and Pfizer: Speakers Bureau. le Coutre:Novartis: Research Funding; Novatis, BMS, Pfizer: Honoraria. Paquette:ARIAD, BMS, Novartis: Consultancy, Honoraria, Speakers Bureau. Chuah:Novartis, Bristol-Myers Squibb: Honoraria. Nicolini:Novartis, Ariad, Teva, Pfizer: Membership on an entity’s Board of Directors or advisory committees; Novartis, BMS, Teva: Speakers Bureau; Novartis, BMS, Teva, Pfizer, Ariad: Honoraria; Novartis & Bristol Myers Squibb: Research Funding; Novartis, Ariad and Teva: Consultancy. Apperley:Novartis: Research Funding; Ariad, Bristol Myers Squibb, Novartis, Pfizer, Teva: Honoraria. Talpaz:Ariad, BMS, Sanofi, INCYTE: Research Funding; Ariad, Novartis: Speakers Bureau; Ariad, Sanofi, Novartis: Membership on an entity’s Board of Directors or advisory committees. DeAngelo:Araid, Novartis, BMS: Consultancy. Abruzzese:BMS, Novartis: Consultancy. Rea:BMS, Novartis, Pfizer, Ariad, Teva: Honoraria. Baccarani:Ariad, Novartis, BMS: Consultancy; Ariad, Novartis, BMS, Pfizer, Teva: Honoraria, Speakers Bureau. Müller:Novartis, BMS, Ariad: Consultancy, Honoraria; Novartis, BMS: Research Funding. Gambacorti-Passerini:Pfizer: Research Funding; Pfizer, BMS: Honoraria. Lustgarten:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Rivera:ARIAD: Employment. Clackson:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Turner:ARIAD: Employment. Haluska:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Deininger:BMS, ARIAD, NOVARTIS: Consultancy; BMS, NOVARTIS, CELGENE, GILEAD: Research Funding; ARIAD, NOVARTIS: Advisory Boards, Advisory Boards Other. Hochhaus:Ariad, Novartis, BMS, MSD, Pfizer: Research Funding; Novartis, BMS, Pfizer: Honoraria. Hughes:Novartis, BMS, ARIAD: Honoraria, Research Funding. Goldman:Ariad: Honoraria. Shah:Ariad, Bristol-Myers Squibb: Consultancy, Research Funding. Kantarjian:ARIAD, Novartis, BMS, Phizer: Research Funding.

Efficacy and Safety Of Ponatinib Following Failure Of Nilotinib In Patients With Chronic Phase Chronic Myeloid Leukemia (CP-CML) In The PACE Trial

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2738-2738 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Jorge E. Cortes ◽  
Dong-Wook Kim ◽  
Javier Pinilla-Ibarz ◽  
Philipp D. le Coutre ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Board Of Directors ◽  
Stock Options ◽  
Research Funding ◽  
Anticancer Therapy ◽  
Advisory Board ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Group I ◽  
Grade 3

Abstract Background Information is generally lacking regarding the efficacy and safety of subsequent TKIs after failure of nilotinib. This post-hoc analysis explored the efficacy and safety of ponatinib, a potent oral pan-BCR-ABL inhibitor, following failure of nilotinib in CP-CML patients in the phase 2 PACE trial. Methods The PACE trial enrolled 449 patients, including 270 with CP-CML. Patients had to be resistant or intolerant to dasatinib or nilotinib, or have the T315I mutation at baseline. The primary end point in CP-CML was MCyR at any time within 12 months after treatment initiation. The trial is ongoing. Data as of 1 April 2013 are reported, with a minimum follow-up of 18 months for patients remaining on study. The efficacy and safety of ponatinib (45 mg QD) in 106 CP-CML patients following failure of nilotinib as the most recent prior anticancer therapy, irrespective of other TKI therapy, is presented (Group N). Eleven patients who experienced failure of nilotinib but received ≥1 anticancer therapy, other than hydroxyurea or anagrelide, prior to ponatinib treatment were excluded from the analyses. Data are also presented for 2 subsets of Group N: 33 patients whose only TKI therapy was imatinib followed by nilotinib (Group I-N), and 68 patients whose only TKI therapy was imatinib, then dasatinib, and then nilotinib (Group I-D-N). An analysis of cross-intolerance was also conducted in 43 patients with prior nilotinib treatment at any time who discontinued nilotinib due to intolerance. Results Baseline characteristics are shown in the table. Group I-N tended to be younger, with less time since diagnosis versus Group I-D-N. At the time of analysis, 59%, 64%, and 56% of patients in Groups N, I-N, and I-D-N remained on study. The most common reasons for discontinuation were adverse events (AEs; 12%, 12%, 13%) and progressive disease (9%, 6%, 9%) in Groups N, I-N, and I-D-N. Efficacy endpoints are shown in the table. In Group N, MCyR was observed in patients with the following nilotinib-resistant mutations at baseline: Y253H, 1/2 (50%); E255K, 5/6 (83%); T315I, 12/22 (55%); F359V, 3/7 (43%); F359C, 1/2 (50%); F359I, 2/3 (67%). The most common treatment-related AEs were thrombocytopenia (38%, 33%, 40%), rash (35%, 30%, 37%), and dry skin (35%, 42%, 31%) in Groups N, I-N, and I-D-N. Serious cardiovascular, cerebrovascular, and peripheral vascular AEs occurred in 6%, 4%, and 2% of patients in Group N (treatment-related: 3%, 1%, 2%). Forty-four of 184 patients discontinued prior nilotinib at any time due to intolerance. Of these 44 patients, 24 experienced the same AE(s) with ponatinib that led to nilotinib intolerance; 12 patients had grade 3/4 thrombocytopenia, 6 patients had other grade 3 AEs (2 with dyspnea, 1 each with atrial fibrillation, musculoskeletal pain, abdominal pain, pain in extremity), 6 patients had grade 1/2 AEs. 7 of the 24 patients discontinued ponatinib due to the same AE that led to nilotinib intolerance. Thrombocytopenia (5 patients) was the primary AE involved in cross-intolerance; atrial fibrillation and pain in extremity each occurred once. Conclusions Ponatinib has substantial activity in patients with CP-CML following failure of nilotinib, with a safety profile reflective of this heavily pretreated population. Cross-intolerance between nilotinib and ponatinib was infrequent. Disclosures: Kantarjian: ARIAD: Research Funding; Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding. Cortes:Ariad, Pfizer, Teva: Consultancy; Ariad, BMS, Novartis, Pfizer, Teva: Research Funding. Kim:BMS: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; IL-Yang: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; ARIAD: Research Funding. Pinilla-Ibarz:Novartis: Research Funding, Speakers Bureau; ARIAD: Research Funding, Speakers Bureau; BMS: Speakers Bureau; Pfizer: Speakers Bureau. le Coutre:Novartis: Research Funding; Novatis, BMS, Pfizer: Honoraria. Paquette:ARIAD: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Chuah:Novartis: Honoraria; Bristol-Myers Squibb: Honoraria. Nicolini:Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; ARIAD: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Teva: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Apperley:Novartis: Honoraria, Research Funding; ARIAD: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Teva: Honoraria. Talpaz:Ariad, BMS, Sanofi, INCYTE: Research Funding; Ariad, Novartis: Speakers Bureau; Ariad, Sanofi, Novartis: Membership on an entity’s Board of Directors or advisory committees. DeAngelo:ARIAD: Consultancy; Novartis: Consultancy; BMS: Consultancy. Abruzzese:BMS, Novartis: Consultancy. Rea:Pfizer: Honoraria; ARIAD: Honoraria; Teva: Honoraria; Novartis: Honoraria; BMS: Honoraria. Baccarani:ARIAD: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Teva: Honoraria, Speakers Bureau. Müller:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; ARIAD: Consultancy, Honoraria. Gambacorti-Passerini:Pfizer: Honoraria, Research Funding; BMS: Honoraria. ARIAD: Employment. Rivera:ARIAD: Employment. Clackson:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Turner: ARIAD: Employment. Haluska: ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Deininger:BMS: Consultancy, Research Funding; ARIAD: advisory board, advisory board Other, Consultancy; Novartis: advisory board, advisory board Other, Consultancy, Research Funding; Celgene: Research Funding; Gilead: Research Funding. Hochhaus:Pfizer: Honoraria, Research Funding; ARIAD: Research Funding; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; MSD: Research Funding. Hughes:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding. Goldman:Ariad: Honoraria. Shah:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding.

scholarly journals A Quality-Adjusted Survival (Q-TWiST) Analysis to Assess Benefit-Risk of Acalabrutinib Versus Idelalisib/Bendamustine Plus Rituximab or Ibrutinib Among Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL) Patients

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3722-3722
Author(s):  
John F. Seymour ◽  
Priyanka Gaitonde ◽  
Ugochinyere Emeribe ◽  
Ling Cai ◽  
Anthony R. Mato
Keyword(s):  
Disease Progression ◽  
Board Of Directors ◽  
Stock Options ◽  
Research Funding ◽  
Publicly Traded ◽  
Advisory Committees ◽  
The Difference ◽  
Grade 3 ◽  
Definition Of

Abstract Background: Acalabrutinib (Acala) is a next-generation, highly selective, covalent BTK inhibitor (BTKi) approved for the treatment of CLL. The phase 3 ASCEND study demonstrated significant progression-free survival (PFS) benefit with Acala vs investigator's choice of chemoimmunotherapy (bendamustine + rituximab [BR]) or pi3K inhibitor (idelalisib) + rituximab (IR) in R/R CLL patients (pts) (Ghia et al. J Clin Oncol. 2020). In ELEVATE-RR, Acala demonstrated non-inferior PFS vs a first-generation BTKi (ibrutinib [Ibr]) in R/R CLL pts with high-risk genomics (Byrd et al. J Clin Oncol. 2021). Acala was well tolerated in both trials. Quality-adjusted Time Without Symptoms and Toxicity (Q-TWiST) analysis balances risks (toxicity) and benefits (prolonged survival without symptoms of disease progression or adverse events [AEs]) of oncology treatments. We conducted a Q-TWiST analysis using data from these trials to assess risk-benefit of Acala vs comparators among R/R CLL pts. Methods: Patient survival time with 16 months (ASCEND) and 41 months (ELEVATE-RR) of median follow-up data were partitioned into 3 states: time with toxicity before disease progression (TOX); time without progression or toxicity (TWiST); and time from disease progression until death or end of follow-up (relapse [REL]). Toxicity was defined as grade 3/4 AEs and, for the comparison vs Ibr, an additional definition of toxicity included AEs of any grade with frequency ≥10% (AE ≥10%). Sensitivity analyses with toxicity defined as grade 2-4 AEs will be presented. Kaplan-Meier survival curves were constructed for TOX, PFS, and overall survival (OS). For the TOX curve, event time for each pt was calculated by summing days with AEs (per toxicity definition) before disease progression, with no pt censored. Restricted means were calculated for the longest PFS time among treatment arms. Restricted mean TWiST duration was estimated using the difference between restricted means of PFS and TOX. Restricted mean REL duration was estimated using the difference between restricted means of OS and PFS. Q-TWiST was calculated by summing weighted restricted mean durations of TOX, TWiST, and REL. Utility of 1.0 for TWiST and 0.5 for TOX and REL (Gelber et al. Am Statistician. 1995) were applied. Sensitivity analysis was conducted using utility measures from trial data. Two-sided p<0.05 indicated statistical significance. Results: Among Acala vs IR/BR-treated pts, significantly longer duration of TWiST (mean diff, 3.58 months [95% CI, 2.42, 4.74]) and shorter duration of REL (mean diff, −2.51 months [95% CI, −3.50, −1.60]) and TOX (mean diff, −0.73 months [95% CI, −1.24, −0.24]) were found, indicating Acala vs IR/BR-treated pts had longer time without disease progression and toxicity and shorter time with toxicity. Q-TWiST was significantly different (1.96 months [95% CI, 1.13, 2.81]) between Acala (17.48 months) and IR/BR (15.52 months). In the Acala and Ibr comparison, differences in durations of TWiST and TOX varied based on the toxicity definition while the difference in REL durations remained consistent (mean diff, 0.37 months [95% CI, −1.82, 2.60]; p=0.33]). With the toxicity definition of AE ≥10%, Q-TWiST was significantly different (2.56 months [95% CI, 0.19, 4.83]) for Acala (33.02 months) vs Ibr (30.46 months). When toxicity was defined as grade 3/4 AEs, Q-TWiST had higher estimates for Acala but the difference was not statistically significant (1.28 months [95% CI, −1.34, 3.80]). In the sensitivity analysis, Q-TWiST gains were not statistically significant, most likely because the study was not designed to collect EQ-5D data post-treatment discontinuation. Conclusions: Q-TWiST analyses integrate efficacy, safety, and quality of life into a more appropriate measure useful for detailed benefit-risk assessment of cancer treatment. This analysis demonstrated that Acala treatment is significantly superior to IR/BR treatment. Quality-adjusted survival gains of Acala over Ibr varied by toxicity definition, but was numerically higher for Acala. Overall, Acala demonstrated a favorable benefit-risk profile vs different comparators in R/R CLL. Figure 1 Figure 1. Disclosures Seymour: Mei Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Morphosys: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sunesis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gaitonde: AstraZeneca: Current Employment, Current holder of stock options in a privately-held company, Research Funding. Emeribe: AstraZeneca: Current Employment, Current holder of stock options in a privately-held company. Cai: Celgene Corporation: Ended employment in the past 24 months; Google: Current equity holder in publicly-traded company; AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Mato: Johnson and Johnson: Consultancy, Research Funding; MSKCC: Current Employment; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; Genentech: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Genmab: Research Funding; Acerta/AstraZeneca: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; Nurix: Research Funding; BeiGene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; DTRM BioPharma: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; AstraZeneca: Consultancy.

scholarly journals Identifying Factors That Predict for Unplanned Readmissions for Acute Myeloid Leukemia Patients Receiving Consolidation Cytarabine Based Therapies

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3433-3433
Author(s):  
Caitlin Siebenaller ◽  
Madeline Waldron ◽  
Kelly Gaffney ◽  
Brian P. Hobbs ◽  
Ran Zhao ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Smoking Status ◽  
Consolidation Therapy ◽  
Peripheral Vascular ◽  
Consolidation Chemotherapy ◽  
Advisory Committees ◽  
History Of ◽  
Acute Myeloid

Background: Younger patients (pts) with acute myeloid leukemia (AML) who enter a remission after intensive induction chemotherapy routinely receive at least one cycle of consolidation therapy with high dose cytarabine (HiDAC). This is commonly administered over a five-day inpatient stay, after which pts are discharged home as their blood counts nadir. It is thus a natural consequence of therapy that readmission for febrile neutropenia (FN) occurs, which can impact measures of quality and value in this population. Precise descriptions of incidence, type, and severity of infection, if identified, are lacking, and thus it is unknown to what standard cancer centers should be held for anticipated readmission. We measured these rates, and attempted to identify predictive factors for readmission. Methods: Adult AML pts ≥ 18 years of age who received at least one cycle of HiDAC consolidation (1000-3000 mg/m2 for six doses) in 2009-2019 were included. Our primary aim was to identify predictive factors for readmission after the first cycle of consolidation chemotherapy. The following pt characteristics and co-morbid conditions were analyzed: age, gender, body mass index (BMI), smoking status, AML cytogenetic risk status, history of diabetes, peripheral vascular disease, cardiovascular disease, chronic pulmonary disease, hepatic impairment, and other cancers. Secondary aims included: estimating rates of all-cause readmissions among all HiDAC cycles, defining the rate of FN readmissions, estimating rates of intensive care unit (ICU) admissions, clinical (e.g., probable pneumonia per imaging) and microbiologically-documented infections, prophylactic (ppx) medications used, and mortality. Statistical analyses interrogated potential risk factors for evidence of association with hospital readmission after the first cycle of consolidation chemotherapy. Results: We identified 182 AML pts who fit inclusion criteria. The median age was 50 years (range 19-73); 55% were female and 45% were male. Statistical analyses revealed no association with readmission after cycle 1 for cytogenetic risk (p=0.85), history of heart failure (p= 0.67), chronic pulmonary disease (p=1), connective tissue disease (p=0.53), cerebrovascular accident (p=0.63), diabetes (p=0.63), gender (p=0.07), history of lymphoma (p=0.53), other solid tumors (p=0.53), liver disease (p=1), myocardial infarction (p=0.71), peripheral vascular disease (p=1), or smoking status (p= 0.52). For 480 HiDAC cycles analyzed (88% at 3000 mg/m2), the overall readmission rate was 50% (242/480), of which 85% (205/242) were for FN. Those readmissions which were not FN were for cardiac complications (chest pain, EKG changes), non-neutropenic fevers or infections, neurotoxicity, bleeding or clotting events, or other symptoms associated with chemotherapy (nausea/vomiting, pain, etc.). Median time to FN hospital admission was 18 days (range 6-27) from the start of HiDAC. Of the 205 FN readmissions, 57% had documented infections. Of these infections, 41% were bacteremia, 23% fungal, 16% sepsis, 12% other bacterial, and 8% viral. Of 480 HiDAC cycles, ppx medications prescribed included: 92% fluoroquinolone (442/480), 81% anti-viral (389/480), 30 % anti-fungal (142/480), and 3% colony stimulating factor (14/480). Only 7% (14/205) of FN readmissions resulted in an ICU admission, and 1% (3/205) resulted in death. Conclusions: Approximately half of patients treated with consolidation therapy following intensive induction therapy can be expected to be readmitted to the hospital. The majority of FN readmissions were associated with clinical or microbiologically documented infections and are not avoidable, however ICU admission and death associated with these complications are rare. Readmission of AML pts following HiDAC is expected, and therefore, should be excluded from measures of value and quality. Disclosures Waldron: Amgen: Consultancy. Hobbs:Amgen: Research Funding; SimulStat Inc.: Consultancy. Advani:Macrogenics: Research Funding; Abbvie: Research Funding; Kite Pharmaceuticals: Consultancy; Pfizer: Honoraria, Research Funding; Amgen: Research Funding; Glycomimetics: Consultancy, Research Funding. Nazha:Incyte: Speakers Bureau; Abbvie: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmacutical: Research Funding; Novartis: Speakers Bureau; MEI: Other: Data monitoring Committee; Tolero, Karyopharma: Honoraria. Gerds:Imago Biosciences: Research Funding; Roche: Research Funding; Celgene Corporation: Consultancy, Research Funding; Pfizer: Consultancy; CTI Biopharma: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Sierra Oncology: Research Funding. Sekeres:Syros: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees. Mukherjee:Partnership for Health Analytic Research, LLC (PHAR, LLC): Consultancy; McGraw Hill Hematology Oncology Board Review: Other: Editor; Projects in Knowledge: Honoraria; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees.

scholarly journals A Phase I Trial of Janus Kinase (JAK) Inhibition with INCB039110 in Acute Graft-Versus-Host Disease (aGVHD)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 390-390 ◽  
Author(s):  
Mark A. Schroeder ◽  
H. Jean Khoury ◽  
Madan Jagasia ◽  
Haris Ali ◽  
Gary J. Schiller ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Janus Kinase ◽  
Cell Transplant ◽  
Employment Equity ◽  
Advisory Committees ◽  
Daily Dose ◽  
Equity Ownership ◽  
Grade 3 ◽  
Steroid Refractory

Abstract Background: Corticosteroids are considered standard first-line systemic therapy for patients with aGVHD, but this approach is effective in only approximately half of all cases. For patients who progress or do not respond to corticosteroids, no specific agent has been identified as standard, and regimens are typically selected based on investigator experience and patient co-morbidities. In preclinical models, JAK inhibition has been shown to impair production of cytokines as well as the differentiation and trafficking of T cells implicated in the pathogenesis of aGVHD. Retrospective studies have suggested that JAK1/JAK2 inhibition with ruxolitinib treatment provides clinical benefit in patients with steroid-refractory GVHD (Zeiser et al, Leukemia 2015;29:2062-2068). Herein, we report preliminary safety results from a prospective randomized, parallel-cohort, open-label phase 1 trial evaluating the potent and selective JAK 1 inhibitor INCB039110 in patients with aGVHD. Methods: Male or female patients 18 years or older who underwent their first allo-hematopoietic stem cell transplant (HSCT) from any donor source and developed grades IIB-IVD aGVHD were eligible for the study. Patients were randomized 1:1 to either a 200 or 300 mg oral daily dose of INCB039110 in combination with corticosteroids, and were stratified based on prior treatment status (treatment-naive [TN] versus steroid-refractory [SR]). The primary endpoint of the study was safety and tolerability; secondary endpoints included overall response rate at Days 14, 28, 56, and 100, non-relapse mortality, and pharmacokinetic (PK) evaluations. Patients were assessed through Day 28 for dose-limiting toxicities (DLTs) and response. A Bayesian approach was used for continuous monitoring of DLTs from Days 1-28. Treatment continued until GVHD progression, unacceptable toxicity, or withdrawal from the study. Acute GVHD was graded according to MN-CIBMTR criteria; adverse events (AEs) were graded according to NCICTCAE v 4.03. Results: Between January and June 2016, 31 patients (TN, n=14; SR, n= 17) were randomized. As of July 25, 2016, data were available from 30 patients who received an oral daily dose of 200 mg (n=14) or 300 mg (n=16) INCB039110 in combination with 2 mg/kg methylprednisolone (or equivalent dose of prednisone). The median durations of treatment were 60.8 days and 56.5 days for patients receiving a daily dose of 200 mg and 300 mg INCB039110, respectively. One DLT of Grade 3 thrombocytopenia was reported. The most frequently reported AEs included thrombocytopenia/platelet count decrease (26.7%), diarrhea (23.3%), peripheral edema (20%), fatigue (16.7%), and hyperglycemia (16.7%). Grade 3 or 4 AEs occurred in 77% of patients and with similar frequency across dose groups and included cytomegalovirus infections (n=3), gastrointestinal hemorrhage (n=3), and sepsis (n=3). Five patients had AEs leading to a fatal outcome, including multi-organ failure (n=2), sepsis (n=1), disease progression (n=1), and bibasilar atelectasis, cardiopulmonary arrest, and respiratory distress (n=1); none of the fatal events was attributed to INCB039110. Efficacy and PK evaluations are ongoing and will be updated at the time of presentation. Conclusion: The oral, selective JAK1 inhibitor INCB039110 can be given safely to steroid-naive or steroid-refractory aGVHD patients. The safety profile was generally consistent in both dose groups. Biomarker evaluation, PK, and cellular phenotyping studies are ongoing. The recommended phase 2 dose will be selected and reported based on PK studies and final safety data. Disclosures Schroeder: Incyte Corporation: Honoraria, Research Funding. Khoury:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Jagasia:Incyte Corporation: Research Funding; Therakos: Research Funding; Janssen: Research Funding. Ali:Incyte Corporation: Research Funding. Schiller:Incyte Corporation: Research Funding. Arbushites:Incyte Corporation: Employment, Equity Ownership. Delaite:Incyte Corporation: Employment, Equity Ownership. Yan:Incyte Corporation: Employment, Equity Ownership. Rhein:Incyte Corporation: Employment, Equity Ownership. Perales:Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chen:Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. DiPersio:Incyte Corporation: Research Funding.

scholarly journals Long Term Outcome of Lenalidomide-Dexamethasone (Rd) Vs Melphalan-Lenalidomide-Prednisone (MPR) Vs Cyclophosphamide-Prednisone-Lenalidomide (CPR) As Induction Followed By Lenalidomide-Prednisone (RP) Vs Lenalidomide (R) As Maintenance in a Community-Based Newly Diagnosed Myeloma Population: Updated Analysis of EMN01 Phase III Study

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 901-901
Author(s):  
Sara Bringhen ◽  
Massimo Offidani ◽  
Pellegrino Musto ◽  
Anna Marina Liberati ◽  
Giulia Benevolo ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Phase Iii ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Community Based ◽  
Advisory Committees ◽  
Risk Of Death ◽  
Grade 3 ◽  
To Receive

Abstract Introduction : Rd and MPR showed to be effective combinations in elderly newly diagnosed multiple myeloma (NDMM) patients (pts). Cyclophosphamide is a less toxic alkylating alternative agent. EMN01 is the first trial to formally compare these three different Lenalidomide-based combinations. Maintenance with Lenalidomide has been recently approved in patients eligible for autologous stem cell transplant (ASCT). Few data are available about the best combination as maintenance in patients not eligible for ASCT. Methods : 662 pts with NDMM were randomized to receive 9 28-day cycles of Rd (lenalidomide 25 mg/day for 21 days; dexamethasone 40 mg on days 1,8,15 and 22 in pts 65-75 years old and 20 mg in those >75 years), MPR (lenalidomide 10 mg/day for 21 days; melphalan orally 0.18 mg/Kg for 4 days in pts 65-75 years old and 0.13 mg/Kg in >75 years pts; prednisone 1.5 mg/Kg for 4 days) or CPR (lenalidomide 25 mg/day for 21 days; cyclophosphamide orally 50 mg/day for 21 days in pts 65-75 years old and 50 mg every other day in >75 years pts; prednisone 25 mg every other day). After induction, pts were randomized to receive maintenance with lenalidomide alone (R; 10 mg/day for 21 days) or with prednisone (RP; R, 10 mg/day for 21 days and P, 25 mg every other day), until disease progression. Results : Pts characteristics were well balanced in all groups; 217 pts in Rd, 217 in MPR and 220 in CPR arms could be evaluated. After a median follow-up of 63.7 months, median PFS was 23.2 months in MPR, 18.9 months in CPR and 18.6 months in Rd (MPR vs CPR p=0.02; MPR vs Rd p=0.08). Median overall survival (OS) was 79.9 months in MPR, 69.4 months in CPR and 68.1 months in Rd (MPR vs CPR p=0.98; MPR vs Rd p=0.64). The most common grade ≥3 adverse event (AEs) was neutropenia: 64% in MPR, 29% in CPR and 25% in Rd pts (p<0.0001). Grade ≥3 non hematologic AEs were similar among arms. At the end of induction, 402 pts were eligible for maintenance, 198 in the RP and 204 in the R groups. PFS from start of maintenance was 22.2 months in the RP group and 17.6 in the R group, with 20% reduced the risk of death/progression for pts receiving RP maintenance (HR 0.81, p=0.07; Figure 1). A subgroup analysis was performed to determine the consistency of RP vs R treatment effect in different subgroups using interaction terms between treatment and cytogenetic abnormalities, ISS, age, sex, induction treatment and response before maintenance (Figure 1). No difference in OS was observed (HR 1.02, p=0.93) but the OS analysis was limited by the low number of events. Median duration of maintenance was 23.0 months in RP pts and 20.5 months in R pts, 14% and 13% of pts discontinued due to AEs, in RP and R groups, respectively. Conclusion : This phase III trial compared 2 different Lenalidomide-containing induction regimens and 2 different Lenalidomide-containing maintenance regimens in an elderly community-based NDMM population. MPR prolonged PFS by approximately 5 months, yet the higher incidence of hematologic toxicity should be carefully considered. The addition of low-dose prednisone to standard lenalidomide maintenance reduced the risk of death/progression by 20%, with a good safety profile. Updated results will be presented at the meeting. Disclosures Bringhen: Mundipharma: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Celgene: Honoraria; Bristol Myers Squibb: Honoraria; Karyipharm: Membership on an entity's Board of Directors or advisory committees. Offidani: celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Musto: Celgene: Honoraria; Janssen: Honoraria. Gaidano: Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. De Sabbata: Celgene: Membership on an entity's Board of Directors or advisory committees. Palumbo: Sanofi: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Binding Site: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Genmab A/S: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Employment, Equity Ownership, Honoraria, Research Funding. Hájek: Amgen, Takeda, BMS, Celgene, Novartis, Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria; Pharma MAR: Consultancy, Honoraria. Boccadoro: Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding.

scholarly journals Phase I Study of Ixazomib Added to Chemotherapy in the Treatment of Acute Lymphoblastic Leukemia in Older Adults

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 41-42
Author(s):  
Philip C. Amrein ◽  
Karen K. Ballen ◽  
Kristen E. Stevenson ◽  
Traci M. Blonquist ◽  
Andrew M. Brunner ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Lymphoblastic Leukemia ◽  
Complete Remission ◽  
Board Of Directors ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Advisory Committees ◽  
Survival Estimate ◽  
Grade 3 ◽  
Experienced Grade

Introduction: While progress has been made in the treatment of childhood leukemia, the outlook for patients >60 years of age with acute lymphoblastic leukemia (ALL) is poor with complete remission rates (CR) of approximately 60% and 3-year survivals (OS) of less than 15%. Intensified treatment in a later CALGB trial showed little improvement with a CR=61% and 5-year OS=6% (Stock, Cancer 2013). Ixazomib is an oral proteasome inhibitor, which has shown single agent activity and promising combination activity in pediatric ALL patients (Messinger, Blood 2012). We sought to assess the safety and tolerability, as well as early efficacy of adding ixazomib to a current MGH-DFCI/HCC multi-agent regimen for older adults with ALL. Methods: Patients aged 51 to 75 years of age with newly diagnosed B-ALL and T-ALL were screened for eligibility. Patients with mature ALL (including Burkitt's) were excluded. Patients with Philadelphia chromosome positive ALL (BCR-ABL1+) were eligible, and dasatinib was added to the chemotherapy on Day 10 for these patients. The chemotherapy treatment schedule from induction through maintenance is outlined in Table 1. A standard 3 + 3 patient cohort dose escalation design was used to determine the maximum tolerated dose (MTD) of ixazomib during induction for these patients, the primary objective of the trial. After consolidation I, patients in complete remission (CR) with a suitable donor were offered a hematopoietic stem cell transplantation (HSCT) as per institutional guidelines. Those not going to HSCT continued therapy as noted in the table. Results: There were 19 patients with B-ALL enrolled, none with T-ALL. Among these patients, 7 harbored BCR-ABL1 rearrangements. The median age was 65 years, 74% were male, and 90% had a performance status 0 or 1. The MTD was 2.3 mg of ixazomib, as 2 patients at 3.0 mg developed DLT's: a grade 3 peripheral neuropathy and a grade 5 acute kidney injury (Table 2). Grade 3 and 4 toxicities encountered at any time consisted mainly of grade 4 neutropenia in 13 patients and grade 4 thrombocytopenia in 12 patients. One patient experienced grade 3 neutropenia and 5 patients experienced grade 3 thrombocytopenia. Two patients with grade 2 neuropathy did not meet the definition of DLT. Among the 19 patients, 15 (79%, [95% confidence interval (CI), 54-94%]) achieved CR (14) or CRi (1), and 5 patients went on to HSCT. The median follow-up time was 2 years (range, 1-5) for 8 patients remaining alive. The 1-year overall survival estimate was 53% [95% CI, 29-72%], while the 2-year overall survival estimate was 47% [95% CI, 24-67%]. Conclusions: A dose of 2.3 mg of ixazomib in combination with induction chemotherapy among older patients with ALL was well-tolerated and associated with a promising rate of complete remission. Disclosures Amrein: Takeda: Research Funding; AstraZeneca: Consultancy, Research Funding; Amgen: Research Funding. Brunner:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; AstraZeneca: Research Funding; Forty-Seven Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Hobbs:Novartis: Honoraria; Celgene/BMS: Honoraria; Jazz: Honoraria; Constellation: Honoraria, Research Funding; Incyte: Research Funding; Merck: Research Funding; Bayer: Research Funding. Neuberg:Celgene: Research Funding; Pharmacyclics: Research Funding; Madrigak Pharmaceuticals: Current equity holder in publicly-traded company. Fathi:Takeda: Consultancy, Research Funding; Agios: Consultancy, Research Funding; PTC Therapeutics: Consultancy; Amphivena: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Newlink Genetics: Consultancy; Pfizer: Consultancy; Blueprint: Consultancy; Trillium: Consultancy; Kura Oncology: Consultancy; Forty Seven: Consultancy; Jazz: Consultancy; Boston Biomedical: Consultancy; BMS/Celgene: Consultancy, Research Funding; Kite: Consultancy; Trovagene: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Abbvie: Consultancy. OffLabel Disclosure: MLN 9708, ixazomib is FDA approved for multiple myeloma. In this trial it is used to treat acute lymphoblastic leukemia.

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