Cost-Effectiveness Analysis (CEA) of Sequential Treatment with Tyrosine Kinase Inhibitors (TKIs) for Chronic Myelogenous Leukemia (CML)

Abstract Background: Imatinib has been approved for treatment of newly diagnosed CML since 2001. For patients failing imatinib, other treatment options such as dasatinib, nilotinib, bosutinib, and high-dose imatinib are recommended. Previous economic analyses assumed that patients are treated until progression, despite guidelines recommending changing treatments for non-responders. The objective was to perform a CEA of sequential treatment with 2nd line TKIs, from a commercial payer perspective in the United States (US). Methods: A Markov-cohort model was used to simulate lifetime treatment costs and health outcomes (discounted 3.0% per annum) for patients resistant or intolerant to 1st line imatinib. It compared six treatment sequences, starting from 2nd line (shown in the results table). The model included five health states: chronic phase 2nd line TKI, chronic phase 3rd line TKI, chronic phase no TKI, post-progression, and death. After 12 months of TKI treatment, patients without a major molecular or complete cytogenetic response (MMR or CCyR) moved to the next line of therapy (per NCCN guidelines). Patients could also move to the next treatment line if they lost MMR or CCyR, or discontinued due to drug-related toxicity. Data for response achievement, risks of progression, death, adverse events, and discontinuation were primarily based on data in published trials. Due to the lack of head-to-head studies for dasatinib vs. nilotinib in 2nd line, and a lack of time-to-response data for all three 2nd line treatments, MMR and CCyR rates were interpolated from available data points in 2nd line, while dasatinib and nilotinib rates were assumed to be equal in 3rd line. Dasatinib and imatinib progression, loss of response, and survival rates for 2nd line responders were assumed equal, due to data limitations. In each health state, patients accrued drug costs, resource use (related to monitoring, AE management, and disease management) costs and quality-adjusted life years (QALYs). Resource use, cost, and utility estimates were based on FDA labels, RedBook, Medicare and AHRQ Healthcare Cost Utilization Project data, and published economic analyses. Multi-way uncertainty analyses evaluated key contributors to uncertainty in the results, by testing various assumptions for probabilities of discontinuation, response, loss of response, progression, and survival. Results: The model predicts that 2nd line dasatinib provides increased survival (ΔLYs = ~0.4-2.6 years) and QALYs (ΔQALYs = ~0.4-2.8 years) in all patient groups when compared with 2nd line high-dose imatinib or nilotinib sequences. Also, 2nd line dasatinib was more costly (ΔLifetime Costs = ~$65,000 - $225,000) than high-dose imatinib and nilotinib, primarily due to longer survival and corresponding longer time on TKI treatment. In ±20% univariate sensitivity analyses, the model was most sensitive to 2nd line progression and survival estimates. Conclusions: This analysis suggests that dasatinib may be associated with increased life expectancy and quality of life when compared with high dose imatinib or nilotinib, among patients who are resistant or intolerant to 1st line imatinib, primarily based on higher cytogenetic response rates observed in studies of dasatinib. Other studies have shown improved quality of life for responders, and landmark analyses have shown improved survival for patients achieving cytogenetic response, but head-to-head clinical studies of sequential use of dasatinib and nilotinib are needed to confirm the model result. Based on the threshold of $150,000/QALY, dasatinib can be considered cost-effective in the US. Results Table: Sequence # Sequence 1 Sequence 2 Sequence 3 Sequence 4 Sequence 5 Sequence 6 1st line (not modeled – assumes 1st line imatinib for all sequences) 2nd line DAS NIL HDI DAS NIL HDI 3rd line NIL DAS NIL BOS BOS DAS Imatinib-resistant population LYs 7 6.5 4.5 7.3 6.8 4.5 QALYs 5.9 5.4 3.6 6.2 5.7 3.6 Lifetime Cost $497,391 $431,346 $270,308 $496,897 $431,084 $270,051 ICERs: DAS followed by NIL vs. NIL followed by DAS - $129,139 DAS followed by NIL vs. HDI followed by NIL - $96,356 Imatinib-intolerant population LYs 7.8 7.1 -- 8.1 7.4 -- QALYs 6.7 6.0 -- 7.0 6.3 -- Lifetime Cost $599,270 $509,456 -- $598,766 $509,174 -- ICERs: DAS followed by NIL vs. NIL followed by DAS - $125,800 BOS=bosutinib; DAS=dasatinib; HDI= high-dose imatinib; NIL=nilotinib; ICER=incremental cost-effectiveness ratio Disclosures Whalen: Evidera, Inc.: Consultancy, Employment; Bristol-Myers Squibb: Research Funding. Stillman:Evidera, Inc.: Consultancy, Employment; Bristol-Myers Squibb: Research Funding. Ambavane:Evidera, Inc.: Consultancy, Employment; Bristol-Myers Squibb: Research Funding. Felber:Bristol-Myers Squibb: Employment, Equity Ownership. Makenbaeva:Bristol-Myers Squibb: Employment, Equity Ownership. Bolinder:Bristol-Myers Squibb: Employment, Equity Ownership.

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Bosutinib as Third-Line Treatment for Chronic Phase Chronic Myeloid Leukemia Following Failure of Second-Line Therapy with Dasatinib or Nilotinib

Blood ◽

10.1182/blood.v116.21.892.892 ◽

2010 ◽

Vol 116 (21) ◽

pp. 892-892

Author(s):

H. Jean Khoury ◽

Dong-Wook Kim ◽

Andrey Zaritskey ◽

Carlo Gambacorti-Passerini ◽

Andreas Hochhaus ◽

...

Keyword(s):

Research Funding ◽

Chronic Phase ◽

Cytogenetic Response ◽

Employment Equity ◽

Advisory Committees ◽

Line Therapy ◽

Third Line Therapy ◽

Equity Ownership ◽

Third Line ◽

Grade 3

Abstract Abstract 892 Bosutinib (SKI-606) is an orally available, dual Src/Abl tyrosine kinase inhibitor (TKI) with minimal inhibitory activity against PDGFR or c-kit. This open-label, phase 1/2 study evaluated the safety and efficacy of bosutinib as third-line therapy in patients with Philadelphia chromosome-positive (Ph+) chronic phase (CP) chronic myeloid leukemia (CML). Adults (aged ≥18 years) who had failed prior imatinib (IM) therapy and were resistant or intolerant to dasatinib (DAS; n = 35 and n = 51, respectively) or resistant to nilotinib (NIL; n = 28) received oral daily treatment with a starting dose of 500 mg bosutinib. Of the 118 patients enrolled, 46% were male, the median age was 56 years (range, 20–79 years), and the median time from CML diagnosis to start of bosutinib was 6.7 years (range, 0.6–19.2 years). The median daily dose of bosutinib was 446 mg (range, 140–563 mg). At week 24, 26% of patients achieved a major cytogenetic response (MCyR), including 13% with a complete cytogenetic response (CCyR; see Table). Cumulative response rates were 34% for MCyR and 22% for CCyR. The majority (81%) of patients who achieved a MCyR still retained their response as of the data snapshot date (median follow-up duration of 23 months). Comparable rates of response were observed across Bcr-Abl kinase domain mutations, except for the T315I mutation. The most frequently reported treatment-emergent adverse events (TEAEs; ≥20% of patients, all grades) were diarrhea (83%), nausea (45%), vomiting (36%), rash (26%), headache (25%), and fatigue (22%). The incidence of TEAEs was generally similar for DAS-resistant, DAS-intolerant, and NIL-resistant patients. Gastrointestinal events were predominantly grade 1/2, had an early onset, and usually subsided within the first 4 weeks of treatment. The only grade 3/4 TEAE reported in ≥5% of patients was diarrhea (8%). One grade 3 pleural effusion was observed in a patient with concomitant pneumonia and a history of recurrent pleural effusions on DAS. Grade 3/4 hematologic laboratory abnormalities included thrombocytopenia (23%), neutropenia (16%), and anemia (8%); all were usually transient. Other grade 3/4 laboratory abnormalities (≥5% of patients) included elevations of magnesium (12%), alanine transaminase (ALT; 7%), and lipase (5%). Grade 3/4 transaminase elevations were observed more frequently in NIL-resistant patients (ALT, 18% [grade 4, n = 1]; aspartate transaminase [AST], 11% [grade 4, n = 1]) compared with DAS-resistant/intolerant patients (ALT, 3–4%; AST, 0–3%). On-treatment QTcF interval prolongation was observed in 13 patients (11%), but was only grade 1/2 (≤500 msec) with a reported rate of arrhythmia of <1%. Adverse events led to treatment discontinuation in 27% of DAS-intolerant patients, 14% of DAS-resistant patients, and 11% of NIL-resistant patients; thrombocytopenia (4%), neutropenia (3%), and increased ALT (3%) were the only events resulting in discontinuation of >2 patients. In conclusion, bosutinib has an acceptable safety profile in patients with CP CML following failure of IM and DAS or NIL, with primarily low-grade and transient gastrointestinal TEAEs. Bosutinib also demonstrated clinical activity as a third-line therapy, with over one-third of patients achieving a MCyR. These results emphasize the therapeutic potential of bosutinib for CP CML patients with resistance or, particularly, intolerance to other second-generation TKI therapies. Table 1: Table. IM failure + DAS resistant IM failure + DAS intolerant IM failure + NIL resistant Total Cytogenetic response at week 24, n (%) Evaluablea 26 29 15 70 MCyR 5 (19) 9 (31) 4 (27) 18 (26) CCyR 2 (8) 5 (17) 2 (13) 9 (13) Cytogenetic response(cumulative), n (%) Evaluableb 32 38 21 91 MCyR 10 (31) 14 (37) 7 (33) 31 (34) CCyR 3 (9) 13 (34) 4 (19) 20 (22) Patients retaining MCyR at time of latest data snapshot, n (%) 7 (70) 11 (79) 7 (100) 25 (81) Median follow-up time (range), months 12 (3–47) 27 (0.3–43) 7 (1–42) 23 (0.3–47) Median duration of MCyR (range), weeks 24 (6–64) 68 (7–124) 18 (6–185) 37 (6–185) a Evaluable patients had baseline and week 24 cytogenetic assessments. Patients who had experienced early progression or death before having a post-baseline assessment were also evaluable. b Evaluable patients had baseline and post-baseline cytogenetic assessments. Patients who had experienced early progression or death before having a post-baseline assessment were also evaluable. Disclosures: Khoury: BMS, Novartis: Honoraria. Kim:BMS, Novartis, Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Gambacorti-Passerini:Pfizer Inc: Research Funding. Hochhaus:Novartis, BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer Inc: Research Funding. Dorlhiac-Llacer:Novartis: Research Funding; BMS: Research Funding; Pfizer Inc: Research Funding. Kelly:Pfizer Inc: Employment, Equity Ownership. Besson:Pfizer Inc: Employment, Equity Ownership. McMullan:Pfizer Inc: Employment, Equity Ownership. Kantarjian:Pfizer, Novartis, BMS: Research Funding; Novartis: Consultancy. Cortes:Pfizer Inc: Consultancy, Research Funding.

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Efficacy of Bosutinib in Imatinib-Resistant Vs Dasatinib/Nilotinib-Resistant Chronic Phase Chronic Myeloid Leukemia: Results from the Phase 4 BYOND Study

Blood ◽

10.1182/blood-2019-122230 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1650-1650 ◽

Cited By ~ 3

Author(s):

B. Douglas Smith ◽

Tim H Brümmendorf ◽

Gail J. Roboz ◽

Carlo Gambacorti-Passerini ◽

Aude Charbonnier ◽

...

Keyword(s):

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Chronic Phase ◽

Cytogenetic Response ◽

Molecular Response ◽

Employment Equity ◽

Advisory Committees ◽

Imatinib Resistant ◽

Equity Ownership

Introduction: The tyrosine kinase inhibitor (TKI) bosutinib is approved for patients with Philadelphia chromosome (Ph)+ chronic myeloid leukemia (CML) resistant/intolerant to prior therapy and newly diagnosed patients in chronic phase (CP). Methods: The ongoing phase 4 BYOND study (NCT02228382) is further evaluating the efficacy and safety of bosutinib for CML resistant/intolerant to prior TKIs. Patients were administered bosutinib at a starting dose of 500 mg once daily (QD). Primary results were previously reported. Here, we report the efficacy of bosutinib 500 mg QD in patients with Ph+ CP CML and resistance to imatinib (but not to nilotinib or dasatinib) vs patients with resistance to ≥1 second-generation TKI (dasatinib and/or nilotinib), as well as in patients with intolerance to all prior TKIs. Data are reported at ≥1 year after last enrolled patient; 85% of patients had a minimum follow-up of 2 years. Results: Of 163 patients who received bosutinib, 156 had Ph+ CP CML: 52 had resistance only to imatinib, 31 had resistance to dasatinib/nilotinib, and 73 were intolerant to all prior TKIs. Corresponding median treatment duration (range) was 24.1 (0.2-42.2), 8.9 (0.9-41.6), and 25.3 (0.4-41.9) months, and median dose intensity (range) was 360 (125-500), 431 (195-561) and 292 (80-500) mg/day. In all, 69.2%, 41.9%, and 53.4% of imatinib-resistant, dasatinib/nilotinib-resistant, and TKI-intolerant patients, respectively, were still receiving treatment as of the data cutoff date. The main reason for discontinuation was adverse events (AEs), with 10 (19.2%), 8 (25.8%), and 21 (28.8%) imatinib-resistant, dasatinib/nilotinib-resistant, and TKI-intolerant patients, respectively, discontinuing due to AEs. Corresponding discontinuations due to insufficient response occurred in 2 (3.8%), 5 (16.1%), and 1 (1.4%) patients. No patient experienced on-treatment transformation to advanced phase CML or discontinued treatment due to disease progression. In the evaluable cytogenetic population, cumulative major cytogenetic response (MCyR) rates were 85.4%, 69.0%, and 88.1% in imatinib-resistant, dasatinib/nilotinib-resistant, and TKI-intolerant patients, respectively (Table). The majority of patients, across all cohorts, achieved a complete cytogenetic response (CCyR). In the evaluable molecular population, cumulative major molecular response (MMR) rates were 72.3%, 44.8%, and 82.2% in imatinib-resistant, dasatinib/nilotinib-resistant, and TKI-intolerant patients, respectively; the 50th percentile of the cumulative incidence curve was 5.66 months, not reached and 3.22 months, respectively. Correspondingly, 59.6%, 24.1%, and 68.5% achieved molecular response (MR)4, and 48.9%, 17.2%, and 56.2% achieved MR4.5. In imatinib-resistant, dasatinib/nilotinib-resistant, and TKI-intolerant patients, respectively, Kaplan-Meier estimated overall survival rates (95% confidence interval) were 96.1% (85.2-99.0), 100% (100-100), and 98.6% (90.5-99.8) at 1 year, and 96.1% (85.2-99.0), 92.6% (73.4-98.1), and 97.2% (89.2-99.3) at 2 years with 4, 3, and 3 deaths occurring on study. Conclusions: Cytogenetic and molecular responses were seen in a high proportion of patients with Ph+ CP CML and TKI-resistance or TKI-intolerance. Response rates were similar between patients with resistance to imatinib and patients who were intolerant to all prior TKIs. Although to a lesser degree, responses were also seen in patients with resistance to second-generation TKIs, including patients achieving MR despite the shorter treatment duration. These results further support bosutinib use for patients with Ph+ CP CML and resistance/intolerance to prior TKIs. Disclosures Smith: Agios: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Celgene: Consultancy; Jazz: Consultancy. Brümmendorf:Janssen: Consultancy; Novartis: Consultancy, Research Funding; Ariad: Consultancy; Merck: Consultancy; University Hospital of the RWTH Aachen: Employment; Pfizer: Consultancy, Research Funding. Roboz:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Gambacorti-Passerini:Bristol-Meyers Squibb: Consultancy; Pfizer: Honoraria, Research Funding. Charbonnier:Novartis: Consultancy; Pfizer: Consultancy; Incyte: Speakers Bureau. Viquiera:Pfizer: Employment, Equity Ownership. Leip:Pfizer: Employment, Equity Ownership. Giles:Novartis: Consultancy; Epigene Therapeutics Inc: Consultancy, Other: leadership, stock/other ownership ; Actuate Therapeutics Inc: Employment. Ernst:Novartis: Research Funding. Hochhaus:Incyte: Research Funding; MSD: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Novartis: Research Funding. Rosti:BMS: Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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Subset Analysis of Response to Treatment of Chronic Phase CML in a Phase 1 Study of Ponatinib in Refractory Hematologic Malignancies

Blood ◽

10.1182/blood.v118.21.602.602 ◽

2011 ◽

Vol 118 (21) ◽

pp. 602-602 ◽

Cited By ~ 3

Author(s):

Jorge E. Cortes ◽

Hagop M. Kantarjian ◽

Neil Shah ◽

Dale Bixby ◽

Michael J. Mauro ◽

...

Keyword(s):

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Phase 1 ◽

Chronic Phase ◽

Hematologic Malignancies ◽

Employment Equity ◽

Advisory Committees ◽

Mutation Status ◽

Equity Ownership

Abstract Abstract 602 Background: Ponatinib is a potent, oral, pan-BCR-ABL inhibitor active against the native enzyme and all tested resistant mutants, including the uniformly resistant T315I mutation. Initial findings of a phase 1 trial in patients (pts) with refractory hematologic malignancies have been reported. The effect of duration of treatment, prior treatment, and mutation status on response to treatment was examined in CML chronic phase (CP) pts who responded to ponatinib. Methods: An open-label, dose escalation, phase 1 trial of ponatinib in pts with hematologic malignancies is ongoing. The primary aim is to assess the safety; anti-leukemic activity is also being investigated. Pts resistant to prior treatments or who had no standard treatment available were enrolled to receive a single daily oral dose of ponatinib (2 mg to 60 mg). Subset analyses of factors impacting cytogenetic and molecular response endpoints (MCyR and MMR) were performed for pts with CP-CML. Data are presented through April 15, 2011. Results: In total, 81 pts (54% male) received ponatinib. Overall, 43 pts had CP with 34 ongoing at analysis. MCyR was observed as best response in 31/43 (72%), 27 (63%) CCyR. The median time to MCyR was 12 (3 to 104) wks. Response rates were assessed by duration of treatment (1 pt in CCyR at entry was excluded; 6 pts in PCyR had to achieve CCyR). At the 3 month assessment, 22/42 (52%) CP pts achieved MCyR; at 6 months, 24/42 (57%); at 12 months, 29/42 (69%) had MCyR. The impact of prior treatment on response and time to response was assessed. 42 pts (98%) had >2 prior TKIs and 28 (65%) ≥3 prior TKIs, including investigational agents. Of approved TKIs, all pts were previously treated with imatinib, 19 dasatinib or nilotinib after imatinib, and 21 both dasatinib and nilotinib after imatinib. MCyR rate decreased with number of prior TKIs (2 prior TKIs 13/14 [93%], ≥3 prior TKIs 17/28 [61%]) and number of approved TKIs (imatinib followed by dasatinib or nilotinib 17/19 [90%], or by both dasatinib and nilotinib 12/21 [57%]). Time to response was prolonged in pts more heavily treated with prior TKIs. Median time to MCyR increased with the number of prior TKIs and approved TKIs (2 TKIs 12 wks, ≥3 TKIs 32 wks). The effect of mutation status on response and time to response was also evaluated. At entry, 12 pts had the T315I mutation, 15 had other BCR-ABL kinase domain mutations, 12 had no mutations detected, 4 did not allow sequencing. MCyR response rate for CP pts with T315I was 11/12 (92%); for other mutations, 10/15 (67%); and no mutation, 7/12 (58%). Similarly, mutation status had an impact on time to response: median time to MCyR was 12 wks for those with T315I or other mutations and 32 wks in resistant pts with no mutation. All CP patients were evaluable for MMR. At analysis, MMR was 17/43 (40%). MMR rate was inversely related to number of prior TKIs (2 TKIs 10/14 [71%], ≥3 TKIs 6/28 [21%]), approved TKIs (imatinib followed by dasatinib or nilotinib 12/19 [63%], or by both dasatinib and nilotinib 4/21 [19%]), and was higher for T315I pts (7/12, 58%) and those with other mutations (7/15, 47%) compared with no mutation (2/12, 17%). Median time to MMR for CP pts was 97 wks; median time to MMR was shorter for pts who were less heavily treated (2 prior TKIs 24 wks) and those with T315I or other mutations (63 wks). Conclusion: In this subset analysis of the phase 1 data, ponatinib had substantial activity in all subgroups analyzed. Time on treatment, less prior therapy and kinase domain mutations were associated with higher response rates and early responses in CP pts. Cytogenetic responses improved over the first 12 months of treatment and were higher in less heavily treated pts. Disclosures: Cortes: Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Kantarjian:Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; ARIAD: Research Funding. Shah:Ariad: Consultancy, Research Funding. Bixby:Novartis: Speakers Bureau; BMS: Speakers Bureau; GSK: Speakers Bureau. Mauro:ARIAD: Research Funding. Flinn:ARIAD: Research Funding. Hu:ARIAD: Employment. Clackson:ARIAD: Employment, Equity Ownership. Rivera:ARIAD: Employment, Equity Ownership. Turner:ARIAD: Employment, Equity Ownership. Haluska:ARIAD: Employment, Equity Ownership. Druker:MolecularMD: OHSU and Dr. Druker have a financial interest in MolecularMD. Technology used in this research has been licensed to MolecularMD. This potential conflict of interest has been reviewed and managed by the OHSU Conflict of Interest in Research Committee and t. Deininger:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Genzyme: Research Funding. Talpaz:ARIAD: Research Funding.

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Health Related Quality of Life of Bosutinib in Imatinib-Resistant or Imatinib-Intolerant Patients with Advanced Chronic Myeloid Leukemia

Blood ◽

10.1182/blood.v120.21.4448.4448 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4448-4448 ◽

Cited By ~ 1

Author(s):

Jennifer Whiteley ◽

Arlene Reisman ◽

Virginia Kelly ◽

Jorge E Cortes ◽

David Cella

Keyword(s):

Myeloid Leukemia ◽

Research Funding ◽

Well Being ◽

Health Related Quality ◽

Employment Equity ◽

Blast Phase ◽

Related Quality ◽

Health Related ◽

Equity Ownership

Abstract Abstract 4448 Purpose: Bosutinib is a dual Src/Abl tyrosine kinase inhibitor (TKI), which has demonstrated efficacy in a phase I/II study of patients with Advanced Phase Chronic Myeloid Leukemia (CML). The objective was to evaluate the effect of bosutinib on health -related quality of life (HRQoL) in patients with advanced CML after failure with imatinib. Methods: Patient reported HRQoL was an exploratory objective in the clinical trial and measured using the 44-item Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu). The FACT-Leu is a modular approach to assess patient HRQoL using a core set of general cancer questions as well as a cancer site specific leukemia subscale with 5 domains: Social Well-being (SWB), Emotional Well-being (EWB), Physical Well-being (PWB), Functional Well-being (FWB) and Leukemia Subscale (LeuS); and 3 summary scales: FACT-General, FACT Trial Outcome Index (TOI) and FACT-Leu Total. The item responses for each scale are summed to provide scores; higher scores indicate better HRQoL. The FACT-Leu was completed at weeks 4, 8, 12 and every 12 weeks thereafter, as well as treatment completion. Within cohort comparisons were assessed using paired t-tests. Results: Of the 164 patients with advanced leukemia included in the trial, 76 had accelerated phase (AP) CML and 64 blast phase (BP) CML. At 24 weeks, AP patients reported statistically significant improvements in PWB (p=0.02), EWB (p<0.001), LeuS (p<0.001), FACT-G (p<0.001), FACT-Leu (p<0.001) and FACT-TOI (p<0.001) with the PWB, FACT-G, LeuS, TOI and FACT-Leu exceeding minimally important differences (MID) at 24 weeks. Blast phase patients reported significant improvements in PWB (p=0.02), EWB (p=0.02), FWB (p=0.04), LeuS (p=0.01), FACT-G (p<0.001), FACT-Leu (p<0.001) and FACT-TOI (p=0.01) at 24-weeks with all scales exceeding MID except the SWB. At 48-weeks the AP patients continued to have statistically significant improvements in PWB (p=0.05), EWB (p=0.02), and FACT-G (p=0.03) and PWB, FACT-G, TOI and FACT-Leu exceeded the MID at 48 weeks. There were no statistically significant deteriorations in HRQoL through week 48 (Figure 1) Conclusions: These data suggest that CML patients treated with bosutinib demonstrate improved HRQoL. Confirmation in a controlled study is needed. Disclosures: Whiteley: Pfizer Inc: Employment, Equity Ownership. Reisman:Pfizer Inc: Employment, Equity Ownership. Kelly:Pfizer Inc: Employment, Equity Ownership. Cortes:Novartis, Bristol Myers Squibb, Pfizer, Ariad, Chemgenex: Consultancy, Research Funding. Cella:Pfizer Inc: Honoraria, Research Funding.

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Efficacy and Tolerability of Bosutinib and Imatinib in Older Versus Younger Patients with Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia–BELA Trial

Blood ◽

10.1182/blood.v120.21.4442.4442 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4442-4442 ◽

Cited By ~ 3

Author(s):

Carlo Gambacorti-Passerini ◽

Tim H Brümmendorf ◽

Dong-Wook Kim ◽

Irina Dyagil ◽

Hagop M Kantarjian ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Research Funding ◽

Age Groups ◽

Chronic Phase ◽

Newly Diagnosed ◽

Employment Equity ◽

Kaplan Meier ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 4442 Bosutinib (BOS) is an orally active, dual Src/Abl kinase inhibitor with activity and manageable toxicity in the phase 3 BELA trial of patients (pts) with newly diagnosed (≤6 mo) chronic phase (CP) chronic myeloid leukemia (CML). The current analysis of the BELA trial summarizes the activity and tolerability of BOS 500 mg/d and imatinib (IM) 400 mg/d among older (≥65 y; BOS n = 30; IM n = 27) versus younger pts (<65 y; BOS n = 220; IM n = 225). Sokal risk scores were balanced between treatment arms but, as expected, higher among older pts (4% low; 72% intermediate; 25% high) versus younger pts (39% low; 44% intermediate; 17% high). Minimum follow-up duration was 24 mo. BOS was discontinued by 37% of pts (57% older vs 35% younger; P = 0.023); difference between age groups was primarily due to adverse events (AEs; 39% vs 22%; most commonly increased alanine aminotransferase [ALT]). IM was discontinued by 27% of pts (35% older vs 28% younger; P= 0.496); disease progression was the primary reason. In the intent-to-treat population, cumulative rate of complete cytogenetic response (CCyR) by 24 mo in older/younger pts was 70%/80% on BOS and 78%/80% on IM. Median time to CCyR was 24.0 wk for older versus 12.7 wk for younger pts on BOS and 24.4 wk versus 24.7 wk on IM; in younger pts CCyR was achieved significantly faster on BOS versus IM (P<0.001). Among older/younger pts with a CCyR, 57%/79% on BOS and 76%/85% on IM were still on treatment and retained their CCyR as of the data cutoff. Cumulative rates of major molecular response (MMR) by 24 mo in older/younger pts were 53%/60% on BOS and 48%/49% on IM. Median time to MMR was 48.1 wk for older versus 48.0 wk for younger pts on BOS and 60.6 wk versus 84.1 wks on IM; for younger pts MMR was achieved significantly faster on BOS versus IM (P<0.001). Among older/younger pts with a MMR, 63%/84% on BOS and 92%/89% on IM were still on treatment and retained their MMR as of the data cutoff. Kaplan-Meier event-free survival in older/younger pts at 2 y was 100%/91% on BOS and 81%/88% on IM. Kaplan-Meier on-treatment transformation to accelerated/blast phase CML by 2 y was 0% for older and 2% (4 transformations) for younger pts on BOS (4 total), and 9% (2 transformations) for older and 5% (11 transformations) for younger pts on IM (13 total). Kaplan-Meier overall survival in older/younger pts at 2 y was 100%/97% on BOS and 92%/95% on IM. The majority of deaths were due to disease progression (BOS, n = 6; IM, n = 10); few deaths due to AEs on BOS (n = 1) or IM (n = 2) were reported, none treatment related. BOS was associated with higher rates of gastrointestinal TEAEs, elevated ALT and aspartate aminotransferase (AST), and pyrexia; IM was associated with higher rates of musculoskeletal TEAEs and edema (Table). Rates of common TEAEs were generally similar or higher among older pts. Pleural/pericardial effusion occurred in 6 (21%) older pts (3/6 with treatment-related events; median event duration, 36.5 d) versus 5 (2%) younger pts (all with treatment-related events) on BOS, and in no IM pts. Overall grade 3/4 TEAEs were more frequent among older pts on both BOS and IM, as was dose modification (Table). Grade 3/4 lab abnormalities of elevated ALT (BOS, 18% older/24% younger; IM, 4% each) and AST (BOS, 7%/12%; IM, 4% each) were more frequent with BOS versus IM, but similar between age groups. Grade 3/4 lab abnormalities of neutropenia were more frequent with IM (23% older/22% younger) versus BOS (11% each) regardless of age; grade 3/4 anemia (6%-14%) and thrombocytopenia (14%-23%) were generally similar regardless of age or treatment arm. In conclusion, BOS demonstrated activity in both older and younger pts with newly diagnosed CP CML. Although the frequency of certain toxicities as well as treatment discontinuations due to TEAEs was higher among older pts, the toxicity profile of BOS remained manageable and distinct from that of IM regardless of age. Event, % BOS IM ≥65 y (n = 28) <65 y (n = 220) ≥65 y (n = 26) <65 y (n = 225) Non-hematologic TEAEsa Diarrhea 86 68 46 22 Rash 36 22 27 18 Nausea 36 32 31 37 Vomiting 32 32 19 15 Dyspnea 32 5 12 3 Pyrexia 29 17 4 13 Elevated ALT 29 32 15 8 Elevated AST 25 27 15 8 Elevated lipase 25 12 19 10 Headache 21 12 8 12 Asthenia 21 5 4 7 Dyspepsia 14 6 23 5 Muscle spasms 14 3 35 21 Periorbital edema 7 <1 35 12 Any grade 3/4 TEAE 89 65 73 56 Dose reduction due to AE 64 40 42 18 Dose interruption due to AE 89 63 69 42 Treatment discontinuation due to AE 39 22 8 9 All treated pts were included in the safety analyses. a Includes TEAEs reported for ≥20% of older or younger pts. Disclosures: Gambacorti-Passerini: Pfizer Inc: Consultancy, Research Funding; Novartis, Bristol Myer Squibb: Consultancy. Brümmendorf:Bristol Myer Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; Patent on the use of imatinib and hypusination: Patents & Royalties. Kim:BMS, Novartis, Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kantarjian:Pfizer Inc: Research Funding. Pavlov:Pfizer Inc: Employment, Equity Ownership. Gogat:Pfizer Inc: Employment, Equity Ownership. Duvillie:Pfizer Inc: Employment. Shapiro:Pfizer Inc: Employment, Equity Ownership. Cortes:Novartis, Bristol Myers Squibb, Pfizer, Ariad, Chemgenex: Consultancy, Research Funding.

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Haploidentical Donors in Addition to Transplantation in Chronic Phase Associate with Improved Gvhd-Free Relapse-Free Survival (GRFS) for Patients with Advanced CML

Blood ◽

10.1182/blood.v128.22.4583.4583 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4583-4583

Author(s):

Piyanuch Kongtim ◽

Kehinde U. A. Adekola ◽

Denái R. Milton ◽

Reshma Ramlal ◽

Antonio M. Jimenez ◽

...

Keyword(s):

Research Funding ◽

Multivariable Analysis ◽

Chronic Phase ◽

Cytogenetic Response ◽

Molecular Response ◽

Relapse Free Survival ◽

Free Survival ◽

Post Transplant ◽

Donor Type ◽

Equity Ownership

Abstract Introduction: Despite the successes of treatment with tyrosine kinase inhibitors (TKIs) in patients with CML, allogeneic hematopoietic stem cell transplantation (ASCT) continues to be a potentially curative option for patients with advanced disease of who fail TKI therapy. Here we analyzed outcomes of patients with advanced CML (aCML) (beyond first chronic phase-CP1) who received an ASCT at our institution to identify factors associated with improved survival. Methods:207 consecutive patients withaCML treated at The University of Texas MD Anderson Cancer Center after year 2000 were included. The median age was 44 years (range 2-70 years), 135 (65%) were male, 77% had less than 5% bone marrow (BM) blasts, 129 (65%) had persistentPh-chromosome positive, and 176 patients (85%) were less than a major molecular response at transplant. Forty of 114 tested patients (35%) had resistant BCR-ABL mutations and 10 patients (8.7%) had T315I mutation at transplant. Conditioning regimen wasmyeloablative (MAC) in 140 patients (68%). Donors were matched related (MRD), matched unrelated (MUD),haploidentical (HAPLO), mismatched unrelated (MMUD), umbilical cord blood (UCB) and 1Ag mismatched related (MMRD) in 79 (38%), 75 (36%), 18 (9%), 17 (8%), 11 (5%) and 7 (3%) patients, respectively. The median time from diagnosis to transplant was 27 months (range 1-318 months) while the median follow-up duration was 20 months (range 1-194 months). Results:At 30 days post-transplant, 180 of 200 tested patients (90%) and 134 of 201 tested patients (67%) achieved a complete cytogenetic and at least a major molecular response, respectively. The response to transplant by day 30assessment correlated significantly with the disease status before transplant. A higher percentage of patients who experienced cytogenetic response before transplant experienced molecular response post-transplant (77%) compared with those who did not (61%; p=0.027). For the entire group, the 1-year cumulative incidence (CI) of acute GVHD (aGVHD) grade II-IV and grade III-IV were 41% and 15%, respectively; 5-year CI of extensive chronic GVHD (cGVHD) was 31%.Haploidentical transplant patients had lesscGVHD compared with HLA matched donor transplants (14% vs. 32% for HLA matched transplants). The CI of non-relapse mortality at 100 days and 1 year was 14% and 30%, respectively. Sixty-five patients (31%) had molecular relapse after transplant, which correlated with the degree of disease control before transplant. The CI of cytogenetic and molecular relapse at 5 years was 22% and 31%, respectively. Overall the 5-year survival (OS), progression free survival (PFS) and GVHD-free, relapse-free survival (GRFS)was49%, 34%, and 22%, respectively. Adjusting for all significant measures, percentage of BM blasts before transplant and donor type were significantly associated with PFS and GRFS (Table1, Figure 1).Haplodenticaltransplant patients had longer PFS and GRFS compared with other donor types including matched related or unrelated donor (5-year GRFS for HAPLO, MRD, MUD, MMUD, UCB and MMRD were 53%, 19%, 23%, 29%, 9%, and 0%, respectively; p=0.033) (Table 1, Figure 1). Cytogenetic and molecular response before transplant as well as year of transplant did not predict survival after transplant. Conclusions: ASCT is curative for a proportion of patients withaCML. PFS and GRFS are favorably influenced by percentage of BM blasts and donor type, withhaploidentical donor having at least as good outcomes as HLA matched donors, while molecular and cytogenetic response before transplant do not appear to correlate with survival post-transplant. Table 1 Multivariable analysis for PFS and GRFS Table 1. Multivariable analysis for PFS and GRFS Figure 1 PFS and GRFS based on percentage of BM blasts before transplant and donor types Figure 1. PFS and GRFS based on percentage of BM blasts before transplant and donor types Disclosures Cortes: Arog: Research Funding; Teva: Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Research Funding; Ambit: Research Funding. Champlin:Intrexon: Equity Ownership, Patents & Royalties; Ziopharm Oncology: Equity Ownership, Patents & Royalties. Ciurea:Spectrum Pharmaceuticals: Other: Advisory Board; Cyto-Sen Therapeutics: Equity Ownership.

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Patient-Reported Outcomes (PRO) Data from Patients (Pts) with Essential Thrombocythemia (ET) Enrolled in the MOST Study

Blood ◽

10.1182/blood-2019-124527 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1665-1665

Author(s):

Ellen K. Ritchie ◽

Anas Al-Janadi ◽

Philomena Colucci ◽

Patricia Kalafut ◽

Dilan Paranagama ◽

...

Keyword(s):

Quality Of Life ◽

Global Health ◽

Research Funding ◽

Symptom Burden ◽

Advisory Board ◽

Employment Equity ◽

Scale Scores ◽

Equity Ownership ◽

Eortc Qlq

Introduction: ET is a chronic myeloproliferative neoplasm (MPN) characterized by thrombocytosis and an increased risk for thrombotic and hemorrhagic events. ET can be associated with substantial symptom burden, impaired quality of life (QoL), and reduced survival. PRO data pertaining to the impact of ET on QoL and symptom burden in these pts are limited. The ongoing Myelofibrosis and Essential Thrombocythemia Observational STudy (MOST) was designed to collect data about the demographics, disease burden, PROs, and management of pts with ET or myelofibrosis (MF) in clinical practices throughout the United States. This analysis describes PROs from pts with ET enrolled in MOST. Methods: MOST is a longitudinal, multicenter, noninterventional, prospective, observational study (NCT02953704). Eligible adults with ET were ≥60 years of age, had a history of thrombotic events, or were receiving ET-directed therapy. PROs were collected in conjunction with usual-care visits approximately every 6 months over a planned observation period of 36 months. Patient-reported symptom burden was assessed with the disease-specific MPN Symptom Assessment Form Total Symptom Score (MPN-SAF TSS), composed of 10 items (fatigue, early satiety, abdominal discomfort, inactivity, concentration problems, night sweats, itching, bone pain, fever [>100oF], weight loss). The MPN-SAF numbness/tingling item was also included in the questionnaire but was not included in the TSS calculation. Symptom severity was graded from 0 (absent) to 10 (worst imaginable), with a possible TSS ranging from 0 to 100. Health-related QoL was evaluated with the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30 v3.0), composed of 5 functional scales, 3 symptom scales, 6 additional single-symptom items, and a global health/QoL scale. For functional and global health/QoL scales, higher scores indicate higher functioning and better global health/QoL, respectively. For symptom scales/items, higher scores indicate greater symptom burden. High-risk pts and low-risk pts receiving ET-directed therapy (excluding aspirin only) with baseline PRO data were included in this analysis. Data were summarized with descriptive statistics. Results: The MOST study enrolled 1234 pts with ET between Nov 29, 2016 and March 29, 2019 at 124 sites. Of these pts, 794 qualified for this analysis (data cut-off date, June 17, 2019); median age was 70 (range, 19-93) years, 80% were ≥60 years of age, 68% were women, 90% were white, 42% were working full or part-time, and 4% had a documented family history of MF, ET, or polycythemia vera. The majority of pts (87%) had high-risk ET. At enrollment, 768 pts completed the MPN-SAF. Mean (SD) TSS was 17.1 (15.6); 33% of pts had TSS ≥20. Women had higher mean (SD) TSS than men (18.5 [15.8] vs 14.2 [14.9]) and had higher mean individual symptom scores, except for weight loss and fever. The highest mean (SD) individual symptom scores were fatigue (3.4 [2.7]), numbness/tingling (2.3 [3.0]), inactivity (2.3 [2.8]), and early satiety (2.3 [2.7]) (Fig A). The most frequently reported severe symptoms (ie, score ≥7) were fatigue (17% [127/746]), numbness/tingling (14% [107/767]), and inactivity (11% [86/762]). At enrollment, 794 pts completed the EORTC QLQ-C30. The highest mean (SD) symptom scale scores (score ≥15) were fatigue (29.6 [25.8]), insomnia (28.6 [30.6]), pain (22.1 [27.9]), dyspnea (17.2 [25.5]), and constipation (15.7 [25.2]) (Fig B). The mean (SD) global health status/QoL score was 72.7 (21.9); functional scores ranged from 79.9 (21.9) for emotional functioning to 85.2 (24.1) for social functioning (Fig C). The average functional scale scores and symptom scale scores indicate higher functioning and less symptom burden, respectively, in men vs women. Conclusion: Pts with ET experienced a high symptom burden; fatigue was the most common and highest in severity. Symptom burden and quality of life scores in the current study were similar to prior reports (Emanuel J Clin Oncol 2012; Scherber Blood 2011). Women reported higher symptom burden than men in both the MPN-SAF and EORTC QLQ-30. Of note, numbness/tingling, which is not included in the MPN-SAF TSS calculation, was one of the most frequently reported severe symptoms for pts with ET in MOST. Future analyses from this trial will continue to increase understanding of the symptom burden and its impact on QoL in pts with ET. Disclosures Ritchie: Celgene, Incyte, Novartis, Pfizer: Consultancy; Genentech: Other: Advisory board; Tolero: Other: Advisory board; Pfizer: Other: Advisory board, travel support; agios: Other: Advisory board; Celgene: Other: Advisory board; Jazz Pharmaceuticals: Research Funding; Celgene, Novartis: Other: travel support; AStella, Bristol-Myers Squibb, Novartis, NS Pharma, Pfizer: Research Funding; Ariad, Celgene, Incyte, Novartis: Speakers Bureau. Al-Janadi:Incyte: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Celgene: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Genentech/Abbvie: Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Genentech/Roche: Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Gilead Sciences: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Sandoz-Novartis: Consultancy, Honoraria; Alexion Pharmaceuticals: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; MEI Pharma: Research Funding; Seattle Genetics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses. Colucci:Incyte: Employment, Equity Ownership. Kalafut:Incyte: Employment, Equity Ownership. Paranagama:Incyte: Employment, Equity Ownership. Mesa:Genotech: Research Funding; Promedior: Research Funding; Sierra Onc: Consultancy; Celgene: Research Funding; AbbVie: Research Funding; Novartis: Consultancy; La Jolla Pharma: Consultancy; CTI Biopharma: Research Funding; Samus: Research Funding; Incyte: Research Funding.

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IPH4102; An Anti-KIR3DL2 Monoclonal Antibody in Refractory Sezary Syndrome: Results from a Multicenter Phase 1 Trial

Blood ◽

10.1182/blood-2018-99-118021 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 684-684 ◽

Cited By ~ 1

Author(s):

Martine Bagot ◽

Pierluigi Porcu ◽

Basem M. William ◽

Maxime Battistella ◽

Maarten Vermeer ◽

...

Keyword(s):

Quality Of Life ◽

Monoclonal Antibody ◽

Board Of Directors ◽

Research Funding ◽

Phase 1 ◽

Employment Equity ◽

Advisory Committees ◽

Multicenter Phase ◽

Equity Ownership

Abstract Aims: Sezary Syndrome (SS) is the most aggressive form of cutaneous T cell lymphoma (CTCL), characterized with high blood involvement and expression of Killer cell immunoglobulin like receptor 3DL2 (KIR3DL2). IPH4102 is a first-in-class monoclonal antibody that targets KIR3DL2. Very limited effective treatment options are available for SS patients with refractory disease. We conducted a phase 1 study testing IPH4102 in patients with refractory CTCL. Here we report results from the SS subset. Methods: IPH4102-101 study is a multicenter phase I trial composed of a dose escalation and cohort expansion portions that evaluated IPH4102 in patients with refractory CTCL. Key eligibility criteria included failure of ≥ 2 prior systemic therapies. KIR3DL2 testing was performed for all patients at baseline and at different time points throughout the study. IPH4102 was given Q1w x 4 weeks, followed by Q2w x 10 weeks then Q4w until disease progression or unacceptable toxicity. Primary endpoint is safety. Main 2ry endpoints include best global response (BGR) using the Olsen criteria, progression-free survival (PFS), duration of response (DOR), quality of life (QOL) and biomarker analyses. Results: The study included 35 SS patients, 20 in the dose escalation and 15 in the cohort expansion, with a median age of 70 years (37-90). Median time from initial SS diagnosis to starting IPH4012 was 22.8 months. Nineteen patients (54%) received IPH4102 as ≥ 4th line of systemic therapy and 7 (20%) were previously treated with mogamulizumab. Thirteen patients (37%) had lymph node involvement as per investigator assessment and based on radiological examination while 7 patients (20%) had evidence of large cell transformation. KIR3DL2 expression was observed in either skin or blood in 33 patients (94%) and in both in 28 patients (80%). Most common adverse events (AEs) were asthenia (26%), peripheral edema (26%), and fatigue (23%), which were all grade 1-2. Possibly related grade ≥ 3 AEs were observed in 7 patients (20%), and only 2 patients (6%) stopped treatment for an AE. Table 1 shows BGR and response by compartment. Overall response rate was 42.9% [95% CI: 28.0% - 59.1%], with median time to response of 4.8 months. Median DOR and PFS were 5.6 months [95% CI: 3.2-not reached] and 12.8 months [95% CI: 8.1-not reached], respectively. Mogamulizumab pretreated patients showed BGR, median DOR and PFS of 42.9%, 13.8 and 20.9 months, respectively. Quality of life assessment was performed using the Pruritus VAS score andSkinDex29. Patients with CR, PR or SD showed marked improvement overtime of all evaluated parameters including SkinDex29 global, symptoms, emotional, and functional scores. Biomarker analysis showed progressive decrease in CD4/CD8 ratio in responding patients. The decrease of KIR3DL2+ expressing cells in skin evaluated by immunohistochemistry at week 5 and 14 was able to predict BGR (AUC=0.749, 0.714, respectively). Figure 1 shows reduction in KIR3DL2 expressing cells at week 5 and week 14 in a patient who had PR as BGR. To date, 9 patients are still ongoing treatment. Updated clinical and correlative research analyses will be presented at the meeting. Conclusions: IPH4102 is highly effective in patients with refractory SS. It induces meaningful clinical activity and improves quality of life placing it as an encouraging treatment option for these patients. Further development in SS and other T-cell malignancies is underway. Disclosures Bagot: Actelion: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees. Porcu:Innate Pharma: Consultancy. Khodadoust:Innate Pharma: Research Funding. Sicard:Innate Pharma: Employment, Equity Ownership. Azim:Innate Pharma: Employment, Equity Ownership. Kim:miRagen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Horizon Pharma: Consultancy, Research Funding; Galderma: Research Funding; Tetralogic: Research Funding; Neumedicine: Consultancy, Research Funding; Soligenix: Research Funding; Portola: Research Funding; Forty Seven Inc: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Medivir: Membership on an entity's Board of Directors or advisory committees; Kyowa-Kirin-Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Comparative Efficacy Among 3rd Line Post-Imatinib Chronic Phase-Chronic Myeloid Leukemia (CP-CML) Patients after Failure of Dasatinib or Nilotinib Tyrosine Kinase Inhibitors

Blood ◽

10.1182/blood.v124.21.4551.4551 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4551-4551 ◽

Cited By ~ 2

Author(s):

Jeffrey H. Lipton ◽

Dhvani Shah ◽

Vanita Tongbram ◽

Manpreet K Sidhu ◽

Hui Huang ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Kinase Inhibitors ◽

Cytogenetic Response ◽

Comparative Efficacy ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Abstract INTRODUCTION Patients with chronic myeloid leukemia (CP-CML) failing 1st line imatinib are most commonly treated with the second-generation (2G) tyrosine kinase inhibitors (TKIs) dasatinib and nilotinib. However, for patients who experience resistance or intolerance (R/I) to 2G-TKIs in 2nd line, there currently is no consensus on the optimal therapy sequence for 3rd line treatment. The comparative efficacy of using ponatinib in the 3rd line after 2G TKI failure was examined in a previous study (Lipton et al., ASH 2013). This study assesses the comparative efficacy of ponatinib versus sequential treatment of alternate 2G TKIs in 3rdline setting in two separate patient populations, post-imatinib and dasatinib patients and post-imatinib and nilotinib patients. METHODS A systematic review was conducted in MEDLINE, EMBASE and the Cochrane Libraries (2002-2014), as well as 3 conferences (ASH (2008-2014), ASCO (2008-2014), and EHA (2008-2013)). Studies evaluating any TKI were included if they enrolled 10 or more post-imatinib adult patients with CP-CML who were also R/I to dasatinib or nilotinib. All study designs were considered and no restriction was applied with respect to therapy dose, due to incomplete reporting of doses in the available studies. Analyses was run on two groups of patients, those failing imatinib and dasatinib (Group Ima/Das) and those failing imatinib and nilotinib (Group Ima/Nil). Bayesian methods were used to synthesize major cytogenetic response (MCyR) and complete cytogenetic response (CCyR) from individual studies and estimate the overall response probability with 95% credible interval (CrI) for each treatment. Bayesian analysis also was used to estimate the likelihood that each treatment offers the highest probability of CCyR/MCyR based on available evidence. RESULTS Six studies evaluating bosutinib, nilotinib and ponatinib for Group Ima/Das (n= 419) and five studies evaluating bosutinib, dasatinib and ponatinib for Group Ima/Nil (n=83) were included in the analysis. All studies reported CCyR in both groups. Five studies evaluating bosutinib, nilotinib and ponatinib reported MCyR in Group Ima/Das and three studies evaluating bosutinib and ponatinib reported MCyR in Group Ima/Nil. Synthesized treatment-specific probabilities and 95% CrI for CCyR are presented in Figure 1. Synthesized treatment-specific probabilities of CCyR for Group Ima/Das were 27% for nilotinib, 20% for bosutinib and 54% (95% CrI 43%% to 66%) for ponatinib. Treatment-specific probabilities of MCyR for Group Ima/Das were 41% for nilotinib, 28% for bosutinib and 66% (95% CrI 55%% to 77%) for ponatinib. The probability of ponatinib providing superior response to all other included treatments for group Ima/Das was estimated to be >99% for both CCyR and MCyR. Synthesized treatment-specific probabilities of CCyR for Group Ima/Nil were 25% for dasatinib, 26% for bosutinib and 67% (95% CrI 51%% to 81%) for ponatinib. Treatment-specific probabilities of MCyR for Group Ima/Nil were 33% for bosutinib and 75% (95% CrI 60%% to 87%) for ponatinib. The probability of ponatinib providing superior response to all other included treatments for group Ima/Nil was estimated to be >99% for both CCyR and MCyR. CONCLUSIONS The post imatinib and dasatinib group included more studies with larger sample sizes compared with the post imatinib and nilotinib group. Overall, response rates appear higher for TKIs in the post imatinib and nilotinib group compared with the post imatinib and dasatinib group. For both groups, patients on ponatinib had higher CCyR and MCyR rates compared with the sequential 2G TKIs included in this analysis. Based on available data, ponatinib appears to provide a higher probability of treatment response for patients failing imatinib and dasatinib/ nilotinib compared with sequential 2G TKI therapy commonly used in this indication. Figure 1 Figure 1. Disclosures Lipton: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ariad: Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Shah:Ariad Pharmaceuticals: Research Funding. Tongbram:Ariad Pharmaceuticals: Research Funding. Sidhu:Ariad Pharmaceuticals Inc.: Research Funding. Huang:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. McGarry:ARIAD Pharmaceutical, Inc.: Employment, Equity Ownership. Lustgarten:ARIAD Pharmaceuticals Inc: Employment, Equity Ownership. Hawkins:Ariad Pharmaceuticals Inc.: Research Funding.

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Subcutaneous Omacetaxine (OM) Treatment of Chronic Phase (CP) Chronic Myeloid Leukemia (CML) Patients Following Multiple Tyrosine Kinase Inhibitor (TKI) Failure

Blood ◽

10.1182/blood.v116.21.2290.2290 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2290-2290 ◽

Cited By ~ 2

Author(s):

Jorge E. Cortes ◽

Meir Wetzler ◽

Jeff Lipton ◽

Franck E Nicolini ◽

Michele Baccarani ◽

...

Keyword(s):

Bone Marrow ◽

Adverse Events ◽

Median Duration ◽

Bone Marrow Failure ◽

Single Agent ◽

Chronic Phase ◽

Cytogenetic Response ◽

Employment Equity ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 2290 Introduction: Multiple TKI failure is a growing problem in a subset of CML patients. Treatment with a third TKI after two have failed often yields poor results. New treatment options are needed for this patient population. OM is a first-in-class cetaxine with demonstrated activity as a single agent in CML. It inhibits the production of short-lived oncoproteins (such as Mcl-1) involved in cancer cell survival via a mechanism independent of Bcr-Abl binding. Several studies have suggested that OM has a favorable toxicity profile when given to patients with CML via the subcutaneous route. We explored OM efficacy and safety in a subset of patients who had received therapy with multiple prior approved TKI. Methods: We analyzed a subset of adult CML-CP patients who had received two or more TKI (imatinib, dasatinib, nilotinib), from a combined interim dataset of two prospective Phase 2 studies (CML-202, for patients with the T315I kinase domain mutation, and CML-203, for patients with failure to ≥2 TKI) utilizing OM in the treatment adult patients with all phases of CML who had failed TKI. TKI failure was defined as no complete hematologic response (CHR) by 12 weeks (wk), no cytogenetic response by 6 months (mo), no major cytogenetic response (MCyR) by 12 mo, loss of CHR or MCyR, or progressive leukocytosis. The focus of this analysis was to assess the CHR and MCyR response rates as well as the overall safety of OM in these patients. Adverse events presented are Grade 3/4 events that occurred in ≥ 5% of patients (regardless of causality). Results: A total of 73 of the 93 CML-CP patients from these two studies had received two or more TKI prior to OM treatment. Median time from initial CML diagnosis to first dose of OM was 74.4 months. Mutations of any kind were seen in 48% of the patients, whereas 29% had no identified mutation and 23% had no available data on mutation status. Sixty (82%) of these 73 patients achieved or maintained (twelve patients were in CHR at study entry) a CHR and 17 (23%) achieved a MCyR (9 complete and 8 partial). The median duration of MCyR was 4.4+ months (range 1.2–14.1+). Median overall survival for patients treated with OM after failure of 2 or more TKI has not yet been reached [95% Confidence Interval (CI) 22.9, NA months] (Figure 1). Eleven patients had a treatment—emergent adverse event leading to death, and two deaths were probably related to study drug. Median progression-free survival was 11.1 months (95% CI 6.5, 13.8 months). Median follow-up time was 7.5 months for all patients with twenty-five patients remaining on study at the time of this data cut. A total of 36 of the 93 CP patients from these two studies had been treated with three or more TKI; 27 (75.0%) achieved or maintained a CHR and 7 (19.4%) achieved a MCyR (4 complete and 3 partial) on OM treatment. The median duration of MCyR in this group was 4.0+ months (range 1.2–11.5+) at the time of data cut-off. The primary Grade 3/4 adverse events in patients who received OM after failure of 2 or more TKI were hematologic, including thrombocytopenia (64%), neutropenia (48%) and anemia (40%) most commonly, followed by febrile neutropenia (12%), bone marrow failure (12%), pancytopenia (7%) and febrile bone marrow aplasia (6%). These events were dosing schedule dependent. Clinical sequelae were uncommon and managed with transient treatment interruptions and dose adjustments. Grade 3/4 non-hematologic adverse events were infrequent, with only fatigue (6%) occurring ≥5% of patients. Conclusions: OM, through a mechanism of action independent of Bcr-Abl, may offer a clinically viable option for patients who have progressed on multiple TKI treatment. Disclosures: Off Label Use: The drug is currently in development and has an NDA submitted for use in TKI resistant CML. Cram: ChemGenex: Employment, Equity Ownership. Humphriss: ChemGenex: Employment, Equity Ownership. Benichou: ChemGenex: Consultancy, Equity Ownership. Craig: ChemGenex: Employment, Equity Ownership, Executive Management Level.

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