Bosutinib As Therapy for Chronic Phase Chronic Myeloid Leukemia Following Failure with Imatinib Plus Dasatinib and/or Nilotinib: 24-Month Minimum Follow-up Update

Abstract Abstract 3785 Bosutinib (BOS) is an orally active, dual Src/Abl tyrosine kinase inhibitor (TKI). This open-label, phase 1/2 study evaluated BOS in patients (pts) with chronic phase chronic myeloid leukemia (CP CML) following TKI failure. A total of 119 pts aged ≥18 y with prior imatinib (IM) failure plus dasatinib (DAS) resistance (n = 38), DAS intolerance (n = 50), nilotinib (NIL) resistance (n = 27), NIL intolerance (n = 1), or failure of DAS and NIL (n = 3) received BOS starting at 500 mg/d. Median age was 56 y (range, 20–79 y); 45% of pts were male; median time from CML diagnosis was 6.5 y (range, 0.6–18.3 y). Median BOS duration was 8.6 mo (range, 0.2–60.8 mo); 24% of pts are still on treatment. Dose escalation to BOS 600 mg/d occurred in 19% of pts. Time from last pt's first dose to data cutoff was 25 mo (median follow-up duration of 31.4 mo [range, 0.3–66.0 mo]). A confirmed complete hematologic response (CHR) was attained/maintained by 73% of evaluable pts (Table). The Kaplan-Meier (KM) probability of maintaining a CHR at 2 y was 67%. A major cytogenetic response (MCyR) was attained/maintained by 41%, including 32% with a complete cytogenetic response (CCyR). Among evaluable pts without a baseline CCyR, 36% (n = 37/102) achieved a MCyR, including 28 (28%) with a CCyR. The KM probability of maintaining a MCyR at 2 y was 71%. Of 86 pts with baseline mutation status, 40 (47%) pts had 19 unique Bcr-Abl kinase domain mutations, including 7 (8%) pts with T315I. Responses were seen across mutations (75% CHR, 43% MCyR excluding T315I), including those conferring resistance to other TKIs; responses in pts with T315I were low (29% CHR; 14% MCyR). Nine of 37 pts evaluated at baseline and treatment discontinuation had ≥1 new mutation (V299L, n = 4; L248V, n = 2; T315I, n = 2; F359C, n = 1; G250E, n = 1); 8 of 9 pts had discontinued BOS due to disease progression or lack of efficacy. On-treatment transformation to accelerated phase CML occurred in 5 (4%) pts after 16 to 428 d on study; no pt transformed to blast phase CML. KM-estimated on-treatment progression-free survival (PFS) at 2 y was 75%; KM-estimated overall survival (OS) at 2 y was 84% (Table). There were 23 (19%) deaths on study, with 6 deaths occurring ≤30 d after the last BOS dose. Most deaths were due to disease progression (n = 10 [8%]) or an adverse event (AE; n = 10 [8%]; including 1 treatment-related death due to gastrointestinal bleeding). Three deaths were due to unknown cause ≥509 d after the last BOS dose. Non-hematologic treatment-emergent AEs (TEAEs) seen in ≥20% of pts (all grades; grade 3/4) included diarrhea (82%; 8%), nausea (49%; 1%), vomiting (40%; 1%), rash (27%; 3%), headache (26%; 3%), fatigue (24%; 1%), and abdominal pain (20%; 1%). The incidence of individual TEAEs was generally similar across groups regardless of prior TKI exposure. Diarrhea TEAEs were predominantly grade 1/2, first reported early during treatment (median time to first event of 1.5 d [range, 1–210 d]), and transient (median event duration of 2 d [range, 1–524 d]). The incidence of pleural effusion was highest among DAS-intolerant pts (n = 11 [22%], including 3 pts with grade 3 events); for 9 of 11 pts pleural effusion had been indicated as a reason for intolerance to prior DAS. Grade 3/4 laboratory abnormalities reported in ≥10% of pts included thrombocytopenia (25%), neutropenia (19%), lymphopenia (17%), and hypermagnesemia (12%). Dose reductions and interruptions were used to manage AEs in 50% and 66% of pts. A total of 32 (27%) pts discontinued treatment due to an AE, most commonly hematologic events. In conclusion, BOS therapy continues to demonstrate durable efficacy and manageable toxicity after follow-up of ≥24 mo in CP CML following resistance or intolerance to multiple TKIs, with a majority of pts maintaining response at 2 y and few new transformations, deaths, TEAEs, or discontinuations due to AEs since the prior report ∼1 y earlier (Blood 2012;119:4303–12). n (%) IM + DAS-R IM + DAS-I IM + NIL-R IM + DAS ± NILa Total Evaluableb 37 49 25 4 115 CHR 23 (62) 39 (80) 19 (76) 3 (75) 84 (73) Evaluableb 36 44 26 4 110 MCyR 12 (33) 21 (48) 10 (39) 2 (50) 45 (41) CCyR 7 (19) 19 (43) 7 (27) 2 (50) 35 (32) Treated 38 50 27 4 119 PFS at 2 yc 70% 81% 79% 38% 75% OS at 2 yc 77% 85% 92% 75% 84% R, resistant; I, intolerant. a Includes 3 pts with prior exposure to all 3 TKIs and 1 NIL-I pt. KM rates may be unreliable due to the small number of pts in this cohort. b Received ≥1 dose of BOS and had a valid baseline response assessment. c Based on KM estimates Disclosures: Gambacorti-Passerini: Pfizer Inc: Consultancy, Research Funding; Novartis, Bristol Myer Squibb: Consultancy. Kantarjian:Pfizer: Research Funding. Kim:BMS, Novartis, Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Marin:Novartis: Research Funding; BMS: Research Funding. Dorlhiac-Llacer:Novartis, Bristol Myer Squibb, Pfizer: Research Funding. Bullorsky:Novartis, BMS: Consultancy, Speakers Bureau. Leip:Pfizer Inc: Employment. Kelly:Pfizer Inc: Employment, Equity Ownership. Turnbull:Pfizer Inc, l3/Inventiv Clinical Solutions: Employment. Besson:Pfizer Inc: Employment. Cortes:Novartis, Bristol Myers Squibb, Pfizer, Ariad, Chemgenex: Consultancy, Research Funding.

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Bosutinib Versus Imatinib in Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia – BELA Trial: 24-Month Follow-up

Blood ◽

10.1182/blood.v118.21.455.455 ◽

2011 ◽

Vol 118 (21) ◽

pp. 455-455 ◽

Cited By ~ 2

Author(s):

Jorge E Cortes ◽

Anish Maru ◽

Carmino Antonio Antonio De Souza ◽

François Guilhot ◽

Ladan Duvillie ◽

...

Keyword(s):

Overall Survival ◽

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Research Funding ◽

Chronic Phase ◽

Primary Reason ◽

Newly Diagnosed ◽

Function Test ◽

Grade 3

Abstract Abstract 455 Introduction: Bosutinib (SKI-606) is an orally active, dual competitive inhibitor of the Src and Abl tyrosine kinases. The phase 3 BELA study compared bosutinib with imatinib in patients (pts) with newly diagnosed chronic phase (CP) chronic myeloid leukemia (CML). Methods: Pts were randomized 1:1 to open-label oral bosutinib 500 mg/d (n = 250) or imatinib 400 mg/d (n = 252) and stratified by Sokal score risk group (low, medium, high) and geographical region. The primary efficacy endpoint was complete cytogenetic response (CCyR) at 12 mo in the intent-to-treat population. Key secondary and exploratory efficacy endpoints included major molecular response (MMR) at 12 mo, time to CCyR and MMR, duration of CCyR and MMR, time to and incidence of transformation to accelerated/blast phase (AP/BP) CML, event-free survival (EFS), and overall survival. Safety analyses included all treated pts. Results: The median treatment duration was 19.3 mo for bosutinib and 19.5 mo for imatinib; 67% and 74% of pts, respectively, are still receiving therapy. The primary reason for discontinuation of bosutinib was toxicity (23%), while the primary reason for discontinuation of imatinib was disease progression (13%). Rates of CCyR and MMR are shown in the table. The rate of cumulative CCyR by 18 mo was 79% in both arms, and the cumulative rate of MMR by 18 mo was 55% in the bosutinib arm versus 45% in the imatinib arm. Median time to CCyR was faster for bosutinib versus imatinib (12.7 vs 24.6 wk); median time to MMR was also faster for bosutinib versus imatinib (36.9 vs 72.3 wk). Transformation to AP/BP CML while on treatment occurred in 4 (2%) pts on bosutinib and 13 (5%) pts on imatinib. On-study deaths from any cause occurred in 6 (2%) pts receiving bosutinib versus 13 (5%) pts receiving imatinib, and included 5 (2%) and 9 (4%) pts, respectively, who died due to CML progression. Median on-treatment EFS and overall survival were not yet reached for either arm. At 18 mo, the Kaplan-Meier estimates of EFS were 95% for bosutinib versus 91% for imatinib, and the estimates of overall survival were 99% versus 95%, respectively. Bosutinib was associated with higher incidences compared with imatinib of gastrointestinal events (diarrhea [69% vs 22%, respectively], vomiting [32% vs 14%], pyrexia [18% vs 10%], and abdominal pain [13% vs 7%]). In contrast, bosutinib was associated with lower incidences of edema (peripheral edema [4% vs 11%] and periorbital edema [1% vs 14%]) and musculoskeletal events (myalgia [5% vs 11%], muscle cramps [4% vs 22%], and bone pain [4% vs 10%]). Fewer pts on bosutinib experienced grade 3/4 laboratory abnormalities of neutropenia (11% vs 24% with imatinib), while the incidences of grade 3/4 anemia and thrombocytopenia were similar between treatment arms (8% with anemia and 14% with thrombocytopenia). Grade 3/4 liver function test abnormalities occurred more frequently with bosutinib versus imatinib (increased alanine aminotransferase [23% vs 4%] and aspartate aminotransferase [12% vs 3%]). Although common with bosutinib, gastrointestinal events and liver function test abnormalities were typically transient, managed with dose modifications, and not life threatening. Conclusions: The study did not meet the primary endpoint (CCyR at 12 mo); early discontinuation of bosutinib due to adverse events may have contributed to this observed lack of difference. However, bosutinib did result in a higher rate of MMR at 12 mo, faster times to MMR and CCyR, fewer events of transformation to AP/BP CML, and fewer overall and CML-related deaths compared with imatinib, suggesting superiority of bosutinib in pts with newly diagnosed CP CML. In addition, the 18-mo estimates for both EFS and OS currently favor bosutinib. Bosutinib and imatinib were each associated with acceptable but distinct toxicity profiles. Based on these results, bosutinib may offer a new therapeutic option for pts with newly diagnosed CP CML. Minimum of 24 mo of follow-up will be presented for all pts. Disclosures: Cortes: Pfizer Inc: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Guilhot:CHU de Poitiers: Employment; Pfizer Inc: Consultancy; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria. Duvillie:Pfizer Inc: Employment. Powell:Pfizer Inc: Employment, Equity Ownership. Countouriotis:Pfizer Inc: Employment. Gambacorti-Passerini:Pfizer Inc: Honoraria, Research Funding; BMS: Research Funding; Novartis: Honoraria; Biodiversity: Honoraria.

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Outcomes of Patients with Chronic Phase CML Who Discontinued Ponatinib in the Frontline Setting

Blood ◽

10.1182/blood.v126.23.1580.1580 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1580-1580

Author(s):

Preetesh Jain ◽

Hagop M Kantarjian ◽

Elias Jabbour ◽

Zeev Estrov ◽

Gautam Borthakur ◽

...

Keyword(s):

Clinical Trial ◽

Median Time ◽

Research Funding ◽

Chronic Phase ◽

Cytogenetic Response ◽

The Other ◽

Molecular Response ◽

Vascular Events ◽

Grade 3

Abstract Background: Ponatinib is a novel TKI efficacious in relapsed refractory patients (pts) with CML and in those with T315I mutation. Despite the achievement of deep early responses in most pts observed in the frontline setting, the concern for arterio-thrombotic events led to the discontinuation (DC) of ponatinib frontline clinical trial. In this study, we have assessed the outcomes after DC of ponatinib of pts in a clinical trial of frontline ponatinib in CML-CP. Methods: Fifty one pts with CML-CP were treated with frontline ponatinib in a single-arm, clinical trial between May 2012 and September 2013. Initial dose of ponatinib was 45 mg orally daily in 43 pts and, after amendment, 30 mg in 8 pts. All pts DC ponatinib therapy after June 2014 and were switched to another TKI. Patients were assessed for cause of DC, treatment received after ponatinib DC, response achieved/maintained on subsequent TKI, adverse events (AE) and survival after ponatinib DC. Survival was calculated from the time of ponatinib DC to the time of last follow up. Results: All 51 patients DC ponatinib: 38 per FDA recommendation and 13 due to AE. Median duration of ponatinib therapy was 13.2 months (range-2.1-25.4). At the time of DC, 47/51 (92%) pts were in complete cytogenetic response (CCyR) and 4 (8%) in partial cytogenetic response (PCyR); 1 pt DC before 3-mo evaluation. Forty (78%) pts were in MMR and 26 (51%) in molecular response 4.5-log (MR4.5). Thirty-six (70%) pts were switched to dasatinib, 7 (14%) to imatinib, and 4 (8%) each to nilotinib and bosutinib. After switching to another TKI, with a median of 13 months (range, 0.2 to 26.3) of follow-up, 2 pts have lost their cytogenetic response (both PCyR on ponatinib), 1 pt improved from PCyR to CCyR and one maintained PCyR; all 47 (92%) pts with CCyR on ponatinib maintained this response. Molecular responses improved in some pts: 6 improved from no MMR to MMR; 1 to MR4.5 (median time on ponatinib 4 months; median time on subsequent TKI 17 months); 11 from MMR to MR4.5 (median time on ponatinib 13 months; median time on subsequent TKI 17 months). One pt (treated with imatinib 400) lost MR4.5 to no MMR after 2 months. At last follow-up 37 pts (72%) had MR4.5 and 45 (90%) MMR. Two pts died after ponatinib DC. One pt was treated with imatinib 400 and developed grade-3 edema and recurrent lung cancer; the second was switched to dasatinib and had recurrent progressive peripheral arterial disease (PAD). Four pts had events (2 deaths, 1 secondary MDS with -7 and 1 pt lost major CyR). Median post ponatinib survival (Figure-1) and median post ponatinib event free survival (not shown) was not reached (1-year OS 98% and EFS 95%). Forty five pts continued on their first post-ponatinib TKIs, 5 required 2 post-ponatinib TKI and 1 pt received 3 different TKIs after DC. The most common cause for post-ponatinib TKI switch was toxicity (n=6). Of the 36 pts switched to dasatinib, 5 discontinued: 4 due to pleural effusion and 1 with acute renal failure. 29/36 pts (81%) were in MMR before switch and all maintained MMR; 4 pts achieved MMR after switch to dasatinib. Four pts developed grade 3-4 non hematological vascular AEs (3 among pts with such events while on ponatinib and 1 new vascular event within 3 months of ponatinib DC). Of the 4 pts switched to nilotinib, 1 DC within 3 months due to grade-3 pancreatitis and also developed grade-1 pulmonary hypertension with 1 month of discontinuing ponatinib. This pt was then switched to bosutinib. The other 3 pts maintained MMR and had no vascular events. Of the 4 pts switched to bosutinib, one developed MDS, one was switched back to ponatinib off protocol (patient's choice), 1 lost cytogenetic response and one DC therapy after 1 month and maintains MR4.5 (this pt had TIA while on ponatinib, developed cerebral infarct within 1 month post ponatinib). Seven pts switched to imatinib. One developed a new PAD within 3 months of ponatinib DC (history of MI while on ponatinib). The other 6 pts maintained MMR on imatinib. Overall, 15 pts who had aggravated hypertension on ponatinib were under control after DC of ponatinib. Conclusion: Treatment with 2nd generation TKIs and imatinib was effective and safe in pts who DC ponatinib, and most pts were able to maintain/improve the responses achieved on ponatinib. Ponatinib-associated hypertension was usually reversible after DC and most vascular events with subsequent TKIs occurred in patients with prior such events while on ponatinib. Figure 1. Post ponatinib survival in patients Figure 1. Post ponatinib survival in patients Disclosures Jabbour: pfizer: Research Funding; ariad: Research Funding; teva: Consultancy; teva: Research Funding; pfizer: Consultancy; bms: Consultancy; ariad: Consultancy. Estrov:incyte: Consultancy, Research Funding. Pemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Cortes:Pfizer: Consultancy, Research Funding; BerGenBio AS: Research Funding; Novartis: Consultancy, Research Funding; Teva: Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy.

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Blast Phase Chronic Myeloid Leukemia: A Pooled Analysis of Subcutaneous Omacetaxine Mepesuccinate in Treatment-Resistant Patients

Blood ◽

10.1182/blood.v120.21.3753.3753 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3753-3753 ◽

Cited By ~ 1

Author(s):

H. Jean Khoury ◽

Jorge E. Cortes ◽

Meir Wetzler ◽

Jeffrey H. Lipton ◽

Michele Baccarani ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Disease Progression ◽

Myeloid Leukemia ◽

Research Funding ◽

Chronic Phase ◽

Clinical Activity ◽

Protein Synthesis Inhibitor ◽

Synthesis Inhibitor ◽

Omacetaxine Mepesuccinate ◽

Grade 3

Abstract Abstract 3753 Background Subcutaneous omacetaxine mepesuccinate (“omacetaxine”) is a first-in-class cephalotaxine. Omacetaxine is a protein synthesis inhibitor that does not depend on direct binding of Bcr-Abl. Omacetaxine reduces levels of multiple oncoproteins, including Bcr-Abl, and induces apoptosis in leukemic stem cells. Omacetaxine has shown clinical activity and adequate tolerability in two phase 2, open-label, international, multicenter studies in patients with chronic myeloid leukemia (CML): the first in patients with history of T315I mutation who had failed prior imatinib and the second in patients with resistance or intolerance to ≥2 tyrosine kinase inhibitors (TKIs). This is a pooled analysis of the efficacy and safety data of omacetaxine in patients with CML in the blast phase (BP). Methods Data from patients with CML-BP were included from two phase 2 studies. All patients received omacetaxine 1.25 mg/m2 subcutaneously twice daily for up to 14 consecutive days every 28 days for induction and the same dosage for up to 7 days every 28 days as maintenance. The number of consecutive days of dosing could be adjusted, as clinically indicated. Recombinant growth factor support was allowed in the event of febrile neutropenia. The primary outcome measures were major hematologic response (MaHR) and major cytogenetic response (MCyR). MaHR was defined as complete hematologic response (CHR) lasting ≥4 weeks, no evidence of leukemia, or return to chronic phase. MCyR included confirmed or unconfirmed complete or partial response. Secondary endpoints included duration of response, time to disease progression, overall survival and safety. Results Forty-four patients with CML-BP (median age 53.5 years [range, 19–68]) received treatment with omacetaxine. Forty-two patients (96%) had ECOG status ≤2. All but 1 patient had prior treatment with imatinib; 5 (11%) patients received imatinib only, 20 (45%) received 2 approved TKIs (imatinib, dasatinib, or nilotinib), and 19 (43%) were treated with all 3 approved TKIs. Most common non-TKI agents included hydroxyurea in 18/44 (41%), anthracyclines and related agents in 17 (39%), cytarabine in 14 (32%), and interferons in 11 (25%). Mutation analysis was not performed per protocol; however, point mutations were detected in 23 patients, and 17 (74%) of these had the T315I mutation. No mutations were identified in 7 patients and 14 were not assessed for mutations. The median number of cycles of omacetaxine administered was 2 (range 1–12) with a median duration of exposure of 1.5 months (range 0–13.8). Four patients (9%) had a MaHR (3 with CHR and 1 returned to chronic phase); additional 2 patients had hematologic improvement as a best response. No patient achieved MCyR; 3 patients (7%) achieved a minimal cytogenetic response. Median duration of MaHR was 1.7 months (range 1.7–4.9 months). Median survival was 3.5 months (95% CI 2.2–4.5); in 4 patients with MaHR, median survival was not reached as of >1 year of follow-up by Kaplan-Meier analysis (95% CI 2.4 to not reached) versus 3.5 months (95% CI 2.2–3.9) in patients without MaHR (Figure). Median time to disease progression was 2.2 months (95% CI 1.5–2.9). Grade 3/4 laboratory hematologic toxicities included thrombocytopenia (43/44 patients), anemia (36/44), neutropenia (36/44), and leukopenia (29/44), with most of the thrombocytopenia and neutropenia toxicities occurring in earlier cycles and attenuating in later cycles. The most common (≥5%) grade 3/4 nonhematologic AEs were hypercalcemia and bone pain (4/44 each), followed by confusional state (3/44). The most common reasons for discontinuation were progressive disease (21 patients) and death (14 patients); 2 patients discontinued due to AEs. One patient discontinued due to transfer for stem cell transplantation (7 cycles received on study over 6.7 months). Nineteen deaths occurred on study and 19 during follow-up; disease progression was the most common cause (25/38). One death was deemed related to the study drug (sepsis). Conclusions Among heavily pretreated patients with CML-BP who had failed prior TKI therapy, omacetaxine demonstrated limited activity, although 13% of patients had hematologic improvement, 2 patients had responses with duration longer than one year. Most grade 3/4 events were hematologic; grade 3/4 nonhematologic AEs were less common. Support: Teva Pharmaceutical Industries Ltd. Disclosures: Off Label Use: Subcutaneous omacetaxine mepesuccinate (“omacetaxine”) is a protein synthesis inhibitor that does not depend on direct binding of Bcr-Abl. Omacetaxine has shown clinical activity in 2 studies of chronic myeloid leukemia (CML), one in patients with a history of the T315I Bcr-Abl mutation and the other in patients failing at least 2 tyrosine kinase inhibitors. Cortes:Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Chemgenex (Teva): Consultancy, Research Funding; Deciphera: Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding. Wetzler:BMS: Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees. Baccarani:Teva: Research Funding. Douer:Teva: Consultancy. Craig:Teva: Consultancy. Kantarjian:ChemGenex (Teva): Research Funding. Akard:Celgene: Research Funding, Speakers Bureau; Millenium: Speakers Bureau; Eisai: Speakers Bureau; Pfizer: Research Funding; Merck: Research Funding; Ariad: Research Funding; Teva: Research Funding; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau.

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Results of Dasatinib Therapy in Patients With Early Chronic-Phase Chronic Myeloid Leukemia

Journal of Clinical Oncology ◽

10.1200/jco.2009.25.4920 ◽

2010 ◽

Vol 28 (3) ◽

pp. 398-404 ◽

Cited By ~ 165

Author(s):

Jorge E. Cortes ◽

Dan Jones ◽

Susan O'Brien ◽

Elias Jabbour ◽

Farhad Ravandi ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Chronic Phase ◽

Cytogenetic Response ◽

Initial Therapy ◽

Molecular Response ◽

Nonhematologic Toxicity ◽

Significant Difference ◽

Grade 3

PurposeDasatinib is effective therapy for chronic myeloid leukemia (CML) after imatinib failure. In this study, we investigate the efficacy of dasatinib as initial therapy for patients with CML in early chronic phase.Patients and MethodsPatients with newly diagnosed CML in early chronic phase were randomly assigned to receive dasatinib 100 mg once daily or 50 mg twice daily as initial therapy.ResultsAmong 50 patients observed for at least 3 months, 49 patients (98%) achieved a complete cytogenetic response (CCyR), and 41 patients (82%) achieved a major molecular response (MMR). Responses occurred rapidly, with 94% of patients achieving CCyR by 6 months. There was no difference in response rate by treatment arm. The projected event-free survival rate at 24 months is 88%, and all patients are alive after a median follow-up time of 24 months. Grade ≥ 3 neutropenia and thrombocytopenia occurred in 21% and 10% of patients, respectively. Nonhematologic toxicity was usually grade 1 to 2. There was no significant difference in toxicity between the two arms, and the actual median dose at 12 months was 100 mg (range, 20 to 100 mg).ConclusionDasatinib is an effective agent for the initial management of CML in early chronic phase, producing high rates of CCyR and MMR.

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Efficacy and Safety of Radotinib Compared with Imatinib in Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia Patients: 12 Months Result of Phase 3 Clinical Trial

Blood ◽

10.1182/blood.v126.23.476.476 ◽

2015 ◽

Vol 126 (23) ◽

pp. 476-476 ◽

Cited By ~ 5

Author(s):

Jae-Yong Kwak ◽

Hawk Kim ◽

Jeong A Kim ◽

Young Rok Do ◽

Hyeoung Joon Kim ◽

...

Keyword(s):

Myeloid Leukemia ◽

Research Funding ◽

Blast Crisis ◽

Chronic Phase ◽

Cytogenetic Response ◽

Molecular Response ◽

Newly Diagnosed ◽

Phase 3 ◽

Grade 3

Abstract Background Radotinib is a second generation BCR-ABL1 tyrosine kinase inhibitor (TKI) developed by IL-YANG Pharm. Co., Ltd (Seoul, South Korea) and approved by the Korea FDA for the treatment of chronic phase chronic myeloid leukemia (CML-CP) patients who have failed prior TKIs. We conducted the randomized, open-label, phase 3 study to assess the efficacy and safety of radotinib, as compared with imatinib, for the first-line treatment of newly diagnosed CML-CP. Methods Based on baseline demographics and Sokal risk score, 241 patients were randomized 1:1:1 to radotinib 300 mg twice daily (bid) (n=79), radotinib 400 mg bid (n=81), or imatinib 400 mg once daily (qd) (n=81). The primary endpoint was the rate of major molecular response (MMR) by 12 months and molecular response was assessed by RQ-PCR at baseline and every 3 months. Secondary endpoints were the rate of complete cytogenetic response (CCyR), MR4.5 by 12 months, and the rate of progression to accelerate phase or blast crisis. Results All three study groups were well balanced with baseline age, gender, race and Sokal risk score. With minimum follow-up of 12 months, the proportions of patients receiving a study drug were 86.3% (69/79) in radotinib 300 mg bid group, 71.6% (58/81) in radotinib 400 mg bid group, and 81.5% (66/81) in imatinib 400 mg qd group. By 12 months, rates of MMR were significantly higher in patients receiving radotinib 300 mg bid (51.9%, P = .0044) and radotinib 400 mg bid (45.7%, P = .0342) compared with imatinib (29.6%). The median time to MMR among responders were shorter on radotinib 300 mg bid (5.7 months) and radotinib 400 mg bid (5.6 months) than imatinib group (8.2 months). The MR4.5 rates by 12 months were also higher for both radotinib 300 mg bid (15.2%) and 400 mg bid (13.6%) compared to imatinib (8.6%). The CCyR rates by 12 months were also higher for radotinib 300 mg bid (91.1%, P = .0120) compared with imatinib (76.5%). There was no progression to accelerated phase or blast crisis in all groups by 12 months. Discontinuation due to adverse events (AEs) or laboratory abnormalities occurred in 7 (8.8%), 16 (19.8%), and 5 (6.2%) patients for radotinib 300 mg bid, radotinib 400 mg bid and imatinib, respectively. Grade 3/4 thrombocytopenia occurred in 16.5% of patients receiving radotinib 300 mg bid, in 13.6% for radotinib 400 mg bid, and in 19.8% receiving imatinib. And grade 3/4 neutropenia occurred in 19.0%, 23.5%, and 29.6% for radotinib 300 mg bid, 400 mg bid and imatinib, respectively. The most common any grade non-laboratory AEs were skin rash (35.4% and 33.3%), nausea/vomiting (22.8% and 23.5%), headache (19.0% and 30.9%), and pruritus (19.0% and 30.0%) in radotinib 300 mg bid and radotinib 400 mg bid, respectively; AEs in the imatinib group were edema (34.6%), myalgia (28.4%), nausea/vomiting (27.2%), and skin rash (22.2%). Overall, grade 3/4 non-laboratory AEs were uncommon in all groups. Conclusions With minimum 12 months follow-up, radotinib demonstrated significantly higher and faster rates of CCyR and MMR than imatinib in patients with newly diagnosed CML-CP. The safety profiles of the radotinib and imatinib were different, and most AEs were manageable with optimal dose reduction. The results of this trial support that radotinib can be one of the standard of care in newly diagnosed CML-CP. Table. Baseline Characteristics, Molecular and Cytogenetic Response Rates Radotinib 300mg BID Radotinib 400mg BID Imatinib 400mg QD (N=79) (N=81) (N=81) Age, median (range), years 45 (20-75) 43 (18-84) 45 (18-83) Gender, n (%) Male 52 (65.8) 47 (58.0) 52 (64.2) Female 27 (34.2) 34 (42.0) 29 (35.8) Sokal risk, n (%) Low 21 (26.6) 22 (27.2) 22 (27.2) Intermediate 38 (48.1) 38 (46.9) 39 (48.2) High 20 (25.3) 21 (25.9) 20 (24.7) MMR by 12 months, % 51.9 45.7 29.6 P = .0044 P = .0342 Cumulative Incidence of MMR by 12 months¢Ó, % 57.0 58.0 35.0 P = .0040 P = .0037 MR4.5 by 12 months, % 15.2 13.6 8.6 CCyR by 12 months, % 91.1 81.5 76.5 ¢Ó Kaplan-Meier estimates of MMR Disclosures Kim: IL-YANG Pharm. Co. Ltd: Research Funding. Kim:Alexion Pharmaceuticals: Research Funding. Chung:Alexion Pharmaceuticals: Research Funding. Choi:Alexion Pharmaceuticals: Research Funding.

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Efficacy of Ponatinib after Multiple Lines of Therapy for Chronic Myeloid Leukemia

Blood ◽

10.1182/blood-2018-99-119914 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3013-3013

Author(s):

Mahesh Swaminathan ◽

Hagop M. Kantarjian ◽

Koji Sasaki ◽

Farhad Ravandi ◽

Gautam Borthakur ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Median Time ◽

Myeloid Leukemia ◽

Research Funding ◽

Chronic Phase ◽

Cytogenetic Response ◽

Molecular Response ◽

Genetics Research ◽

Line Therapy ◽

Line Of Therapy

Abstract Background: Ponatinib, a third-generation pan-tyrosine kinase inhibitor (TKI), was found to be effective in heavily pretreated patients (pts) with chronic myeloid leukemia (CML). With the availability of multiple TKI, these agents are used in different sequences, and there is limited information on the value of various TKI in different lines of therapy. Since ponatinib has been effective in 3rd and subsequent lines of therapy, we performed an analysis of a cohort of pts with CML who received ponatinib as a different line of treatment. Method: A total of 80 pts with chronic phase of CML and received ponatinib from 2009 to 2018 were analyzed. Only pts who received ponatinib as a second or subsequent line of therapy of CML were included. Major cytogenetic response (MCyR), complete cytogenetic response (CCyR), major molecular response (MMR), molecular response (MR) 4, and MR 4.5 were assessed. Event-free (EFS), transformation-free (TFS), failure-free (FFS) and overall survival (OS) were also analyzed. Results: Nine pts (11%) received ponatinib as a 2nd line therapy (prior TKI imatinib in 6, dasatinib in 1, and nilotinib in 2 pts); 21 (26%) as a 3rd line, 26 (33%) as a 4th line, and 24 (30%) as a 5th and above line. The median age was over 50 years (Y) in all the groups except for pts who received ponatinib as a 3rd line [38 Y (23-76)]. Among pts who received ponatinib as 2nd line, 9 (100%) achieved CCyR and MR 4.5; the median time to achieve CCyR and MR 4.5 was 3 and 6.8 months (mo), respectively (Table 1). In pts treated in 3rd line CCyR and MR 4.5 were 67% and 57%, respectively and the median time to response was 4.8 and 19.3 mo, respectively. Of the 26 pts treated in 4th line, 13 (50%) achieved CCyR (median time to CCyR 3 mo) and 7 (27%) achieved MR 4.5 (median time 11.6 mo). In 5th line and above 14 (58%) achieved CCyR (median time 6.4 mo) and 8 (33%) achieved MR 4.5 (median time 12.3 mo) (Figure 1). After a median follow-up of 59.8 months (range, 4.7 to 114.3) for all pts, the median OS was not reached in pts treated in 2nd to 4th line and 81.4 mo in ≥5th line. The median FFS was not reached in 2nd line, and was 45.6, 20.2, and 17.8 mo in 3rd, 4th, and ≥5th line, respectively. The median EFS and TFS was not reached in any line of treatment. The TFS was significantly better in pts who received ponatinib as a 2nd-4th line therapy as compared to ≥5th [p=0.0026, HR-55.97 (4.076-768.7)] (Figure 2). Conclusion: Our results suggest that CCyR and MR 4.5 were higher when ponatinib was used in up to 4th line of therapy for resistant CML, and it was particularly effective in 2nd or 3rd line where high rates of MR4.5 can be achieved. These results underscore the efficacy of ponatinib in these settings. Disclosures Sasaki: Otsuka Pharmaceutical: Honoraria. Ravandi:Jazz: Honoraria; Macrogenix: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Abbvie: Research Funding; Jazz: Honoraria; Xencor: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Orsenix: Honoraria; Sunesis: Honoraria; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Astellas Pharmaceuticals: Consultancy, Honoraria; Sunesis: Honoraria; Orsenix: Honoraria; Macrogenix: Honoraria, Research Funding; Xencor: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau. Kadia:Takeda: Consultancy; Jazz: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy; Celgene: Research Funding; Takeda: Consultancy; Abbvie: Consultancy; Novartis: Consultancy; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Consultancy, Research Funding; Abbvie: Consultancy; BMS: Research Funding; Amgen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. DiNardo:Agios: Consultancy; Bayer: Honoraria; Medimmune: Honoraria; Karyopharm: Honoraria; Celgene: Honoraria; Abbvie: Honoraria. Konopleva:Stemline Therapeutics: Research Funding; abbvie: Research Funding; cellectis: Research Funding; Immunogen: Research Funding. Pemmaraju:stemline: Consultancy, Honoraria, Research Funding; cellectis: Research Funding; novartis: Research Funding; samus: Research Funding; plexxikon: Research Funding; daiichi sankyo: Research Funding; celgene: Consultancy, Honoraria; Affymetrix: Research Funding; SagerStrong Foundation: Research Funding; abbvie: Research Funding. Daver:ARIAD: Research Funding; BMS: Research Funding; Novartis: Research Funding; Incyte: Consultancy; Incyte: Research Funding; Karyopharm: Research Funding; Kiromic: Research Funding; Pfizer: Research Funding; Daiichi-Sankyo: Research Funding; Sunesis: Research Funding; Alexion: Consultancy; ImmunoGen: Consultancy; Karyopharm: Consultancy; Otsuka: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Sunesis: Consultancy. Wierda:Genentech: Research Funding; AbbVie, Inc: Research Funding. Jabbour:novartis: Research Funding. Cortes:novartis: Research Funding.

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Bosutinib As Therapy for Chronic Phase Chronic Myeloid Leukemia Following Resistance or Intolerance to Imatinib: 36-Month Minimum Follow-up Update

Blood ◽

10.1182/blood.v120.21.3779.3779 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3779-3779 ◽

Cited By ~ 1

Author(s):

Jorge E. Cortes ◽

Hagop M. Kantarjian ◽

Dong-Wook Kim ◽

Anna G Turkina ◽

Zhi-Xiang Shen ◽

...

Keyword(s):

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Chronic Phase ◽

Cytogenetic Response ◽

Baseline Assessment ◽

Advisory Committees ◽

Abl Kinase ◽

Grade 3

Abstract Abstract 3779 Bosutinib (BOS) is an oral, dual Src/Abl kinase inhibitor with minimal inhibitory activity against PDGFR or c-KIT. This open-label, phase 1/2 study evaluated BOS in patients (pts) with chronic phase chronic myeloid leukemia (CP CML) following imatinib resistance (IM-R) or intolerance (IM-I). Pts aged ≥18 y with IM-R (n = 195) or IM-I (n = 91) CP CML received oral BOS 500 mg/d. Of 286 pts, 53% were male, median age was 53 y (range, 18–91 y), and median time from CML diagnosis was 3.7 y (range, 0.1–15.1 y). Median treatment duration was 24.6 mo (range, 0.2–72.3 mo); median BOS dose intensity was 443 mg/d (range, 61–600 mg/d); 12% of pts received dose escalation to BOS 600 mg/d. Minimum time from last enrolled pt's first dose was 38 mo; 42% of pts are still receiving BOS. A confirmed complete hematologic response (CHR) was attained/maintained by 167/194 (86%) IM-R and 77/91 (85%) IM-I pts with a valid baseline assessment; Kaplan-Meier (KM)–estimated probabilities of maintaining a CHR at 3 y were 65% and 83%. A major cytogenetic response (MCyR) was attained/maintained by 106/182 (58%) IM-R and 49/82 (60%) IM-I pts with a valid baseline assessment. A complete cytogenetic response (CCyR) was attained/maintained by 88/182 (48%) and 42/82 (51%) evaluable pts. Among evaluable pts without a CCyR at baseline, 101/177 (57%) IM-R and 39/71 (55%) IM-I pts achieved a MCyR including 83 (47%) IM-R and 33 (47%) IM-I pts who achieved a CCyR. The KM-estimated probability of maintaining a MCyR at 3 y was 71% for IM-R and 88% for IM-I pts. Of 210 pts with baseline mutation status assessed, 78 (37%) pts had 42 unique Bcr-Abl kinase domain mutations (P loop, 9% of pts; non-P loop, 30% of pts), including 9 (4%) pts with the T315I mutation. Responses to BOS were seen across different Bcr-Abl baseline mutations, including those associated with resistance to other TKIs, but were low (22% for both CHR and MCyR) among pts with T315I. When pts with T315I at baseline were excluded, response rates for the remaining pts with ≥1 mutation were 93% for CHR and 62% for MCyR. Eighteen of 68 pts evaluated at baseline and treatment discontinuation had ≥1 new Bcr-Abl mutation (T315I, n = 8; V299L, n = 3; E255V, E450A, E450G, G250E, K378E, L273M, and M244V, n = 1 each); 15 of these 18 pts had discontinued due to disease progression or lack of efficacy. On-treatment transformation to accelerated or blast phase CML occurred in 10 (5%) IM-R and 2 (2%) IM-I pts. KM-estimated on-treatment progression-free survival (PFS) at 3 y was 72% for IM-R pts and 89% for IM-I pts. KM-estimated overall survival (OS) at 2 y was 88% for IM-R and 98% for IM-I pts (3-y OS not provided as results may be unreliable since per study protocol pts were followed for OS for only 2 y after BOS discontinuation). There were 34 (12%) deaths on study, with 5 deaths occurring within 30 d of the last BOS dose. Most deaths were due to disease progression (n = 17 [6%]) or an adverse event (AE) unrelated to BOS (n = 12 [4%]); only 1 treatment-related death occurred (due to febrile neutropenia 78 d after the last BOS dose in the IM-R group). Four additional deaths were due to unknown causes ≥136 d after the last BOS dose. The most frequent non-hematologic treatment-emergent AEs (TEAEs; all grades/grade 3/4) were diarrhea (85%/10%), nausea (46%/1%), vomiting (37%/4%), rash (36%/9%), pyrexia (26%/1%), abdominal pain (25%/1%), and fatigue (25%/1%). Diarrhea was predominantly grade 1/2 in severity, had an early onset (median time to first event of 2 d [range, 1–1,330 d]), and was typically transient (median event duration of 1 d [range, 1–830 d]). Grade 3/4 on-treatment hematologic and non-hematologic lab abnormalities in ≥10% of pts included thrombocytopenia (25%), neutropenia (18%), lymphocytopenia (16%), anemia (14%), hypermagnesemia (11%), alanine transaminase elevation (11%), and hypophosphatemia (10%). Toxicities were manageable with medications and/or BOS dose modification; 45% of IM-R and 57% of IM-I pts had ≥1 dose reduction, and 66% of IM-R and 84% of IM-I pts had ≥1 dose interruption. AEs led to BOS discontinuation in 32 (16%) IM-R and 37 (41%) IM-I pts; the most common reason was thrombocytopenia. Overall, the rates of TEAEs and BOS discontinuation due to AEs showed little increase from the prior 24-mo analysis. In conclusion, BOS therapy continues to demonstrate durable efficacy and manageable toxicity in pts with CP CML following IM-R or IM-I after a minimum of 36 mo of follow-up, emphasizing the therapeutic potential of BOS in this population. Disclosures: Cortes: Novartis, Bristol Myer Squibb, Pfizer, Ariad, Chemgenex: Consultancy, Research Funding. Kantarjian:Pfizer Inc: Research Funding. Kim:BMS, Novartis, Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Turkina:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Brümmendorf:Bristol Myer Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; Patent on the use of imatinib and hypusination: Patents & Royalties. Schafhausen:Bristol Myers Squibb, Novartis, Pfizer: Consultancy, Honoraria. Porkka:Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Leip:Pfizer Inc: Employment. Kelly:Pfizer Inc: Employment, Equity Ownership. Besson:Pfizer Inc: Employment. Gambacorti-Passerini:Pfizer Inc: Consultancy, Research Funding; Novartis, Bristol Myer Squibb: Consultancy.

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Bosutinib As Therapy For Chronic Phase Chronic Myeloid Leukemia Following Failure With Imatinib Plus Dasatinib and/Or Nilotinib: 36-Month Update

Blood ◽

10.1182/blood.v122.21.4025.4025 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4025-4025

Author(s):

Jorge E. Cortes ◽

H. Jean Khoury ◽

Hagop M. Kantarjian ◽

Jeff H. Lipton ◽

Dong-Wook Kim ◽

...

Keyword(s):

Disease Progression ◽

Board Of Directors ◽

Cumulative Incidence ◽

Research Funding ◽

Chronic Phase ◽

Cytogenetic Response ◽

Advisory Committees ◽

Mutation Status ◽

Grade 3

Abstract Bosutinib (BOS) is an oral dual Src/Abl tyrosine kinase inhibitor (TKI). This open-label, phase 1/2 study evaluated BOS in patients (pts) with chronic phase chronic myeloid leukemia (CP CML) following TKI failure. Pts (n=118) aged ≥18 y with prior imatinib (IM) failure plus dasatinib (D) resistance (D-R; n=38) or intolerance (D-I; n=50), nilotinib (N) resistance (N-R; n=26), or N-I or D-R/I + N-R/I (n=4) received BOS starting at 500 mg/d. Median (range) age was 56 (20–79) y; time from CML diagnosis was 6.6 (0.6–18.3) y; follow-up duration was 33.1 (0.3–84.8) mo; BOS treatment duration was 8.5 (0.2–78.1) mo. Escalation to BOS 600 mg/d occurred in 21 (18%) pts. For the last enrolled pt, time from first dose was ≥36 mo; 19% are still receiving BOS. Confirmed complete hematologic response (CHR) was newly attained or maintained from baseline by 73% of pts (Table). Major cytogenetic response (MCyR) was attained/maintained by 40% of pts (32% with complete cytogenetic response [CCyR]). Kaplan-Meier probability of maintaining CHR or MCyR at 3 y was 65%.IM + D-R (n=38)IM + D-I (n=50)IM + N-R (n=26)IM + N-I or D-R/I + N-R/Ia (n=4)Total (n=118)Evaluable,b n3849254116Confirmed CHR, n (%)26 (68)37 (76)19 (76)3 (75)85 (73)Probability of maintaining CHR at 3 yc57%74%62%NR65%Evaluable,b n3645254110MCyR, n (%)14 (39)19 (42)9 (36)2 (50)44 (40)CCyR , n (%)8 (22)18 (40)7 (28)2 (50)35 (32)Probability of maintaining MCyR at 3 yc29%87%75%NR65%Treated, n3850264118PD/death at 3 yd26%16%35%NR25%OS at 2 yc80%83%92%NR84%D=dasatinib; I=intolerant; IM=imatinib; N=nilotinib; NR=not reported (small sample size); OS=overall survival; PD=progressive disease; R=resistant.aIncludes 3 pts with prior exposure to all 3 TKIs and 1 N-I pt.bReceived ≥1 BOS dose and had a valid baseline efficacy assessment for the respective endpoint.cBased on KM estimates.dBased on cumulative incidence adjusting for competing risk of treatment discontinuation without PD or death. Of 85 pts with known baseline mutation status, 19 unique BCR-ABL mutations occurred in 39 (46%) pts, including 7 (8%) with T315I. Responses were seen across mutations, but were low in pts with T315I (29% CHR; 14% MCyR). In pts with ≥1 mutation, excluding T315I, 75% had CHR and 40% had MCyR. 38 pts had known baseline and end of treatment mutation status; 8/38 had ≥1 new mutation (V299L, n=4; T315I, n=2; F359C, G250E, L248V, n=1 each); 7/8 discontinued BOS due to disease progression or lack of efficacy. Cumulative incidence of on-treatment transformation to accelerated-phase (AP) CML at 3 y was 4%; 77% discontinued without transformation. No pt transformed to blast-phase (BP); no transformations occurred after 2 y. Cumulative incidence of on-treatment progression (transformation to AP/BP CML, increasing white blood cell count [doubling over ≥1 mo with 2nd count >20×109/L and confirmed ≥1 wk later], or loss of confirmed CHR or unconfirmed MCyR) or death at 3 y was 25%; 55% of pts discontinued without an event. Overall survival (OS) at 2 y was 84% (Table; 3-y OS estimates unreliable; pts followed for OS for only 2 y after BOS discontinuation]). Overall, 96 (81%) pts discontinued treatment, the most common primary reasons were adverse event (AE; n=29 [25%]), disease progression (n=25 [21%]), or unsatisfactory efficacy (n=23 [19%]). 26 (22%) deaths occurred on study, 5 within 30 d of last BOS dose. Most deaths were due to disease progression (n=11 [9%]) or AE (n=11 [9%], including 1 death reported as treatment-related due to lower gastrointestinal bleeding). 4 deaths had unknown cause 33–615 d after the last BOS dose. Non-hematologic treatment-emergent AEs in ≥20% of pts (all grades; grade 3/4) were diarrhea (83%; 9%), nausea (48%; 1%), vomiting (38%; 1%), rash (27%; 3%), headache (26%; 3%), fatigue (23%; 2%), and abdominal pain (24%; 1%); common hematologic toxicities included thrombocytopenia (38%; 26%), neutropenia (20%; 15%), and anemia (19%; 7%). Cardiac events occurred in 15% of pts (8% grade 3/4). Grade 3/4 laboratory abnormalities in ≥10% of pts were thrombocytopenia (26%), neutropenia (20%), lymphopenia (16%), and hypermagnesemia (12%). 78 (66%) pts had ≥1 dose delay; 59 (50%) had ≥1 dose reduction. 31 (26%) pts discontinued BOS due to AE, most commonly thrombocytopenia (7%). BOS continues to demonstrate durable efficacy and manageable toxicity after ≥36 mo follow-up in CP-CML pts following resistance or intolerance to multiple TKIs. Disclosures: Cortes: Pfizer: Consultancy, Research Funding; Novartis: Research Funding; Bristol Myer Squibb: Research Funding; Teva: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Kantarjian:Pfizer Inc: Research Funding. Lipton:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squib: 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. Kim:Pfizer: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Conlan:Pfizer Inc: Employment. Leip:Pfizer Inc: Employment. Turnbull:Pfizer Inc: Employment. Brümmendorf:Ariad: Consultancy; Patent on the use of imatinib and hypusination inhibitors: Patents & Royalties; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria. Gambacorti-Passerini:Bristol Myer Squibb: Consultancy; Pfizer Inc: Consultancy, Research Funding; Novartis: Consultancy.

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Nilotinib in Chronic Myeloid Leukemia Patients in Accelerated Phase (CML-AP) with Imatinib Resistance or Intolerance: 2-Year Follow-up Results of a Phase 2 Study

Blood ◽

10.1182/blood.v112.11.3229.3229 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3229-3229 ◽

Cited By ~ 11

Author(s):

Philipp D. le Coutre ◽

Francis Giles ◽

Andreas Hochhaus ◽

Jane F. Apperley ◽

Gert Ossenkoppele ◽

...

Keyword(s):

Overall Survival ◽

Chronic Myeloid Leukemia ◽

Adverse Events ◽

Myeloid Leukemia ◽

Cytogenetic Response ◽

Phase 2 ◽

Time To Progression ◽

Phase 2 Study ◽

Grade 3

Abstract Background: Nilotinib is a rationally designed, potent and highly selective BCR-ABL kinase inhibitor, and binds to ABL with higher affinity and improved topological fit compared to imatinib. Nilotinib is approved for the treatment of patients (pts) with Philadelphia chromosome-positive chronic myeloid leukemia pts in chronic (CML-CP) or accelerated phase (CML-AP) resistant or intolerant to prior therapy including imatinib. Methods: This open-label, single-arm, phase 2 study was designed to evaluate the efficacy and safety of nilotinib in CML-AP pts who are resistant or intolerant to imatinib. Nilotinib was dosed at 400 mg twice daily with the option to dose escalate to 600 mg twice daily for lack of response. The primary endpoint was confirmed hematologic response (HR). Complete hematologic response (CHR) was defined as meeting all of the following criteria: myeloblast count <5% in bone marrow, no myeloblast in peripheral blood, neutrophil count ≥1.5 × 109/L, platelet count ≥100×109/L, basophils <5%, no evidence of extramedullary involvement. Secondary endpoints included major cytogenetic response (MCyR), time to progression, overall survival, and safety. Results: A total of 138 CML-AP pts (80% imatinib resistant; 20% imatinib intolerant) who received at least 1 dose of nilotinib were included in the analysis. Median age was 57 years (range, 22–82 years); median duration of prior imatinib treatment was 28 months. Seventy-nine percent of pts received prior imatinib doses ≥600 mg/day; overall, 45% received ≥800 mg/day imatinib. Median dose intensity of nilotinib was near planned dose at 775 mg/day with a median duration of exposure of 253 days (8.4 months). Of 134 pts with at least 6 months of follow-up included in the efficacy analysis, 56% had confirmed HR and 30% had CHR. Responses were rapid, with a median time to first HR of 1 month. Hematologic responses were durable at 1 year, with 78% of pts who achieved HR maintaining their response. MCyR and complete cytogenetic response (CCyR) occurred in 32% and 19% of pts, respectively. Cytogenetic responses were also durable, with 69% of pts maintaining MCyR at 18 months. Median time to progression was 16 months in this population of pts with advanced disease. Progression was defined as any of the following: investigator’s evaluation as progression, development of CML-AP or blast crisis, loss of CHR, loss of MCyR. Estimated overall survival at 1 year is 82%. Longer follow-up has not significantly changed the safety profile of nilotinib. The most frequently reported grade 3/4 laboratory abnormalities were thrombocytopenia (40%), neutropenia (40%), anemia (25%), elevated serum lipase (17%), and hypophosphatemia (12%). Grade 3/4 non-hematologic adverse events were uncommon (<1%) and included rash, nausea, fatigue, and diarrhea. Brief dose interruptions were sufficient to manage most adverse events. Conclusions: The long-term follow-up results of this phase 2 study confirm that nilotinib induces rapid and durable responses in pts with CML-AP who failed prior imatinib therapy due to intolerance or resistance, with a favorable toxicity profile.

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Dasatinib Is Well-Tolerated and Efficacious in Imatinib-Intolerant Patients with Chronic-Phase Chronic Myeloid Leukemia (CP-CML).

Blood ◽

10.1182/blood.v114.22.1128.1128 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1128-1128 ◽

Cited By ~ 2

Author(s):

Hanna Jean Khoury ◽

Michael J. Mauro ◽

Yousif Matloub ◽

Tai-Tsang Chen ◽

Erkut Bahceci ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Median Duration ◽

Myeloid Leukemia ◽

Research Funding ◽

Kinase Inhibitor ◽

Chronic Phase ◽

Phase Iii ◽

Hematologic Toxicity ◽

Molecular Response

Abstract Abstract 1128 Poster Board I-150 Imatinib (IM), a tyrosine kinase inhibitor (TKI), has been the mainstay of treatment for chronic phase chronic myeloid leukemia (CP-CML). However, IM resistance and intolerance are of considerable clinical relevance. Dasatinib (DAS), a second-line TKI, is effective in the IM-intolerant patient population. The purpose of this study was to determine baseline factors that can affect DAS response and evaluate long term efficacy in this population. Intolerance to IM was defined as ≥ Grade 3 non-hematologic toxicity and/or Grade 4 hematologic toxicity lasting > 7 days. A total of 271 Ph+ CP-CML IM-intolerant patients who received DAS were pooled from two randomized trials (Phase II-trial, CA 180013 and Phase III trial, CA 180034). DAS doses were 50 mg BID (n=43), 70 mg BID (n=141), 100 mg QD (n=43) or 140 mg QD (n=44). At baseline, the median duration of disease for the IM-intolerant patients was 24 months (range: 0.9-182.5) and the median duration of IM therapy was 9 months (range: 0.03-69.06). Of these patients, 46 (17%) had hematologic toxicity and 228 (84.1%) had non-hematologic toxicity to IM. Seventy-nine (29%) patients had prior complete cytogenetic response (CCyR) on IM and 171 (63%) patients did not. The data for prior CyR to IM was not reported for 21 (7.7%) patients. Of the 79 patients who had achieved CCyR on IM, 30 patients had maintained CCyR and 49 patients had lost this response prior to start of DAS. Of the 171 patients who did not achieve CCyR on IM, 62 (36.3%) had been on IM for 3 12 months and 109 (63.7%) for < 12 months. At 2-year follow up of the 271 patients treated with DAS, 121 (44.6%) discontinued DAS (7.4% due to hematologic toxicity and 14% due to non-hematologic toxicity). Of the patients who were intolerant of IM due to hematologic toxicity (n=46), 10 (21.7%) discontinued DAS due to hematologic toxicity, and 3 (6.5%) due to other toxicities. Of the patients with non-hematologic IM-intolerance (n=228), 10 (4.4%) discontinued DAS due to hematologic toxicity, and 35 (15.4%) due to other toxicities. The median average daily dose of DAS was 99 mg/day in the population who achieved CCyR on DAS and 71.5 mg/day in the population who did not achieve CCyR on DAS. The probability of achieving CCyR on DAS was 43.5% in patients with hematologic IM-intolerance versus 78.9% with non-hematologic IM-intolerance. The CCyR, major molecular response (MMR), progression-free survival (PFS) and overall survival (OS) at 2-year follow up for the groups classified by their CCyR status at start of DAS or IM-intolerance status are summarized in Table 1. Conclusions DAS was well-tolerated and associated with high rates of CyR in IM-intolerant patients. Patients with a prior CCyR to IM and those who switched due to non-hematologic imatinib-intolerance had the highest rates of CCyR and MMR on DAS, while patients without CCyR after more than 12 months of IM therapy or IM-intolerance due to hematologic toxicity had the lowest rates of CCyR and MMR. Disclosures Khoury: BMS: Honoraria; Wyeth: Honoraria; Novartis Pharmaceuticals: Honoraria; Chemgenex: Honoraria; Genzyme: Honoraria. Mauro:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding. Matloub:Bristol-Myers Squibb: Employment. Chen:Bristol-Myers Squibb: Employment. Bahceci:Bristol-Myers Squibb: Employment. Deininger:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Calistoga: Research Funding; Genzyme: Research Funding.

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