Intolerant Chronic-phase Chronic Myeloid Leukemia Research Articles

Flumatinib for the Treatment of Adult Patients with Resistant or Intolerant Chronic-Phase Chronic Myeloid Leukemia: Results from Real-World Data

Introduction Over the past decades, BCR-ABL1 tyrosine kinase inhibitors (TKIs) as the initial treatment for chronic phase Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML-CP) have dramatically turned CML-CP into a manageable and potentially curable chronic disease. Nonetheless, in spite of the massive improvement in CML treatment over the last years with the introduction of TKIs, some patients (20%-30%) display intrinsic or acquired resistance to treatment during the disease course. Flumatinib Mesylate is a newer and orally available TKI with higher selectivity and potency against BCR-ABL1 kinase versus imatinib. According to the previous data，flumatinib can be an effective first-line treatment for CML-CP. Patients and Methods This study was initiated mainly to observe the safety and efficacy of flumatinib in the treatment of adult patients with resistant or intolerant Chronic-Phase Chronic Myeloid Leukemia, especially in second-line or above treatment in the real world. Efficacy and safety assessments were collected for the intent-to-treat population. Major molecular response (MMR) was defined as BCR-ABL1 transcript level ≤ 0.1% on the International Scale (IS), molecular response (MR4) was defined as BCR-ABL1 transcript level (IS) ≤ 0.01%; MR4.5 was defined as a BCR-ABL1 (IS) transcript level ≤ 0.0032%. DMR was defined as MR 4.0 or MR 4.5. Results Among the 58 evaluable patients with CML-CP, 54% were male, 47% were female. The median age of these patients is 45Y. During the observation period, there were 28 second-line conversion patients (48%), 19 third-line conversion patients (33%), and 11 fourth-line and above patients (19%). Prior therapies included imatinib, dasatinib, nilotinib, olverembatinib, radotinib and ponatinib. All patients converted to treatment of 600mg flumatinib daily. Among the 58 evaluable patients, 20 patients who had been treated with imatinib alone were converted to flumatinib, including 9 cases of IM resistance, 8 cases of IM intolerance and 2 case of personal reasons. During the 1-year follow-up, 52% of patients (n=30) were evaluable for the achievement of MMR. The patients with BCR-ABL1 (IS) > 10% at baseline, 3, 6 and 12 months were 48%, 17%, 23% and 26%, respectively; for patients with BCR-ABL1 (IS) < 0.1% were 26%, 40%, 49% and 52%, respectively; for patients with DMR were 26%, 40%, 49% and 52%, respectively. For imatinib-intolerant or -resistant patients, MMR was 44%. Subgroup analyses showed that the imatinib-intolerant or -resistant patients with BCR-ABL1 (IS) >10% at baseline, 3, 6 and 12 months were 65%, 0%, 10% and 0%, respectively; for patients with BCR-ABL1 (IS) < 0.1% were 10%, 33%, 80% and 44%, respectively; for patients with DMR were 5%, 11%, 30% and 11%, respectively. Meanwhile, 11% of patients could not be detected at molecular level (0.000%). Of the 58 patients, only Grade 1 AEs were reported, including diarrhea, rash and eye edema. Conclusion Flumatinib has good efficacy and safety in the treatment of adult patients with resistant or intolerant Chronic-Phase Chronic Myeloid Leukemia, it will be a good choice for second-line or above treatment for CML-CP In clinical practice.

Ponatinib for the treatment of adult patients with resistant or intolerant Chronic-Phase Chronic Myeloid Leukemia

ABSTRACT Introduction Patients with chronic myeloid leukemia in chronic phase (CP-CML) who are resistant or intolerant to second-generation tyrosine kinase inhibitors (TKIs) may benefit from treatment with a third-generation TKI, like ponatinib. Areas covered In this review, the authors discuss the role of ponatinib, an oral pan-inhibitor of BCR-ABL1, with potent activity in heavily pretreated patients, including T315I mutation. In the long-term follow-up of the PACE trial, 60% of patients with prior TKIs exposure achieved a major cytogenetic response with ponatinib and 40% a major molecular response; 5-year overall survival was 73%. Cardiovascular adverse events represent the major toxicity associated with ponatinib. Adopting a dose-reduction approach appeared to be safe: starting with 45 or 30 mg and decreasing to 15 mg once BCR-ABL1/ABL1≤1% is achieved. In patients who are not candidates for ponatinib therapy, asciminib or other novel TKIs like HQP1351, represent alternative options. Expert opinion In patients with CP-CML resistant or intolerant to second-generation TKIs, we favor using a third-generation TKI such as ponatinib. Although we initiate a donor search as soon as a patient fails a second-generation TKI, we still prefer treating patients with ponatinib and will only consider transplantation in the event of no response or disease progression.

Dose Modification Dynamics of Ponatinib in Patients with Chronic-Phase Chronic Myeloid Leukemia (CP-CML) from the PACE and Optic Trials

Dose Modification Dynamics of Ponatinib in Patients with Chronic-Phase Chronic Myeloid Leukemia (CP-CML) from the PACE and Optic Trials

Efficacy and Safety of Ponatinib (PON) in Patients with Chronic-Phase Chronic Myeloid Leukemia (CP-CML) Who Failed One or More Second-Generation (2G) Tyrosine Kinase Inhibitors (TKIs): Analyses Based on PACE and Optic

Efficacy and Safety of Ponatinib (PON) in Patients with Chronic-Phase Chronic Myeloid Leukemia (CP-CML) Who Failed One or More Second-Generation (2G) Tyrosine Kinase Inhibitors (TKIs): Analyses Based on PACE and Optic

Seven-Year (yr) Follow-up of Patients (pts) with Imatinib-Resistant or -Intolerant Chronic-Phase Chronic Myeloid Leukemia (CML-CP) Receiving Dasatinib in Study CA180-034, Final Study Results

Background: Dasatinib is a potent BCR-ABL tyrosine kinase inhibitor (TKI) currently approved at 100 mg once daily (QD) as a first-line therapy in CML-CP pts and a second-line therapy in pts with CML resistant/intolerant to prior therapy. CA180-034 (NCT00123474), a prospective, randomized phase 3 study, was designed to compare the dose and schedule of dasatinib therapy for the optimal benefit/risk ratio among pts with imatinib-resistant or -intolerant CML-CP. Results from this study have previously demonstrated significant efficacy of dasatinib in this pt population. Here, we report the final 7-yr analysis of efficacy and safety outcomes of CA180-034, which represents the longest follow-up of any second-generation BCR-ABL TKI to date. Methods: The CA180-034 2 X 2 factorial study design has previously been described (Shah 2010, J Clin Oncol). Pts (n=670) were randomized to dasatinib: 100 mg QD (n=167), 50 mg twice daily (BID; n=168), 140 mg QD (n=167), or 70 mg BID (n=168). To manage inadequate response or adverse events (AEs), dose escalation (up to a total daily dose [TDD] of 180 mg) and dose interruption or reduction (down to a TDD of 20 mg) were allowed. After 2 yrs, the protocol was amended to allow switching to a QD regimen with the same TDD after at least one dose reduction for recurrent anemia, thrombocytopenia, neutropenia, pleural effusion, or any other fluid retention during study progress or at the investigator’s discretion (Shah 2014, Blood). Results: Approximately 55% (50 mg BID) and 51% (70 mg BID) of pts treated after the protocol amendment switched to QD dosing by the last recorded dose. The overall median duration of therapy was longer for the 100 mg QD group (37.4 months [mos]) compared with the 50 mg BID, 140 mg QD, and 70 mg BID groups (28.1 mos, 26.6 mos, and 28.9 mos, respectively).At 7 yrs of follow-up, progression-free survival (PFS) andoverall survival (OS) rates were similar for all doses, as were the proportions of pts with a best on-study molecular response of MMR (Table 1). In an exploratory landmark analysis, pts in the 100 mg QD arm with BCR-ABL ≤10% (on the International Scale) at 3 mos had improved PFS and OS rates at 7 yrs relative to pts with BCR-ABL>10% (Table 2). BCR-ABL mutations were assessed in pts prior to the start of dasatinib (baseline), at the time of disease progression, or at end of treatment. Three mutations persisted or developed in pts who discontinued dasatinib due to loss of response on 100 mg QD: V299L (n=3), T315I (n=6), and F317L (n=7). For 100 mg QD, most nonhematologic and hematologic AEs (all grades) typically first occurred within the first 24 mos of treatment. Rates of nonhematologic AEs (all grades) over 7 yrs for 100 mg QD compared with other treatment arms included fluid retention (51% vs 54%), diarrhea (42% vs 47%), nausea/vomiting (27% vs 43%), myalgias/arthralgias (38% vs 33%), fatigue (37% vs 34%), and rash (33% vs 36%). Within yr 7 of the study, new cases of pleural effusion occurred in 5% (2/42) of pts at risk treated with dasatinib 100 mg QD compared with 8% (7/88) in other treatment arms. Severe (grade 3–4) AEs (any relationship) occurred less frequently in the 100 mg QD group (98/165, 59%) relative to other treatment arms (341/497, 69%). Three pts died due to study drug toxicity (1 due to sepsis; 1 due to pulmonary edema, congestive heart failure, neck pain, and pleural effusion; 1 due to necrosis of the colon). Conclusions: Long-term follow-up of dasatinib continues to demonstrate durable efficacy and benefit for pts with CML-CP following imatinib therapy, particularly if achieving BCR-ABL ≤10% at 3 mos. Dasatinib is well-tolerated amongst pts, with most AEs occurring early on during the course of treatment; however, pleural effusion did occur through 7 yrs of treatment. No new safety signals were detected. Disclosures Shah:ARIAD: Research Funding; Bristol-Myers Squibb: Research Funding. Rousselot:Bristol-Myers Squibb: Consultancy, Research Funding. Schiffer:Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Ariad: Research Funding; Teva: Membership on an entity9s Board of Directors or advisory committees; Pfizer: DSMB Other. Rea:Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Ariad: Honoraria. Cortes:Ariad: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Consultancy, Research Funding. Milone:Roche: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau. Mohamed:BMS: Employment. Healey:Bristol-Myers Squibb: Employment. Kantarjian:ARIAD: Research Funding; Pfizer: Research Funding; Amgen: Research Funding. Hochhaus:Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Ariad: Research Funding; MSD: Research Funding. Saglio:BMS: Consultancy, Fees for occasional speeches Other; Novartis: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; Pfizer: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; ARIAD: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other.

ABCDE steps to prevent heart disease in breast cancer survivors.

Breast cancer is the most common invasive cancer diagnosed in women. Of every 8 women, 1 woman is diagnosed with breast cancer in her lifetime. In 2013, more than 230 000 women were diagnosed with breast cancer in the United States alone, resulting in nearly 40 000 deaths. Breast cancer can also occur in men, although the incidence is much lower, with a total of 2240 men diagnosed in 2013 (accounting for less than 1% of all breast cancers). Over the past 2 decades, death resulting from breast cancer has been declining each year. This decrease in mortality is due in part to improvements in cancer treatment. These treatments have come about as a result of collaborations among physicians in various specialties. These physicians include medical oncologists (who give systemic treatments like chemotherapy and hormonal therapy), surgeons (who perform surgery such as mastectomy and lumpectomy), and radiation oncologists (who treat patients with radiation therapy). Radiation therapy, in particular, has increasingly become an important part of management of most patients with breast cancer. Radiation therapy has been demonstrated not only to prevent recurrence of cancer in the breast or chest wall area but also to improve long-term survival in women. In addition, radiation therapy allows women to undergo a less radical form of surgery in which the breast tissue is conserved, thus improving body image for breast cancer survivors without compromising survival. As a result of this progress in treatment and improved detection of early breast cancer, in 2012, there were nearly 3 million breast cancer survivors in the United States alone, a number that will increase in the coming years. Women who survive breast cancer may face many health challenges, but the number 1 cause of death in breast cancer survivors (and, in fact, all women) remains heart disease. Unfortunately, although systemic …

Long-term outcome with dasatinib after imatinib failure in chronic-phase chronic myeloid leukemia: follow-up of a phase 3 study

AbstractWe present long-term follow-up of a dasatinib phase 3 study of patients with imatinib-resistant/-intolerant chronic myeloid leukemia (CML). In the CA180-034 study, 670 patients with imatinib-resistant/-intolerant CML in chronic phase (CML-CP) received dasatinib 100 mg once daily, 50 mg twice daily, 140 mg once daily, or 70 mg twice daily. At 6 years, 188 (28%) of 670 patients remained on study treatment. Estimated 6-year protocol-defined progression-free survival (PFS) rates were 49%, 51%, 40%, and 47%, respectively, and estimated 6-year overall survival (OS) rates were 71%, 74%, 77%, and 70%, respectively (intent-to-treat population, including protocol-defined progression or death after discontinuation). Estimated 6-year rates of survival without transformation on study treatment were 76%, 80%, 83%, and 74%, respectively. Major molecular response was achieved in 43% (100 mg once daily) and 40% (all other arms) of patients by 6 years. Molecular and cytogenetic responses at 3 and 6 months were highly predictive of PFS and OS. Notably, estimated 6-year PFS rates based on ≤1%, >1% to 10%, and >10% BCR-ABL transcripts at 3 months were 68%, 58%, and 26%, respectively. Most adverse events occurred by 2 years. Imatinib-resistant/-intolerant patients with CML-CP can experience long-term benefit with dasatinib therapy, particularly if achieving BCR-ABL ≤10% at 3 months. This study was registered at ClinicalTrials.gov: NCT00123474.

The Association Of Dasatinib-Induced Lymphocytosis With Treatment Outcome In Patients With Chronic Myeloid Leukemia (CML)

The Association Of Dasatinib-Induced Lymphocytosis With Treatment Outcome In Patients With Chronic Myeloid Leukemia (CML)

Treatment Patterns Among Patients with Philadelphia Chromosome Positive Chronic Myeloid Leukemia (Ph+ CML) Treated with Imatinib in a Community Setting.

AbstractAbstract 3179 Introduction:Imatinib mesylate has been a standard first-line treatment for newly diagnosed chronic phase chronic myeloid leukemia (CP-CML) patients at a recommended initial dose of 400mg. Dose escalation of imatinib has been shown to overcome imatinib resistance in some patients; however, recent National Comprehensive Cancer Network (NCCN) guidelines recommend switching to second generation tyrosine kinase inhibitors (TKIs) for imatinib resistant or intolerant CP-CML patients. Limited evidence exists regarding the real-world treatment patterns among CP-CML patients initiating treatment with imatinib. Thus, the objectives of the study were to evaluate treatment patterns including dosing patterns and reasons for dose modification; rates of treatment interruption (i.e., drug holiday), discontinuation, and switching to second generation TKIs; and investigate the reasons for treatment interruption, and discontinuation among newly diagnosed CP-CML patients initiating treatment with imatinib in the real-world setting. Methods:We conducted a retrospective study utilizing the Georgia Cancer Specialist (GCS) electronic medical record system. CP-CML patients initiating treatment with imatinib from 01-01-2002 to 11-01-2011 were identified. Patients in clinical trials, diagnosis with accelerated/blast crisis, having less than 6-month follow-up time or receiving concurrent treatment for other primary cancers were excluded. Data on imatinib dosing, rates of treatment interruption, discontinuation defined as patients with no record of resuming imatinib treatment, switching, with corresponding reasons for the observed patterns were extracted through comprehensive chart reviews and summarized using standard descriptive statistics. Results:A total of 177 patients with CP-CML initiating treatment with imatinib between 01-01-2002 and 11-01-2011 met study inclusion criteria. The median duration of treatment with imatinib was 35 months. The average age of patients treated with imatinib was 61 years and the majority (n = 144, 81%) had a good (0–1) Eastern Cooperative Oncology Group (ECOG) performance status score. Hypertension (n = 52, 29%) was the most common comorbidity in this cohort followed by diabetes mellitus (n = 17, 9.6%). Dose modification was noted for 33% (n = 59) of the patients. The initial dose for patients with a dose modification was 400 mg for the majority (n = 55, 93%) of patients. Major reasons for dose modification among the 59 patients with dose modification included lack of efficacy as documented in the physician notes (n = 20, 34%), leading to a dose increase for all 20 patients, and intolerance (n = 23, 39%), leading to a dose reduction in more than half of the patients who did not tolerate imatinib (n = 13, 56%). Rates of treatment interruption, discontinuation and switching to another therapy were 16% (n = 29), 24% (n = 43), and 23% (n = 41), respectively. The major reason for treatment interruption among the 29 patients with treatment interruption was intolerance (n = 15, 52%) due to side effects such as rash, pancytopenia and myalgia. Primary reasons for treatment discontinuation among the 43 patients discontinuing imatinib treatment included lack of efficacy (n = 27, 63%) and intolerance to imatinib (n = 13, 30%). Of the 27 patients discontinuing imatinib treatment due to lack of efficacy, 9 patients (33%) had an initial dose escalation to 600mg or 800 mg and most patients (n = 26, 96%) eventually switched to a second generation TKI. Among the 41 patients who switched therapies, 23 (56%) switched to dasatinib while 18 (44%) switched to nilotinib over a median time of 14 months (range: 1.3 – 94.9 months). Conclusions:This retrospective review of patients with CP-CML receiving imatinib in a community outpatient setting found that almost a quarter to one-third of patients initiating treatment with imatinib experienced changes in treatment that included dose modification, treatment interruption, or discontinuation. These changes were primarily due to lack of efficacy or intolerance. Although imatinib is highly effective and generally well tolerated as a first-line treatment for CP-CML, alternative and more effective second generation TKIs could be considered as first-line therapy, or alternative to high dose imatinib among those who are resistant to imatinib. Disclosures:Sail:Novartis: Received funding from Novartis for research study Other. Chen:Novartis Oncology: Employment, Own stock in Novartis Other. Jackson:Novartis: Received funding from Novartis for research study Other. Ericson:Novartis Pharmaceuticals Corp: Employment, Equity Ownership.

Six-year (yr) follow-up of patients (pts) with imatinib-resistant or -intolerant chronic-phase chronic myeloid leukemia (CML-CP) receiving dasatinib.

6506 Background: Dasatinib, a potent BCR-ABL inhibitor, is approved for use as 1st- and 2nd-line therapy for CML pts with newly diagnosed disease or resistance/intolerance to imatinib. This ongoing study in pts with imatinib-resistant/-intolerant CML provides the longest follow-up of a second-generation BCR-ABL inhibitor. Methods: Study design has been described (Shah, J Clin Oncol 2008). Pts with imatinib-resistant/-intolerant CML (N=670) were randomized to dasatinib 100 mg once daily (QD), 50 mg twice daily (BID), 140 mg QD, or 70 mg BID. Results: Five-yr data are reported here; 6-yr data will be presented. After a minimum of 5 yrs, 151 pts (74%) remain on QD dosing, 85 of whom (56%) are on ≥100 mg QD dosing. Overall, 205 pts (31%) remain on study therapy with 55 pts (53%) originally randomized to BID dosing having switched to QD dosing. For pts randomized to the 100 mg QD arm (n=167), progression-free survival (PFS) at 5 yrs is 57%, overall survival (OS) is 78% with an overall 5% rate of transformation to advanced disease. In exploratory analyses, 42% and 60% of pts had BCR-ABL levels ≤10% (International Scale) at 1 and 3 months (mos), respectively. In a landmark analysis, BCR-ABL ≤10% at 1 or 3 mos was associated with higher 5-yr PFS. For dasatinib 100 mg QD, nonhematologic adverse events (AEs; all grades) generally first occurred in <24 mos. Cumulative rates of AEs in the 100 mg QD arm were headache (33%), diarrhea (28%), fatigue (26%), and pleural effusion (24%). For dasatinib 100 mg QD, cytopenias (grades 3/4) generally first occurred in <12 mos. The most common hematologic AEs (grades 3/4) in the 100 mg QD arm were neutropenia (36%) and thrombocytopenia (24%). AEs were managed by dose/schedule modifications. Conclusions: Five-yr follow-up of pts who switched to dasatinib 100 mg QD after imatinib-resistance/intolerance shows high rates of PFS, and OS with an overall low rate of transformation. Exploratory analyses suggest that achievement of a fast and deep response (≤10% BCR-ABL) at 1 or 3 mos after initiation of dasatinib 100 mg QD may be associated with a higher PFS. Dasatinib 100 mg QD was generally well tolerated over 5 yrs. Six-yr data will be presented.

Efficacy and safety of nilotinib in Japanese patients with imatinib-resistant or -intolerant Ph+ CML or relapsed/refractory Ph+ ALL: a 36-month analysis of a phase I and II study

Although the tyrosine kinase inhibitor (TKI) imatinib is often used as first-line therapy for newly diagnosed chronic myelogenous leukemia (CML), some patients fail to respond, or become intolerant to imatinib. Nilotinib is a potent and selective second-generation TKI, with confirmed efficacy and tolerability in patients with imatinib-resistant or -intolerant CML. A phase I/II study was conducted in Japanese patients with imatinib-resistant or -intolerant CML or relapsed/refractory Ph+ acute lymphoblastic leukemia. Thirty-four patients were treated with nilotinib for up to 36 months. Major cytogenetic response was achieved in 15/16 patients (93.8%) with chronic-phase CML within a median of approximately 3 months. Major molecular response was achieved in 13/16 patients (81.3%). These responses were sustained at the time of the most recent evaluation in 13 patients and 11 patients, respectively. Hematologic and cytogenetic responses were also observed in patients with advanced CML. The BCR-ABL mutation associated with the most resistance to available TKIs, T315I, was observed in three patients. Common adverse events included rash, nasopharyngitis, leukopenia, neutropenia, thrombocytopenia, nausea, headache and vomiting. Most adverse events resolved following nilotinib dose interruptions/reductions. These results support the favorable long-term efficacy and tolerability of nilotinib in Japanese patients with imatinib-resistant or -intolerant chronic-phase chronic myeloid leukemia.

Spotlight on Dasatinib in Chronic Myeloid Leukemia and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia†

Dasatinib (Sprycel®) is an orally administered small molecule inhibitor of multiple tyrosine kinases, including BCR-ABL and SRC family kinases, which is indicated for the treatment of adults with newly diagnosed chronic-phase chronic myeloid leukemia (CML), CML (chronic-, accelerated- or blast-phase) with resistance or intolerance to prior therapy, including imatinib, or Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) with resistance or intolerance to prior therapy. Dasatinib is ≈325-fold more active than imatinib in inhibiting wild-type BCR-ABL kinase in vitro and is active against a wide variety of imatinib-resistant BCR-ABL mutants, except for T315I. This article reviews the efficacy and tolerability of dasatinib in the treatment of patients with newly diagnosed chronic-phase CML or imatinib-resistant or -intolerant CML or Ph+ ALL, as well as summarizing its pharmacologic properties. In clinical trials, oral dasatinib was effective in achieving major or complete cytogenetic responses in both newly diagnosed and imatinib-resistant or -intolerant chronic-phase CML. Dasatinib was likewise effective in achieving major or overall hematologic responses in imatinib-resistant or -intolerant, accelerated- or blast-phase CML, or Ph+ ALL. Responses were rapidly achieved within 1-3 months and were durable over 1-5 years of follow-up. The majority of adverse events with dasatinib were of mild or moderate severity. Fluid retention (including pleural effusion) was the most common adverse event. Hematologic abnormalities were common and cytopenias were the most common grade 3/4 adverse events. Dasatinib 100 mg administered once daily was as effective as dasatinib 70 mg administered twice daily, and was better tolerated, being associated with lower incidences of pleural effusion and grade 3/4 thrombocytopenia, in particular. Dasatinib was more effective than high-dose imatinib in the treatment of patients with imatinib-resistant chronic-phase CML and was more effective than standard dosages of imatinib, as well as being associated with less frequent fluid retention, in patients with newly diagnosed chronic-phase CML. Dasatinib was generally equally effective in patients with or without BCR-ABL mutations at baseline. Therefore, oral dasatinib is a highly effective, once-daily therapy for the first-line treatment of newly diagnosed patients with chronic-phase CML, as well as for the treatment of patients with imatinib-resistant or -intolerant chronic- and advanced-phase CML or Ph+ ALL.

Five-year follow-up of patients with imatinib-resistant or -intolerant chronic-phase chronic myeloid leukemia (CML-CP) receiving dasatinib.

6512 Background: Dasatinib, a potent BCR-ABL inhibitor, is indicated as a second-line therapy for patients (pts) with imatinib-resistant or -intolerant CML. This 5-year (yr) analysis is the longest follow-up of CML-CP pts treated with a second-generation BCR-ABL inhibitor. Methods: Study design and endpoints have been described previously (Shah 2008, J Clin Oncol). Pts (N=670) were randomized to dasatinib: 100 mg once daily (QD), 50 mg twice daily (BID), 140 mg QD, or 70 mg BID. Results: Results herein are based on 4-yr data; 5-yr data will be presented. After 4 yrs minimum follow-up, 251 (37%) pts remain on treatment. More pts remain on treatment in the dasatinib 100 mg QD arm (n=74) compared with all other arms. Efficacy data for pts randomized to 100 mg QD (n=167) are: 66% progression-free survival (PFS), 82% overall survival (OS), and 4% transformation to advanced disease. In a landmark analysis of dasatinib 100 mg QD, achievement of complete cytogenetic response (CCyR with or without major molecular response) at 12 months (mos) is associated with an 87% PFS, and achievement of a partial CyR is associated with 78% PFS compared with PFS of 45% for pts with other/no CyR. For dasatinib 100 mg QD, non-hematologic adverse events (AEs; all grades) generally first occur <24 mos and cumulatively include: headache (33%), diarrhea (28%), fatigue (25%), and pleural effusion (24%); and hematologic AEs (grades 3/4) generally occur <12 mos: neutropenia (36%) and thrombocytopenia (24%). Dose/schedule modifications were permitted to manage AEs. Analysis of dosing by last dose available demonstrates that, across the 4 arms, 178 (71%) pts were on QD dosing, of which 107 (60%) pts were on ≥100 mg QD. Switching from BID to QD dosing occurred in 44% of pts. Conclusions: The majority of pts on treatment after 4 yrs continue on the QD dosing schedule. Long-term follow-up of dasatinib 100 mg QD further demonstrates durable efficacy and a generally better tolerated safety profile for pts with CML-CP following prior imatinib therapy.

Cardiac Safety Profile of Imatinib and Nilotinib In Patients (pts) with Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP): Results From ENESTnd

Abstract 2291 Background: Nilotinib is a potent and the most selective inhibitor of BCR-ABL. In the phase 3 ENESTnd trial, nilotinib demonstrated superior efficacy vs imatinib with higher and faster molecular responses and a significantly lower rate of progression on treatment to accelerated or blast phases of CML. Nilotinib has been previously shown to prolong the QT interval. The cardiac safety profile of nilotinib was previously described in pts with imatinib-resistant and -intolerant CML-CP enrolled in phase 2 clinical trials. Here, we report cardiac safety data on nilotinib 300 and 400 mg twice daily (bid), and imatinib, in pts with newly diagnosed CML-CP from the ENESTnd trial. Methods: A total of 836 pts were included in the safety analysis of ENESTnd (279, 277, and 280 pts in the nilotinib 300 mg bid, nilotinib 400 mg bid, and imatinib arms, respectively) with a median follow-up of 18 months. Pts were excluded from study participation if they had known uncontrolled or medically significant cardiac disease, left ventricular ejection fraction (LVEF) 450 msec. Prospective cardiac monitoring was conducted throughout the study for QT prolongation (via electrocardiogram) and LVEF (via echocardiogram) at regular intervals. Results: QTcF increases of > 30 msec from baseline occurred in 26% of pts in each nilotinib arm and in 18% of pts in the imatinib arm. QTcF increases of > 60 msec from baseline were uncommon, occurring in 500 msec. Analysis was conducted to identify any potential case of clinically symptomatic QT prolongation. Only events of syncope were identified (1 pt in each arm with drug-related events) by this analysis and none of these could be attributed to QT prolongation; there were no episodes of torsades de pointes in any treatment arm. Additionally, there was no decrease from baseline in mean LVEF observed anytime on treatment in any arm (Table). No patient in any treatment arm had a LVEF of 15%. Importantly, no pt discontinued therapy due to QT prolongation or LVEF change. An analysis of grouped adverse event terms was performed to identify cases consistent with ischemic heart disease (IHD) or left ventricular dysfunction. A total of 11 pts in all treatment arms experienced IHD events after median treatment duration of 18 months: 3 (1%) on nilotinib 300 mg bid, 6 (2%) on nilotinib 400 mg bid, and 2 ( Conclusions: Overall, QT prolongation, changes in LVEF, and clinical cardiac events were uncommon in all arms and seldom led to discontinuation. There was no cumulative effect of nilotinib exposure on cardiac safety with a median of 18 months follow-up. Nilotinib at both doses had a favorable cardiac safety profile that was similar to imatinib in pts with newly diagnosed CML-CP. Disclosures: Larson: Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Hochhaus: Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Saglio: Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Rosti: Novartis: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau; Roche: Speakers Bureau. Lopez: Novartis: Consultancy; Bristol Myers Squibb: Consultancy. Goldberg: Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Gallagher: Novartis Pharma AG: Employment, Equity Ownership. Hoenekopp: Novartis: Employment. Ortmann: Novartis: Employment. Hughes: Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Research Funding; Ariad: Honoraria. Kantarjian: Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Pfizer: Research Funding.

Patterns and Management of Selected Adverse Events of Adult Patients with Imatinib-Resistant or -Intolerant Chronic Myeloid Leukemia (CML) From the ENACT (Expanding Nilotinib Access in Clinical Trials) Study.

Abstract 1115Poster Board I-137 IntroductionNilotinib, a potent and highly selective BCR-ABL kinase inhibitor, is approved for the treatment of patients (pts) with Philadelphia chromosome-positive chronic myelogeneous leukemia (Ph+ CML) in chronic phase (CML-CP) or accelerated phase (CML-AP) who are resistant or intolerant to prior therapy, including imatinib. The ENACT study is a Phase IIIb, open-label, multicenter study that evaluated the efficacy and safety of nilotinib in adult pts with imatinib-resistant or intolerant CML in a clinical practice setting outside of a registration program. It is the largest single source of efficacy and safety information of any available tyrosine kinase inhibitor (TKI) in CML. Data from ENACT are used to characterize the patterns and management of adverse events (AEs) in nilotinib pts with imatinib-resistant or -intolerant CML-CP or -AP. MethodsPts received nilotinib 400 mg twice daily. Safety assessments included monitoring for all AEs and cardiac procedures. The first occurrence of the following AEs were selected on the basis of the following criteria: 1) the most frequently reported hematologic or biochemical laboratory abnormalities; or 2) identified by participating investigators as AEs of interest that may lead to study drug discontinuation: thrombocytopenia, neutropenia, hyperglycaemia, elevated lipase, elevated amylase, hyperbilirubinaemia, elevated alanine transaminase (ALT), and elevated aspartate transaminase (AST). There were no differences observed between the pattern of management between AEs suspected and regardless of study drug relationship as well as all grades vs. grade 3/4. For this reason this analysis covers management of grade 3/4 AEs suspected of study-drug relationship including duration and subsequent management. The following actions taken were reported by the treating physicians: study drug dose adjusted or temporarily interrupted, non-drug therapy given, no action taken, study drug permanently discontinued, concomitant medication taken or hospitalization/ prolonged hospitalization. More than one action was allowed to be selected. ResultsThe AEs experienced by 1,603 pts (1,422 CP and 181 AP) were generally identified during nilotinib treatment and lasted for short durations. The number of the grade 3 and 4 AEs in CP and AP, median time from start of treatment and median duration are reported in Table. For all included AEs, the overall most common action taken for the first occurrence was dose adjustment or temporary interruption with the exception of hyperglycaemia which was most often managed by treatment with concomitant medications (8/11 of hyperglycaemia AEs in CP and 1/2 in AP). In the majority of the biochemical abnormalities other than hyperglycaemia there was no additional action taken. 49/308 (16%) events of thrombocytopenia in CP pts (9 in AP) were managed by non-drug therapy. 31/204 (15%) events of neutropenia in CP pts were managed by concomitant medication (6/33 events in AP). Permanent discontinuation of study drug was infrequently observed (number of pts in CP; AP): thrombocytopenia (25; 7), neutropenia (15; 2), hyperglycaemia (1; 0), elevated lipase (3; 0), elevated amylase (0; no pts), hyperbilirubinaemia (2; 0), elevated ALT (3; 0), and elevated AST (1; 0). ConclusionsBased on a large cohort of 1,603 nilotinib pts with CML-CP and CML-AP, nilotinib is well-tolerated. Most study drug-related grade 3/4 AEs could be managed by temporary treatment interruption or dose adjustment, such that permanent discontinuation of study drug due to AEs was infrequent. The only events requiring concomitant medication administration or non-drug therapy were thrombocytopenia, neutropenia, hyperglycaemia and hyperbilirubinaemia. The AE profile observed was predictable and similar to that seen in registration trial.CML-CP (N=1,422)Number of AEsDays from start of treatmentDuration of AEN%MedianMedianThrombocytopena30821.7%4216Neutropenia20414.3%4914Elevated lipase936.5%79Hyperbilirubinaemia594.1%188Elevated ALT302.1%1910Elevated AST120.8%4514Elevated amylase120.8%147Hyperglycaemia110.8%721CML-AP (N=181)Number of AEsDays from start of treatmentDuration of AEN%MedianMedianThrombocytopena5832.0%2714Neutropenia3318.2%2810Hyperbilirubinaemia95.0%712Elevated lipase63.3%716Hyperglycaemia21.1%1912Elevated ALT10.6%14812Elevated AST10.6%8341Elevated amylase00.0%−− Disclosuresle Coutre:Novartis: Honoraria, Research Funding; BMS: Honoraria. Ceglarek:Novartis Pharmaceuticals: Honoraria. Turkina:Novartis Pharmaceuticals: Honoraria. Kim:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Wyeth: Research Funding. Shen:Novartis Pharmaceuticals: Honoraria. Smith:Novartis Pharmaceuticals: Honoraria. Rizzieri:Novartis Pharma: Honoraria, Research Funding, Speakers Bureau. Szczudlo:Novartis: Employment. Berton:Novartis Pharmaceuticals: Employment. Wang:Novartis Pharmaceuticals: Employment. Dial:Novartis Pharmaceuticals: Research Funding. Nicolini:Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Chemgenex: Honoraria, Speakers Bureau.

Prognostic Factors for Progression-Free Survival in Patients with Imatinib-Resistant or -Intolerant Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Treated with Nilotinib Based On 24 Month Data.

Abstract Abstract 3298 Poster Board III-186 Background Nilotinib is a potent and highly selective BCR-ABL kinase inhibitor, approved for the treatment of patients with Ph+ CML in CP or AP who are resistant or intolerant to imatinib therapy. After 24 months (mos) of follow-up of imatinib-resistant and -intolerant patients treated with nilotinib in the pivotal phase II study, achievement of major cytogenetic response (MCyR) was demonstrated in 59% of patients and complete cytogenetic response rates (CCyR) in 44% of patients. The purpose of the analysis was to identify baseline disease factors or time-dependent response endpoints that predict for progression-free survival (PFS). Methods Imatinib-resistant and -intolerant CML-CP patients (N = 321) were treated with nilotinib 400 mg twice daily. A Cox regression model was performed on 21 baseline disease factors or response endpoints. The effect of these factors on PFS was evaluated. Progression was defined as death or discontinuation due to disease progression or progression to accelerated phase or blastic phases. Q-PCR data for BCR-ABL were not included. Patients with T315I mutation at study entry were excluded (n=6). Results Ten factors were included in the multivariate analysis that were all identified as significant factors in the initial univariate analysis (at a significance level of 0.05): minor CyR (≤ 65% Ph+ metaphases) at or before 6 mos, MCyR at or before 12 mos, baseline complete hematologic response (CHR), highest prior imatinib dose (&lt; 600 mg/day), absence of baseline mutations, absence of mutations with low sensitivity (E255K/V, Y253H, F359C/V), intolerance to imatinib (vs resistance), baseline hemoglobin (Hb; continuous variable), baseline basophilia (continuous variable), and baseline percent Philadelphia positive (Ph+) metaphases (continuous variable). One other marginally significant factor was included in the multivariate analysis (prior response to CML therapy). Following the multivariate analysis of these 11 factors, only 4 were found to be independently significant, including: MCyR at or before 12 mos (hazard ratio, HR = 0.359, P &lt; 0.0001); baseline hemoglobin ' 120 g/L (HR = 0.985, P = .0291); baseline basophils &lt; 4% (HR = 1.070, P = .0128) and the presence of baseline mutations with low sensitivity to nilotinib (E255K/V, Y253H, F359C/V) (HR = 6.097, P = &lt;.0001). The four binary factors (baseline basophilia ≥ 4%, baseline Hb &lt; 120 g/L, low sensitivity mutations and MCyR at or within 12 mos nilotinib therapy) were then combined to create a single prognostic score with values between 0 (best) and 4 (worst). Based on these scores, patients were stratified into 5 prognostic subsets with the best group having none of the 3 unfavorable disease risk factors and had MCyR at 12 mos while patients in the worst group had all of the 3 unfavorable disease risk factors and no MCyR at 12 mos. The 24 mo PFS rates for patients based on prognostic scores are shown in Table 1. As expected, PFS rates decreased with increasing risk scores. When only considering patients with at least 12 months follow-up the respective 24 mo PFS rates are 90%, 79%, 67%, and 37% (no patients with prognostic score of 4), for patients with prognostic scores of 0, 1, 2, and 3, respectively. The multivariate analysis did not find that at least minor CyR or PCyR responses at or within 6 mos of initiation of nilotinib significantly influenced 24 mo PFS compared to these other factors. Conclusion The preliminary results of this multivariate analysis of 21 disease or response factors identified 4 factors that predict for PFS in imatinib-resistant and -intolerant patients receiving nilotinib therapy in this large dataset. The achievement of MCyR by 12 mos, lack of baseline mutations with low sensitivity to nilotinib, baseline Hb &gt; 120 g/L, and baseline basophilia (&lt; 4%) were all associated with the most favorable PFS on nilotinib therapy. These results suggest that even in the presence of poor disease characteristics, nilotinib therapy provides patients with clinical benefit as measured by PFS. This developed risk model may be useful to determine the benefit of continued nilotinib therapy versus allogeneic transplant. Disclosures Jabbour: Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau. Giles:Novartis: Consultancy, Research Funding; BMS: Research Funding; Merck: Research Funding; Clavis: Research Funding. Bhalla:Novartis: Honoraria, Research Funding; Merck: Honoraria. Pinilla-Ibarz:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Larson:Novartis: Consultancy, Honoraria, Research Funding. Gattermann:Novartis, Celgene: Honoraria, Participation in Advisory Boards on deferasirox clinical trials, Research Funding. Ottmann:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding. Wang:Novartis: Employment. Woodman:Novartis: Employment. Baccarani:Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Mayer Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau. le Coutre:Novartis: Honoraria, Research Funding; BMS: Honoraria. Cortes:Novartis: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Wyeth: Honoraria, Research Funding, Speakers Bureau.

Dasatinib Time to and Durability of Major and Complete Cytogenetic Response (MCyR and CCyR) in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

Dasatinib (SPRYCEL®) is a potent BCR-ABL inhibitor that is 325-fold more potent than imatinib and 16-fold more potent than nilotinib in vitro against unmutated BCR-ABL. In this analysis, time to, duration, and rates of cytogenetic responses to dasatinib were determined using Kaplan-Meier analysis in patients recruited to phase II trials in imatinib-resistant or -intolerant CML-CP (START-C and -R), which have more than 2 years of follow-up. In both trials, patients received dasatinib at the previous dose of 70 mg twice daily (the approved dose in CML-CP is now 100 mg once daily following phase III dose optimization demonstrating improved tolerability). In START-C, imatinib-resistant and -intolerant patients were recruited, and separate analyses were performed for each group. In START-R, a randomized trial of dasatinib vs escalated-dose imatinib, only imatinib-resistant patients were recruited and patients from the dasatinib arm were analyzed prior to cross over. In all dasatinib trials, MCyRs and CCyRs were determined using conventional bone marrow cytogenetic assessment. Progression was defined as increasing white blood cell count, loss of complete hematologic response, loss of MCyR, transformation to accelerated or blast phase, or death. Among imatinib-resistant patients treated in START-C, a MCyR had been achieved at 3, 6, and 12 months by 29%, 40%, and 51%, and a CCyR had been achieved by 18%, 28%, and 39%, respectively (Table). At 24 months, MCyR and CCyR had been achieved by 55% and 44%, respectively. Among responding patients, median time to MCyR was 2.9 months and to CCyR was 5.5 months. In resistant patients who had achieved a MCyR, 94% and 84% had maintained this response 12 and 24 months after it had been initially achieved. For CCyR, 95% and 86% had maintained their response at 12 and 24 months, respectively. Progression-free survival (PFS) at 12 and 24 months for imatinib-resistant patients was 88% and 75%. In START-R, dasatinib response rates and durability were similar to those observed in the imatinib-resistant population of START-C, and median times to MCyR and CCyR were 2.8 and 4.1 months, respectively. Among imatinib-intolerant patients treated in START-C, MCyRs had been achieved at 3, 6, and 12 months by 62%, 74%, and 80%, and CCyRs by 44%, 65%, and 74%, respectively. Rates at 24 months had reached 82% for MCyR and 78% for CCyR. Median times to achieve MCyR and CCyR in the intolerant population were both 2.8 months. Among responding patients, 99% and 97% of intolerant patients were without loss of MCyR 12 and 24 months after responding, and 100% and 98% were without loss of CCyR, respectively. The 12- and 24-month PFS rates were 98% and 94%. In conclusion, dasatinib treatment results in high rates of durable MCyRs and CCyRs in patients with imatinib-resistant or -intolerant CML-CP, and responses are achieved rapidly in most patients.TableSTART-CSTART-ROverall (N=387)Resistant (n=288)Intolerant (n=99)Resistant (n=101)CCyR achieved (%)3 months251844226 months372865299 months4434733512 months4839743718 months5142784324 months53447844Median time to CcyR (months)3.25.52.84.1Patients without loss of CCyR (%)12 months97951009724 months90869894PFS (%)12 months9188989124 months80759486

Intermittent Target Inhibition With Dasatinib 100 mg Once Daily Preserves Efficacy and Improves Tolerability in Imatinib-Resistant and -Intolerant Chronic-Phase Chronic Myeloid Leukemia

Dasatinib is a BCR-ABL inhibitor, 325-fold more potent than imatinib against unmutated BCR-ABL in vitro. Phase II studies have demonstrated efficacy and safety with dasatinib 70 mg twice daily in chronic-phase (CP) chronic myelogenous leukemia (CML) after imatinib treatment failure. In phase I, responses occurred with once-daily administration despite only intermittent BCR-ABL inhibition. Once-daily treatment resulted in less toxicity, suggesting that toxicity results from continuous inhibition of unintended targets. Here, a dose- and schedule-optimization study is reported. In this open-label phase III trial, 670 patients with imatinib-resistant or -intolerant CP-CML were randomly assigned 1:1:1:1 between four dasatinib treatment groups: 100 mg once daily, 50 mg twice daily, 140 mg once daily, or 70 mg twice daily. With minimum follow-up of 6 months (median treatment duration, 8 months; range, < 1 to 15 months), marked and comparable hematologic (complete, 86% to 92%) and cytogenetic (major, 54% to 59%; complete, 41% to 45%) response rates were observed across the four groups. Time to and duration of cytogenetic response were similar, as was progression-free survival (8% to 11% of patients experienced disease progression or died). Compared with the approved 70-mg twice-daily regimen, dasatinib 100 mg once daily resulted in significantly lower rates of pleural effusion (all grades, 7% v 16%; P = .024) and grade 3 to 4 thrombocytopenia (22% v 37%; P = .004), and fewer patients required dose interruption (51% v 68%), reduction (30% v 55%), or discontinuation (16% v 23%). Dasatinib 100 mg once daily retains the efficacy of 70 mg twice daily with less toxicity. Intermittent target inhibition with tyrosine kinase inhibitors may preserve efficacy and reduce adverse events.

Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy

AbstractAlthough imatinib induces marked responses in patients with chronic myeloid leukemia (CML), resistance is increasingly problematic, and treatment options for imatinib-resistant or -intolerant CML are limited. Dasatinib, a novel, highly potent, oral, multitargeted kinase inhibitor of BCR-ABL and SRC family kinases, induced cytogenetic responses in a phase 1 study in imatinib-resistant or -intolerant CML and was well tolerated. Initial results are presented from a phase 2 study of 186 patients with imatinib-resistant or -intolerant chronic-phase CML (CML-CP) designed to further establish the efficacy and safety of dasatinib (70 mg twice daily). At 8-months' follow-up, dasatinib induced notable responses, with 90% and 52% of patients achieving complete hematologic and major cytogenetic responses (MCyR), respectively. Responses were long lasting: only 2% of patients achieving MCyR progressed or died. Importantly, comparable responses were achieved by patients carrying BCR-ABL mutations conferring imatinib resistance. Dasatinib also induced molecular responses, reducing BCR-ABL/ABL transcript ratios from 66% at baseline to 2.6% at 9 months. Nonhematologic adverse events were generally mild to moderate, and most cytopenias were effectively managed with dose modifications. Cross-intolerance with imatinib was not evident. To conclude, dasatinib induces notable responses in imatinib-resistant or -intolerant CML-CP, is well tolerated, and represents a promising therapeutic option for these patients. This trial was registered at www.clinicaltrials.gov as CA180013.