Kooperativer Bibliotheksverbund

In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 4025-4025

Abstract: Introduction: Ponatinib is a potent oral tyrosine kinase inhibitor (TKI) approved for use in patients with refractory CML and Ph+ ALL, including patients with the resistant BCR-ABLT315I mutation. To evaluate whether patient characteristics and outcomes with ponatinib differed by extent of pretreatment with other TKIs, this post hoc analysis examines results among CP-CML patients enrolled in the phase 2 PACE trial (NCT01207440) according to the number of TKIs received prior to study entry. Updated data with 4 years of follow-up will be presented. Methods: Patients with CML or Ph+ ALL who were resistant or intolerant to dasatinib or nilotinib or who had the T315I mutation were enrolled (N=449). Ponatinib was initiated at 45 mg once daily. CP-CML patients were evaluated based on previous treatment with 1, 2, 3, or 4 prior TKIs approved for use in CP-CML (ie, imatinib, dasatinib, nilotinib, and bosutinib). Data reported in this abstract are as of February 2, 2015. Results: Overall, 270 CP-CML patients were enrolled and treated in PACE. Patient characteristics and disposition varied by number of prior TKIs (Table 1). Both median age and median time from diagnosis increased with number of prior TKIs; median dose intensity was highest in patients who had received only 1 prior TKI. The most common reasons for discontinuation across groups were adverse events (AEs) and withdrawal by patient request. Responses by number of prior TKIs are shown in Table 2. Rates of cytogenetic and molecular response to ponatinib were higher with fewer prior TKIs. While the frequency of individual AEs did not follow a consistent trend, the incidence of grade ≥3 AEs appeared to increase with the number of prior TKIs received (68%, 86%, 89%, and 100%, respectively); grade ≥3 AEs in ≥10% of CP-CML patients overall were thrombocytopenia (35%), neutropenia (17%), hypertension (13%), increased lipase (12%), and abdominal pain (10%). A similar frequency pattern was observed for serious AEs, which occurred in 58%, 53%, 62%, and 92% of patients who had previously received 1, 2, 3, and 4 approved TKIs, respectively. Serious AEs in ≥5% of CP-CML patients overall were pancreatitis (7%), angina pectoris (5%), and pneumonia (5%). The frequency of arterial occlusive events (AOEs) was 32% (6/19), 26% (25/98), 28% (39/141), and 42% (5/12) by increasing number of prior TKIs; exposure-adjusted incidence rates of new AOEs were 11.75, 10.4, 12.6, and 33.3 events per 100 patient-years, respectively. Conclusions: With 4 years of follow-up, ponatinib continues to provide benefit to ongoing CP-CML patients in the PACE trial. Analysis by treatment history indicates that patients who had received fewer TKIs prior to study entry appear to exhibit better efficacy and safety profiles. However, treatment decisions should be primarily guided by individual patient and disease factors, including mutation status, and physicians should weigh both the benefits and risks of prescribing ponatinib. Table 1. Patient Characteristics and Disposition by Number of Prior TKIs 1 TKI (n=19) 2 TKIs (n=98) 3 TKIs (n=141) 4 TKIs (n=12) Median age at baseline, years 52 58 63 67 Median time from diagnosis to first dose, years 2.8 5.2 7.9 12.4 Median dose intensity, mg/d 34.0 28.7 29.9 31.0 Mutations detected at baseline, % 68 51 43 75 T315I mutation detected at baseline, % 63 31 16 0 Prior TKI exposure, %, imatinib/dasatinib/nilotinib/bosutinib 68/21/5/5 97/66/36/1 100/96/96/7 100/100/100/100 Remain on study, % 53 48 40 8 Discontinued, % 47 52 60 92 Primary reason for discontinuation, % AE 16 18 17 33 Withdrawal by patient request 5 11 11 25 Disease progression 16 5 13 0 Lack of efficacy 0 2 9 8 Death 0 2 3 17 Othera 11 13 8 8 Median follow-up, months 42.3 42.9 42.1 28.2 aIncludes noncompliance, physician decision, protocol violation, and other reasons Table 2 Responses to Ponatinib by Number of Prior TKIs 1 TKI (n=16a) 2 TKIs (n=98) 3 TKIs (n=141) 4 TKIs (n=12) MCyR 12 (75) 69 (70) 69 (49) 7 (58) CCyR 12 (75) 63 (64) 63 (45) 4 (33) MMR 10 (63) 41 (42) 51 (36) 1 (8) MR4 6 (38) 30 (31) 38 (27) 1 (8) MR4.5 4 (25) 22 (22) 34 (24) 1 (8) All responses are n (%) a16/19 patients were evaluable for efficacy Disclosures Hochhaus: Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding. Cortes:ARIAD Pharmaceuticals Inc.: Other: Consulting & Advisory Role, Research Funding. Pinilla-Ibarz:Novartis: Consultancy, Other: Consulting & Advisory Role, Research Funding; ARIAD Pharmaceuticals, Inc.: Consultancy, Other: Consulting & Advisory Role, Research Funding; Teva: Consultancy, Speakers Bureau; Pfizer: Consultancy, Other: Consulting & Advisory Role, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Other: Consulting & Advisory Role, Speakers Bureau. le Coutre:Novartis: Honoraria; BMS: Honoraria; ARIAD Pharmaceuticals Inc.: Honoraria; Pfizer: Honoraria. Paquette:ARIAD Pharmaceuticals Inc.: Honoraria; BMS: Honoraria; Novartis: Honoraria. Chuah:Children International: Honoraria; Novartis: Honoraria; Bristol Meyers Squibb: Honoraria. Nicolini:Ariad Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Apperley:BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ARIAD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Talpaz:Pfizer: Other: CONSULTING OR ADVISORY ROLE; Novartis: Other: CONSULTING OR ADVISORY ROLE; ARIAD Pharmaceutical Inc.: Other: CONSULTING OR ADVISORY ROLE; Pfizer: Other: TRAVEL, ACCOMODATIONS, EXPENSES, Research Funding; Novartis: Other: TRAVEL, ACCOMODATIONS, EXPENSES, Research Funding; ARIAD Pharmaceutical Inc.: Other: TRAVEL, ACCOMODATIONS, EXPENSES, Research Funding; Incyte: Other: TRAVEL, ACCOMODATIONS, EXPENSES, Research Funding; Sanofi: Research Funding. DeAngelo:Incyte: Other: Consulting or Advisory Role; Pfizer: Other: Consulting or Advisory Role; Novartis: Other: Consulting or Advisory Role; BMS: Other: Consulting or Advisory Role; ARIAD Pharmaceuticals Inc.: Other: Consulting & Advisory Role; Amgen: Other: Consulting or Advisory Role. Abruzzese:BMS: Other: Consulting or Advisory Role; ARIAD Pharmaceuticals Inc.: Other: Consulting & Advisory Role; Novartis: Other: Consulting or Advisory Role; Pfizer: Other: Consulting or Advisory Role. Rea:Bristol-Myers Squibb: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Ariad: Honoraria. Baccarani:Pfizer: Other: Travel, Accommodations, Expenses; BMS: Other: Travel, Accommodations, Expenses; Novartis: Other: Travel, Accommodations, Expenses; ARAID Pharmaceutical Inc.: Other: Consulting or Advisory Role, Speakers Bureau; Pfizer: Honoraria, Other: Consulting or Advisory Role, Speakers Bureau; Novartis: Honoraria, Other: Consulting or Advisory Role, Speakers Bureau; BMS: Honoraria, Speakers Bureau; ARIAD Pharmaceutical Inc.: Other: Travel, Accommodations, Expenses. Muller:ARIAD Pharmaceuticals Inc.: Honoraria, Other: Consulting & Advisory Role, Research Funding; Novartis: Honoraria, Other: Consulting or Advisory Role, Research Funding; BMS: Honoraria, Other: Consulting or Advisory Role, Research Funding. Lustgarten:ARIAD Pharmaceuticals Inc.: Employment, Equity Ownership, Other: Stock. Conlan:ARIAD Pharmaceuticals Inc.: Other: Stock. Rivera:ARIAD Pharmaceuticals Inc.: Employment, Other: Full-time Employee & Shareholder (self-managed). Guilhot:Celgene: Consultancy, Other: CONSULTING OR ADVISORY ROLE; Pfizer: Honoraria; Novartis: Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES. Deininger:Incyte: Consultancy, Honoraria, Other: Consulting or Advisory Role; Pfizer: Consultancy, Honoraria, Other: Consulting or Advisory Role; ARIAD Pharmaceutical Inc.: Consultancy, Honoraria, Other: Consulting or Advisory Role; Gilead: Research Funding; Celgene: Research Funding; Novartis: Consultancy, Honoraria, Other: Consulting or Advisory Role, Research Funding; BMS: Consultancy, Honoraria, Other: Consulting & Advisory Role, Research Funding. Hughes:Bristol-Myers Squibb: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Shah:Pfizer: Research Funding; Bristol-Myers Squibb: Research Funding; Plexxikon Inc.: Research Funding. Kantarjian:Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Amgen: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.4025.4025

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 2523-2523

Abstract: Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome caused by excessive immune activation leading to a life-threatening pro-inflammatory cytokine storm. HLH is not an entity of its own, but a clinical syndrome triggered by various conditions like infections, malignancy or autoimmune disorders. HLH pathogenesis is complex and still not fully understood. Contributing factors include immunosuppression (chemotherapy, long-term immunosuppressive therapy), cytokine release from tumor cells, imbalance between infected and immune effector cells as well as genetic predisposition. Despite improved HLH-specific therapy (adapted components from the pediatric HLH-1994 protocol), prognosis is still poor among adult HLH patients. Due to the lack of data on adult HLH in Germany, a national multicenter registry (http://www.hlh-registry.org/) was initiated. Methods: Patients (pts) with proven or suspected HLH were registered by 35 institutions across Germany from August 2010 to July 2016. Both HLH-2004 diagnostic criteria and the HScore (www.saintantoine.aphp.fr/score/) were used to confirm HLH diagnosis. To characterize adult HLH patients, data referring to underlying disease, treatment, outcome, clinical manifestations and laboratory findings were recorded. Where available, patient samples were tested for mutations of the perforin gene PRF1 by standard Sanger sequencing. Results: A total of 125 pts (48 female) were enrolled in our registry, of whom 105 pts either fulfilled diagnostic criteria according to HLH-2004 diagnostic guidelines (n=96) or met at least 4 out of 8 criteria and reached HLH-probability of over 90 % in the HScore (n=9). Among these 105 pts, n=38 (36 %) were female and n=67 (64 %) male. Median age at diagnosis was 49 years (range 17 - 81). Trigger diseases were in line with the literature, with infections (n=34) and malignancy (n=40) being most frequent (Table 1). Patients show a wide spectrum of underlying conditions, i.e. allogeneic stem cell transplantation (alloSCT) or HLH-mimicking diseases due to cytokine release in response to blinatumomab therapy. Late onset hereditary HLH was found in 3 pts (XLP-1 and -2 respectively in EBV-coinfected pts, one pt with perforin mutation - see below). 22 of 105 patients (21 %) were tested for PRF1 mutations. A compound heterozygous PRF1 A91V/Q405X mutation was identified in one pt presenting with NK/T-cell lymphoma. Heterozygous PRF1 A91V mutations were found in 2 pts with B-cell lymphoma and HLH following alloSCT respectively, in one case with available buccal swab DNA to prove germline origin of the mutation. Table 2 summarizes clinical and laboratory findings in the cohort. A median ferritin value of 32,000 µg/L underlines the importance to evaluate pts with highly elevated ferritin with respect to potential HLH diagnosis. Apart from fever and splenomegaly, clinical presentation frequently comprised hepatomegaly, liver failure, hyperbilirubinemia, renal failure, lung involvement like ARDS, or bleeding. Treatment included steroids in the vast majority of pts (n=89), often combined with i.v. immunoglobulins (n=47) and etoposide (n=49). After a median follow up time of 164 days, 48/97 pts (49.5 %) were alive, 8 pts were lost to follow up. Survival analysis revealed median overall survival of 454 days (Figure 1a). Comparing malignancy-associated HLH and HLH after alloSCT with infection- and autoimmune-associated HLH or HLH due to unknown triggers, survival was significantly poorer in the malignancy/alloSCT group (Figure 1b). Conclusions: HLH trigger conditions in adult patients in Germany are in accordance with published case series. Outcome in adult HLH is still poor, with malignancy-associated and HLH after alloSCT showing the worst prognosis. Diagnostic vigilance and early treatment is a prerequisite for improving outcome of adult HLH. In particular, high ferritin values should raise suspicion of HLH. Disclosures Hochhaus: Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.2523.2523

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 132, No. 3 ( 2018-07-19), p. 307-320

Abstract: We have developed a first-in-class C-terminal HSP90 inhibitor (AX) that is effective against TKI-resistant CML and leukemic stem cells. Unlike the majority of HSP90 inhibitors, AX does not induce the HSR as a resistance mechanism.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2017-10-810986

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 13-13

Abstract: Background In newly diagnosed acute myeloid leukemia (AML), the general recommendation is to start treatment immediately after the diagnosis has been made. This paradigm is based both on the observation that untreated acute leukemia has a poor prognosis and on retrospective analyses demonstrating a shorter survival in younger AML patients (pts) in whom treatment was delayed by more than 5 days (Sekeres et al., 2009). A more recent single-center analysis came to a different conclusion, showing no prognostic effect for the time from diagnosis to treatment (TDT; Bertoli et al., 2013). We explored the relationship between TDT and prognosis on a large set of real-world data from the AML registry of the Study Alliance Leukemia (SAL) and compared it to the published cohorts. Methods The SAL runs a transregional AML registry in 46 treatment centers across Germany (NCT03188874). All registered patients with an intensive induction treatment, a minimum follow-up time of 12 months and no acute promyelocytic leukemia were selected (n=2,200). Treatment start was defined by the first day of cytarabine, whereas single agent hydroxyurea (HU) was labeled as pretreatment. We analyzed the influence of TDT on complete remission (CR), early death (ED) and overall survival (OS) in univariable analyses for each day of treatment delay, in groups of 0-5, 6-10, 11-15 and & gt;15 days of TDT, and by using the restricted cubic spline (RCS) method for data modelling. In order to adjust for the influence of established prognostic variables on the outcomes, we used multivariable regression models and propensity score weighting. The influence of HU pretreatment on outcomes was investigated by introducing an interaction term between TDT and the presence of HU pretreatment. Results The median age was 59 years (y) (IQR 50-68), the proportion of pts with favorable, intermediate and adverse genetic risk according to ELN was 27%, 53%, and 20%; & gt;95% of pts received induction treatment with standard 7+3. HU pretreatment was administered in 4% of pts. The median TDT was 3 days (IQR 2-6). Descriptive statistics after grouping of pts showed the highest median age and the lowest proportion of NPM1 mutated and favorable risk in the TDT group 11-15. Of all pts, 79% achieved a CR/CRi; unadjusted CR rates for the patient groups with TDT of 0-5, 6-10, 11-15 and & gt;15 days were 80%, 77%, 74% and 76%, respectively (p=0.317). In multivariable analysis accounting for the influence of ELN risk, age, WBC, LDH, de novo versus secondary AML and ECOG, the OR for each additional day of TDT was 0.99 (95%-CI, 0.97-1.00; p=0.124). Four percent of pts died within the first 30 days from treatment start. The respective rates in the four TDT categories were 4.0%, 3.8%, 5.1% and 4.1% (p=0.960). In multivariable analysis, the OR for TDT was 1.01 (95%-CI, 0.98-1.05; p=0.549). After a median follow-up of 40 months, the 2-y OS of all pts was 51%. The unadjusted 2-y OS rates stratified by TDT of 0-5, 6-10, 11-15, & gt;15 days were 52, 49, 46, and 51% (see Table 1 and Figure 1). The hazard ratio (HR) for each day of treatment delay was 1.00 (95%-CI; 0.99-1.01; p=0.317). In multivariable Cox regression analysis, the HR for TDT as continuous variable was 1.00 (95%-CI, 0.99-1.01; p=0.689). When OS was analyzed separately stratified for age ≤60 and & gt;60 ys and for high versus lower initial WBC defined by a threshold of 50 x 109/L, no significant differences between TDT groups were observed. Multivariable models using TDT as a grouped variable or with RCS did not provide evidence for a significant influence of TDT on outcomes. Propensity score matching of pts in the four TDT groups did not reveal an influence on outcomes. The use of HU was not associated with CR, ED nor OS. Conclusion Our study on 2,200 newly diagnosed registry pts receiving consistent intensive induction with standard-dose cytarabine plus daunorubicin (7+3) suggests that TDT is not related to response or survival, neither in younger nor in older pts. Despite multivariable analyses, a bias towards longer TDT intervals in pts judged to be clinically stable by the treating physician cannot be excluded entirely. As treatment stratification in intensive first-line treatment of AML evolves, the TDT data suggests that it may be a safe and reasonable approach to wait for genetic and other laboratory test results in order to assign clinically stable pts to the best available treatment option before the start of intensive treatment. Disclosures Krämer: Daiichi-Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; BMS: Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hänel:Roche: Honoraria; Amgen: Honoraria; Celgene: Other: advisory board; Novartis: Honoraria; Takeda: Other: advisory board. Jost:Daiichi: Honoraria; Sanofi: Honoraria; Gilead: Other: travel grants; Jazz Pharmaceuticals: Honoraria. Brümmendorf:Merck: Consultancy; Janssen: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; University Hospital of the RWTH Aachen: Employment; Ariad: Consultancy. Krause:Siemens: Research Funding; Takeda: Honoraria; MSD: Honoraria; Gilead: Other: travel; Celgene Corporation: Other: Travel. Scholl:Novartis: Other: Project funding; Pfizer: Other: Advisory boards; Gilead: Other: Project funding; Daiichi Sankyo: Other: Advisory boards; AbbVie: Other: Advisory boards. Hochhaus:Pfizer: Research Funding; Novartis: Research Funding; BMS: Research Funding; Incyte: Research Funding; MSD: Research Funding. Kiani:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Middeke:Sanofi: Research Funding, Speakers Bureau; Roche: Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Gilead: Consultancy; Janssen: Consultancy, Speakers Bureau; MSD: Consultancy. Thiede:AgenDix GmbH: Employment, Equity Ownership; Novartis: Research Funding, Speakers Bureau; Bayer: Research Funding; Daiichi-Sankyo: Speakers Bureau. Stoelzel:JAZZ Pharmaceuticals: Consultancy; Neovii: Other: Travel funding; Shire: Consultancy, Other: Travel funding. Platzbecker:Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-123717

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 1734-1734

Abstract: Introduction: Bosutinib is approved for newly diagnosed chronic phase (CP) chronic myeloid leukemia (CML) and CML resistant or intolerant to prior therapy. Efficacy and safety of first-line bosutinib and imatinib were assessed in older vs younger patients in the ongoing phase 3 BFORE trial (NCT02130557). Methods: In all, 536 patients were randomized 1:1 to receive bosutinib or imatinib (400 mg once daily). We compared outcomes in patients aged ≥65 years (older group) vs 〈 65 years (younger group) after 24 months of follow-up. Efficacy (excluding complete cytogenetic response [CCyR] ) was assessed in the intent-to-treat (ITT) population (Philadelphia chromosome-positive [Ph+] and negative patients) of both age groups and safety in patients who received ≥1 dose of study drug. CCyR was assessed in the modified ITT population (Ph+ patients with e13a2/e14a2 transcripts [N=487] ). Results: In the bosutinib arm (n=268), 53 were older and 215 were younger patients. In the imatinib arm (n=268; 3 untreated), 48 (2 untreated) were older and 220 (1 untreated) were younger patients. Sokal risk scores were balanced between treatment arms but higher in the overall older (8.9% low, 70.3% intermediate, 20.8% high) vs younger (44.1% low, 34.7% intermediate, 21.1% high) populations, reflecting that age is part of the score. Bosutinib was discontinued in 32.1% of older and 28.4% of younger patients; the most common primary reason was treatment-related adverse events (AEs; 18.9% and 15.3%, respectively). Imatinib was discontinued in 32.6% of older and 33.8% of younger patients, most frequently due to suboptimal response or treatment failure (13.0% and 13.2%, respectively). The percentage of patients who discontinued treatment due to treatment-emergent AEs (TEAEs) was similar in the older vs younger group in both arms (bosutinib: 22.6% vs 19.1%; imatinib: 8.7% vs 12.3%). In older vs younger patients, median (range) duration of treatment was similar: 24.8 months (0.3-33.3) vs 24.9 months (0.3-33.5) for bosutinib and 25.6 months (2.9-33.1) vs 24.5 months (0.7-33.4) for imatinib. Median relative dose intensity was slightly lower in older vs younger patients in the bosutinib arm (92.8% vs 99.3%) but was 100% in both age groups in the imatinib arm. The difference in rates of major molecular response (MMR) at 12 months (primary endpoint) with bosutinib vs imatinib was consistent across age groups (older: 43.4% vs 35.4%; younger: 47.4% vs 36.4%; P=0.7879 for test of interaction), as was the difference in rates of CCyR by 12 months (older: 68.8% vs 69.0%; younger: 79.3% vs 65.8%; P=0.1689). MR rates at 24 months (and MR1 at 3 months) were generally similar in older vs younger patients within each arm and higher with bosutinib than with imatinib (Table 1). Time to achieve MMR on bosutinib was not different in older vs younger patients (hazard ratio: 1.227; P=0.2380, after adjustment for baseline and time-dependent covariates in a multivariable proportional subdistribution hazards model). Rates of common TEAEs in each treatment arm were similar ( 〈 10% difference) between age groups, except for higher rates of anemia, rash, and decreased appetite in older patients in the bosutinib arm; higher rate of pruritus in older patients in both arms; and higher rate of peripheral edema and lower rate of neutropenia in older patients in the imatinib arm (Table 2). In older vs younger patients in the bosutinib arm, there were higher rates of grade 3/4 TEAEs (75.5% vs 61.4%), serious TEAEs (39.6% vs 23.3%), and dose delays (69.8% vs 58.1%) and reductions (52.8% vs 37.2%) due to TEAEs. In older vs younger patients in the imatinib arm, rates of grade 3/4 TEAEs (43.5% vs 47.9%), and dose delays (39.1% vs 38.8%) and reductions (23.9% vs 21.5%) due to TEAEs were similar, but the rate of serious TEAEs was higher (28.3% vs 16.9%). Conclusions: In the phase 3 BFORE trial, bosutinib showed clinical activity in older and younger patients with newly diagnosed CP CML. Difference in rates of MMR at 12 months for bosutinib vs imatinib was consistent in older and younger patients. MR rates at 24 months were similar in older and younger patients and higher with bosutinib than with imatinib. Although the incidence of grade 3/4 TEAEs, serious TEAEs, and dose modifications due to TEAEs were higher in older vs younger bosutinib-treated patients, treatment discontinuation rates were similar between age groups, suggesting that, regardless of patient age, TEAEs were manageable with bosutinib. Disclosures Deininger: Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Blueprint: Consultancy. Kota:Pfizer: Honoraria; Xcenda: Honoraria; Novartis: Honoraria; Incyte: Honoraria; BMS: Honoraria. Lipton:Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding. Milojkovic:Incyte: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. García Gutiérrez:Incyte: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Leip:Pfizer: Employment, Equity Ownership. Nick:Pfizer: Employment, Equity Ownership. Hochhaus:Takeda: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Incyte: Research Funding. Gambacorti-Passerini:BMS: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding. Cortes:Astellas Pharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Arog: Research Funding. Brummendorf:Merck: Consultancy; Pfizer: Consultancy, Research Funding; Janssen: Consultancy; Takeda: Consultancy; Novartis: Consultancy, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-110798

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 2932-2932

Abstract: Introduction: Some patients with chronic myeloid leukemia in chronic phase (CML-CP) who have a sustained deep molecular response (DMR) with tyrosine kinase inhibitors (TKIs) can discontinue therapy and achieve treatment-free remission (TFR). Thus far, no consistent variables that predict TFR have been identified. In long-term follow-up of patients who attempted TFR following front- or second-line nilotinib in the ENESTfreedom and ENESTop TFR studies, respectively, 192-week TFR rates were 44.2% (ENESTfreedom) and 46.0% (ENESTop), and adverse event rates tended to decrease over time during TFR. Previous analyses in ENESTfreedom suggested that lower Sokal risk score and consistent MR4.5 (BCR-ABL1 ≤ 0.0032% on the International Scale [IS] ) in the consolidation phase were associated with maintaining TFR, whereas in ENESTop, a longer time in MR4.5 was associated with maintaining TFR. We sought to identify clinical predictors of a durable TFR by analyzing pooled data from ENESTfreedom and ENESTop. Methods: In ENESTfreedom, patients with MR4.5 and ≥ 2 years of frontline nilotinib were enrolled and entered a 1-year nilotinib consolidation phase. Those who maintained a DMR in 4 quarterly assessments (MR4.5 in the last assessment, ≤ 2 assessments between MR4 [BCR-ABL1IS ≤ 0.01%] and MR4.5, and no assessments worse than MR4) could enter the TFR phase to attempt TFR. Patients were required to restart nilotinib upon loss of major MR (MMR [BCR-ABL1IS ≤ 0.1%] ). In ENESTop, patients with 〉 4 weeks of imatinib followed by ≥ 2 years of nilotinib (≥ 3 years of TKI therapy overall) who achieved MR4.5 on nilotinib were enrolled and entered a 1-year nilotinib consolidation phase. Those without a confirmed loss of MR4.5 during the consolidation phase could enter the TFR phase. Patients were required to restart nilotinib upon loss of MMR or confirmed loss of MR4. For the current analysis, data from all patients who entered the TFR phases of ENESTfreedom (n = 190) and ENESTop (n = 126) were pooled, and univariate and multivariate analyses were conducted to identify predictors of a durable TFR (defined for these analyses as remaining in the TFR phase with MR4.5 at 24 weeks after treatment stop [as the majority of molecular relapses occur by week 24]). Age, sex, time since MR4.5 achievement until TFR phase entry, and duration of nilotinib prior to TFR phase entry were assessed as potential predictive factors. All variables other than sex were considered to be continuous. Additionally, receiver operating characteristic (ROC) curve analyses (Youden indices) were conducted separately for each trial to further investigate age, time since MR4.5 achievement until TFR phase entry, and duration of nilotinib prior to TFR phase entry as potential predictors of durable TFR. Results: In ENESTfreedom and ENESTop, 104/190 (54.7%) and 76/126 (60.3%) patients, respectively, remained in the TFR phase with MR4.5 at 24 weeks after TFR phase entry. Thus, in the pooled analysis of both studies, a total of 180/316 patients (57.0%) remained in the TFR phase with MR4.5 at 24 weeks. In the univariate analysis of pooled data, time since MR4.5 achievement until TFR phase entry and duration of nilotinib prior to TFR phase entry were significantly associated with durable TFR at 24 weeks (Table). However, in the multivariate analysis of the pooled data, duration of nilotinib prior to TFR phase entry was the only significant predictor. An increase of 1 month in the duration of nilotinib treatment was associated with an increase of 3.6% (95% CI, 1.5%-5.8%) in the odds of durable TFR at week 24. In the ROC curve analysis of patients who attempted TFR in ENESTfreedom, statistically significant results were not found for any of the assessed factors, including duration of nilotinib prior to TFR phase. In ENESTop, statistical significance was found for time since MR4.5 achievement until TFR phase entry (P = .0165) and duration of nilotinib prior to TFR phase entry (P = .0007) but not for age. Conclusions: Pooled analyses from ENESTfreedom and ENESTop suggest that durable TFR at 24 weeks following nilotinib stop was associated with duration of nilotinib prior to TFR, although this effect seems to be driven by the results of the ENESTop trial, in which both time since achievement of MR4.5 and duration of nilotinib were identified as key factors in an increased likelihood of durable TFR at 24 weeks. These results will help guide physicians with patients who are considering attempting TFR. Disclosures Radich: Novartis: Other: RNA Sequencing; TwinStrand Biosciences: Research Funding. Hochhaus:Novartis: Research Funding; BMS: Research Funding; Incyte: Research Funding; Pfizer: Research Funding; MSD: Research Funding. Ross:Novartis: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; BMS: Honoraria. Saglio:Ariad: Consultancy; BMS: Consultancy; Celgene: Consultancy; Pfizer: Consultancy; Jansen: Consultancy; Incyte: Consultancy; Novartis: Consultancy. Hughes:Novartis: Other: Advisory Board and Symposia, Research Funding; BMS: Research Funding. Kim:Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Il-Yang co.: Research Funding; Takeda: Research Funding. Fellague-Chebra:Novartis: Employment, Equity Ownership, Research Funding. Sondhi:Sanofi: Other: Stock; Novartis: Employment, Other: Stock. Tiwari:Novartis: Employment. Mishra:Novartis: Employment. Mahon:Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; BMS: Honoraria, Other: Travel.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-129393

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 666-666

Abstract: Background. The end phase or metamorphosis is one of the remaining challenges of chronic myeloid leukemia (CML) management. Blast crisis (BC) is a late marker. Earlier diagnosis may improve outcome. The detection of additional chromosomal abnormalities (ACA) at low blast levels might allow earlier treatment when outcome is better. Methods. We made use of 1536 Ph+CML-patients in chronic phase followed in the randomized CML study IV (Hehlmann et al, Leukemia 2017) for a median of 8.6 years. 1510 cytogenetically evaluable patients were analyzed for ACA and blast increase (Flow chart). According to impact on survival ACA were grouped into high-risk (+ 8; +Ph; i(17q); +17; +19 +21; 3q26; 11q23; -7; complex) and low-risk (all other). Prognosis with +8 alone was clearly better than with +8 accompanied by further abnormalities, but still worse than with low-risk ACA. +8 alone was therefore included in the high-risk group. The presence of high- and low-risk ACA was linked to 6 thresholds of blast increase (1%, 5%, 10%, 15%, 20%, and 30%) in a Cox proportional hazards model. Results. 139 patients (9.2%) displayed ACA at any time before BC diagnosis, 88 (5.8%) had high-risk and 51 (3.4%) low-risk ACA. ACA emerged after a median of 17 (0-133) months. 79 patients developed BC. 43 (61%) of 71 cytogenetically evaluable patients with BC had high-risk ACA. 3-year survival after emergence of high-risk ACA was 48%, after emergence of low-risk ACA 92%. At low blast levels (1-15%), high-risk ACA showed an increased hazard to die (ratios: 3.66 in blood; 6.84 in marrow) compared to no ACA in contrast to low-risk ACA. This effect was not observed anymore at blast increases to 20-30% (Figure). 38 patients with high-risk ACA died, 36 with known causes of death which were almost exclusively BC (n=26, 72%) and progression-related transplantation (n=8, 22%). Only 2 patients died of CML-unrelated causes. Conclusions. High-risk ACA herald death by BC already at low blast levels and may help to define CML end phase in a subgroup of patients at an earlier time than is possible with current blast thresholds. Cytogenetic monitoring is indicated when signs of progression surface and response to therapy is unsatisfactory. More intensive therapy may be indicated at emergence of high-risk ACA. Disclosures Hehlmann: Novartis: Research Funding. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Fabarius:Novartis: Research Funding. Krause:Siemens: Research Funding; Takeda: Honoraria; MSD: Honoraria; Gilead: Other: travel; Celgene Corporation: Other: Travel. Baerlocher:Novartis: Research Funding. Burchert:Novartis: Research Funding. Brümmendorf:Novartis: Consultancy, Research Funding; Janssen: Consultancy; Merck: Consultancy; Ariad: Consultancy; Pfizer: Consultancy, Research Funding; University Hospital of the RWTH Aachen: Employment. Hochhaus:Pfizer: Research Funding; Novartis: Research Funding; BMS: Research Funding; Incyte: Research Funding; MSD: Research Funding. Saussele:BMS: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria, Research Funding. Baccarani:Novartis: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Takeda: Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-127127

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 1528-1528

Abstract: Purpose: The enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and key epigenetic regulator involved in transcriptional repression and embryonic development. Loss of EZH2 activity by inactivating mutations is associated with poor prognosis in myeloid malignancies such as MDS. More recently, EZH2 inactivation was shown to induce chemoresistance in acute myeloid leukemia (AML) (Göllner et al., 2017). Data on the frequency and prognostic role of EZH2-mutations in AML are rare and mostly confined to smaller cohorts. To investigate the prevalence and prognostic impact of this alteration in more detail, we analyzed a large cohort of AML patients (n = 1604) for EZH2 mutations. Patients and Methods: All patients analyzed had newly diagnosed AML, were registered in clinical protocols of the Study Alliance Leukemia (SAL) (AML96, AML2003 or AML60+, SORAML) and had available material at diagnosis. Screening for EZH2 mutations and associated alterations was done using Next-Generation Sequencing (NGS) (TruSight Myeloid Sequencing Panel, Illumina) on an Illumina MiSeq-system using bone marrow or peripheral blood. Detection was conducted with a defined cut-off of 5% variant allele frequency (VAF). All samples below the predefined threshold were classified as EZH2 wild type (wt). Patient clinical characteristics and co-mutations were analyzed according to the mutational status. Furthermore, multivariate analysis was used to identify the impact of EZH2 mutations on outcome. Results: EZH2-mutations were found in 63 of 1604 (4%) patients, with a median VAF of 44% (range 6-97%; median coverage 3077x). Mutations were detected within several exons (2-6; 8-12; 14-20) with highest frequencies in exons 17 and 18 (29%). The majority of detected mutations (71% missense and 29% nonsense/frameshift) were single nucleotide variants (SNVs) (87%), followed by small indel mutations. Descriptive statistics of clinical parameters and associated co-mutations revealed significant differences between EZH2-mut and -wt patients. At diagnosis, patients with EZH2 mutations were significantly older (median age 59 yrs) than EZH2-wt patients (median 56 yrs; p=0.044). In addition, significantly fewer EZH2-mut patients (71%) were diagnosed with de novo AML compared to EZH2-wt patients (84%; p=0.036). Accordingly, EZH2-mut patients had a higher rate of secondary acute myeloid leukemia (sAML) (21%), evolving from prior MDS or after prior chemotherapy (tAML) (8%; p=0.036). Also, bone marrow (and blood) blast counts differed between the two groups (EZH2-mut patients had significantly lower BM and PB blast counts; p=0.013). In contrast, no differences were observed for WBC counts, karyotype, ECOG performance status and ELN-2017 risk category compared to EZH2-wt patients. Based on cytogenetics according to the 2017 ELN criteria, 35% of EZH2-mut patients were categorized with favorable risk, 28% had intermediate and 37% adverse risk. No association was seen with -7/7q-. In the group of EZH2-mut AML patients, significantly higher rates of co-mutations were detected in RUNX1 (25%), ASXL1 (22%) and NRAS (25%) compared to EZH2-wt patients (with 10%; 8% and 15%, respectively). Vice versa, concomitant mutations in NPM1 were (non-significantly) more common in EZH2-wt patients (33%) vs EZH2-mut patients (21%). For other frequently mutated genes in AML there was no major difference between EZH2-mut and -wt patients, e.g. FLT3ITD (13%), FLT3TKD (10%) and CEBPA (24%), as well as genes encoding epigenetic modifiers, namely, DNMT3A (21%), IDH1/2 (11/14%), and TET2 (21%). The correlation of EZH2 mutational status with clinical outcomes showed no effect of EZH2 mutations on the rate of complete remission (CR), relapse free survival (RFS) and overall survival (OS) (with a median OS of 18.4 and 17.1 months for EZH2-mut and -wt patients, respectively) in the univariate analyses. Likewise, the multivariate analysis with clinical variable such as age, cytogenetics and WBC using Cox proportional hazard regression, revealed that EZH2 mutations were not an independent risk factor for OS or RFS. Conclusion EZH mutations are recurrent alterations in patients with AML. The association with certain clinical factors and typical mutations such as RUNX1 and ASXL1 points to the fact that these mutations are associated with secondary AML. Our data do not indicate that EZH2 mutations represent an independent prognostic factor. Disclosures Middeke: Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Rollig:Bayer: Research Funding; Janssen: Research Funding. Scholl:Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Abbivie: Other: Travel support; Alexion: Other: Travel support; MDS: Other: Travel support; Novartis: Other: Travel support; Deutsche Krebshilfe: Research Funding; Carreras Foundation: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Hochhaus:Pfizer: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Takeda: Research Funding. Brümmendorf:Janssen: Consultancy; Takeda: Consultancy; Novartis: Consultancy, Research Funding; Merck: Consultancy; Pfizer: Consultancy, Research Funding. Burchert:AOP Orphan: Honoraria, Research Funding; Bayer: Research Funding; Pfizer: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Research Funding. Krause:Novartis: Research Funding. Hänel:Amgen: Honoraria; Roche: Honoraria; Takeda: Honoraria; Novartis: Honoraria. Platzbecker:Celgene: Research Funding. Mayer:Eisai: Research Funding; Novartis: Research Funding; Roche: Research Funding; Johnson & Johnson: Research Funding; Affimed: Research Funding. Serve:Bayer: Research Funding. Ehninger:Cellex Gesellschaft fuer Zellgewinnung mbH: Employment, Equity Ownership; Bayer: Research Funding; GEMoaB Monoclonals GmbH: Employment, Equity Ownership. Thiede:AgenDix: Other: Ownership; Novartis: Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-114421

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 1221-1221

Abstract: Living without treatment has become a realistic target for patients with chronic myeloid leukemia (CML) who achieved durable deep molecular remission under treatment with tyrosine kinase inhibitors (TKI). Recently, we have identified novel BCR-ABL-independent gene mutations in newly diagnosed CML patients that may function as important cofactors in the evolution of CML and persistence of the disease (Schmidt M, Rinke J, et al. Leukemia 2014; 28(12): 2292-9). Here, we sought to investigate the dynamics of such mutations during a 2-year treatment with the second generation TKI nilotinib. To check if BCR-ABL independent mutations are an age associated phenomenon we also screened a cohort of children and adolescents with CML. A total of 51 chronic phase CML patients were analyzed including 31 adults (male, n=23; median age 57 years, range 42 to 73 years) and 20 children/adolescents (male, n= 14; median age 14 years, range 10 months to 27 years). For each adult patient, samples were analyzed at diagnosis, in subsequent complete cytogenetic remission (CCyR) after 3 months and in deep molecular remission (≤ MMR) after 24 months of nilotinib therapy. Children/adolescents samples were investigated at diagnosis only. Targeted deep next-generation sequencing (NGS) was used to analyze a panel of 30 commonly mutated genes in myeloid disorders. Constitutional DNA obtained from buccal swabs at diagnosis was investigated to check whether mutations are of somatic origin. BCR-ABL independent gene mutations were found in 8/31 (26%) adult CML patients at diagnosis affecting the genes ASXL1 (n=3), DNMT3A (n=3), RUNX1 (n=1) and RUNX1 plus TET2 (n=1). No mutation was recognized in corresponding constitutional DNA specimens indicating that all mutations were somatically acquired. Analysis of individual hematopoietic colonies from three adult patients revealed that most mutations were part of the BCR-ABL-positive clone. NGS of subsequent samples obtained after three months of TKI therapy identified two DNMT3A mutations in BCR-ABL-negative cells that were also present in BCR-ABL-positive cells at diagnosis, implying that this mutation preceded the BCR-ABL rearrangement. After 24 months of TKI treatment, NGS revealed these two DNMT3A mutations again as well as a novel low-level EZH2 mutation in a patient with deep molecular remission (MR4.5) that was neither detectable at diagnosis nor after 3 months of treatment indicating the emergence of a BCR-ABL-independent subclone in BCR-ABL-negative cells during long-term nilotinib treatment. Within the children/adolescents cohort BCR-ABL independent gene mutations were identified in 5/20 (25%) subjects all affecting the ASXL1 gene. All mutations were stop codon or frameshift mutations implying loss of ASXL1 gene function. We conclude that BCR-ABL independent gene mutations can be found frequently in CML patients and affect predominately epigenetic modifier genes. The finding of frequent mutations also in children/adolescents implicates that BCR-ABL independent gene mutations are not just age-related events. Such molecular aberrations may play an important role in the evolution and persistence of the disease and may affect therapy in both children and adults with CML. These findings may provide important novel genetic information regarding CML biology and for the design and performance of discontinuation trials. Disclosures Hochhaus: Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; BMS: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.1221.1221

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 1569-1569

Abstract: Resistance and CML stem cell persistence preclude cure for the majority of patients treated with tyrosine kinase inhibitor (TKI) therapies. We demonstrated that the receptor tyrosine kinase (RTK) Axl of the Tyro-3, Axl, Mer (TAM) family is expressed by TKI-sensitive and -resistant CML cells (Erdmann R. et al. ASH 2013 and 2014). We have shown that blockade of the Gas6-Axl axis by the small molecule Axl inhibitor BGB324 (BerGenBio) represents a therapeutic target in AML. We are currently investigating BGB324 in a Phase 1b trial in refractory AML patients and in those non-eligible for intensive chemotherapy (BGBC003, NCT02488408). We hypothesised that Axl represents a tractable therapeutic target even in the most resistant forms of CML. Upon treatment with imatinib KCL-22 and K562 cells showed upregulation of Axl at the protein level indicating that Axl might be involved in resistance towards TKIs in CML. Consistently, Axl levels were higher in MNCs of TKI-resistant patients compared to -sensitive patients after 6 months of treatment (n=17/20, 1±0.4 vs. 0.16±0.03; *p 〈 0.05). Upon combined treatment of KCL-22 and K562 cells with BGB324 and imatinib we detected an additive effect of growth inhibition (KCL-22 cells; n=3, viability 66.0±0.5% BGB324, 52.0±1.1% imatinib, 42.3±1.5% combo; combo vs. IM *p 〈 0.01 and combo vs. BGB324 *(p 〈 0.0001), and not shown). Analysis of intracellular signal transduction in these cell lines indicated that Axl induces phosphorylation of Stat5 by BCR-ABL independent pathways because we detected an additive effect of inhibition of Stat5 phosphorylation when combining imatinib and BGB324. We could not detect an additive inhibitory effect on phosphorylation of Erk and Akt. Consistently, combined BCR-ABL and Axl blockade by means of imatinib and shRNA respectively, demonstrated an additive effect in reducing cell viability in KCL-22 and K562 cells (KCL-22 cells; n=3, viability 84.5±0.8% shControl+imatinib, 74.5±2.6% shAxl, 50.4±0.9% shAxl+imatinib; shAxl+IM vs. IM *(p 〈 0.0001) and vs. shAxl *(p 〈 0.001) and not shown). We next investigated Axl activation in TKI insensitive BCR-ABL+ cell lines. In addition we tested a novel Ponatinib-resistant cell line KCL-22 PonR generated by subcloning parental KCL-22 in increasing concentrations of ponatinib. BCR-ABL is unmutated in these cells; oncoprotein kinase activity is switched off but cell death is not induced with 2mM ponatinib. We found that Axl phosphorylation was higher in the TKI-resistant cell lines BaF3/T315I, KCL-22 T315I and KCL-22 PonR when compared to the parental cell lines (n=3, 139±3.8% KCL-22 T315I, 214±1.3% KCL-22 PonR with respect to KCL-22 WT, *p 〈 0.001 for both comparisons; 169±8.7% with respect to BaF3/p210, *p 〈 0.005). Treatment with BGB324 inhibited cell proliferation with an IC50of 726, 3178 and 2720nM for BaF3/T315I, KCL-22 T315I and KCL-22 PonR, respectively. BGB324 could induce apoptosis and reduce proliferation in these cell lines. Furthermore, BGB324 blocked growth of colonies and induced apoptosis of T315I-mutated and pan-TKI-resistant (including ponatinib) primary CML MNCs. The finding that BGB324 inhibits TKI-resistant CML was further corroborated with KCL-22 T315I mutated and KCL-22 PonR xenograft models. In both models we observed a significant tumor growth reduction upon treatment with 25 mg/kg BGB324 twice daily compared to placebo leading to a 34% and 58% reduction in tumor volume, p=0.0044, p=0.0021 for KCL-22 T315I and KCL-22 PonR, respectively). Cell proliferation was quantified by pHH3 analysis indicating a significant reduction in KCL-22 T315I and KCL-22 PonR tumors (n=8, 242.8±10.9 vs. 182.2±8.1, *p 〈 0.0001; n=9, 259.5±9.3 vs. 213.2±6.8; *p 〈 0.0001, respectively). Furthermore, we observed a significant decrease of Axl, Erk and Stat5 phosphorylation after treatment with BGB324 for 8 days. We also investigated the therapeutic effect of BGB324 in a systemic model, by transplantation of KCL-22 PonR into sublethally irradiated NSG mice. In this model, treatment with 25 mg/kg BGB324 twice daily resulted in significant prolongation of overall survival (median OS 36 days (control) vs 43 days (BGB324), n=5 *p 〈 0.05). In summary, our data highlight the advantage to be gained from inhibition of Axl even in the most resistant CML cells, and support the need for human clinical trials of the novel inhibitor BGB324 alone and in combination with TKIs. Disclosures Schafhausen: Novartis: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Hochhaus:Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding. Holyoake:Novartis: Research Funding; BMS: Research Funding. Loges:BerGenBio: Honoraria, Other: travel support, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.1569.1569

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7