ALBERT

Description: Abstract 899 Introduction: The classic definition of acute (aGVHD) and chronic graft-versus-host disease (cGVHD) was based on a cut-off day 100 after transplantation, but this did not reflect that aGVHD can occur later and that symptoms of aGVHD and cGVHD can occur simultaneously. In 2005 a NIH consensus classification was proposed which included 1) classic aGVHD, occurring before day 100, 2) persistent, recurrent or late aGVHD occurring thereafter, 3) classic cGVHD and 4) an overlap syndrome with simultaneous features of aGVHD and cGVHD. Only few studies have evaluated this classification and no studies have determined the differential impact of reduced intensity (RIC) and myeloablative conditioning (MAC). Method: We retrospectively analyzed 202 AML patients who were transplanted between 1999 and 2008. 102 patients received RIC (generally 6×30 mg/m2 FLU, 4×4 mg/kg BU, 4×10 mg/kg ATG) and immunosuppression with CSA/MMF and 100 patients received MAC (generally 6×2 Gy TBI and 2×60 mg/kg CY) and CSA/MTX. Donors were HLA-matched related (n=82), -matched unrelated (n=88) or -mismatched (n=32). Result: Leukocyte recovery was faster after RIC than after MAC (14 vs. 19 days, P

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

Description: Background Ponatinib is a potent oral pan–BCR-ABL tyrosine kinase inhibitor (TKI) that has demonstrated significant clinical activity in heavily pretreated CP-CML pts. A multivariate analysis of CP-CML pts in the PACE trial found significant associations between major cytogenetic response (MCyR) and higher dose intensity; however, dose reductions and/or interruptions (DR/I) of ponatinib occur often in pts who experience adverse events (AEs). The clinical significance of such DR/I are not well known. Objectives To assess the impact of DR/I and dose intensity of ponatinib on clinical outcomes in pts with CP-CML enrolled in the PACE trial. Methods A total of 270 CP-CML pts were enrolled in this ongoing, phase 2, international, open-label clinical trial. The efficacy population (N=267) was included in this post hoc analysis. Dose reductions were defined as any reduction below the standard 45 mg daily dose; interruptions were defined as a period in which ponatinib was held for ≥3 consecutive days between non-missing doses. Up to 2 reductions (to 30 or 15 mg/day) were permitted for managing AEs. To assess the impact of dose modification on response, pts were grouped according to tertiles of average dose intensity (mg/day), calculated as the cumulative dose divided by treatment exposure. All variables were calculated within 12 mos of the first dose to correspond to the primary outcome measure of MCyR by 12 mos. Secondary efficacy endpoints included complete cytogenetic response (CCyR) and major molecular response (MMR). Responses were assessed every 3 mos. The Cochran–Armitage trend test was used to assess whether response rates increased with higher average dose intensity tertiles; all P-values were 2-sided. Data are as of 01 Apr 2013, with a median follow-up of 20 (0.1–28) mos. Minimum follow-up for pts still on study was 18 mos. Results A total of 209 (78%) pts required DR/I at least once within 12 mos: 172 pts (64%) had at least 1 dose reduction (median time to first dose reduction was 64 days). In pts with 〉1 dose reduction (n=75, 28%), the median time between the first and second reduction was 91 days. Among pts with a dose reduction at any time, 35% re-escalated to 45 mg daily. Dose interruption was experienced by 199 (75%) pts (median total duration of 35 days). The most common reason for DR/I was thrombocytopenia (33%). For pts with average dose intensity ≤27 mg/day (N=89), 〉27 to ≤42 mg/day (N=88), and 〉42 mg/day (N=90), respectively, the median age was 62, 62, and 56 yrs; median time since initial diagnosis was 11, 7, and 6 yrs; each group had received a median of 3 prior TKIs. Among these tertiles, the best response to the most recent dasatinib- or nilotinib-containing regimen was MCyR or better in 21%, 22%, and 35%; CCyR or better in 11%, 14%, and 23%; MMR or better in 1%, 2%, and 6%, respectively. Within 12 mos of the first dose, median duration of treatment exposure was 356 (26–366), 366 (51–366) and 366 (3–366) days, respectively. Twenty-nine pts had 27 to ≤42 mg/day and 〉42 mg/day. Response rates were lower in pts with average dose intensity ≤27 mg/day; however, these pts still achieved MCyR, CCyR, and MMR rates that substantially exceeded those reported with the most recent dasatinib- or nilotinib-containing regimen. Conclusions Higher dose intensity of ponatinib was associated with higher response rates in this heavily pretreated CP-CML population, but lower dose intensity still led to positive clinical outcomes. It should be noted that higher responses to the most recent dasatinib- or nilotinib-containing regimen were also seen in pts with higher average dose intensity. In summary, these data indicate that although optimal responses were seen with average ponatinib dose intensity 〉42 mg/day, pts can be effectively managed with dose reduction or interruption if clinically indicated. Disclosures: Pinilla-Ibarz: Novartis, Ariad: Research Funding; Novartis, Ariad, BMS and Pfizer: Speakers Bureau. Cortes:Ariad, Pfizer, Teva: Consultancy; Ariad, BMS, Novartis, Pfizer, Teva: Research Funding. Kim:BMS, Novartis, IL-Yang: Consultancy; BMS, Novartis, Pfizer, ARIAD, IL-Yang: Research Funding; BMS, Novartis, Pfizer, IL-Yang: Honoraria; BMS, Novartis, Pfizer: Speakers Bureau; BMS, Pfizer: Membership on an entity’s Board of Directors or advisory committees. Le Coutre:Novartis: Research Funding; Novartis, BMS, Pfizer: Honoraria. Paquette:Ariad, BMS, Novartis: Consultancy; Ariad, BMS, Novartis: Honoraria; Ariad, BMS, Novartis: Speakers Bureau. Chuah:Novartis, BMS: Honoraria. Nicolini:Novartis, ARIAD, Teva: Consultancy; Novartis, BMS: Research Funding; Novartis, BMS, Teva, Pfizer, ARIAD: Honoraria; Novartis, BMS, TEva: Speakers Bureau; Novartis, ARIAD, Teva, Pfizer: Membership on an entity’s Board of Directors or advisory committees. Apperley:Novartis: Research Funding; Ariad, Bristol Myers Squibb, Novartis, Pfizer, Teva: Honoraria. DeAngelo:Araid, Novartis, BMS: Consultancy. Abruzzese:BMS, Novartis: Consultancy. Rea:BMS, Novartis, Pfizer, Ariad, Teva: Honoraria. Baccarani:ARIAD, Novartis, BMS: Consultancy; ARIAD, Novartis, BMS, Pfizer, Teva: Honoraria; ARIAD, Novartis, BMS, Pfizer, Teva: Speakers Bureau. Muller:Novartis, BMS, ARIAD: Consultancy; Novartis, BMS: Research Funding; Novartis, BMS, ARIAD: Honoraria. Gambacorti-Passerini:Pfizer: Research Funding; Pfizer, BMS: Honoraria. Lustgarten:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Rivera:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc. Other, Employment. Clackson:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Turner:ARIAD: Employment. Haluska:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Deininger:BMS, ARIAD, NOVARTIS: Consultancy; BMS, NOVARTIS, CELGENE, GILEAD: Research Funding; ARIAD, NOVARTIS: Advisory Boards, Advisory Boards Other. Hochhaus:Ariad, Novartis, BMS, MSD, Pfizer: Research Funding; Novartis, BMS, Pfizer: Honoraria. Hughes:Novartis, BMS, ARIAD: Honoraria, Research Funding. Goldman:ARIAD: Honoraria. Shah:Ariad, Bristol-Myers Squibb: Consultancy, Research Funding. Kantarjian:ARIAD, Novartis, BMS, Phizer: Research Funding. Talpaz:Ariad, BMS, Sanofi, INCYTE: Research Funding; Ariad, Novartis: Speakers Bureau; Ariad, Sanofi, Novartis: Membership on an entity’s Board of Directors or advisory committees.

Description: Abstract 3774 BACKGROUND/METHODS: Data from the ENESTnd phase III trial showed superiority of nilotinib over imatinib leading to accelerated approval of nilotinib as initial treatment of ECPCML at a dose of 300mg BID. ICORG, the All-Ireland Cooperative Oncology Research Group, has been coordinating an international open-label, single stage, multicenter, investigator-initiated phase II study (ClinicalTrials.gov NCT00809211) of the safety and efficacy of nilotinib 300 mg BID in previously untreated patients with ECPCML. The primary study endpoint is the complete cytogenetic response (CCyR) rate at 6 months; secondary endpoints include the kinetics of molecular response, determined by RQ-PCR at baseline and 3 monthly from start of treatment as well as an evaluation of a novel rapid turnaround PCR system “GeneXpert” with IS BCR-ABL1/ABL1 RQ-PCR. The study closed to accrual with 61 patients (median age 54 years [range 20 –77]) enrolled; 53% have low risk Sokal score, 25% intermediate and 22% high risk. Median follow up is currently 12 months (range 1–30) and by November 2011 all patients will have had at least 6 months follow up. RESULTS: At the time of this analysis, 6 and 12 month follow up data were available in 43 and 31 patients, respectively. By intention to treat analysis, 41/43 (95%) have achieved CCyR within 6 months with all patients still on treatment at 12 months achieving CCyR. 26/43 (60%) and 25/31 (81%) of patients have achieved a major molecular response (MMR) (BCR-ABL1/ABL1 IS ≤ 0.1%) within 6 and 12 months, respectively, with 16/31 (52%) and 11/31 (35%) patients on treatment at least 12 months achieving BCR-ABL1/ABL1 IS ≤ 0.01% and ≤ 0.0032%, respectively. Sokal risk had no apparent effect on response with 12/16 (75%) low risk and 13/15 (87%) intermediate/high risk patients achieving MMR within 12 months, p=0.65. Thus far 4/6 (67%) high risk Sokal patients achieved BCR-ABL1/ABL1 IS ≤ 0.0032% within 12 months. No patients have suffered CML progression to date. 53 patients remain on study. Six patients have been removed from study due to adverse events: 4 patients due to persistent drug-related toxicity; 2 patients non drug-related events (death due to progressive multiple system atrophy and colorectal carcinoma, respectively). In addition, one patient was enrolled but never received study drug and an additional patient was lost to follow up. Treatment was generally well tolerated and toxicities easily managed. Haematologic toxicity was minimal with grade III/IV thrombocytopenia seen in 3 (5%) patients and only a single patient (2%) each with grade III/IV neutropenia and anemia, respectively. The most common grade III/IV non-haematologic toxicity was lipase elevation, seen in 14/61 (23%). No cases of acute pancreatitis were seen. Other grade III/IV non-hematologic toxicities were uncommon (〈 5% patients). While treatment was interrupted at least once in 36/59 (61%) patients, the median duration of interruptions was short (5 days). At last follow up 49/59 (83%) of patients were taking ≥ 300mg BID. The study evaluation of the “GeneXpert” PCR system consisted of paired BCR-ABL1/ABL1 measurements performed by RQ-PCR methodologies aligned to International Standard (IS) and by the Xpert BCR-ABL Monitor system on 36 evaluable patients at diagnosis and at 128 subsequent three-monthly time-points. In patients expressing e13a2 or e14a2 BCR-ABL1 transcripts, both techniques had comparable results at diagnosis: IS median BCR-ABL1/ABL1 41.0% vs 44.0% median BCR-ABL1/ABL1 on the Xpert BCR-ABL Monitor. In the 122 paired analyses, correlation between methodologies, without automated system IS conversion, over a five log range (IS BCR-ABL1/ABL1 100–0.001%) was favourable (r2=0.845), however a progressive decline in correlation was noted with each decreasing log IS BCR-ABL1/ABL1 level. No significant difference was observed between the Xpert BCR-ABL Monitor and IS RQ-PCR in identifying MMR (44.3% vs 41.8%). CONCLUSION: In ECPCML, nilotinib 300mg BID induces high rates of CCyR and MMR with a substantial fraction of patients achieving responses in the range of complete molecular response (CMR). This regimen's toxicity is modest. The GeneXpert system provides a reliable and rapid means of assessing CML patients' response to tyrosine kinase inhibitor (TKI) therapy. Development of a reagent lot-specific conversion factor to the IS would enhance GeneXpert's applicability in monitoring TKI therapy in patients with CML. Disclosures: O'Dwyer: Novartis: Honoraria, Research Funding. Giles:Novartis: Consultancy, Honoraria, Research Funding. le Coutre:Novartis: Honoraria, Research Funding, Speakers Bureau. Nagler:Novartis: Honoraria, Research Funding. Egan:Novartis: Employment. Conneally:Novartis: Honoraria.

Description: Background Clonal proliferation of T/NK cells has been noted after the treatment of CML patients with dasatinib. Previous reports have suggested that persistent expansion of clonal cytotoxic T cells or NK cells in dasatinib-treated patients may be associated with higher response rates and increased occurrence of pleural effusions. This retrospective study analyzed the incidence of lymphocytosis and its association with response, progression-free survival (PFS) and overall survival (OS), and pleural effusion in a large sample of dasatinib-treated patients. Methods Analyses were conducted using dasatinib-treated patients from three large studies with ≥3 years of follow-up: CA180-056 (DASISION), which included 258 dasatinib-treated patients with newly diagnosed CML in chronic phase (CML-CP); CA180-034, which included 662 dasatinib-treated patients with CML-CP who were previously treated with imatinib; and CA180-035, which included 316 dasatinib-treated patients with CML in accelerated phase (CML-AP) and 148 dasatinib-treated patients with CML in myeloid blast phase (CML-MBP) who were previously treated with imatinib. Results Lymphocytosis, as defined by ≥2 consecutive lymphocyte counts 〉 3600/µl after 28 days of treatment, was present in 33% of patients (85/258) with newly diagnosed CML-CP in DASISION (median time to onset, 4.6 months) and 31% of patients (206/662) with imatinib-resistant or -intolerant CML-CP in CA180-034 (median time to onset, 3.0 months). The median on-treatment follow-up times were 36.8 months and 29.3 months for DASISION and CA180-034, respectively. For CA180-035, the median on-treatment follow-up time was 6.1 months, and lymphocytosis developed in 35% of patients (110/316) with CML-AP and 34% of patients (51/148) with CML-MBP. Lymphocytosis persisted for 〉12 months in 64% of patients (54/85) with newly diagnosed CML-CP, in 52% of patients (107/206) with imatinib-resistant or -intolerant CML-CP, in 42% (46/110) with CML-AP, and in 18% (9/51) with CML-MBP. The proportion of newly diagnosed patients with complete cytogenetic response (CCyR) or major molecular response (MMR) at any time was higher among those with vs. without lymphocytosis: 89% (76/85) vs. 80% (138/173) for confirmed CCyR and 74% (63/85) vs. 67% (116/173) for MMR. Patients who developed lymphocytosis during treatment with second-line dasatinib were more likely to achieve CCyR, regardless of disease phase; the proportion of patients who achieved CCyR with vs. without lymphocytosis was 62% (127/206) vs. 49% (222/456) for CML-CP, 46% (51/110) vs. 27% (55/206) for CML-AP, and 31% (16/51) vs. 14% (14/97) for CML-MBP. In landmark analyses of patients with CML-CP in DASISION who were still on first-line dasatinib at 3 or 8 months, lymphocytosis status did not significantly affect PFS or OS. Similar results were found in the second-line studies, when considering patients with CML-CP, -AP, or -MBP who were still on study treatment (second-line dasatinib) at 3 months. Pleural effusions (all grades) developed more often in newly diagnosed patients with lymphocytosis (28% [24/85] vs. 16% [27/173] without lymphocytosis) and in imatinib-resistant or -intolerant patients with CML-CP (38% [79/206] vs. 30% [136/456]) or CML-AP (53% [58/110] vs. 31% [64/206]). The proportion of patients with CML-MBP developing pleural effusions was 27%, regardless of the presence of lymphocytosis (14/51 with lymphocytosis and 26/97 without lymphocytosis). Conclusions Lymphocytosis develops very commonly after treatment with dasatinib and persists for 〉1 year in an appreciable fraction of patients. Immunophenotyping was not done, but it can be presumed that this represents a large granular lymphocyte proliferation in most patients, based on other studies. Lymphocytosis was associated with higher CCyR rates in all stages of CML, as well as higher rates of pleural effusions in CML-CP and -AP. Lymphocytosis was also associated with higher MMR rates in patients with CML-CP receiving first-line dasatinib. There appears to be no significant association, however, between lymphocytosis and PFS or OS in this analysis. Prospective studies are warranted to more carefully characterize the functional activity of these cells and to help assess whether an immunologic effect against CML is detectable in some patients, particularly advanced phase patients with unexpected long responses to treatment with dasatinib alone. Disclosures: Schiffer: Novartis: Consultancy, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Teva: Consultancy; Eisai: Consultancy; Ariad: Research Funding; Pfizer: Research Funding. Cortes:Ariad: Consultancy, Grant to institution Other, Honoraria; BMS: Grant to institution, Grant to institution Other; Novartis: Grant to institution, Grant to institution Other; Pfizer: Consultancy, Grant to institution, Grant to institution Other, Honoraria; Teva: Consultancy, Grant to institution Other, Honoraria; Tragara: Membership on an entity’s Board of Directors or advisory committees; Ambit: Grants/grants pending for institution Other; Astellas: Grants/grants pending for institution, Grants/grants pending for institution Other; Incyte: Grants/grants pending for institution, Grants/grants pending for institution Other; Arog: Grants/grants pending for institution Other; Celgene: Grants/grants pending for institution, Grants/grants pending for institution Other; sanofi: Grants/grants pending for institution, Grants/grants pending for institution Other. Saglio:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. le Coutre:Novartis: Honoraria, Research Funding; BMS: Honoraria; Pfizer: Honoraria. Porkka:BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Mustjoki:BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Mohamed:BMS: Employment, Stock/stock options; travel/accommodations/meeting expenses unrelated to activities listed Other. Shah:BMS: Consultancy, Grants/grants pending to institution for costs related to clinical research Other; Ariad: Consultancy, Grants/grants pending to institution for costs related to clinical research, Grants/grants pending to institution for costs related to clinical research Other.

Description: Abstract LBA-1 Background: Nilotinib is a highly potent and the most selective inhibitor of BCR-ABL, the only proven molecular target for CML therapy. ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients) is a phase 3, randomized, open-label, multicenter study comparing the efficacy and safety of 300 or 400 mg bid nilotinib with 400 mg qd imatinib in patients (pts) with newly diagnosed Ph+ CML in chronic phase (CML-CP). Methods: 846 pts with newly diagnosed Ph+ CML-CP, diagnosed within 6 mos, and stratified by Sokal risk score, were randomized 1:1:1 to nilotinib 300 mg bid (n=282), nilotinib 400 mg bid (n=281), and imatinib 400 mg qd (n=283) arms. The primary endpoint was rate of major molecular response (MMR) at 12 months (mos). All pts had a minimum of 12 mos of treatment or discontinued early; median follow-up was 14 mos. MMR was defined as a value of ≤ 0.1% of BCR-ABL/ABL ratio on the International Scale. Molecular response was assessed by RQ-PCR at baseline, monthly for 3 mos and every 3 mos thereafter. Samples were analyzed at a central PCR laboratory. The major secondary endpoint was rate of complete cytogenetic response (CCyR) by 12 mos based on bone marrow cytogenetics. Results: Baseline demographics, disease characteristics, and Sokal scores were well balanced among the 3 arms; pts with high-risk Sokal scores were 28% in all arms. Median dose intensities of nilotinib delivered were 592 mg/day for 300 mg bid and 779 mg/day for 400 mg bid; imatinib dose intensity was 400 mg/day. Overall, 84%, 82%, and 79% of pts remained on the study for 300 mg bid nilotinib, 400 mg bid nilotinib, and 400 mg qd imatinib, respectively. Rates of MMR at 12 mos (Table) were superior for nilotinib 300 mg bid compared with imatinib 400 mg qd (44% vs. 22%,P 〈 .0001) and also for nilotinib 400 mg bid compared with imatinib 400 mg qd (43% vs. 22%,P 〈 .0001). Median time to MMR among pts who achieved MMR was faster for nilotinib 300 mg bid (5.7 mos) and nilotinib 400 mg bid (5.8 mos) compared with imatinib 400 mg qd (8.3 mos). Rates of CCyR by 12 mos were significantly higher for both nilotinib at either 300 mg bid compared with imatinib 400 mg qd (80% vs. 65%,P 〈 .0001) and for nilotinib 400 mg bid compared with imatinib 400 mg qd (78% vs. 65%,P = .0005). Overall, progression to advanced disease was lower for nilotinib 300 mg bid (2 pts) and nilotinib 400 mg bid (1 pt) compared with imatinib 400 mg qd (11 pts). Overall, both drugs were well-tolerated. Rates of discontinuation due to adverse events or laboratory abnormalities were 7% for nilotinib 300 mg bid, 11% for nilotinib 400 mg bid, and 9% for imatinib 400 mg qd. Pts were monitored for QT prolongation and LVEF. No patients in any treatment arm showed a QTcF interval 〉 500 msec. There was no decrease from baseline in mean LVEF anytime during treatment in any arm. The study is ongoing. Conclusions: Nilotinib at both 300 mg bid and 400 mg bid induced significantly higher and faster rates of MMR and CCyR compared with imatinib 400 mg qd, the current standard of care in pts with newly diagnosed CML. Nilotinib was effective across all Sokal scores. After only one year of treatment, both nilotinib arms resulted in a meaningful clinical benefit compared to imatinib, with reduction of transformation to AP/BC. Nilotinib exhibited a favorable safety and tolerability profile. The superior efficacy and favorable tolerability profile of nilotinib compared with imatinib suggests that nilotinib may become the standard of care in newly diagnosed CML. Disclosures: Saglio: Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Off Label Use: Nilotinib is not currently approved for first-line treatment of CML. The presentation will report the results from a randomized study of imatinib versus nilotinib in patients with newly diagnosed Ph+ CML-CP. Kim:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Wyeth: Research Funding. le Coutre:Novartis: Honoraria, Research Funding; BMS: Honoraria. Reiffers:Novartis: Research Funding. Pasquini:Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees; BMS: Membership on an entity’s Board of Directors or advisory committees; Schering: Membership on an entity’s Board of Directors or advisory committees. Clark:Novartis: Honoraria, Research Funding, Speakers Bureau. Hughes:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Hochhaus:Novartis: Research Funding. Gallagher:Novartis: Employment, Equity Ownership. Hoenekopp:Novartis: Employment. Dong:Novartis: Employment, Equity Ownership. Haque:Novartis: Employment. Larson:Novartis:

Description: Abstract 5002 Background: Janus kinases are critical components of cytokine signaling pathways that regulate hematopoiesis, growth, immunity, inflammation, and development. Oncogenic mutations of the non-receptor tyrosine kinase JAK2 are found in many Philadelphia chromosome negative myeloproliferative neoplasms. The V617F mutation in JAK2 occurs in 95% of patients with polycythemia vera, 50% of those with essential thrombocythemia and 50% of primary myelofibrosis patients. Preclinical results strongly support that JAK2 inhibitors could be effectively used in these three indications. Replacement of valine 617 with phenylalanine upregulates the tyrosine kinase activity of JAK2, causing constitutive activation of the JAK-STAT pathway and growth factor-independent cell proliferation. JAK2 has also been postulated to play an important role in BCR-ABL signal transduction. Therefore, inhibitors of the tyrosine kinase activity of JAK2 are under investigation as new therapy strategies for CMPNs. In this study the role of the novel JAK2 inhibitor, NVP-BSK805 (Novartis Pharmaceuticals), has been investigated in cells expressing either BCR-ABL or mutant JAK2. Possible synergistic effects between NVP-BSK805 and the already established tyrosine kinase inhibitors imatinib and nilotinib were assessed. Methods: The in vitro activity of NVP-BSK805 was analyzed in 12 hematopoietic cell lines, including 7 BCR-ABL positive (K562, KCL22, KU812, Lama87, BV173, EM3, SUP-B15), 4 JAK2 mutated (CHRF288, SET2, UKE1, HEL), the T-cell leukemia cell line Jurkat, and the neuroendocrine colonic tumour line LCC-18. Concentration kinetics from 0 up to 25 μM were established using XTT proliferation assays and flow cytometry for measuring apoptosis. Protein levels of JAK2, phospho-JAK2, STAT5, phospho-STAT5 and BCR-ABL were analyzed using Western blotting. NVP-BSK805 was also tested in combination with imatinib and nilotinib. JAK2 was sequenced in all cell lines in order to detect possible mutations in the gene. Results: Of the JAK2 mutated cell lines tested, 3 of 4 (CHRF288, SET2, UKE1) showed a significant reduction of proliferation, as well as viability, compared to the other cell lines. CHRF288 responded best to NVP-BSK805 with an IC50 value of 0.22 ± 0.04 μM. UKE1 and SET2 had similar values of 0.35 ± 0.03 μM and 0.37 ± 0.05 μM. Interestingly, HEL (V617F positive) cells showed only an IC50 value (1.8 ± 0.17 μM) for NVP-BSK805, comparable with that of the non-mutated BCR-ABL positive cell lines (1.5 to 2.7 μM). LCC-18 showed the weakest response of all cell lines tested, with an IC50 value of 9.93 ± 0.202 μM. Each cell line responded to concentrations higher than 5 μM with a strong reduction of proliferation due to inhibition of various kinases. Combination of the JAK2 inhibitor with imatinib and nilotinib showed no significant additive or synergistic effects, although all BCR-ABL positive cell lines responded well to both CML therapeutic agents. Western blotting of proteins of the JAK-STAT pathway confirmed the results of the proliferation and apoptosis tests showing a strong reduction of phoshorylated STAT5 in CHRF288 cells after a 30 min incubation even with NVP-BSK805 concentrations as low as 0.01 μM. UKE-1 and SET-2 showed reduction of pSTAT5 from 0.1 μM. Levels of total STAT5 were not affected. In all the other cell lines no changes were detected in any of the proteins tested. Conclusions: Here, we tested a novel JAK2 inhibitor in cells carrying the V617F mutation. Interestingly, not every cell line with the JAK2 V617F mutation showed a good response upon JAK2 inhibition, indicating that there are additional factors determining response. On the other hand, clinical trials with JAK inhibitors in myelofibrosis have shown responses in V617F-mutated and non-mutated patients, warranting further research to identify predictors of response. In BCR-ABL mutant cells not harbouring JAK2 mutations no significant inhibition of proliferation or apoptosis was detected following JAK2 inhibition, indicating that there are JAK2 independent signal transduction pathways of BCR-ABL to avoid apoptosis. Disclosures: le Coutre: Novartis Pharmaceuticals: Honoraria, Research Funding.

Description: Purpose: Allogeneic stem cell transplantation (alloSCT) following standard MAC is associated with a considerable treatment-related mortality (TRM) and, therefore, is usually limited to medically fit patients younger than 55 years. In contrast, RIC allows to offer alloSCT to patients ineligible to transplantation following standard MAC due to substantial comorbidities or advanced age. However, depending on the presence of additional factors, i.e. favorable, intermediate, or poor risk cytogenetics, it is not clear whether the reduced TRM in patients undergoing alloSCT following RIC is outweighed by an increased relapse rate. Patients and Methods: Here, we present a retrospective single-institution analysis of 53 AML patients (median age 38 (17 – 68) years) who underwent alloHSCT in CR1 between 1999 and 2007 (median follow-up of the surviving patients 60 (8 – 114) months). All patients had an intermediate risk karyotype as defined by the SWOG/ECOG (Slovak et al., Blood 2000): normal, +8, +6, -Y, del(12p). As stem cell source 48/53 patients (91%) received peripheral blood stem cells (PBSC), whereas bone marrow (BM) was given in 5/53 patients (9%). In 32/53 patients (60%) standard MAC (12 Gy total body irradiation + 120 mg/kg cyclophosphamide) (MAC group) was given. 21/53 (40%) patients received RIC (fludarabine 180 mg/m2 + oral busulfane 8 mg/kg + anti-thymocyte globulin 30 mg/kg) (RIC group). A matched-related donor was available for 35/53 patients (66%), whereas alloHSCT was performed from a matched unrelated donor or a mismatched unrelated donor in 16/53 (30%) or in 2/53 (4%) patients. Graft-versus-host disease (GvHD) prophylaxis consisted of cyclosporin (CSA) + metothrexate (MTX) in the MAC group or CSA + mycophenolate mofetil (MMF) in the RIC group. Notably, 35/53 patients (66%) had an intermediate (1–2 points) hematopoietic cell transplantation-specific comorbidity index (HCT-CI), whereas or 18/53 patients (34%) had an unfavorable (33 points) HCT-CI. As expected, patients in the RIC group were significantly older (RIC: 48 (21 – 48) years versus MAC: 33 (17 – 66) years; p = 0.003) or had a significantly higher HCT-CI (p = 0.003). Results: Projected overall survival (OS) or disease-free survival (DFS) of the whole cohort at 1, 3, and 5 years was 83%, 69%, and 66% or 72%, 65%, 65%. Causes of death were relapse (10/53 patients, 19%) or TRM (7/53 patients, 13%). The OS in the MAC group versus the RIC group at 1, 3, and 5 years was 76% versus 86%, 64% versus 66%, and 64% versus 66% and did not differ significantly (p = 0.79). Furthermore, there was no significant difference in the 1, 3, and 5-year DFS (75%, 64%, and 64% versus 75%, 68%, and 68%) between the MAC group and the RIC group (p = 0.78). Notably, OS and DFS reached a plateau at 39 months (MAC group) or 23 months (RIC group). There were no significant differences in the cumulative incidences of relapse in the MAC group versus the RIC group at 1 year (11% versus 5%), 3 years (23% versus 21%), or 5 years (27% versus 21%) (p = 0.63). The cumulative incidences of TRM were 13% versus 10%, 13% versus 17%, and 13% versus 17% at 1, 3, and 5 years and did not differ significantly between both groups (p = 0.88). Also, there was no significant difference in the incidence of chronic GvHD between the MAC group and the RIC group. Conclusions: AML patients with an intermediate risk karyotype may achieve durable long-term remissions after alloSCT following RIC. Furthermore, relapse rates were not increased as compared to alloSCT upon standard myeloablative conditioning, which supports the high efficacy of the graft-versus-leukemia (GvL) effect. Consequently, alloHSCT following RIC may represent a therapeutic option for all AML patients with an intermediate risk karyotype.

Description: Background: Imatinib, nilotinib, and dasatinib are BCR-ABL tyrosine kinase inhibitors (TKIs), with different selectivity profiles, approved for the treatment of patients (pts) with Philadelphia positive chronic myeloid leukemia (Ph+ CML). Given the differences in their kinase selectivity profiles, the safety profiles of these agents also differ, particularly with regard to episodes of fluid retention. The incidence of pleural/pericardial effusions in resistant or intolerant CML pts who failed imatinib, or both imatinib and dasatinib, therapy was evaluated. Methods: The occurrence of pleural/pericardial effusions in resistant or intolerant CML pts following therapy with imatinib, or imatinib and dasatinib sequentially, was evaluated in 915 pts with Ph+ CML in chronic phase (CML-CP, 60%), accelerated phase (CML-AP, 23%), and blast crisis (CML-BC 17%) who entered the nilotinib compassionate use program between June 2006 and April 2008. At the time of medical review for compassionate use approval, safety information including the presence of or the history of pleural/pericardial effusions was collected along with dosing information for imatinib and dasatinib. Nearly all pts analyzed (94%) had not received nilotinib therapy prior to inclusion in the compassionate use program. Resistance and intolerance as well as CML phase were defined using similar criteria as previously reported in the nilotinib pivotal phase I/II study. Results: The median age was 52 years (range: 11 – 87 years); 22 pts (2%) were 18 years old or younger. Most pts (734; 80%) had received prior imatinib only (64% discontinued due to resistance, 20% with resistance and intolerance and 16% due to intolerance) and 170 pts received both imatinib and dasatinib (29% resistant; 17% with resistance and intolerance, 54% intolerant), with most dasatinib failures being due to toxicity. Information on past treatment is currently unavailable for 11 pts. Of pts who were pretreated with imatinib alone, less than 2% of pts (n = 11) had pleural and/or pericardial effusions reported. Among those pts pretreated with both imatinib and dasatinib, 51 pts (30%) had pleural and/or pericardial effusions, with 50 (98%) having pleural effusions, 10 of which were bilateral. Fifty-five percent of pts with pleural and/or pericardial effusions were in chronic phase. Of the pts with dasatinib-associated pleural/pericardial effusions; 11% were noted on daily doses 〉 140 mg, 29% on doses of 140 mg, 20% on doses of 100 mg, and 10% on doses of 〈 100 mg. There were 14 pts who developed pleural and/or pericardial effusions in which the dasatinib dose was not available. Of the 33 pts with pleural and/or pericardial effusions on daily 140 mg dasatinib, 16 pts (48%) discontinued dasatinib due to pleural effusion and 6 pts exhibited persistent pleural effusions despite dasatinib dose reductions. One pediatric patient (age 11 years) had a pleural effusion with once daily 80 mg dasatinib. Pleural/pericardial effusions occurred in all age groups: 〉50 years old – 6 pts, 51–60 years old – 10 pts; 61–70 years old – 13 pts; 71–80 years old – 16 pts and 〉81 years old – 4 pts (2 of unknown age). No pts who developed dasatinib-associated pleural/pericardial effusions had a history of pleural/pericardial effusions during imatinib therapy. Conclusions: This large dataset supports earlier reports that pleural/pericardial effusions are frequently reported among CML pts treated with dasatinib compared with imatinib. Furthermore, the occurrence of dasatinib-associated pleural/pericardial effusions may occur at any dose, even below the standard 140 mg/day dose and in some cases with doses less than 100 mg/day.

Description: Background: Nilotinib is a rationally designed, potent and highly selective BCR-ABL kinase inhibitor with significant clinical efficacy in the treatment of patients with Philadelphia chromosome-positive chronic myeloid leukemia patients in chronic (CML-CP) or accelerated phase (CML-AP) who are resistant or intolerant to prior therapy including imatinib. This subanalysis of the phase 2 registration study of nilotinib was designed to examine the occurrence of cross-intolerance to nilotinib in patients with prior intolerance to imatinib. Methods: Imatinib intolerance was defined as discontinuation of imatinib due to grade 3/4 adverse events (AEs) or persistent (〉1 month) or recurrent (recurred 〉3 times) grade 2 AEs despite optimal supportive care. Additionally, patients with major cytogenetic response (MCyR) at baseline were excluded from the trial. Cross-intolerance between nilotinib and imatinib was defined as treatment with nilotinib and occurrence (regardless of causality) of grade 3/4, or persistence or recurrent grade 2, of the same AE(s) that previously led to discontinuation of imatinib therapy. Nilotinib was dosed at 400mg twice daily with the option to escalate to 600 mg twice daily for lack of response. Results: Ninety-five of 321 (30%) CML-CP patients and 27 of 138 (20%) CML-AP patients were included in this subanalysis of cross-intolerance following imatinib intolerance. Patients experiencing multiple reasons for imatinib intolerance were counted for each AE category and these included patients (8 CML-CP, 3 CML-AP) with unusual symptoms during imatinib therapy, none of these patients discontinued nilotinib due to the same AE. Median dose intensity for nilotinib (CML-CP 688mg/day, range 151–800; CML-AP 769mg/day range 184–1149) closely approximated the planned dose of 800mg/day. Among these patients, 64% of CML-CP and 52% of CML-AP patients experienced dose interruptions, however, the median cumulative duration of dose interruptions were short (CML-CP 24 days, range 1–301; CML-AP 17 days, range 4–234). Of the 72 patients (57 CML-CP, 15 CML-AP) who discontinued imatinib due to non-hematologic AEs, 3/72 (4%) experienced same persistent grade 2 AEs, only 1 patient (1%) experienced a recurrence of same grade 3/4 AE during nilotinib therapy, and none discontinued nilotinib due to cross intolerance. Approximately one-third of patients were imatinib intolerant due to hematologic AEs. Of 39 patients (30 CML-CP, 9 CML-AP) with hematologic intolerance to imatinib, 3/39 (8%) experienced same persistent grade 2 hematologic AEs, 20/39 (51%) of patients experienced a recurrence of same grade 3/4 AEs during nilotinib therapy, however, only 7 (18%) discontinued nilotinib and all occurred in CML-CP patients due to thrombocytopenia. Nilotinib therapy exhibited significant efficacy in imatinib-intolerant patients. Among the imatinib-intolerant patients included in this subanalysis who did not have complete hematologic response (CHR) at baseline, 90% of patients with CML-CP and 37% with CML-AP achieved a CHR on nilotinib therapy. Among all imatinib-intolerant patients included in this subanalysis, MCyR was achieved by 63% and 32% of patients with CML-CP and CML-AP, respectively; CCyR was achieved by 49% of CML-CP and 19% of CML-AP patients. Conclusions: These results confirm that there is minimal cross-intolerance with nilotinib in imatinib-intolerant CML-CP and CML-AP patients. Thrombocytopenia was the only laboratory abnormality leading to imatinib intolerance that has recurred with any significant frequency during nilotinib therapy.