Abstract: Abstract 1932 High dose chemotherapy followed by autologous hematopoietic stem cell transplantation (HSCT) is an effective treatment for patients with non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). At present, G-CSF-mobilized peripheral blood stem cells (PBSCs) are the preferred stem cell source for autologous HSCT. Fludarabine and lenalidomide are essential drugs in the front line treatment of NHL and MM respectively. Data suggests that fludarabine and lenalidomide therapy may have a deleterious effect on stem cell mobilization. Prior to the drug approval in Europe, a plerixafor compassionate use program (CUP) was available from July 2008 to August 2010 to provide access to the drug for patients with MM or lymphoma who had previously failed a mobilization attempt, and who were not eligible for another specific plerixafor trial. In the European CUP, 48 patients (median age 57 years; range, 36–69), previously treated with fludarabine (median 5 cycles; range, 1–7 cycles) were given plerixafor plus G-CSF for remobilization following a primary mobilisation attempt. All 48 patients had a diagnosis of NHL. The overall median number of CD34+ cells collected was 2.3×106 /Kg (range, 0.3–13.4). The minimum required number of CD34+ cells (≥2.0×106 per kg) was collected from 58% of patients, while only 3 patients (6%) collected ≥5.0×106 CD34+ cells. The collection target of 2.0×106/Kg was reached in a median of 2 apheresis sessions (range, 1–3). Thirty-five patients (median age 57 years; range, 34–66), previously treated with lenalidomide (median 5 cycles; range, 1–10 cycles) were given plerixafor plus G-CSF for remobilization. All patients the 35 patients had MM. The overall median number of CD34+ cells collected was 3.4×106/Kg (range, 1.1–14.8). The minimum required number of CD34+ cells (≥2.0×106 per kg) was collected from 69% of patients, including 12 patients (34%) who were able to collect ≥5.0×106 cells/Kg. In the Len group, 7 patients (20%) had received a prior autologous HSCT before salvage mobilization with plerixafor. Both targets were reached with a median of 2 apheresis sessions (range, 1–4). In conclusion, salvage mobilization with plerixafor plus G-CSF is successful in the majority of patients with MM previously treated with lenalidomide. In fludarabine-exposed patients, only 58% of patients will achieve successful salvage mobilization with plerixafor plus G-CSF, suggesting the need for large prospective studies evaluating the efficacy of plerixafor for frontline mobilization in this subgroup of patients.Table 1.Study population characteristicsCharacteristic (%)Fludarabine (N=48)Lenalidomide (N=35)Patient age, median (range)57 (36–69)57 (34–66)Patient gender    Male26 (54)18 (51)    Female22 (46)17 (42)Fludarabine or Lenalidomide cycles, median (range)5 (1–7)5 (1–10)Diagnosis and disease statusIndolent NHL48 (100)0 (0)Multiple myeloma0 (0)35 (100)Previous chemotherapy: number of lines, median (range)3 (1–6)4 (1–9)Previous autograft    Yes07 (20)    No43 (90)20 (57)    Data missing5 (10)8 (23)Radiotherapy    Yes5 (10)3 (9)    No36 (75)24 (68)    Data missing7 (15)8 (23)Mobilization strategy with plerixafor    Steady-state GCSF mobilization38 (79)27 (77)    Chemotherapy+GCSF mobilization10 (21)8 (23)No. of patients collected44 (92)34 (97)CD34+ cells collected per Kg, median (range)2.3 (0.3–13.4)3.4 (1.1–14.8)No. of patients who reached ≥ 2.106 CD34+28 (58)24 (69)No. of apheresis days to reach ≥ 2.106 CD34+2 (1–3)2 (1–4)No. of patients who reached ≥ 5.106 CD34+3 (6)12 (34)No. of apheresis days to reach ≥ 5.106 CD34+2 (1–3)2 (1–3)NHL, non-Hodgkin lymphoma Disclosures: Mohty: Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract: BACKGROUND. Tyrosine Kinase Inhibitors (TKIs) are part of the successful clinical management of patients with Chronic Myeloid Leukaemia (CML). However, optimal clinical management of CML requires a robust, standardized laboratory assay used at key clinical milestones to ensure a successful outcome for patients on TKIs. Quantitative monitoring of %BCR-ABL1IS by reverse transcription quantitative PCR (RT-qPCR) is the gold standard strategy for evaluating patient response to therapy and classification into prognostic subgroups. However, it can be challenging to perform in a reproducible manner. Reverse-Transcription Digital PCR (RT-dPCR) is an adaptation of this method that could provide the robust and standardized workflow needed for patient stratification. AIM. In this study, we compared three different dPCR platforms and investigated whether they could be applied to a clinical setting to quantify BCR-ABL1 transcripts in CML patients. METHODS. BCR-ABL1 and ABL1 transcript copy numbers were quantified in a total of 102 samples; 70 CML patients undergoing TKI therapy and 32 non-CML individuals. Three commercially available RT-dPCR platforms (QS3D, QX200 and RainDrop) were compared with the routinely used RT-qPCR platform using a modified version of the Europe Against Cancer (E.A.C.) assay. RESULTS. Measurements on all instruments correlated well when the %BCR-ABL1IS was ≥0.1% (R2 = 0.91, 0.93, 0.95 for QS3D, QX200, RainDrop, respectively)(Figure 1A). RT-dPCR quantification of the BCR-ABL1 transcript copy numbers however correlated well with RT-qPCR across all three platforms down to ≥0.1% (R2 = 0.85, 0.94, 0.92 for QS3D, QX200, RainDrop, respectively) (Figure 1B). Below this level, while the correlation was maintained, there was greater variation among instruments between RT-dPCR and RT-qPCR. Agreement between instruments was consistently higher for BCR-ABL1 copies than for ABL1 copies on the same patient set; thus changing the %BCR-ABL1 ratio values frequently varying by one order of magnitude when compared to RT-qPCR (R2 = 0.89, 0.92, 0.97 for QS3D, QX200, RainDrop, respectively) (Figure 1C). Furthermore, none of the platforms were able to substantially improve the sensitivity of quantification by RT-qPCR in relation to patients samples with %BCR-ABL1IS level 〈 0.001%. When using the QS3D there was good correlation down to approximately 20 copies of BCR-ABL1 transcripts, below which a plateau was observed (Figure 2). For quantification of the lowest two CML categories, 0.001% and 〈 0.001%, all three RT-dPCR instruments detected amplification of BCR-ABL1 targets (Figure 2). However, the comparison between these groups and the non-CML control groups showed a positive measurement in the absolute quantification of BCR-ABL1 in the negative control groups (false positive rate; FPR) that clearly affected the sensitivity of measurement in these two lowest CML categories (Figure 2). For the QX200 platform, the plateau was less pronounced than that observed with the QS3D. The FPR was visibly lower than those of the QS3D and Raindrop platforms. However, for the QX200, the lowest three CML categories (≤0.01%) were indistinguishable from the negative control patient groups (Figure 2). Only the Raindrop platform was able to measure % BCR-ABL1 IS in the 〈 0.001% range at a level higher than the FPR in the control patient groups (Figure 2). This was possibly related to the larger volume of cDNA added to each reaction (10 µl as opposed to 1 µl). However, in the CML patient samples, the Raindrop platform did not quantify any difference in the BCR-ABL1 transcripts in proportion to the disease level they were assigned (0.01%, 0.001% or 〈 0.001%) (Figure 2). CONCLUSION. RT-dPCR was able to quantify low level BCR-ABL1 transcript copies but was unable to improve sensitivity below the level of detection achieved by RT-qPCR. However, RT-dPCR was able to perform these sensitive measurements without calibration curve. Adaptions to the protocol to increase the amount of RNA measured, a redesign of the assay used and an alternative reference gene to ABL1 are likely to be necessary to improve the analytical sensitivity of BCR-ABL testing. Disclosures Griffiths: Affymetrix: Research Funding. Apperley:Bristol Myers Squibb: Honoraria, Speakers Bureau; Incyte: Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Ariad: Honoraria, Speakers Bureau.

Abstract: The NF-κB transcription factor pathway is aberrantly activated in multiple myeloma (MM) and many other cancers, where it promotes malignancy by upregulating survival genes, thus providing a compelling rationale for therapeutically targeting this pathway in MM. However, despite aggressive efforts to develop a specific NF-κB or IκB kinase (IKK)β inhibitor, no such inhibitor has been approved, due to the preclusive toxicities associated with the general suppression of NF-κB. As a key pathogenetic activity of NF-κB in MM is to block apoptosis through the induction of target genes, an attractive alternative to globally inhibiting NF-κB would be to therapeutically target the non-redundant, cancer-specific downstream effectors of the NF-κB survival pathway. Recently, we identified the interaction between the NF-κB-regulated antiapoptotic factor, GADD45β, and the JNK kinase, MKK7, as a pathogenically critical and cancer cell-restricted survival module downstream of NF-κB and novel therapeutic target in MM. Further, we developed a D-tripeptide inhibitor of the GADD45β/MKK7 complex, DTP3, which effectively kills MM cells by inducing MKK7/JNK-dependent apoptosis and, importantly, is not toxic to normal tissues. Due to this cancer-cell specificity, DTP3 has similar anti-cancer efficacy to bortezomib, but more than 100-fold higher cancer-cell specificity in patient MM cells, ex vivo. DTP3 also displays potent and cancer-selective activity against MM in preclinical animal models, with no apparent side-effects, and far greater therapeutic index than existing treatments. DTP3 further displays synergistic activity with conventional MM therapies, such as bortezomib, suggesting a clinical utility as frontline combination therapy. Additionally, it retains therapeutic efficacy in MM cells that are resistant to most common MM treatments, suggesting further clinical utility. We currently aim to conduct a phase I/IIa clinical trial of DTP3 in MM to deliver clinical Proof of Concept for a cancer-selective NF-κB-targeting strategy as a highly effective novel therapy. This first-in-man study will commence in late 2015. We report here the results from the regulatory pharmacodynamics (PD), safety pharmacology, pharmacokinetic (PK), and toxicology studies. 28-day intravenous (i.v.) repeat dose toxicology studies in rat and dog demonstrate that DTP3 is well tolerated, with no significant target organs of toxicity at up to 17 times the optimal exposure in mouse efficacy models. Toxicokinetic (TK) analyses indicate that DTP3 does not accumulate on repeat dosing. Safety pharmacology studies indicate no adverse effect on the central nervous, cardiovascular or respiratory systems. In an Ames assay, DTP3 was not mutagenic. In the rat, i.v. DTP3 rapidly and extensively distributes to tissues, does not pass the blood-brain barrier, and is readily eliminated in urine (30%) and faeces (60%). No major metabolites have been identified. In vitro, DTP3 did not inhibit or induce major human cytochrome P450 isoforms, suggesting no potential for drug interactions via P450. In vitro, DTP3 is neither a substrate for nor inhibitor of P-gp or BCRP, nor is it a substrate or inhibitor of most transporters evaluated. However, DTP3 is a substrate for the uptake transporters, MATE1, MATE2-K and OATP1B3, with some inhibitory potential for MATE1 and MATE2-K at high concentrations. PD studies in a mouse xenograft model show that i.v. bolus injection of at least 10 mg/kg of DTP3 over 2 weeks, daily, every other day, or every 3 days, is highly effective in causing complete tumour regression. The PK and TK evaluation of DTP3 in rat and dog identified long plasma half-lives, modelled into a half-life of 20-24 hr in man. On these bases, we have proposed an initial clinical dosing regimen of DTP3 of three times per week i.v., testing doses from 0.5 to 20 mg/kg. The data also support a subcutaneous route of administration, and an i.v. bolus regimen of twice per week. Collectively, the preclinical package demonstrates the outstanding selective pharmacology and efficacy of DTP3, combined with excellent i.v. tolerability, wide therapeutic window, and favourable PK profile, and supports progression into clinical development. A companion biomarker programme has also been developed in order to inform patient stratification, demonstrate pathway-specific PD activity and proof of mechanism, and so maximise the chance of a positive clinical response. Disclosures Tornatore: Kesios Therapeutics Ltd.: Consultancy, Equity Ownership, Honoraria, Patents & Royalties. Adams:Kesios Therapeutics Ltd.: Consultancy. Kelly:Kesios Therapeutics Ltd.: Consultancy. Ruvo:Kesios Therapeutics Ltd.: Equity Ownership, Patents & Royalties. Oakervee:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Schey:Celgene Corporation: Honoraria. Apperley:Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: 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; ARIAD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Franzoso:Kesios Therapeutics Ltd.: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

Abstract: Introduction: Ponatinib is a potent, oral, third-generation tyrosine kinase inhibitor (TKI) that is FDA approved for treatment of patients with relapsed/refractory CML. Patients with resistant or intolerant CP-CML demonstrated deep, lasting responses to ponatinib 45 mg once daily in the pivotal phase 2 PACE trial (Ponatinib Ph+ ALL and CML Evaluation, NCT01207440; completed). The phase 2 OPTIC trial (Optimizing Ponatinib Treatment in CP-CML, NCT02467270; ongoing) prospectively evaluated a response-based dose-reduction strategy in an attempt to optimize the dose schedule of ponatinib in patients with CP-CML resistant to second-generation (2G) BCR-ABL1 TKI therapy or with a T315I mutation. Unique dosing strategies in the 2 trials (PACE and OPTIC) provide the opportunity to closely evaluate the dose and schedule of ponatinib. Here, we conduct an in-depth analysis of dosing dynamics between the 2 trials and compare efficacy and safety outcomes. Methods: In this analysis, adults with resistant or intolerant CP-CML from the PACE and OPTIC trials were enrolled and received an initial dose of ponatinib 45 mg once daily (PACE) or were randomly assigned (1:1:1) to an initial oral dose of ponatinib 45 mg, 30 mg, or 15 mg once daily (OPTIC). In PACE, proactive dose reductions were mandated in ≈2 years from initiation of first patient (in 2013) as arterial occlusive events (AOEs) emerged as notable adverse events (AEs); patients who achieved major cytogenetic response (MCyR) had doses reduced to 15 mg once daily and those without MCyR reduced to 30 mg once daily, unless benefit-risk analysis justified treatment with a higher dose. OPTIC was designed to incorporate a mandatory response-based dose-reduction strategy; patients in the 45-mg and 30-mg cohorts in OPTIC achieving ≤1% BCR-ABL1 IS reduced their dose to 15 mg once daily; doses also were reduced to manage AEs. Data from patients with CP-CML in PACE and from the 45-mg starting dose cohort in OPTIC are included in this analysis. Efficacy outcomes included ≤1% BCR-ABL1 IS, progression-free survival (PFS), and overall survival (OS). Safety and dosing data are also presented, including treatment-emergent adverse events (TEAEs) and treatment-emergent AOE (TE-AOE) rates. Results: Overall, 364 patients with CP-CML had at least 1 prior 2G TKI or had a T315I mutation and received a starting dose of ponatinib 45 mg (PACE, n=270; OPTIC, n=94). Median follow-up, 57 months (PACE) and 32 months (OPTIC). Efficacy outcomes were generally comparable or better in OPTIC when compared with PACE, including ≤1% BCR-ABL1 IS response by 24 months (PACE, 52%; OPTIC, 56%), 2-year PFS (68%; 80%), and 2-year OS (86%; 91%). Median time to ≤1% BCR-ABL1 IS response, 5.6 months (PACE) and 6 months (OPTIC). Median duration of response was not reached in either trial. Overall, median relative dose intensity (Table 1) was 27 mg/d in PACE and 15 mg/d in OPTIC, and dose reduction occurred more rapidly compared with PACE median (Figure). Dose reductions due to AEs occurred in 82% of patients in PACE and 46% in OPTIC. Median time to dose reduction for AEs was 2.85 months in PACE and 3.64 months in OPTIC. Median time on therapy was 12.6 months in PACE and 19.5 months in OPTIC. Exposure-adjusted TE-AOEs were 15.8 events per 100-patient years at 0 to & lt;1 year in PACE and 7.6 events per 100-patient years at 0 to & lt;1 year in OPTIC (Table 2). There were differences in baseline characteristics between the 2 trials, including differences in cardiovascular baseline status; however, these were accounted for in the propensity score analyses comparing AOE incidence, which after adjusting for baseline differences, showed a 60% reduction in relative risk for AOEs in OPTIC vs PACE. In-depth individual dosing dynamics by safety and efficacy will be presented. Conclusions: The response-based dose-reduction strategy in the OPTIC trial resulted in more rapid dose reductions, lower overall median relative dose intensity, fewer dose reductions related to AEs, and longer median time on therapy in OPTIC compared with PACE, further demonstrating the benefit of the response-based dosing regimen used in OPTIC. These data from the PACE and OPTIC trials suggest that treatment with a response-based dose-reduction strategy may provide comparable or better efficacy while mitigating risk of AEs/AOEs with ponatinib. Furthermore, this abstract supports the rationale to explore response-based dose-modification strategies for other BCR-ABL1 TKIs. Figure 1 Figure 1. Disclosures Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Deininger: SPARC, DisperSol, Leukemia & Lymphoma Society: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding; Novartis: Consultancy, Research Funding; Fusion Pharma, Medscape, DisperSol: Consultancy; Sangamo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding; Incyte: Consultancy, Honoraria, Research Funding. Abruzzese: Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Apperley: Bristol Myers Squibb, Novartis: Honoraria, Speakers Bureau; Incyte, Pfizer: Honoraria, Research Funding, Speakers Bureau. Cortes: Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Astellas, Novartis, Pfizer, Takeda, BioPath Holdings, Incyte: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sun Pharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bio-Path Holdings, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Chuah: Pfizer: Other: Travel, Research Funding; Steward Cross: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Novartis, Korea Otsuka Pharmaceutical: Honoraria. DeAngelo: Abbvie: Research Funding; Takeda: Consultancy; Servier: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Jazz: Consultancy; Incyte: Consultancy; Forty-Seven: Consultancy; Autolus: Consultancy; Amgen: Consultancy; Agios: Consultancy; Blueprint: Research Funding; Glycomimetrics: Research Funding. Hochhaus: Bristol-Myers Squibb: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Incyte: Research Funding. Lipton: Bristol Myers Squibb, Ariad, Pfizer, Novartis: Consultancy, Research Funding. Nicolini: BMS: Honoraria; Sun Pharma Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte Biosciences: Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau; Kartos Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Research Funding. Pinilla Ibarz: AbbVie, Janssen, AstraZeneca, Takeda: Speakers Bureau; MEI, Sunesis: Research Funding; Sellas: Other: ), patents/royalties/other intellectual property; AbbVie, Janssen, AstraZeneca, Novartis, TG Therapeutics, Takeda: Consultancy, Other: Advisory. Rea: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rosti: Pfizer: Research Funding, Speakers Bureau; Bristol Myers Squibb, Incyte, Novartis: Speakers Bureau. Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Mauro: Novartis: Consultancy, Research Funding; Takeda: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Pfizer: Consultancy; Sun Pharma / SPARC: Research Funding. Shah: Bristol-Myers Squibb: Research Funding. Talpaz: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Other: Grant/research support ; Constellation: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Imago: Consultancy; Celgene: Consultancy. Vorog: Takeda: Current Employment. Lu: Takeda: Current Employment. Kantarjian: Daiichi-Sankyo: Research Funding; AbbVie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; BMS: Research Funding; Astra Zeneca: Honoraria; Ipsen Pharmaceuticals: Honoraria; KAHR Medical Ltd: Honoraria; Pfizer: Honoraria, Research Funding; Jazz: Research Funding; Novartis: Honoraria, Research Funding; Astellas Health: Honoraria; NOVA Research: Honoraria; Ascentage: Research Funding; Aptitude Health: Honoraria; Immunogen: Research Funding; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria.

Abstract: 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.

Abstract: Information is generally lacking regarding the efficacy and safety of subsequent TKIs after failure of nilotinib. This post-hoc analysis explored the efficacy and safety of ponatinib, a potent oral pan-BCR-ABL inhibitor, following failure of nilotinib in CP-CML patients in the phase 2 PACE trial. Methods The PACE trial enrolled 449 patients, including 270 with CP-CML. Patients had to be resistant or intolerant to dasatinib or nilotinib, or have the T315I mutation at baseline. The primary end point in CP-CML was 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 patients remaining on study. The efficacy and safety of ponatinib (45 mg QD) in 106 CP-CML patients following failure of nilotinib as the most recent prior anticancer therapy, irrespective of other TKI therapy, is presented (Group N). Eleven patients who experienced failure of nilotinib 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 N: 33 patients whose only TKI therapy was imatinib followed by nilotinib (Group I-N), and 68 patients whose only TKI therapy was imatinib, then dasatinib, and then nilotinib (Group I-D-N). An analysis of cross-intolerance was also conducted in 43 patients with prior nilotinib treatment at any time who discontinued nilotinib due to intolerance. Results Baseline characteristics are shown in the table. Group I-N tended to be younger, with less time since diagnosis versus Group I-D-N. At the time of analysis, 59%, 64%, and 56% of patients in Groups N, I-N, and I-D-N remained on study. The most common reasons for discontinuation were adverse events (AEs; 12%, 12%, 13%) and progressive disease (9%, 6%, 9%) in Groups N, I-N, and I-D-N. Efficacy endpoints are shown in the table. In Group N, MCyR was observed in patients with the following nilotinib-resistant mutations at baseline: Y253H, 1/2 (50%); E255K, 5/6 (83%); T315I, 12/22 (55%); F359V, 3/7 (43%); F359C, 1/2 (50%); F359I, 2/3 (67%). The most common treatment-related AEs were thrombocytopenia (38%, 33%, 40%), rash (35%, 30%, 37%), and dry skin (35%, 42%, 31%) in Groups N, I-N, and I-D-N. Serious cardiovascular, cerebrovascular, and peripheral vascular AEs occurred in 6%, 4%, and 2% of patients in Group N (treatment-related: 3%, 1%, 2%). Forty-four of 184 patients discontinued prior nilotinib at any time due to intolerance. Of these 44 patients, 24 experienced the same AE(s) with ponatinib that led to nilotinib intolerance; 12 patients had grade 3/4 thrombocytopenia, 6 patients had other grade 3 AEs (2 with dyspnea, 1 each with atrial fibrillation, musculoskeletal pain, abdominal pain, pain in extremity), 6 patients had grade 1/2 AEs. 7 of the 24 patients discontinued ponatinib due to the same AE that led to nilotinib intolerance. Thrombocytopenia (5 patients) was the primary AE involved in cross-intolerance; atrial fibrillation and pain in extremity each occurred once. Conclusions Ponatinib has substantial activity in patients with CP-CML following failure of nilotinib, with a safety profile reflective of this heavily pretreated population. Cross-intolerance between nilotinib and ponatinib was infrequent. Disclosures: Kantarjian: ARIAD: Research Funding; Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding. Cortes:Ariad, Pfizer, Teva: Consultancy; Ariad, BMS, Novartis, Pfizer, Teva: Research Funding. Kim:BMS: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; IL-Yang: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; ARIAD: Research Funding. Pinilla-Ibarz:Novartis: Research Funding, Speakers Bureau; ARIAD: Research Funding, Speakers Bureau; BMS: Speakers Bureau; Pfizer: Speakers Bureau. le Coutre:Novartis: Research Funding; Novatis, BMS, Pfizer: Honoraria. Paquette:ARIAD: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Chuah:Novartis: Honoraria; Bristol-Myers Squibb: Honoraria. Nicolini:Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; ARIAD: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Teva: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Apperley:Novartis: Honoraria, Research Funding; ARIAD: Honoraria; BMS: Honoraria; Pfizer: Honoraria; 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:ARIAD: Consultancy; Novartis: Consultancy; BMS: Consultancy. Abruzzese:BMS, Novartis: Consultancy. Rea:Pfizer: Honoraria; ARIAD: Honoraria; Teva: Honoraria; Novartis: Honoraria; BMS: Honoraria. Baccarani:ARIAD: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Teva: Honoraria, Speakers Bureau. Müller:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; ARIAD: Consultancy, Honoraria. Gambacorti-Passerini:Pfizer: Honoraria, Research Funding; BMS: Honoraria. ARIAD: 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: Consultancy, Research Funding; ARIAD: advisory board, advisory board Other, Consultancy; Novartis: advisory board, advisory board Other, Consultancy, Research Funding; Celgene: Research Funding; Gilead: Research Funding. Hochhaus:Pfizer: Honoraria, Research Funding; ARIAD: Research Funding; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; MSD: Research Funding. Hughes:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding. Goldman:Ariad: Honoraria. Shah:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding.

Abstract: Abstract 2993 High-dose chemotherapy followed by autologous stem cell transplantation is an approved therapeutic intervention in relapsed Hodgkin-lymphoma (HL) and Non-Hodgkin lymphoma (NHL). In multiple myeloma (MM) it remains standard of care in first remission. Unfortunately, a significant portion of patients fail to mobilize and collect a sufficient amount of hematopoietic stem cells, being considered as “poor-mobilizers”. The effectiveness of the hematopoietic stem cell mobilizing agent plerixafor was evaluated in nationwide compassionate use programs in 13 European countries and reported to the European Consortium of Stem Cell Mobilization (ECOSM). Here we describe the mobilization success of 580 proven poor-mobilizers (304 male, 276 female) with NHL, HL and MM in Europe between May 2008 and August 2009. Furthermore, we analyzed the mobilization of stem cells in major NHL subgroups. All patients received plerixafor plus granulocyte colony-stimulating factor in standard doses with or without chemotherapy. Two-hundred seventy patients with NHL (138 male, 132 female) with a median age of 56 years (range 12 – 75 years) and a median of two prior chemotherapy regimens (range 0 – 10) were enrolled. Median cell yield was 2.56 × 10 ^6 CD34+ cells/kg BW (range 0 – 17.37). The general accepted minimum of 2.0 × 10 ^6 CD34+ cells / kg bodyweight (BW) for transplantation was reached by 175 patients (64.8%) in a median of two apheresis sessions (range 1 – 4). Thirty-four patients (12.6%) yielded more than 5.0 × 10 ^6 CD34+ cells/kg BW. There were no significant differences in in stem cell harvests regarding number of prior mobilization attempts or number of prior chemotherapeutic regimens, as well as in comparing patients with diffuse large B cell lymphoma (n=28), follicular lymphoma (n=15), and mantle cell lymphoma (n=24), respectively. Fifty-four HL patients (24 male, 30 female) with a median age of 36 years (range 19 – 76) and a median of three prior lines of therapy (range 1 – 5) were enrolled. Median cell yield was 3.14 × 10^6 CD34 cells/kg BW (range 0 – 32.6). Forty-four patients (81.5%) collected the minimum of 2.0 × 10^6 CD34+ cells/kg BW in a median of two apheresis sessions (range 1 – 4). Twelve patients (22.2%) collected more than 5.0 × 10 ^6 CD34+ cells/kg BW. A total of 256 patients (148 male, 108 female) with a median age of 60 years (range 28 – 76) diagnosed with MM were enrolled. Patients had received a median of two prior lines of treatment and collected a median of 3.60 × 10 ^6 CD34+ cells/kg BW (range 0 – 15.27) in a median of two apheresis sessions (range 1 – 5). The minimum of 2.0 × 10 ^6 CD34+ cells/kg BW was collected by 209 patients (81.6%). Eighty-two patients (32.0%) yielded more than 5.0 × 10 ^6 CD34+ cells/kg BW allowing tandem transplantation. Overall, the CD34+ cell yield was significantly higher in MM patients than in NHL patients (p 〈 0.0001) and also significantly higher in HL patients than in NHL patients (p =0.013). CD34+ cell yield was not statistically significant between MM patients and HL patients. Furthermore, the number of patients collecting the minimum of 2.0 × 10 ^6 CD34+ cells/kg BW was significantly higher in MM patients compared to NHL patients (p 〈 0.0001) and also significantly higher in HL compared to NHL patients (p =0.017). Analyzing the mobilization strategies and collection success of individual countries demonstrated only minor variations compared to the global results. Chemomobilization and steady state mobilization are used in most countries; however, there is a clear preference for chemotherapy combined with G-CSF/plerixafor in the Czech Republic, Germany, Hungary, Italy and Poland. The data emphasize the role of plerixafor in patients who failed prior mobilization attempts, but the development of improved strategies in poor mobilizers especially with NHL is required. Disclosures: Duarte: Genzyme: Membership on an entity's Board of Directors or advisory committees. Kröger:Genzyme: Membership on an entity's Board of Directors or advisory committees. Mohty:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hübel:Genzyme: Membership on an entity's Board of Directors or advisory committees.