Dean, James P.

BACKGROUND Our knowledge of how the genomic landscape of chronic lymphocytic leukemia (CLL) is impacted by the selective pressure imposed by chemotherapy and targeted agents remains incomplete. We hypothesize that the extent of clonal evolution, baseline transcriptional state, and the overall and clone-specific growth kinetics of CLL will vary under native conditions or following exposure to chemotherapy and targeted therapy. METHODS We report the systematic genomic analysis of leukemia-normal whole-exome sequencing (WES) of 420 samples collected from 170 patients who were >65 years of age with treatment-naïve CLL. The treatment-cohort consisted of 83 patients who received ibrutinib (420mg daily) and 40 patients who received chlorambucil (0.5 mg/kg up to maximum 0.8 mg/kg, on days 1 and 15 of a 28-day cycle, up to 12 cycles) as part of the RESONATE-2 trial (NCT01722487). The ‘watch and wait’ (WW) cohort comprised 47 age-matched patients whose samples originated from the CLL Research Consortium and were untreated for their CLL during sampling. Sampling occurred at baseline and at day 300, and/or day 600, following initiation of therapy or following a diagnosis of CLL for those in the WW cohort. The WW cohort had more cases with a mutated IGHV (72% vs 40%), del17p (14% vs 0%), and del13q (72% vs 45%) when compared to the treatment cohort. Baseline CLL RNA-seq data were available for 150 patients. We used PhylogicNDT to reconstruct the clonal architecture from WES. By determining the fraction of cancer cells with each mutation (cancer cell fraction [CCF]) and their multiplicities (number of DNA molecules carrying a mutation per cancer cell), subclones were identified through clustering of CCFs of mutational events across samples from each patient. This allowed us to estimate the phylogenetic relationships and significant clonal shifts (defined as a distribution shift of CCF in a subclone of >95% between two timepoints, corresponding to a median ΔCCF of 18%) for each patient's CLL and to relate these shifts to somatic and clinical features. RESULTS In total, we identified 791 subclonal clusters across the three patient cohorts (ibrutinib = 406, chlorambucil = 189, WW = 196). We observed higher rates of significant clonal shifts between any two time points in patients exposed to chlorambucil (68%, q=0.008) and ibrutinib (77%, q<0.0001) when compared to patients on WW (36%). There was no significant difference in the number of patients exhibiting a clonal shift between those receiving ibrutinib and chlorambucil (q=0.3). More patients treated with ibrutinib (54%, q=0.0002) and chlorambucil (50%, q=0.004) harbored a clone that reduced in size than those on WW (17%). More patients treated with ibrutinib (71%, q<0.0002) and chlorambucil (55%, q=0.12) possessed at least one clone that increased in size during therapy than patients receiving WW (34%). In ibrutinib-treated patients, SF3B1 mutations (q=0.13, 14% vs 5%) and XPO1 mutations (q=0.13, 5% vs 0.3%) were enriched in subclones that significantly reduced over the complete time period. We also observed more BIRC3 mutations in subclones that had a significant shift in CCF when compared to subclones that remained stable over time (q=0.2, 5% vs 2%). Consistent with the overall study, with 8 years of follow-up in this patient subset, long-term progression-free survival (PFS) was significantly higher in the patients treated with ibrutinib when compared to chlorambucil (P<0.0001). This PFS benefit was also seen regardless of subclonal growth patterns. Using baseline RNA-seq data, we identified 7 of the 8 recently defined CLL expression clusters (EC), that were identified in the context of chemoimmunotherapy for CLL (Knisbacher et al. Nat Gen 2022), and could recapitulate the relationship to outcomes in individuals treated with chlorambucil. However, despite the larger cohort, no significant relationship between EC clusters and PFS were observed in ibrutinib-treated patients, suggesting that a distinct predictive baseline transcriptional signature may be present in ibrutinib-treated patients. CONCLUSION Our analyses highlight the need to interrogate the molecular features of CLL in relation to the impact of therapeutic selective pressure imposed by BTK inhibition, which appear distinct from exposure to chemotherapy. Ongoing analyses aim to identify relationships between patterns of growth and subclonal growth rates molecular and clinical features.

Background : The presence of TP53 aberrations (defined as del(17p) or TP53 gene mutation) is a strong negative predictor of survival in patients (pts) with CLL. First-line chemoimmunotherapy is suboptimal in pts with CLL bearing TP53 aberrations, with 3-year progression-free survival (PFS) and overall survival (OS) rates of only 18% and 38%, respectively, with fludarabine, cyclophosphamide, and rituximab (Hallek, Lancet 2010). Ibrutinib is the only once-daily Bruton's tyrosine kinase (BTK) inhibitor with significant PFS and OS benefit demonstrated in multiple randomized phase 3 studies (eg, RESONATE-2, ECOG1912) in the first-line treatment of CLL/small lymphocytic lymphoma (SLL). Previous reports of single-agent ibrutinib or ibrutinib-based combination treatments have further demonstrated favorable PFS benefit in pts with TP53 aberrations in both the first-line and relapsed/refractory settings. Despite these study-specific subgroup analyses, there are limited data on long-term outcomes in pts with TP53 aberrations treated with first-line BTK inhibitors. We performed a pooled analysis of data across 4 studies to evaluate the long-term efficacy and safety of first-line ibrutinib-based therapy in pts with CLL bearing TP53 aberrations. Methods : Data for first-line ibrutinib treatment in pts with TP53 aberrations were pooled across 4 clinical trials in CLL/SLL: PCYC-1122e (NCT01500733; single-agent ibrutinib; n=34), PCYC-1130 (NCT02264574; ibrutinib + obinutuzumab; n=18), ECOG1912 (NCT02048813; ibrutinib + rituximab; n=26), and RESONATE-2 (NCT01722487; single-agent ibrutinib; n=11). ECOG1912 and RESONATE-2 excluded pts with del(17p) but did not exclude pts with TP53 mutations. Long-term PFS (assessed by investigator), OS, and safety are reported. Results : Eighty-nine pts with TP53 aberrations receiving first-line ibrutinib treatment were included in this pooled analysis. Median age was 65 years (range 33-87), and 69% of pts were male. At baseline, 53% had Rai stage III/IV, 38% had bulky disease (lymph nodes ≥5 cm), and 69% (of 87 evaluable) had unmutated IGHV. All patients had either del(17p) or TP53 mutation; 53% (of 89 evaluable) had del(17p) and 91% (of 58 evaluable) had TP53 mutation. Among 16 pts with del(17p) who had TP53 sequencing results available, 11 (69%) had both del(17p) and TP53 mutation. Forty-five pts received ibrutinib as a single agent and 44 received ibrutinib in combination with an anti-CD20 agent. With a median follow-up of 50 months (range 0.1 to 95.9 months), median PFS was not reached (95% CI: 67 months to not estimable; Figure 1A). At 48 months, the PFS rate was 79% and the OS rate was 88% (Figure 1B). Median duration of ibrutinib treatment was 46 months (range 0.1 to 95.5 months). Reasons for treatment discontinuation were progressive disease (20%), study closure (12%), adverse event (10%), withdrawal by pt (7%), death (3%), and other (physician decision due to scheduled pt surgery; 1%). Grade ≥3 adverse events of clinical interest with up to 8 years of treatment with ibrutinib were infection (22%; most commonly pneumonia in 7%), hypertension (13%), atrial fibrillation (12%), and major hemorrhage (7%). With the current follow-up, 46% of pts with TP53 aberrations remained on ibrutinib treatment. Conclusions : With a median follow-up of 4 years, first-line ibrutinib-based treatment resulted in sustained efficacy with high PFS and OS rates in CLL pts with TP53 aberrations, a population with historically poor outcomes. Although pts with TP53 aberrations remain at risk for progression, first-line treatment with ibrutinib has partially overcome the poor prognosis in this high-risk population with 4-year PFS and OS rates of 79% and 88%, respectively. No new safety signals were identified in this analysis. These results from a large, pooled, multi-study dataset demonstrated the long-term benefit of first-line ibrutinib-based treatment in pts with TP53 aberrations. Disclosures Allan: Janssen, AbbVie, and AstraZeneca: Other: Travel/accommodations/expenses; Celgene, Genentech, AstraZeneca, TG Therapeutics, and Janssen: Research Funding; AstraZeneca, Pharmacyclics LLC, an AbbVie Company, Genentech, AbbVie, Ascentage, and Cellectar: Consultancy; Janssen, AstraZeneca, and AbbVie: Honoraria. Shanafelt:Genentech, Pharmacyclics LLC, an AbbVie Company, AbbVie, GlaxoSmithKline, and Merck: Research Funding; Mayo Clinic: Patents & Royalties: and other intellectual property. Wiestner:Pharmacyclics LLC, an AbbVie Company; Acerta, Merck, Nurix, Verastem, and Genmab: Research Funding; National Institutes of Health: Patents & Royalties: and other intellectual property. Moreno:Janssen, AbbVie, Sunesis, and AstraZeneca: Consultancy; AbbVie and Janssen: Research Funding; Janssen: Speakers Bureau. O'Brien:Eisai: Consultancy; Juno Therapeutics: Consultancy; Aptose Biosciences: Consultancy; GlaxoSmithKline: Consultancy; Sunesis: Research Funding; Acerta: Research Funding; Amgen: Consultancy; Celgene: Consultancy; Pfizer: Research Funding; Pharmacyclics: Research Funding; Astellas: Consultancy; Gilead: Consultancy; TG Therapeutics: Research Funding; Vida Ventures: Consultancy; KITE: Research Funding; Vaniam Group LL: Consultancy; Alexion: Consultancy; Regeneron: Research Funding; AbbVie: Consultancy; Verastem: Consultancy; Janssen Oncology: Consultancy. Braggio:DASA: Consultancy; Bayer: Other: Stock Owner; Acerta Pharma: Research Funding. Liu:AbbVie: Current equity holder in publicly-traded company; Pharmacyclics LLC, an AbbVie Company: Current Employment. Dean:AbbVie: Current equity holder in publicly-traded company; Pharmacyclics LLC, an AbbVie Company: Current Employment. Lai:Pharmacyclics LLC, an AbbVie Company: Current Employment; AbbVie and Bristol-Myers Squibb: Current equity holder in publicly-traded company; AbbVie: Other: Travel/accommodations/expenses.

Abstract Introduction: There are few effective treatment options available for patients (pts) with myelofibrosis (MF). Pts with thrombocytopenia, a risk factor for shorter overall survival, have poorer prognosis (Gangat, J Clin Oncol 2010). Pacritinib is a kinase inhibitor with specificity for JAK2, FLT3, IRAK1, and CFSR1 and has demonstrated minimal myelosuppression in clinical trials (Hart, Leukemia 2011; Komrokji, Blood 2015; Mesa, ASCO 2015). In the phase III open-label PERSIST-1 trial, a significantly greater proportion of pts treated with pacritinib achieved spleen volume reductions (SVR) ≥35% vs BAT (ITT: 19.1% vs 4.7%, p=0.0003; pts evaluable at baseline and Week 24: 25.0% vs 5.9%, p=0.0001; Mesa, ASCO 2015). This analysis examines pt responses across subgroups. Methods: Pts naive to treatment with JAK inhibitors were randomized 2:1 to receive oral pacritinib 400 mg once daily or BAT. Stratification factors included DIPSS risk status and baseline platelet count. Pts were eligible who had DIPSS Intermediate (Int)-1, Int-2, or High risk disease; absolute neutrophil count >500/µL; palpable splenomegaly ≥5 cm; and baseline Total Symptom Score (TSS) ≥13 using the Modified MPN Symptom Assessment Form Total Symptom Score (MPN-SAF TSS and TSS 2.0). There was no restriction on baseline platelets or hemoglobin (Hgb) levels. The primary endpoint was the proportion of pts achieving SVR ≥35% at Week 24 by centrally-reviewed MRI or CT and the secondary endpoint was the proportion of pts achieving ≥50% reduction in TSS from baseline at Week 24 using 6 symptoms from the MPN-SAF TSS. Pt responses were analyzed by baseline risk factors for MF including platelet counts (<50,000/µL vs ≥ 50,000/µL and <100,000/µL vs ≥100,000/µL), sex, age (≥65 y vs <65 y), JAK2V617F mutation status (positive vs negative), baseline MF diagnosis (primary MF [PMF] vs secondary MF), reticulin and collagen fibrosis staging (> 1 vs ≤1), TSS (≥20 vs <20), white blood cell count (>25×109/L vs ≤25×109/L), peripheral blasts (≥5% vs <5%), Hgb (<10 g/dL vs ≥10 g/dL), transfusion dependency by Gale criteria (Y vs N), time from diagnosis (<12 mos vs ≥12 mos), ECOG PS (2-3 vs 0-1), and bone pain (>3 vs ≤3). In multivariate logistic regressions, the odds of SVR ≥35% and TSS reduction ≥50% at Week 24 were modeled as a function of prognostic factors for MF and adjusted for treatment (pacritinib vs BAT). Results for the 6 symptoms common to both TSS versions are reported. Results: 327 pts were enrolled and randomized (pacritinib: 220, BAT: 107). Overall, 62% of pts had PMF; 32% had baseline platelets <100,000/µL and 16% had <50,000/µL; 75% were positive for JAK2V617F. After a median follow-up of 8.4 months, treatment with pacritinib resulted in consistent rates of SVR across subgroups (Figure 1). When comparing vs BAT, the greatest differences in SVR ≥35% rates between treatment arms were observed in pts with baseline platelets <50,000/μL (+22.9% vs BAT), JAK2V617F-negative pts (+23.0% vs BAT) and those aged <65 y (+21.2% vs BAT). Improvements in TSS (TSS and TSS 2.0 reduction ≥50%) were also consistent for pts receiving pacritinib (Figure 2). By multivariate analysis, SVR ≥35% was significantly correlated only with ECOG PS ≥2 (odds ratio [OR]=2.97, p=0.030) and TSS reduction ≥50% was significantly correlated only with bone pain >3 (OR=0.35, p=0.004). Conclusions: Treatment with pacritinib resulted in consistent rates of SVR ≥35% and TSS reduction ≥50% irrespective of baseline characteristics. Comparisons vs BAT were favorable for all patient subpopulations examined for both endpoints. These results support the use of pacritinib across all intermediate- or high risk MF pt subgroups analyzed. Figure 1. Proportion of Patients Receiving PAC who Achieved ≥35% SVR from baseline to Week 24 (95% CI) Figure 1. Proportion of Patients Receiving PAC who Achieved ≥35% SVR from baseline to Week 24 (95% CI) Figure 2. Proportion of Patients Receiving PAC who Achieved ≥50% TSS reduction (6 common symptoms in MPN-SAF TSS and MPN-SAF TSS 2.0) from baseline to Week 24 (95% CI) Figure 2. Proportion of Patients Receiving PAC who Achieved ≥50% TSS reduction (6 common symptoms in MPN-SAF TSS and MPN-SAF TSS 2.0) from baseline to Week 24 (95% CI) Disclosures Vannucchi: Shire: Speakers Bureau; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees. Off Label Use: This abstract discusses off-label use of pacritinib. Mesa:Gilead: Research Funding; NS Pharma: Research Funding; Incyte Corporation: Research Funding; Genentech: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Promedior: Research Funding; Pfizer: Research Funding; CTI Biopharma: Research Funding. Cervantes:Novartis: Consultancy, Speakers Bureau; Sanofi-Aventis: Consultancy; CTI-Baxter: Consultancy, Speakers Bureau. Prasad:BIOGEN IDEC: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Speakers Bureau. Elinder:Celgene: Consultancy. Recher:Sunesis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Chugai: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. te Boekhorst:CTI Biopharma: Consultancy; Novartis: Consultancy. Somervaille:Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees. Dean:CTI Biopharma: Employment, Equity Ownership. Harrison:Shire: Speakers Bureau; Gilead: Honoraria; CTI Biopharma: Consultancy, Honoraria, Speakers Bureau; Sanofi: Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau.

Abstract Background: PAC is an oral kinase inhibitor with specificity for JAK2, FLT3, IRAK1, and CSF1R that has demonstrated significant and sustained spleen volume reduction (SVR) and symptom control vs BAT (excluding JAK2 inhibitors) in MF pts regardless of platelet count (PERSIST-1). The PERSIST-2 study was a randomized, controlled, open-label, phase 3 trial of PAC 200 mg BID and PAC 400 mg QD vs BAT (including JAK1/JAK2 inhibitor ruxolitinib [RUX]) in pts with 10 or 20 MF whose platelet counts were ≤100,000/µL, a recognized adverse prognostic variable. Prior JAK2 inhibitor use was allowed. Methods: Pts were randomized 1:1:1 to PAC BID, PAC QD, or BAT. The co-primary efficacy endpoints were the percentages of pts achieving ≥35% SVR (MRI or CT) and ≥50% reduction in total symptom score (TSS; MPN-SAF TSS 2.0), both from baseline to Week 24. The primary objective was to compare the efficacy of pooled PAC (BID+QD) to BAT and the secondary objectives were to compare PAC BID and PAC QD individually to BAT. PK samples were collected and analyzed for PAC. Safety analyses were based on all pts exposed to study treatment of any duration (safety population); efficacy analyses were based on ITT pts with a randomization date allowing Week 24 endpoint evaluations prior to the full clinical hold* (ITT efficacy population). Results: 311 pts were randomized (107 PAC BID, 104 PAC QD, 100 BAT), 308 received study drug, and 221 were included in the ITT efficacy population (74 PAC BID, 75 PAC QD, 72 BAT). Demographics and baseline disease characteristics were generally balanced among the treatment arms (Table) and analysis populations. A total of 32 (44%) BAT pts in the ITT efficacy population received RUX as treatment at some point on study. Population PK analyses showed that the steady-state plasma levels achieved with BID were higher than with QD, however the Cmax levels were lower. A significantly higher percentage of pts in the pooled PAC arm achieved SVR ≥35% (18% [27/149]) vs the BAT arm (3% [2/72]; p=0.001; Figure 1A). 25% of PAC pts (37/149) had ≥50% reduction in TSS vs 14% of BAT pts (p=0.079; Figure 1B). In secondary analyses vs BAT, PAC BID demonstrated significant improvement over BAT for both efficacy endpoints with 22% achieving SVR ≥35% (BAT=3%; p=0.001) and 32% achieving ≥50% reduction in TSS (BAT=14%; p=0.011). The PAC QD arm had a significant SVR ≥35% (15% v 3%, respectively; p=0.017), but a similar proportion with ≥50% reduction in TSS (17% v 14%, respectively; p=0.652). More PAC pts reduced their red blood cell transfusion dependence at Week 24 (defined as a ≥50% reduction in average transfusions/month for 3 months relative to baseline) with 19% (7/37) in the PAC QD arm, 22% (8/36) in PAC BID, and 9% (3/35) in BAT. There was no significant difference observed in OS across the treatment arms (Figure 2). Hazard ratios for OS (95% confidence intervals) were 0.68 (0.30, 1.53) for PAC BID v BAT, 1.18 (0.57, 2.44) for PAC QD v BAT, and 0.61 (0.27, 1.35) for PAC BID v QD. PAC BID maintained this survival advantage vs BAT across nearly all demographic and MF-associated risk factors. During the course of the study, 10 (9%), 15 (14%), and 15 (14%) died on PAC BID, PAC QD, and BAT, respectively. The most common treatment-emergent adverse events (AEs) associated with PAC were gastrointestinal (diarrhea, nausea, vomiting) and hematologic (anemia and thrombocytopenia), and were generally less frequent for BID vs QD administration. Grade 3/4 cardiac AEs occurred in 7%, 13% and 9% of PAC BID, PAC QD, and BAT pts, respectively, and grade 3/4 bleeding AEs occurred in 14%, 7%, and 7%, respectively. Grade 3/4 bleeding AEs were associated with grade 3/4 thrombocytopenia, which was also more common in the PAC BID group. Nine pts had cardiac failure (2% PAC QD, 4% PAC BID, 3% BAT) and 1 (1%, PAC QD) had intracranial hemorrhage.* Conclusions: The PERSIST-2 study is the only randomized, controlled trial to date in pts with MF and thrombocytopenia (platelets ≤100,000/µL), allowed prior JAK2 inhibitor treatment exposure (including RUX), and allowed RUX as BAT comparator. Irrespective of prior JAK2 inhibitor treatment, both PAC arms were more effective at SVR than BAT; however, PAC BID appeared more active than QD dosing and achieved significance versus BAT for both SVR and TSS. The most frequent AEs with PAC were gastrointestinal and hematologic toxicities. *PAC on full clinical hold by the FDA on 2/8/2016 based on concerns around excess deaths and cardiac and hemorrhagic events in PERSIST-1. Disclosures Mascarenhas: Incyte: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; CTI BioPharma: Research Funding; Janssen: Research Funding; Roche: Research Funding; Promedior: Research Funding. Talpaz:CTI BioPharma: Research Funding; Pfizer: Research Funding; Incyte Corporation: Research Funding; Ariad: Other: Expense reimbursement, travel accomodation expenses, Research Funding; Gilead: Other: Travel, Accommodations, Expenses, Research Funding; BMS - Canada: Consultancy. Gerds:CTI BioPharma: Research Funding; Astra-Zeneca: Research Funding; Roche: Research Funding; Incyte: Research Funding. Stein:Incyte Corporation: Consultancy. Gupta:Incyte Corporation: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Drummond:CTI BioPharma: Honoraria; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Roche: Speakers Bureau. Granston:CTI BioPharma Corp.: Employment. Daly:CTI BioPharma Corp.: Employment. Dean:CTI BioPharma Corp.: Employment, Equity Ownership. Al-Fayoumi:CTI BioPharma Corp.: Employment, Equity Ownership. Callahan:CTI BioPharma: Employment. Singer:CTI BioPharma Corp.: Employment, Equity Ownership, Other: Leadership . Gotlib:Novartis: Other: Travel, Accommodations, Expenses; Steering Committee Chairman, Research Funding; Promedior: Research Funding; CTI BioPharma: Research Funding; Gilead: Research Funding; Incyte: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding. Jamieson:GSK: Research Funding; Johnson & Johnson: Research Funding; CTI BioPharma: Research Funding. Harrison:Novartis: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; CTI BioPharma: Consultancy, Honoraria, Speakers Bureau; Baxter: Consultancy, Honoraria; Shire: Speakers Bureau; Gilead: Speakers Bureau; Incyte: Speakers Bureau. Mesa:Novartis: Consultancy, Honoraria; Incyte: Research Funding; Gilead: Research Funding; CTI BioPharma: Research Funding; Celgene: Research Funding; Genetech: Research Funding; Promedior: Research Funding. Verstovsek:CTI BioPharma Corp: Research Funding.

Abstract Background: The majority of pts with MF present with a mutation in exon 14 of the JAK2 gene (JAK2V617F). Studies have suggested that in pts with MF and this mutation, a lower AB is associated with a myelodepletive phenotype and shortened survival (Tefferi, Leukemia 2008; Guglielmelli Blood 2009; reviewed in Vannucchi, Ther Adv Hematol 2011). For example, in a Cox proportional hazard model for factors predictive of overall survival (OS) in pts with primary MF, a JAK2V617F AB of <25% was associated with a shortened OS (p=0.002; Guglielmelli, Blood 2009). In the phase III trials of ruxolitinib (RUX) therapy in JAK inhibitor-naïve MF, RUX-treated pts had a median decrease in AB of 16% (maximal) in COMFORT-I followed up to 216 weeks and 7% in COMFORT-II at 48 weeks. The median AB at the start of therapy was not reported for COMFORT-I and in COMFORT-II was 84.5% (Cervantes, Blood 2013; Deininger, Blood2015). Methods: In this communication, we report on clinical correlates of quantitative baseline JAK2 mutational status and the effect of treatment on JAK2V617Fmutational burden in the PERSIST-1 trial. This trial enrolled JAK inhibitor-naïve pts with primary or secondary MF without restrictions on baseline platelet counts, randomized 2:1 between PAC and BAT (excluding JAK2 inhibitors) arms. Stratifications included Dynamic International Prognostic Scoring System (DIPSS) risk category, and baseline platelet counts (<50,000/μL, 50,000-100,000/μL, >100,000/μL). Following the 24-week primary analysis, crossover was allowed by physician/pt choice and 90/107 BAT-treated pts (84%) crossed over to receive PAC. Baseline characteristics have been previously reported (Mesa, ASCO 2016) and included 203/327 (62%) pts with Primary MF, 42 (13%) with post-essential thrombocythemia MF and 81 (25%) with post-polycythemia vera MF. 320 of 327 pts had informative PCR testing for JAK2V617F. We report the baseline characteristics of pts with high (≥50%) AB of JAK2V617F, low (<50%) AB of JAK2V617Fand those without a detectable mutation at baseline (<0.1%), as well as the effect of PAC and BAT on AB and correlation with outcome measures. Results: 131 (40.9%) had AB >50% (high AB), 115 (35.9%) had an AB ≥0.1% and ≤50% (low AB), and 74 (23.1%) had AB <0.1% (wild-type JAK2). Median AB values were 80.3% for the high AB group and 30.3% for the low AB group. Baseline characteristics that were significantly different between high and low AB pts are shown in the Table. No differences were noted in the DIPSS risk category or baseline percentage of blasts between pts with low or high AB. There were a higher percentage of pts with a lower AB in the PAC arm (64% vs. 48%; p=0.01). PAC therapy resulted in a median decrement in AB at Week 24 of −15.8% vs −7.9% for pts in the BAT arm (Figure). The median greatest reduction from baseline in AB in PAC-treated pts was −31.6%. Decrease in AB was strongly correlated with spleen volume reduction (p=0.003) and trended towards correlation with improvement in total symptom score (p=0.07) in PAC-treated, but not in BAT-treated pts. Overall survival was shorter in PAC-treated pts with a minimal AB reduction vs pts with greater decreases in AB. Conclusions: In the PERSIST-1 trial, pts with a JAK2V617FAB of <50% had substantially different disease and demographic characteristics when compared with those pts with a >50% AB despite similar distribution of DIPSS scores. In this trial, reduction in AB associated with PAC, but not BAT correlated with clinical benefit. Disclosures Vannucchi: Novartis: Consultancy, Research Funding, Speakers Bureau; Baxalta: Speakers Bureau; Shire: Speakers Bureau. Mead:Baxalta: Consultancy, Honoraria. Perkins:Novartis Oncology: Consultancy, Honoraria; Bristol-Myers Squibb: Other: Travel, Accommodations, Expenses. Mayer:CTI BioPharma Corp.: Other: Travel, Accommodations, Expenses, Research Funding. Schouten:Sanofi: Consultancy; Novartis: Consultancy. Farber:Alexion: Equity Ownership; Celgene: Honoraria, Research Funding, Speakers Bureau; Genentech: Research Funding, Speakers Bureau; Acerta: Research Funding; Gilead: Research Funding, Speakers Bureau; TG Therapeutics: Research Funding; Seattle Genetics: Speakers Bureau; Pharmacyclics: Speakers Bureau. Kiladjian:Novartis: Honoraria, Research Funding; AOP Orphan: Consultancy, Research Funding. Nangalia:Novartis: Consultancy, Other: Travel, Accommodations, Expenses. Dean:CTI BioPharma Corp.: Employment, Equity Ownership. Zhou:CTI BioPharma Corp.: Employment, Equity Ownership. Singer:CTI BioPharma Corp.: Employment, Equity Ownership, Other: Leadership . Mesa:Novartis: Consultancy, Honoraria; Incyte: Research Funding; Gilead: Research Funding; CTI BioPharma: Research Funding; Celgene: Research Funding; Genetech: Research Funding; Promedior: Research Funding. Harrison:Novartis: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; CTI BioPharma: Consultancy, Honoraria, Speakers Bureau; Baxter: Consultancy, Honoraria; Shire: Speakers Bureau; Gilead: Speakers Bureau; Incyte: Speakers Bureau.

LBA7006 Background: PAC is a potent JAK2 inhibitor without significant JAK1 inhibition with minimal myelosuppression in early-phase studies in MF. Methods: The efficacy and safety of daily oral PAC was compared to BAT (2:1 randomization stratified for risk and platelet count). The 10 endpoint was the proportion of ITT patients (pts) achieving ≥ 35% spleen volume reduction (SVR) at week (wk) 24 by centrally reviewed MRI or CT. Secondary endpoints included the proportion achieving ≥ 50% reduction in total symptom score (TSS) at wk 24 using the MPN Symptom Assessment Form. Results: Patients:327 were enrolled (PAC:220, BAT:107), 62% with 10 MF. Median time from diagnosis was 1.12 years (PAC 0.99, BAT 1.60): 32% and 15% had a platelet counts < 100,000/µL or <50,000/ µL; 75% were JAK2V617F positive. Efficacy: The median duration of treatment was 16.2 months PAC and 5.9 months BAT. Sixty-two percent of BAT patients received active disease directed therapy. The SVR rates at week 24 were 19.1% for PAC vs. 4.7% for BAT (p=0.0003) in ITT and 25% vs. 5.9% (p=0.0001) in the evaluable population. 79% of BAT patients crossed over to PAC; 21% had achieved a >35% reduction in spleen volume at data cutoff. TSS composite V1 + V2 response rates were 24.5%for PAC vs. 6.5% for BAT (p<0.0001) by ITT, and were 40.9% vs. 9.9% in evaluable pts (p<0.0001). Efficacy with baseline cytopenias: In pts with <100,000 and <50,000 platelets/μ/L, the SVR rates were 16.7% for PAC vs. 0% for BAT (p=0.009), and 22.9% vs. 0% (p=0.045) by ITT and 23.5% vs. 0% (p=0.007) and 33.3% vs. 0% (p=0.037) in evaluable pts. In RBC transfusion dependent pts, 25.7% of PAC pts became RBC independent vs. 0% of BAT pts (p=0.043). Safety: The most common adverse events (AE) for PAC were diarrhea, nausea, and vomiting; (grade 3 were <5%, <1%, <1% respectively). Hematologic AEs were similar between PAC and BAT. Conclusions: This study demonstrated PAC was well tolerated and induced significant and sustained SVR and symptom control even in patients with severe thrombocytopenia. PAC therapy resulted in RBC transfusion independence in a significant proportion of pts. Clinical trial information: NCT01773187.