Citations

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 Abstract 3211 Poster Board III-148 Although autologous stem cell transplantation (ASCT) has become standard of care for many patients with hematologic malignancies, many patients fail to collect a minimum number of CD34 + stem cells to support high dose chemotherapy and ASCT. Recently, plerixafor, a CXCR4 antagonist, was FDA approved for use in combination with G-CSF for autologous peripheral blood stem cell mobilization in patients with NHL or Multiple Myeloma. In February 2009, we commenced a risk adapted approach to the utilization of plerixafor. The study was restricted to patients mobilized with GCSF alone and patients undergoing chemotherapy primed PBSC mobilization were excluded. Peripheral blood stem cell mobilization was commenced with G-CSF at 10 mcg/kg/day. On day 4, a peripheral blood (PB) CD34 count was measured. For patients whose PB CD34 was ≥10/μL, apheresis was commenced the following morning. For patients whose PB CD34 was <10/μL, it was measured again on day 5; if ≥10/μL then apheresis was commenced the following morning. If PB CD34 was <10/μL on day 5, plerixafor (0.24 mg/kg sc) was administered on the evening of day 5 and apheresis was commenced the following day (Group A). In addition, during apheresis, for patients whose collection yield was < 0.5 × 106 CD34/kg, in the absence of instrument failure or problems with the collection procedure, plerixafor was added (Group B). Morning administration of G-CSF and evening dosing of plerixafor continued daily until apheresis was complete. From February to July 2009, 174 mobilization attempts occurred; 27 with chemotherapy and 147 with cytokines alone. The 147 pts who underwent mobilization with cytokines alone are presented here. The underlying diagnosis was as follows: Myeloma 61 pts, NHL 54 pts, Amyloid 17 pts, Hodgkin 10 pts, POEMS 4 pts and 1 pt with a solid tumor. For the entire group the median number of CD34 cells collected was 5.5 × 106 CD34/kg (range 0.1-17). The median number of apheresis was 3 (range 1-12). 67 patients (46%) received plerixafor; 37 patients started plerixafor during mobilization (Group A) and 30 patients during collections due to a poor yield (Group B). 12 pts of the 37 received plerixafor on day 4 because of prior mobilization failure or high risk of mobilization failure and are included in Group A. Table 1 outlines the details of mobilization and collection by groups. By disease category, of the 61 patients with MM, 28 (46%) received plerixafor (8 Group A and 20 Group B). Median apheresis in all the MM pts was 2 (range 1-12) with a total of 6.8 × 106 CD34/kg (2.2-16.7). In the 54 NHL pts, 32 (59%) received plerixafor (24 Group A and 8 Group B). Median apheresis for all pts with NHL was 3 (range 1-7) with a total of 4.6 × 106 CD34/kg (range 0-11.4). Overall, only 7 of 147 (5%) mobilization attempts failed to achieve a minimum of 2 × 106 CD34/kg. This compares to a 22% failure rate prior to institution of this risk adapted approach. In conclusion, implementing this risk adapted approach allows poor mobilizers to be identified promptly and for plerixafor to be initiated during mobilization and collection, thereby reducing the number of mobilization failures. In patients who predictably would not have successful collection based on a PB CD34 <10/μL, addition of plerixafor results in a majority of patients achieving an adequate collection. This risk adapted approach may be more cost effective than reattempting mobilization after a prior failure or utilizing combination G-CSF and plerixafor for upfront mobilization. Table 1. Mobilization and Collection data. All patients N=147 Group A1 N=37 Group B2 N=30 No Plerixafor N=80 PB CD34 day 4 Median 11 0 7 19 Range 0-331 0-7 0-32 0-331 PB CD34 day 5 Median 10 4.5 12 15 Range 0-51 2-9 11-23 9-51 Apheresis Yield Median 5.5 4.4 6.0 6.2 Range 0.1-17 3.1-12.7 3.0-12.2 2-17 Number of Apheresis Median 3 3 5 2 Range 1-12 1-7 4-12 1-8 Days of Plerixafor Median n/a 3 2 n/a Rang 1-7 1-8 1 Group A – Plerixafor initiated prior to apheresis 2 Group B – Plerixafor initiated during apheresis Disclosures No relevant conflicts of interest to declare.

Abstract Abstract 2142 Poster Board II-119 High-dose chemotherapy in conjunction with autologous SCT is the preferred treatment of relapsed Hodgkin disease and non-Hodgkin lymphoma and newly diagnosed multiple myeloma. Failure to achieve optimal stem cell mobilization results in multiple subsequent attempts, which consumes large amounts of growth factors and potentially requires antibiotics and transfusions. We retrospectively reviewed the natural history of stem cell mobilization attempts at our institution from 2001 through 2007 to determine the frequency of suboptimal mobilization in patients with hematologic malignancy undergoing autologous transplant and analyzed the subsequent resource utilization in patients with initially failed attempts. Of 1,775 patients undergoing mobilization during the study period, stem cell collection (defined by the number of CD34+ cells/kg) was “ optimal” (≥5×106) in 53%, “low” (≥2 to 5×106) in 25%,“ poor” (<2×106) in 10%, and “failed” (<10 CD34+ cells/mL) in 12%. In the 47% of collections that were less than optimal, increased resource consumption included increased use of growth factors and antibiotics, subsequent chemotherapy mobilization, increased transfusional support, more apheresis procedures, and more frequent hospitalization. Other costs often omitted include the need for hospitalization, which was seen in 5% to 11% of the patients in our study. Parenteral antibiotics were needed when fever developed in 7% of patients with Hodgkin disease, 4% with non-Hodgkin lymphoma, and 24% with multiple myeloma who underwent mobilization using a chemotherapy pulse. When stem cell mobilization was not immediately optimal, subsequent attempts to mobilize failed completely in 3 of 42 patients (7%) with Hodgkin disease (3% of the original Hodgkin disease cohort), 56 of 157 (36%) with multiple myeloma (6% of the original myeloma cohort), and 50 of 328 (15%) with non-Hodgkin lymphoma (7% of the original non-Hodgkin lymphoma cohort). These usually unappreciated costs of stem cell mobilization failure highlight the need for more effective mobilization strategies. Disclosures: Gertz: genzyme: Research Funding.

Abstract Abstract 1638 Introduction: Hodgkin lymphoma (HL) represents the most common subtype of malignant lymphoma in young people in the Western world. Most of the patients can be cured with modern treatment strategies. However, about 20% of patients still die due to relapse or progressive disease. Recently, elevated numbers of tumor-associated macrophages in diagnostic pretreatment and relapse biopsies have been associated with poor long-term outcomes. Furthermore, high expression of CSF1R on the malignant Hodgkin Reed Sternberg cells has been linked to shorter progression-free survival, providing the rationale to test PLX3397, a highly selective inhibitor of CSF1R (also known as Fms) and Kit receptor tyrosine kinases, in HL patients. Patients and Methods: Patients with relapsed or refractory HL were enrolled in this single-agent multicenter trial. All patients had progressed after or were ineligible for autologous stem cell transplantation, had radiographically measurable disease, and had discontinued all previous HL therapy. Patients were treated with oral PLX3397 at a dose of 900 mg/day continuously until occurrence of unacceptable toxicity or disease progression. The primary endpoint was the objective response rate according to the 2007 consensus criteria. Results: A total of 20 patients were enrolled (9 male, 11 female, median age 36 years). Six patients had tumor reduction ranging between 3% and 54% including one partial remission (overall response rate of 5%) (Figure). The median duration of progression-free survival was 56 days. The most common drug-related adverse effects were asthenia, fatigue, hair depigmentation, anemia, leukopenia, and increased LDH, all of which were grade 1 or 2 except for one grade 3 neutropenia. CD14dim/16+ labeled peripheral blood monocytes were markedly reduced in all patients at 4 weeks vs. Baseline (median=83% reduction, range of 44%-96% reduction), confirming inhibition of CSF1R signaling. Increases were observed for adiponectin in 82% of patients (median=2.6-fold, range 1.2 to 12-fold) and for CSF-1 in 94% of patients (median=4.0-fold, range 1.4 to 16.5-fold), also consistent with CSF1R inhibition. Archival formalin-fixed paraffin-embedded lymphoma tissues of sufficient quality were available for 12 patients. Biopsy material was obtained from either initial diagnosis or after relapse. CD68+ and CD163+ macrophages were highly elevated (>25% cellularity) in 42% and 58% of patients, respectively. The number of tumor-associated macrophages was not significantly associated with a reduction in lesion size after PLX3397 treatment in this small study cohort. Discussion: In this phase 2 clinical trial, PLX3397 at a dose of 900 mg/day showed limited activity in this heavily pretreated patient cohort. However, target inhibition of both Fms and Kit was clearly demonstrated. Although the efficacy of single agent PLX3397 in this study population was modest, the manageable safety profile and evidence of target inhibition may warrant further testing in combination therapy trials. Disclosures: Younes: Seattle Genetics, Inc.: Consultancy, Research Funding; Millennium: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria; Affimed: Research Funding; Gilead: Research Funding; Johnson & Johnson: Research Funding. Gascoyne:Plexxikon Inc.: Consultancy, Research Funding. West:Plexxikon Inc.: Employment. Nolop:Plexxikon Inc.: Employment. Steidl:Plexxikon Inc.: Research Funding.

Abstract Background: It is well established that the incidence of skin cancers in patients with CLL are significantly elevated compared to age- and sex- matched controls. However, little is known about the characteristics of CLL patients who develop skin cancer. Herein, we evaluate the associations of CLL clinical and prognostic characteristics, along with UV radiation exposure, with risk of first skin cancer following CLL diagnosis. Methods: Newly diagnosed CLL patients from Minnesota, Iowa, and Wisconsin were enrolled in the Mayo Clinic case-control study from 2002-2015 and systematically followed in the Iowa/Mayo Lymphoma SPORE. Clinical and prognostic CLL data were obtained from the Mayo Clinic CLL database, and skin cancer clinical data were abstracted from medical records using a standard protocol. The CLL international prognostic index (CLL-IPI) was computed using a weighted average of five independent CLL prognostic factors (IGHV mutational status, serum b2-microglobulin, Rai stage, age, and FISH 17p deletion/TP53 status). Self-reported history of midday sun exposure at various ages (birth to age 12; 13 to 21 years; 22 to 40 years, and 41+ years) was obtained from a risk factor questionnaire. For each age, we asked the extent of mid-day sun as: practically no exposure (under 3 hours per week), little exposure (4-7 hours per week), moderate exposure (8 to 14 hours per week) and extensive exposure (15+ hours per week). Midday sun exposure was modeled as an ordinal covariate. To evaluate associations with risk of skin cancer following CLL diagnosis, we calculated time from date of CLL diagnosis to date of first skin cancer, death, or last known follow-up. We used Cox regression analysis to estimate hazard ratios (HRs) and 95% CIs. CLL treatment was considered a time-dependent covariate. Results: Among 846 CLL patients enrolled, the median age at diagnosis was 63 years (range 28-91), 68% were male, 7% had Rai stage III-IV at diagnosis. Based on the CLL-IPI, 42% were categorized as low risk, 33% as intermediate risk, and 25% as high or very-high risk. 109 CLL cases (13%) had one or more reported skin cancers at or prior to CLL diagnosis. Melanoma was observed in 19 (2%) cases and non-melanoma was in 90 (11%) cases. At a median follow-up of 7 years from CLL diagnosis, 165 patients (20%) had one or more skin cancers after CLL diagnosis. Among these patients, 49 had skin cancer before CLL diagnosis. The most frequent skin cancer was squamous cell carcinoma (59%), followed by basal cell (31%), melanoma (5%), and Merkel cell (1%). 552 (65%) of the 846 patients returned a questionnaire. Significant associations of clinical and prognostic characteristics with risk of first skin cancer were observed for age (HR=1.35 per 10 year increase, 95% CI=1.17-1.56, P<0.001), male sex (HR=1.38, 95% CI 0.98-1.96, p=0.07), prior history of skin cancer (HR=4.19, 95% CI=2.98-5.88, P<0.001), and CLL-IPI (HR=1.26, 95% CI= 1.03-1.54, P=0.026, after adjusting for age, sex, and prior skin cancer). Of note, the risk of first skin cancer in those CLL patients categorized as very high via CLL-IPI had 2.28 fold risk (95% CI 1.02-5.11). Midday sun exposures for each of the ages considered showed no evidence of association with risk of first skin cancer (all P>0.05). 50 CLL patients were treated prior to first skin cancer following CLL diagnosis; we observed no evidence of association between treatment and risk of first skin cancer (HR=1.44, 95% CI= 0.93-1.92, P=0.12). Conclusion: CLL patients who are at an increased risk of skin cancer following CLL diagnosis are those who either have had a prior history of skin cancer or a more aggressive CLL disease at diagnosis, according to CLL IPI. Routine skin cancer screening is currently recommended for CLL patients. Our data suggest that more frequent screening would be particularly important among patients with aggressive CLL and who have a prior history of skin cancer. Unexpectedly, we found no evidence of association of skin cancer risk with UV radiation following CLL diagnosis or with CLL treatment. Further investigation is needed to determine whether other factors increase the risk of skin cancer following CLL diagnosis. Disclosures Shanafelt: Genentech: Research Funding; GlaxoSmithkKine: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Cephalon: Research Funding; Pharmacyclics: Research Funding; Hospira: Research Funding.

Abstract Background: Acute graft versus host disease (aGVHD) is the leading cause of morbidity and mortality following allogenic hematopoietic cell transplantation (HCT). Corticosteroids are the first line treatment although <50% of patients with severe aGVHD (grades III-IV) achieve durable remissions. Monoclonal antibodies (mAb) are often used as second line agents for steroid refractory aGVHD (SR-aGVHD) (Patriarca et. al.; 2004). However, data regarding their tolerability and efficacy is retrospective and limited. We carried out this study to assess the clinical outcomes related to mAb therapy (Infliximab and Tocilizumab) for SR-aGVHD. Methods: Patients with SR-aGVHD that received therapy with either Infliximab or Tocilizumab between January 2003 and May 2016 were retrospectively identified. Clinical grading of aGVHD was per the Glucksberg criteria (Glucksberg et. al.; 1974). SR-aGVHD was defined as any grade progression within 3 days or failure to achieve at least one grade improvement within 7 days of initiation of systemic steroids. Infliximab and Tocilizumab were administered intravenously at 10mg/kg and 8mg/kg weekly for a total of 4 doses, respectively. Clinical response was evaluated at 4 weeks and 12 weeks post mAb treatment. Complete response (CR) was defined as sustained resolution of all clinical signs of aGVHD; partial response (PR) was defined as overall improvement of 1 or more grades; no response (NR) was defined as neither improvement nor worsening of the overall aGVHD grade. Overall response (OR) was defined as either CR or PR. Overall survival (OS) was calculated from the first day of mAb treatment until death or last available follow up. Results: Forty-three patients (median age 54, range 29-74 years; male 67%) with severe SR- aGVHD were included in the study. Of these, 35 (81%) received Infliximab for a median of 4 (range 1-6) cycles and 8 (19%) received Tocilizumab for a median of 3 (range 1-4) cycles. Both groups were comparable with regards to age, gender, conditioning regimen, graft source, degree of HLA match, ABO blood group, CMV incompatibility, and GVHD prophylaxis regimens. Only differences seen were a higher proportion of unrelated donor (p = 0.004) and cord blood HCT (p = 0.031) in the Tocilizumab group. Twenty (57%) of 35 patients treated with Infliximab and 6 (75%) of 8 patients treated with Tocilizumab had an overall aGVHD grade of IV prior to initiation of mAb therapy (p = 0.44). Organ specific distribution and severity of aGVHD are described in table 1. At 4 weeks post mAb therapy, 17 (40%) patients had an OR, 7 (16%) had no response, and 19 (44%) had died. Twenty-six (60%) patients died at 12 weeks, with OR and no response observed in 9 (21%) and 8 (19%) patients, respectively (table 2). Overall response for Tocilizumab versus Infliximab was comparable at 4 weeks (38% vs. 40%; p = 1.0) and at 12 weeks (38% vs. 17%; p = 0.33). Outcomes per aGVHD grade and gastrointestinal-specific stage at 4 weeks and 12 weeks are shown in figures 1-A and 1-B, with organ specific responses shown in figures 1-C and 1-D, respectively. The estimated median OS was 41 (range 4-3837) days for patients treated with Infliximab and 60 (range 10-756) days for those treated with Tocilizumab (p = 0.48). Disease relapse occurred in 5 (11%) patients treated with Infliximab and in none (0%) treated with Tocilizumab (p = 0.56). Thirty-four (79%) patients had infectious complications during and up to one month after mAb therapy. These included 31 (72%) patients with bacterial blood stream infection and 10 (23%) with invasive fungal infections. Overall, infectious complications were comparable (Infliximab - 83% vs. Tocilizumab - 63%; p = 0.33). CMV reactivation occurred in 11 (31%) and in 2 (25%) patients who were treated with Infliximab and Tocilizumab, respectively (p = 1.0). Given the retrospective nature of the study and the concomitant presence of aGVHD, it was difficult to attribute and grade gastrointestinal and hepatobiliary side effects. Conclusions: The use of anti-inflammatory monoclonal antibody therapy in patients with steroid refractory acute GVHD is associated with significant infectious complications (~80%) and poor response rates (~20% at 12 weeks). Current data, limited by a small sample size, does not show any advantages of using Tocilizumab over Infliximab or vice versa. Prospective clinical trials addressing this question are needed. Disclosures No relevant conflicts of interest to declare.

Abstract Background Ixazomib, the first oral proteasome inhibitor, is approved by the US FDA, in combination with Rd, for the treatment of MM patients (pts) who have received at least 1 prior therapy. Approval was based on the double-blind, placebo-controlled phase 3 TOURMALINE-MM1 study (NCT01564537) in 722 pts with RRMM (Moreau et al, N Engl J Med 2016), in which IRd showed superior PFS versus placebo-Rd (HR 0.74) at the final prespecified analysis, with limited additional toxicity. Prespecified subgroup analyses showed a consistent PFS benefit with IRd, but with a differential treatment effect according to prior therapy exposure. An exploratory study objective was to evaluate potential relationships between treatment outcomes and tumor gene expression patterns. c-MYC is a proto-oncogene that encodes a transcription factor regulating cell proliferation, growth, protein translation, metabolism, and apoptosis, and increased c-MYC expression is involved in MM pathogenesis/progression. We analyzed the impact of c-MYC expression on PFS in RRMM pts treated with IRd or placebo-Rd. Methods Pts with RRMM after 1-3 prior lines of therapy were randomized 1:1 to receive oral ixazomib or placebo, plus lenalidomide and dexamethasone, until disease progression or unacceptable toxicity. Randomization was stratified by number of prior therapies (1 vs 2-3), proteasome inhibitor exposure, and ISS disease stage. The primary endpoint was PFS by independent review committee assessment. Data reported here are from the final prespecified statistical analysis of PFS (median follow-up ~15 months). Bone marrow aspirate samples were collected at screening for tumor gene expression analysis. Whole transcriptome sequencing (RNAseq) of bone marrow-sorted CD138+ cells was performed using the Illumina Truseq protocol on the Illumina HiSeq platform; this generated a median of 50 million paired-end reads (100 bp length) per sample. c-MYC expression was evaluated by treatment arm and according to number of prior therapies (1 vs 2-3). PFS was analyzed in subgroups dichotomized according to median c-MYC expression (c-MYC-high/c-MYC-low). Results RNAseq data were available for 59% (427/722) of enrolled pts; 213 (50%) had high and 219 (50%) had low c-MYC expression (dichotomized according to the median). Impact of c-MYC expression (high vs low) on PFS, irrespective of treatment arm, was not significant (p=0.98). However, a significant treatment effect of IRd vs placebo-Rd was only seen in pts with high c-MYC expression (interaction p=0.024); in these pts (IRd: n=109; placebo-Rd: n=104) a significant PFS benefit was seen with IRd (HR 0.41; 95% CI: 0.26-0.65, p=0.00011). Impact of c-MYC expression was then analyzed by number of prior therapies. In the overall TOURMALINE-MM1 population, per stratification, 212/213 pts in the IRd/placebo-Rd arms had 1 prior therapy, and 148/149 had 2-3 prior therapies. After median follow-up of ~15 months, median PFS in pts with 1 prior therapy was 20.6 vs 16.6 months with IRd vs placebo-Rd (HR 0.88; 95% CI: 0.65-1.20), and in pts with 2-3 prior therapies was not reached vs 12.9 months (HR 0.58; 95% CI: 0.40-0.84, p=0.0033). The level of c-MYC expression was shown to be significantly higher in pts with 2-3 prior therapies vs 1 prior therapy, with median expression of 6.94 (SD=1.71, n=177) vs 6.52 (SD=1.74, n=250) (log2 scale), t-test p-value 0.0153. In pts with 1 prior therapy, no differences in PFS were observed between pts with low c-MYC expression (HR 1; 95% CI: 0.59-1.8, p=0.934), while a prolonged PFS benefit was observed in pts with high c-MYC expression (HR 0.48; 95% CI: 0.26-0.88, p=0.0146) (Figure, A and B). In pts with 2-3 prior therapies, both the c-MYC-high and c-MYC-low pts showed improved PFS with IRd vs placebo-Rd; the difference in PFS was statistically significant only in c-MYC-high pts (HR 0.36; 95% CI: 0.18-0.72, p=0.00269) (Figure, C and D). Conclusions In TOURMALINE-MM1, c-MYC expression was higher in MM tumor samples from pts with 2-3 vs 1 prior therapies. The IRd regimen was active in c-MYC-high and c-MYC-low pts, but its impact on PFS vs placebo-Rd was greater in c-MYC-high pts, thus providing a potential explanation for the enhanced PFS benefit with IRd vs placebo-Rd in pts with 2-3 prior therapies. The PFS benefit with IRd in c-MYC-low pts with 2-3 prior lines suggests that, in advanced MM, further genomic alterations may also be contributing to ixazomib sensitivity. Disclosures Di Bacco: Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Bahlis:BMS: Honoraria; Onyx: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau. Avet-Loiseau:Takeda: Speakers Bureau; Janssen: Speakers Bureau; Celgene: Speakers Bureau; Sanofi: Speakers Bureau. Masszi:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Ganly:Medipics: Equity Ownership; Novartis: Honoraria; Roche: Honoraria. Cavo:Bristol-Myers Squibb: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Langer:Celgene: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Novartis: Consultancy. Kumar:Array BioPharma: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; AbbVie: Research Funding; Onyx: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Glycomimetics: Consultancy; Kesios: Consultancy; BMS: Consultancy; Millennium: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding. Berg:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Lin:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Li:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Badola:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Shen:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Zhang:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Wang:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Esseltine:Takeda: Equity Ownership; Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment; Johnson and Johnson: Equity Ownership. Luptakova:Takeda Oncology: Employment. van de Velde:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Richardson:Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Moreau:Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria, Speakers Bureau; Novartis: Honoraria; Amgen: Honoraria.

Abstract In chronic lymphocytic leukemia (CLL), the molecular features of the clonotypic B-cell receptor immunoglobulins (BcR IG) are set from the birth of the clone and in contrast to genetic aberrations, remain stable overtime, rendering the BcR IG a reference biomarker that is usually not significantly affected by clonal evolution. Approximately 30% of CLL cases carry quasi-identical BcR IGs and can be assigned to distinct stereotyped subsets. While preliminary evidence alludes to BcR IG stereotypy being relevant from a clinical viewpoint, this aspect has never been explored systematically or in a cohort of adequate size to enable meaningful conclusions. In order to assess the clinical implications of BcR IG stereotypy, we evaluated clinicobiological data from 8593 CLL patients, particularly focusing on 14 major stereotyped subsets of cases with unmutated (U-CLL) or mutated IGHV genes (M-CLL). The largest subset was #2 (n=254, 3%), within which 156 and 98 cases were M-CLL and U-CLL, respectively, followed by U-CLL subsets #1 (n=173, 2%) and #7 (n=123, 1.4%). Amongst M-CLL, the largest subsets were #4 (n=94, 1.1%) and #148 (n=92, 1%). Stereotyped subsets, even of the same mutational category i.e. U-CLL or M-CLL, exhibited significant clinicobiological differences regarding: age at diagnosis (median age ranging from 53-68 years, p<0.001); gender distribution (male/female ratios ranging from 0.85-4.4, p<0.001); the frequency of advanced stage disease (Binet C) at diagnosis (ranging from 9-21%, p<0.001); CD38 positivity (median percentage of positive cells ranging from 2-73%, p<0.05). Moving to cytogenetic findings, we detected subset-biased spectra of FISH-detected aberrations which can be summarized as follows: (i) isolated del(13q) varied from 10% in subset #8 (U-CLL), to 29% in subsets #59 (U-CLL) and #16 (M-CLL), and >75% in M-CLL subsets #77 and #148 (p<0.001); (ii) trisomy 12 was absent in subsets #31 (U-CLL) and #77 (M-CLL), in 20% of subset #201 (M-CLL) and, 60% in subset #8 (U-CLL) (p<0.001); (iii) del(11q) ranged from 69% in subset #31 (U-CLL) to 12% in subset #8 (U-CLL) and 0% in M-CLL subsets #16 and #201 (p<0.001); (iv) del(17p): absent from all M-CLL subsets except #148 (7.5%); absent from U-CLL subsets #5 and #59, and present in 19% and 17% of stereotyped subset #8 and #6 cases, respectively (p<0.05). We considered subset #2 separately since it included both M-CLL and U-CLL and identified a distinctive clinicobiological profile characterized by a constellation of features, including high incidence of Binet stage C disease (21%), CD38 positivity (41%) and certain cytogenetic abnormalities i.e. del(13q) (56%) and del(11q) (23%) and, in contrast, low frequency of del(17p) (4.5%). Notably, no differences were found between U-CLL versus M-CLL subset #2 cases regarding the incidence of these parameters. Survival analysis for time-to-first-treatment (TTFT) revealed that each stereotyped subset exhibited a distinct clinical course, different from that of other subsets even with similar IGHV gene mutational status and/or expressing the same IGHV gene. Interestingly, subsets #1 and #2 demonstrated a similar TTFT to that of del(17p) positive cases, while within subset #2 the clinical outcome was independent of IGHV mutational status. By integrating BcR IG stereotypy into the Döhner cytogenetic prognostication model, we found that subsets #1, #2 and #4, collectively accounting for ~7% of our series, and representing both U-CLL and M-CLL, constituted distinct clinical entities, with the latter exhibiting a particularly indolent disease even when compared to isolated del(13q) cases or cases with no cytogenetic aberrations. Finally, in multivariate analysis for TTFT, assignment to subset #2 emerged as a new independent unfavorable factor (p=0.002); furthermore, when restricting the analysis to Binet A cases, subset #2 exhibited the second highest hazard ratio after U-CLL. In conclusion, the molecular classification of CLL based on BcR IG stereotypy refines prognostication beyond IG mutational status and improves the Döhner hierarchical model. Hence, we suggest that a compartmentalized approach focusing on and comparing different subsets sheds light on CLL clinical behavior and biology and that BcR IG stereotypy represents a companion molecular diagnostic for personalized medicine in CLL. Disclosures Montillo: Janssen: Honoraria.

Key PointsIKZF1 associations with high-risk B-ALL may differ by age and sex. A novel variant on chromosome 14, rs189434316, is associated with over a 3.5-fold risk of normal cytogenetic B-ALL.

Abstract Background: Follicular lymphoma (FL) is the second most common nodal lymphoma worldwide and remains incurable for most patients (pts). FL is recognized to be a highly heterogeneous disease and a subset of pts experience remarkable poor outcome. In a recent study, 19-26% of pts receiving first-line R-CHOP experienced progression of disease (POD) within 24 months after diagnosis and had a 5-year (yr) overall survival (OS) of only 34-50%, as compared to a 5-yr OS of 90-94% for pts without POD within 24 months (Casulo et al., J Clin Oncol 2015). Consequently, event-free survival at 12 (EFS12) and 24 months (EFS24) have been suggested as novel surrogate endpoints for poor overall survival in clinical trials and useful for patient counseling (Maurer et al., ASH 2014). We have previously shown that a clinicogenetic risk model (m7-FLIPI) that includes the mutation status of seven genes (EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11), the FL International Prognostic Index (FLIPI), and the Eastern Cooperative Oncology Group (ECOG) performance status, improves risk stratification for failure-free survival (FFS) and OS in pts with FL receiving first-line immunochemotherapy (Pastore et al., Lancet Oncology 2015). An online tool is available at: http://www.glsg.de/m7-flipi. It would be advantageous to determine prognosis prior to front-line therapy rather than after POD. Thus, we aimed to investigate the predictive utility of the m7-FLIPI for early POD. Patients and Methods: Clinical and mutation data were available from two independent cohorts: 151 pts who received R-CHOP and IFN maintenance as part of a randomized trial of the German Low-Grade Lymphoma Study Group (GLSG), and 107 pts from a population-based registry of the British Columbia Cancer Agency (BCCA) who received R-CVP. Among the latter, 93 (87%) received R-maintenance by intention to treat. All pts had symptomatic, advanced stage or bulky disease considered ineligible for curative radiotherapy, and a biopsy specimen obtained </=12 months prior to the initiation of first-line therapy. POD was defined as progression, relapse, or death due to any cause. POD12 and POD24 were defined based on POD status at 12 and 24 months after therapy initiation, respectively. Logistic regression analysis was performed to assess if m7-FLIPI was predictive of early POD using the statistical software R (version 3.1.2). Results: In the GLSG cohort, median age was 57 yrs (range 27-77), 51% had high-risk FLIPI, and 5-yr failure-free survival (FFS) and OS rates were 66% and 83%, respectively (median follow-up for OS 7.7 yrs). In the BCCA cohort, median age was higher (62 yrs, 37-83), but high-risk FLIPI was similarly frequent (50%); 5-yr FFS and OS rates were 58% and 74%, respectively (median follow-up for OS 6.7 yrs). A total of 43 GLSG (28%) and 24 BCCA pts (22%) were classified as high-risk by m7-FLIPI, with a 5-yr OS of 65% and 42%, respectively. In the GLSG cohort, 8 (5%) and 29 pts (19%) had POD within 12 and 24 months, respectively, 4 and 10 pts were censored before POD12 and POD24 (table). High-risk m7-FLIPI pts were significantly more likely to experience early POD with an Odds Ratio (OR) of 20.80 (95% confidence interval (CI) 3.53-395.96; p=0.0052) for POD12 and 6.33 (95% CI 2.67-15.69; p<0.0001) for POD24. Likewise, in the BCCA cohort, 16 (15%) and 28 pts (26%) experienced POD12 and POD24, respectively (table). The OR for high-risk m7-FLIPI pts was 4.69 (95% CI 1.52-14.65; p=0.0068) for POD12, and 5.36 (95% CI 2.03-14.60; p=0.0008) for POD24. In the GLSG and BCCA cohorts, the m7-FLIPI had a sensitivity of 88% and 50%, a specificity of 75% and 82%, a positive predictive value (PPV) of 16 and 33%, and a negative predictive value (NPV) of 96% and 90% to predict POD12. For POD24, sensitivity was 62% and 46%, specificity 79% and 86%, PPV 42% and 54%, and NPV 82% and 82%, respectively. Conclusion: We conclude that patients classified as high-risk m7-FLIPI are highly enriched among those with early progression of disease. However, approximately one-half of patients with progression by 24 months after therapy initiation are classified as low-risk m7-FLIPI. Thus, further efforts are needed to refine the m7-FLIPI and thereby capture additional cases that may benefit from innovative first-line approaches. Table. Population m7-FLIPI N POD12 POD24 GLSG Total 151 8/147* 29/141* High-risk 43 7 18 Low-risk 108 1 11 BCCA Total 107 16/107 28/107 High-risk 24 8 13 Low-risk 83 8 15 *Pts censored were removed Disclosures Ansell: Bristol-Myers Squibb: Research Funding; Celldex: Research Funding.