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Introduction: Unexplained erythrocytosis is a common reason for consultation in hematology. Identification of JAK2V617F mutation has facilitated the diagnosis of Polycythemia Vera (PV), but a proportion of patients without clear secondary causes for erythrocytosis remain undiagnosed or presumptively diagnosed with an either Exon 12 mutation or JAK2 negative PV. Since 2005, our institution has been performing JAK2V617F testing by PCR. In 2018 we switched to an NGS panel which includes JAK2/exon 12 and 40 other genes implicated in myeloid malignancies. We reviewed all previously diagnosed PV who had NGS myeloid panel performed to determine whether patients with a clinical diagnosis of JAK2 negative PV had other myeloid mutations that might explain their erythrocytosis and alter their management. Methods: We identified all cases with clinically suspected PV or confirmed JAK2 mutated PV who went on to have had NGS testing performed between January 2018 and February 2019 at London Health Sciences Centre, a tertiary care center servicing a population of approximately 2.5 million in Ontario, Canada. The Oncomine Myeloid NGS panel (Thermo-Fisher, MA, USA) examines DNA sequence variants in 40 genes (17 full genes and 23 hotspot genes) along with an RNA-based panel of 29 fusion driver genes and their over 600 fusion partners. Diagnosis was based on the WHO 2016 Classification of Tumours of Haematopoietic and Lymphoid Tissues. The clinical impact was assessed from retrospective review of electronic medical record to determine whether there was a diagnostic or management impact. Results: A total of 143 patients followed for PV or unexplained erythrocytosis had NGS testing during the study period. Of those, 137/143 (95.8%) patients had previous JAK2V617F PCR tested and 48/137 (35%) were identified with JAK2V617F mutation. Of the 48 patients with previous JAK2V617F PCR detected, NGS confirmed JAK2 mutation in 40/48 (83.3%) with additional non-JAK2 mutations in 17/40 (42.5%) patients. Of note 8/48 (16.7%) patients previously detected JAK2V617F by PCR had undetectable JAK2 mutation when repeat testing was performed by NGS. Of those 89/137 (65%) patients with previous JAK2V617F PCR negative result, NGS revealed JAK2 exon 12 mutation in 3/89 (3.4%) patients and JAK2V617F/JAK2L611V mutations in 1/89 (1.1%) patient resulting in diagnosis as PV, whereas non-JAK2 mutations in 6/89 (6.7%) patients. No MPL or CALR positive cases were identified in this cohort. Remaining 79/89 (88.8%) had no mutations identified (Figure1) and in this group, 13/79 (16.5%) patients were discharged from hematology clinic, 7/79 (8.9%) had therapies such as phlebotomy, aspirin or hydroxyurea stopped or reduced, whereas 2/79 (2.5%) patients had further evaluation or testing for unexplained erythrocytosis. (Table 1) Conclusions: In the unexplained erythrocytosis JAK2V617F PCR negative group, JAK2exon 12 mutation was identified in 3.4% in keeping with known incidence of this mutation. Some previously positive PCR JAK2V617F mutation were not identified by NGS panel (16%) which may reflect changes in clone size either with time or therapy or inherent differences in assay sensitivity (2.5% mutational alleles for NGS versus 0.1% for PCR). Lack of identifiable myeloid mutation and clonal hematopoiesis by NGS testing influenced clinical management. Specifically, mutation negative patients were more likely assigned to non-MPN group and called secondary erythrocytosis which resulted in reducing interventions. Non-JAK2 mutations occurred in more than 1/3 of previously identified JAK2 positive PCR tested PV. The clinical impact of most these mutations is uncertain and requires longer follow up. Disclosures No relevant conflicts of interest to declare.

Introduction: Indolent non-Hodgkin lymphomas (iNHL), including follicular lymphoma (FL) and marginal zone lymphoma (MZL), are slow-growing lymphoid malignancies with high response rates to first-line treatment, but most patients (pts) will eventually relapse after initial response to treatment. For those with refractory disease (relapse ≤ 6 months after ending treatment), outcomes are worse. A number of treatment options based on chemo- and/or immunotherapy exist for pts with relapsed/refractory (R/R) iNHL, but currently there is no single standard treatment approach. There is a need to better understand the reported efficacy of available systemic treatments for R/R FL and MZL to guide treatment of iNHL. Methods: A SLR was carried out in accordance with PRISMA guidelines on September 1, 2017. Publications from MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and clinicaltrials.gov databases, as well as proceedings from the European Hematology Association and American Society of Clinical Oncology conferences held from 2015 to 2017, the International Conference on Malignant Lymphomas from 2013, 2015, and 2017, and from the American Society of Hematology, and European Society for Medical Oncology conferences from 2014 to 2016, were included. Studies were limited to articles published in English, sample sizes ≥ 40, and studies evaluating systemic therapy for adults with any-stage R/R FL, MZL, or mixed histologies with ≥ 70% R/R FL/MZL pts. Controlled or uncontrolled clinical trials and observational studies were included. Studies varied with respect to prior treatment received and pt response to prior treatment at enrollment. Pts were classified as relapsed, refractory, refractory to rituximab (R-refractory including double-refractory pts), R/R but sensitive or naïve to rituximab, or as general R/R if the type of relapse and/or refractoriness was not specified. Efficacy measures included overall response rate, complete response rate, progression-free survival (PFS), and duration of response (DoR). Relevant interventions included bendamustine (B) (alone or with rituximab [BR] or obinutuzumab [O+B]), idelalisib (ID), ibrutinib (IB), copanlisib (C), lenalidomide (L) (alone or with rituximab [R2]), R + cyclophosphamide + doxorubicin + vincristine + prednisone (R-CHOP), R + cyclophosphamide + vincristine + prednisone (R-CVP), and R + chlorambucil (R-Chl). Results: Of 58 publications identified representing 36 studies involving 3,759 pts: 1 study reported on R2, 2 on L, 5 on B, 6 on BR, 3 on ID, 3 on IB, 2 on C, 1 on O+B, 1 on R-CHOP, and 12 on R alone. After excluding studies that did not meet criteria for similarity, 19 studies reporting outcomes in iNHL pts were included. Six studies each reported on general R/R pts or R-refractory pts, 4 studies reported on pts with relapsed disease, and 2 studies each reported on pts with refractory disease or R-naïve/sensitive refractory disease. PFS in the general R/R population (n = 1,668) ranged from 4.4 months (mo) in pts treated with L to 17.9 mo in pts treated with BR. Only 1 study reported DoR for pts in the general R/R population. In relapsed pts, PFS was only reported or reached in 1 study (22.9 mo) and DoR ranged from 21.0 to 41.9 mo for BR. In R-refractory pts, PFS ranged from 9.3 mo in B-treated pts to 29.2 mo in O+B-treated pts. DoR ranged from 9.2 to 22.6 mo. BR was investigated in the widest variety of disease subsets (4) with PFS ranging from 17.9 mo in the general R/R population to 34.2 mo in the R-naïve/sensitive R/R population (Table). Outcomes are likely to have been influenced by pt and disease characteristics (e.g., relapsed vs refractory, rituximab sensitive vs refractory, FL International Prognostic Index risk) and response criteria used (Cheson 1999, Cheson 2007, Laboratory of Experimental Oncology and Radiobiology [LEXOR], or unknown). Conclusions: In pts with R/R iNHL (FL and MZL), there is significant variation in reported response and survival outcomes following systemic therapy. Currently, there is no clear standard of care for R/R iNHL, as demonstrated by the use of 9 different therapies across 19 studies identified in this SLR. Limited information is available on treatment outcomes for pts with different disease status and further studies are needed to determine the most appropriate treatment approach for specific subgroups of pts with R/R iNHL. Disclosures Bachy: Roche: Honoraria; Beigene: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Fox:Celgene: Consultancy, Other: travel support, Speakers Bureau; Roche: Consultancy, Other: travel support, Research Funding, Speakers Bureau; Gilead: Consultancy, Other: travel support, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: travel support, Speakers Bureau; Abbvie: Consultancy, Other: travel support, Research Funding, Speakers Bureau; Sunesis: Consultancy. Howlett:Celgene: Employment, Equity Ownership. Snedecor:Celgene: Research Funding. Franek:Celgene Corp.: Consultancy. Zaidi:Celgene Corp.: Consultancy. Tabah:Celgene Corporation: Employment.

Introduction: Salvage immunochemotherapy (IC), followed by high-dose chemotherapy with autologous stem cell transplantation if chemosensitive is standard-of-care second-line (2L) therapy (tx) for fit patients (pts) with relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL) when treated with first-line (1L) R-CHOP as shown in the CORAL study. Outcomes following receipt of salvage IC in the 2L setting for pts with DLBCL or high grade B cell lymphoma/B cell lymphoma unclassifiable (HGBL/BCLU) receiving intensive 1L tx remain unknown, and may be worse than those reported in CORAL given prior exposure to higher-dose IC in 1L setting. Here we report the results of a multicenter retrospective analysis of R/R DLBCL and HGBL/BCLU pts treated with intensive 1L tx who receive standard salvage 2L tx. Methods: Inclusion criteria were histologic diagnosis of DLBCL or HGBL/BCLU, R/R disease following 1L tx with R-EPOCH, R-HyperCVAD or R-CODOX-M/IVAC and receipt of 2L tx with R-ICE, R-DHAP, R-DHAC, R-ESHAP or R-GDP. Exclusion criteria were HIV positivity, post-transplant lymphoproliferative disorder, prior chronic lymphocytic leukemia and inadequate data. Therapy was given at the discretion of the treating physician. Progression free survival (PFS) was defined as the interval between time of first relapse or primary refractory disease and disease progression, change in therapy if no disease response or last follow-up in remission, and overall survival (OS) between time of first relapse or primary refractory disease and death or last follow-up while alive. Pts were treated from 2007-2017 and data were censored on 10/15/17. Results: A total of 195 pts treated at 20 US and Canadian academic medical centers were included. Clinicopathologic characteristics at time of R/R disease were 39% age >60 years, 62% male, 77% stage III-IV, 72% elevated LDH, 24% bone marrow (BM) involvement, 28% B symptoms present, 44% extranodal (EN) disease at >1 site, 19% ECOG performance status (PS) >1, 49% with International Prognostic Index score (IPI) ≥3, 46% HGBL/BCLU histology, 49% Ki67 ≥90%, and 61% germinal center (GCB) cell of origin (COO) by Hans algorithm. Of pts with available fluorescence in situ hybridization (FISH) data, 51%, 45% and 30% demonstrated MYC, BCL2 and BCL6 rearrangements (-R), respectively, and 37% were double hit lymphoma (DHL). Tx received in 1L were R-EPOCH in 82%, R-HyperCVAD in 16% and R-CODOX-M/IVAC in 2% of pts. R-ICE was received by 64% and other platinum-containing regimens by 36% as 2L tx. Most (86%) pts relapsed within 12 months (mo) of completion of 1L tx (early) and 58% of pts had primary refractory disease. For all pts, the median length of follow-up was 25.0 mo with a median PFS of 3.0 mo and median OS of 8.0 mo. Overall response rate to 2L tx among all pts was 44% (23% complete response [CR] and 21% partial response [PR]), and 48% with progressive disease. Pts achieving CR had significantly longer median PFS (32.0 vs 4.0 mo, p = 0.0001) and OS (not reached vs 13.0 mo, p = 0.0004) as compared to pts achieving PR. In pts who achieved CR or PR following 2L tx, 64% received consolidative transplant (42 autologous and 13 allogeneic) and achieved a median PFS and OS of 18.3 mo and 62.0 mo, respectively. As compared to pts relapsing ≥12 mo after completion of 1L tx (late), pts relapsing early were less likely to achieve CR (17% vs. 61%, p=0.0001) and experienced significantly shorter median PFS (2.8 vs. 23.0 mo, p1 site, B symptoms, ECOG PS >1 and Ki67 ≥90%, but not BCL2-R, demonstrated a statistically significant increased HR for death. Multivariate analysis demonstrated only early relapse to have a statistically significant increased HR for progression (HR 2.47, p=0.024) and death (HR 5.90, p=0.001). Conclusion: Relapse Figure. Figure. Disclosures Maddocks: Pharmacyclics: Research Funding; BMS: Research Funding; Teva: Honoraria; AstraZeneca: Honoraria; Novartis: Research Funding; Pharmacyclics/Janssen: Honoraria; Merck: Research Funding. Wagner-Johnston:Novartis: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; ASTEX: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Merck: Research Funding; JUNO: Honoraria, Membership on an entity's Board of Directors or advisory committees. Karmali:Gilead: Speakers Bureau; AstraZeneca: Speakers Bureau. Kahl:Genentech: Consultancy; Juno: Consultancy; Celgene: Consultancy; Seattle Genetics: Consultancy; ADC Therapeutics: Consultancy; Gilead: Consultancy; Acerta: Consultancy; CTI: Consultancy; Abbvie: Consultancy; AstraZeneca: Consultancy. Cohen:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioInvent: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Reddy:MEI Pharma: Research Funding. Ramchandren:Seattle Genetics: Consultancy, Research Funding; Pharmacyclics LLC an AbbVie Company: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Merck: Research Funding; Janssen: Consultancy, Research Funding. Diefenbach:Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Incyte: Research Funding; Trillium: Research Funding; Millenium/Takeda: Research Funding; Denovo: Research Funding; Acerta: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy. Olszewski:TG Therapeutics: Research Funding; Genentech: Research Funding; Spectrum Pharmaceuticals: Consultancy, Research Funding. Barta:Janssen: Membership on an entity's Board of Directors or advisory committees; Merck, Takeda, Celgene, Seattle Genetics, Bayer: Research Funding. Hill:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Assouline:Roche: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding; BMS: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Landsburg:Curis: Consultancy, Research Funding; Takeda: Consultancy.

Patients with double-hit lymphoma (DHL), which is characterized by rearrangements of MYC and either BCL2 or BCL6, face poor prognoses. We conducted a retrospective multicenter study of the impact of baseline clinical factors, induction therapy, and stem cell transplant (SCT) on the outcomes of 311 patients with previously untreated DHL. At median follow-up of 23 months, the median progression-free survival (PFS) and overall survival (OS) rates among all patients were 10.9 and 21.9 months, respectively. Forty percent of patients remain disease-free and 49% remain alive at 2 years. Intensive induction was associated with improved PFS, but not OS, and SCT was not associated with improved OS among patients achieving first complete remission (P = .14). By multivariate analysis, advanced stage, central nervous system involvement, leukocytosis, and LDH >3 times the upper limit of normal were associated with higher risk of death. Correcting for these, intensive induction was associated with improved OS. We developed a novel risk score for DHL, which divides patients into high-, intermediate-, and low-risk groups. In conclusion, a subset of DHL patients may be cured, and some patients may benefit from intensive induction. Further investigations into the roles of SCT and novel agents are needed.

We conducted a clinical trial to determine the feasibility of growth factor mobilization of CD34+ progenitor cells in human immunodeficiency virus type 1 (HIV-1)-infected individuals. Eight asymptomatic, HIV-1-infected adults (median CD4+ T-cell count, 415 cells/microL), received 480 micrograms/d of granulocyte colony-stimulating factor (G-CSF) for 6 days without evidence of viral activation. Despite concerns that HIV-1 might inhibit hematopoiesis, CD34+ cells were successfully mobilized to the periphery of all donors, independent of the baseline CD4+ T-cell count, and the status of antiretroviral therapy. Leukapheresis was performed on day 6, and yielded a median of 194 x 10(6) CD34+ cells per leukapheresis (n = 7). CD34-enriched cells from the leukapheresis were predominantly myeloid-committed, but between 0.2% and 1.7% were primitive CD34+/CD38- progenitors. A median of 21.7% of the mobilized CD34+ cells were dimly positive for CD4. Consequently, CD34(+)-enriched cells were purified on the cell sorter (mean purity, 97.7% +/- 2.4%; n = 7), and examined for HIV-1 DNA. Purified CD34+ cells from two of seven donors were polymerase chain reaction (PCR)-positive for HIV-1, but only from one of three samples from each donor. We conclude that G-CSF can safely mobilize CD34+ progenitor cells in HIV-1-infected subjects, and that these cells are suitable for consideration in gene-transfer strategies.

Introduction: Ibrutinib (Ibr), idelalisib (Ide), andvenetoclax (Ven), are all now approved for treating CLL patients in the US. However, in the absence of head-to-head comparator trials, there is limited guidance as to the optimal sequence of these therapies and to the best choice upon failure of first selected agent. To address these gaps in current literature, 9 large US cancer centers and the Connect CLL Registry collaborated to capture the experience of 683 CLLpts treated with kinase inhibitors (KIs) - focusing on optimal sequencing and patterns of failure. Patients and Methods: We conducted a multicenter, retrospective analysis of CLLpts treated withIbr-, Ide- orVen-based therapy. We examined demographics, discontinuation rates, reasons for discontinuation, overall response rates (ORR), survival, and post kinase inhibitor (KI) salvage strategies. Primary endpoint was progression-free survival (PFS) (time from KI treatment to progression, death, or last follow-up) as determined by the Kaplan Meier (KM) method. Comparisons were made using the log rank (LR) test and COX regression analyses. Results: A total of 683 pts treated with KI therapy (Ibr=621/Ide=62) were identified (Table 1). Baseline characteristics were similar in theIbr and Ide-based groups. ORR toIbr as first KI was 69% [complete response (CR) 11%, partial response (PR) 45%, and PR-L 13%] and Ide was 81% (CR 5%, PR 71%,PR-L 5%). With a median follow-up from start of first KI of 17 months (range 1-60), median PFS and OS for the entire cohort from first KI was 35 months (216 events) and not reached respectively (107 events). Interestingly,pts treated withIbr (vs. Ide) as first KI had a significantly better PFS in all settings; front-line (figure a, HR 2.8, CI 1.3-6.3 p=.01), relapsed-refractory (figure b, HR 2.8, CI 1.9-4.1 p Conclusions: In the largest experience of novel agents published to date in CLL,Ibr appears superior to Ide in all settings as first choice KI. Further, in the setting of KI failure, an alternate KI orVen therapy appear superior to CIT combinations. Alternate KI appear particularly effective in the setting of intolerance to a prior KI. The use ofVen uponIbr failure might be superior to the use of Ide. These data provide guidance for sequencing of novel agents and support the need for trials directly comparing novel agents and sequencing strategies in CLL. Table 1 Table 1. Figure Figure. Disclosures Mato: Abbvie, Gilead Sciences, Pharmacyclics, TG Therapeutics: Consultancy; Abbvie, Acerta Pharma, Gilead Sciences, ProNAi, TG Therapeutics, Theradex: Research Funding. Lamanna:Roche-Genentech: Honoraria, Research Funding; Celgene: Honoraria; Janssen: Honoraria; Pharmacyclics: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Infinity: Research Funding; Acerta: Research Funding; TGR Therapeutics: Research Funding. Barr:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Consultancy. Ujjani:Genentech: Consultancy; Abbvie: Consultancy; Gilead: Consultancy; Pharmacyclics: Consultancy. Brander:Gilead: Honoraria; TG Therapeutics: Research Funding. Cheson:Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kiselev:Celgene: Employment, Equity Ownership. Svoboda:Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding. Schuster:Genentech: Consultancy, Honoraria; Gilead: Research Funding; Pharmacyclics: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Hoffman-LaRoche: Research Funding; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Janssen Research & Development: Research Funding. Nabhan:Celgene Corporation: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Abbvie: Consultancy; Infinity: Consultancy; Cardinal Health: Consultancy; Seattle Genetics: Research Funding; Astellas: Research Funding.

Introduction: Ibrutinib (Ibr) is a kinase inhibitor (KI) indicated for treating CLL. Clinical trials that led to its approval showed that its unique side effects differ from traditional chemotherapy toxicities. We previously reported (Mato et al, ASH 2015) that intolerance was the most common reason for discontinuation of Ibr in 123 patients treated in a real world setting. Whether reasons for discontinuation reported in clinical trials mirror those encountered in the real world is unknown and has not been studied. Therefore, we conducted a retrospective analysis of 621 CLL patients treated with Ibr either on clinical studies or commercially. We aimed to compare the type and frequency of toxicities reported in either setting, assess discontinuation rates, and evaluate outcomes. Patients and Methods: This multicenter, retrospective analysis included Ibr-treated CLL patients at 9 US cancer centers or the Connect® CLL Registry. We examined demographics, dosing, discontinuation rates and reasons, toxicities, and outcomes. The primary endpoint was progression-free survival (PFS) (time from KI treatment to progression, death or last f/u) as determined by the Kaplan Meier method. Comparisons of outcomes data were made using the log rank (LR) test. All other comparisons were descriptive. Results: 621 patients treated with Ibr were identified. Table 1 includes available baseline characteristics stratified by line of therapy. A total of 546 (88%) patients were treated with commercial drug. Clinical trial patients were younger (median age 57 vs. 61 years), had a longer time from diagnosis to Ibr (median 85 vs. 72 months) and were more consistently initiated at 420 mg daily (100% vs. 89%). With a median f/u of 14.5 months, the Ibr discontinuation rate was estimated to be 42% (median time to Ibr discontinuation was 7 months). Reasons for discontinuation are listed in table 2. Notably, Ibr toxicity was the most common reason for discontinuation in all settings. Ibr starting dose (420 mg daily vs. < 420 mg daily) did not impact the proportion of patients who discontinued Ibr due to toxicity (51% vs. 50%). In relapsed CLL, the 5 most common Ibr-related toxicities as a reason for discontinuation included: atrial fibrillation (12.3%), infection (10.7%), pneumonitis (9.9%), bleeding (9%), and diarrhea (6.6%). In front line CLL, the 3 most common Ibr-related toxicities as a reason for discontinuation included arthralgia (41.6%), atrial fibrillation (25%), and rash (16.7%). Median times to discontinuation by toxicity were as follows: bleeding (8 months), diarrhea (7.5 months), atrial fibrillation (7 months), infection (6 months), arthralgia (5 months), pneumonitis (4.5 months), and rash (3.5 months). Median PFS and OS for the entire cohort were 35 months and not reached (median f/u 17 months) respectively. Figure 1 describes PFS for Ibr treated patients stratified by line of therapy (A), reason for discontinuation (B), clinical trial participation (C) and depth of response (D). In a multivariable model, complex karyotype was validated as an independent predictor of PFS (HR 1.6, CI 1.1-2.5 p=.04) but not OS (HR 1.6, CI .9-3.1 p=.1). Conclusions: In the largest reported series on Ibr-treated CLL patients, we show that 40% of patients have discontinued Ibr during this observation period. Intolerance as opposed to CLL progression or transformation was the most common reason for discontinuation. As compared to previous reports from clinical trials, the discontinuation rate appears to be higher suggesting (1) a learning curve in terms of toxicity management, (2) a higher incidence of toxicity in clinical practice, (3) or a lower threshold for discontinuation given alternative choices. Outcomes remain excellent and were not impacted by line of therapy and whether patients were treated on studies or commercially. These data strongly argue to find strategies to minimize Ibr intolerance so that efficacy can be further maximized. Figure 1 Figure 1. Disclosures Mato: Abbvie, Acerta Pharma, Gilead Sciences, ProNAi, TG Therapeutics, Theradex: Research Funding; Abbvie, Gilead Sciences, Pharmacyclics, TG Therapeutics: Consultancy. Lamanna:Acerta: Research Funding; TGR Therapeutics: Research Funding; Janssen: Honoraria; Pharmacyclics: Honoraria, Research Funding; Roche-Genentech: Honoraria, Research Funding; Celgene: Honoraria; AbbVie: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Infinity: Research Funding; Acerta: Research Funding; TGR Therapeutics: Research Funding. Ujjani:Gilead: Consultancy; Abbvie: Consultancy; Genentech: Consultancy; Pharmacyclics: Consultancy. Brander:TG Therapeutics: Research Funding; Gilead: Honoraria. Howlett:Sandoz: Honoraria; Teva: Speakers Bureau; Amgen: Honoraria; Pfizer: Honoraria; Eisai: Honoraria. Skarbnik:Gilead Sciences: Speakers Bureau; Seattle Genetics: Speakers Bureau; Genentech: Speakers Bureau; Abbvie: Consultancy; Pharmacyclics: Consultancy. Cheson:Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kiselev:Celgene: Employment, Equity Ownership. Nasta:Millennium Pharmaceuticals: Research Funding. Schuster:Janssen Research & Development: Research Funding; Hoffman-LaRoche: Research Funding; Gilead: Research Funding; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Research Funding; Merck: Research Funding. Porter:Novartis: Patents & Royalties, Research Funding; Genentech: Employment. Nabhan:Seattle Genetics: Research Funding; Cardinal Health: Consultancy; Infinity: Consultancy; Abbvie: Consultancy; Genentech: Consultancy, Research Funding; Celgene Corporation: Consultancy, Research Funding; Astellas: Research Funding. Barr:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Consultancy.

Background: DLBCL without an event (disease progression, retreatment or death) within 24 months post diagnosis have a subsequent overall survival equivalent to that of the age- and sex-matched general population. In contrast, patients with an event with 24 months post diagnosis have poor survival. Patients experiencing early events are a heterogeneous group, consisting of patients with primary refectory disease and responding patients who later developed relapse. While the outcome of patients with primary refractory disease have been recently studied, little is known about or patients who have a response following immunochemotherapy (IC) and proceed to surveillance. These patients are the subject of recently completed and ongoing post-IC maintenance trials. To provide perspective, we analyzed outcomes of patients from a prospective observational study entering post IC. Methods: Newly diagnosed patients with DLBCL and treated with anthracycline-based immunochemotherapy were enrolled in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER) from 2002-2009. End of immunochemotherapy (EOIC) was defined as the date the patient entered surveillance after completion of anthracycline-based IC as per our previous study of surveillance imaging. Response status at EOIC was abstracted as reported from the clinical and radiographic (CT and/or PET) reports. EFS24 was defined being event-free at 24 months from diagnosis, where events consisted of progression, re-treatment, or death (any cause) after initial immunochemotherapy. Survival from EOIC was compared to the general United States population using standardized mortality ratios (SMR) and expected survival. Logistic regression with EFS24 as the endpoint was used to identify pretreatment variables that inform prognosis at the time of EOIC, using Odds ratios (ORs) and 95% confidence intervals (CI) as the measure of association. A subset analysis was performed in the patients aged 60-80 with aaIPI 1-3. Results: 680 patients with DLBCL were enrolled in the MER and initiated R-CHOP or comparable IC from 2002-2009. 552 pts (81%) completed therapy and proceeded to surveillance. Median age of the 552 patients was 61 years (range 18-92) and 51% were male. At a median FU of 89 months from EOIC (range 5-156), 146 pts (26%) had died, and 467 (86%) achieved EFS24. From EOIC, the 5 year overall survival was 82% compared to 91% expected based on age and sex matched general population; SMR was 1.88 (95% CI: 1.60-2.22). In the patients age 60-80 with aaIP1 1-3, (N=203), 79% achieved EFS24 and the 5-year OS from EOIC was 75% compared to 89% expected; SMR was 2.08 (95% 1.65-2.61). When examining all 552 patients proceeding to surveillance at end of EOIC, several high-risk disease characteristics at diagnosis were associated with higher risk of failing EFS24 after completion of therapy: ECOG PS 2-4 (OR = 2.72, 95% CI: 1.55-4.78) , LDH> ULN (OR = 3.54, 95% CI: 1.99-6.31), Stage III/IV (OR=2.43, 95% CI: 1.41-4.16), and aaIPI (per-point OR = 2.02, 95% CI: 1.54-2.64). Patients reported to be in CR at EOIC were more likely to achieve EFS24 (90%) compared to patients not in CR (72%, p Conclusion: Patients entering surveillance after IC have shortened overall survival when compared with the general US population, with significant proportion of patients having an event within 24 months of diagnosis. Increased aaIPI and response less than CR are risk factors for inferior EFS24 in this group. Assessment of the prognostic value of EOIC response (PR vs. CR based on central review) is ongoing. Disclosures Nowakowski: Celgene: Research Funding; Morphosys: Research Funding; Bayer: Consultancy, Research Funding. Maurer:Celgene: Research Funding; Kite Pharma: Research Funding. Howlett:Celgene: Employment, Equity Ownership. Ansell:BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding.

OBJECTIVE: According to standard protocol, the earliest post treatment marker of response following intensive induction therapy in patients with AML is a D14 marrow biopsy. Some controversy has surrounded this practice. This study aims to evaluate response to induction therapy based on D14 marrow assessment meeting genetic risk classifications as defined by the ELN. METHODS: In a single center, retrospective chart analysis subjects diagnosed with AML treated with 7+3 therapy were included if they had molecular and cytogenetic testing performed at baseline, day 14, and day 28. Baseline characteristics and treatment results at these time points were extracted. Sample demographics and treatment were described descriptively. Risk ratios were calculated to investigate the likelihood of achieving a chemo-ablated[1] bone marrow biopsy at Day 14 across the ELN risk classifications. All analyses were performed using SAS 9.4 (SAS Institute Inc., Cary, NC). RESULTS: One hundred thirty eight pts were included. The median age at diagnosis was 57 years (range 26 to 69). The median white blood cell count at diagnosis was 12,800 (range 0.1 to 122,000 per microliter). 6.5% of the pts had secondary AML and 8.7% had AML arising from an antecedent hematologic disorder. ELN risk classifications at diagnosis were 47.1%, 8.7%, 20.3% and 23.9% for favorable, intermediate-I, intermediate-II and adverse, respectively. Demographic variables and baseline characteristics did not differ across risk groups. The percentage of pts achieving a chemo-ablated marrow biopsy at Day 14 was 88%, 83%, 68% and 67% for the Favorable, Intermediate-I, Intermediate-II and Adverse group, respectively (Table 1, p=0.0385). Similarly, the percentage of patients achieving CR at Day 28 was highest for patients with a favorable ELN risk classification (92%) compared to intermediate-I (83%), intermediate-II (71%) and adverse (79%) (Table 2, p=0.0440). Re-induction rate was significantly different when stratified across ELN risk groups (p=0.0487). Risk ratio analysis showed a 26% increased likelihood of achieving a chemo-ablated marrow biopsy when comparing Favorable ELN risk pts to those to those in the non-favorable ELN risk group (RR:1.2552; 95% CI: 1.0526-1.468). A test of discordance comparing hypocellular/hypercellular results based on the Day 14 marrow biopsy with having CR/non CR at end of cycle 1 were not significant across the ELN risk classifications. CONCLUSION: With the advent of personalized therapy comes the potential to customize treatment and hope to optimize pt outcomes. Our results indicate that karyotype and a range of genetic mutations predict marrow morphology at Day 14. How these results predict long-term outcome needs to be further explored. [1] (defined as cellularity Disclosures Ray: Ipsen Biopharmaceuticals: Employment. Koprivnikar:Alexion: Consultancy, Speakers Bureau. McCloskey:Amgen: Speakers Bureau; Ariad: Consultancy, Speakers Bureau; Novartis: Speakers Bureau; Incyte: Consultancy. Stanislaus:Novartis: Consultancy, Speakers Bureau. Howlett:Pfizer: Honoraria; Sandoz: Honoraria; Teva: Speakers Bureau; Amgen: Honoraria; Eisai: Honoraria. Depadova:Amgen: Speakers Bureau. Goldberg:Novartis: Consultancy; Pfizer: Honoraria; Bristol Myers Squibb, Novartis: Speakers Bureau; Neostem: Equity Ownership; COTA Inc: Employment.

Several inherited human syndromes have combined platelet, auditory, and/or pigment abnormalities. In the mouse the pallid pigment mutant has abnormalities of the otoliths of the inner ear together with a bleeding abnormality caused by platelet storage pool deficiency (SPD). To determine if this association is common, two other mouse pigment mutants, muted and mocha, which are known to have inner ear abnormalities, were examined for hematologic abnormalities. Both mutants had prolonged bleeding times accompanied by abnormalities of dense granules as determined by whole mount electron microscopy of platelets and by labeling platelets with mepacrine. When mutant platelets were treated with collagen, there was minimal secretion of adenosine triphosphate and aggregation was reduced. Lysosomal enzyme secretion in response to thrombin treatment was partially reduced in muted platelets and markedly reduced in mocha platelets. Similar reductions in constitutive lysosomal enzyme secretion from kidney proximal tubule cells were noted in the two mutants. These studies show that several mutations that cause pigment dilution and platelet SPD are associated with abnormalities of the inner ear. Also, these mutants, like previously described mouse pigment mutants, are models for human Hermansky-Pudlak syndrome and provide additional examples of single genes that simultaneously affect melanosomes, lysosomes, and platelet dense granules.

Several inherited human syndromes have combined platelet, auditory, and/or pigment abnormalities. In the mouse the pallid pigment mutant has abnormalities of the otoliths of the inner ear together with a bleeding abnormality caused by platelet storage pool deficiency (SPD). To determine if this association is common, two other mouse pigment mutants, muted and mocha, which are known to have inner ear abnormalities, were examined for hematologic abnormalities. Both mutants had prolonged bleeding times accompanied by abnormalities of dense granules as determined by whole mount electron microscopy of platelets and by labeling platelets with mepacrine. When mutant platelets were treated with collagen, there was minimal secretion of adenosine triphosphate and aggregation was reduced. Lysosomal enzyme secretion in response to thrombin treatment was partially reduced in muted platelets and markedly reduced in mocha platelets. Similar reductions in constitutive lysosomal enzyme secretion from kidney proximal tubule cells were noted in the two mutants. These studies show that several mutations that cause pigment dilution and platelet SPD are associated with abnormalities of the inner ear. Also, these mutants, like previously described mouse pigment mutants, are models for human Hermansky-Pudlak syndrome and provide additional examples of single genes that simultaneously affect melanosomes, lysosomes, and platelet dense granules.

Background: Imatinib revolutionized the treatment of chronic myelogenous leukemia (CML) demonstrating improved survival and durable response to treatment. Earlier and deeper response rates were observed with dasatinib and nilotinib in the front line setting compared to imatinib. Multiple clinical trials have revealed that carefully selected patients may safely discontinue TKI therapy. However, lifelong TKI therapy remains the standard of care outside of clinical trial. Methods: We reviewed the charts of patients with chronic phase CML treated with imatinib, dasatinib or nilotinib for chronic phase CML between January 2010 and April 2015 and identified 29 patients that had discontinued therapy. We collected data on their treatment history, response to therapy, and outcomes following TKI withdrawal. Results: At the time of TKI cessation all the patients had achieved an MMR (MR4) for at least 2 years. The median time in MMR prior to treatment withdrawal was 64 months. Twelve patients (41%) were treated with imatinib, 7 (24%) were treated with dasatinib, and 10 (35%) were treated with nilotinib. More than half of the patients had received prior treatment with an alternative TKI. At the time of data collection, 16 patients (55%) remained in MMR off therapy. The median time off treatment was 7 months (range: 3-24 months). The median time to loss of MMR was 5 months (range: 2-11 months). No significant difference was observed between TKI and time to loss of MMR (Table 1). Of those patients who lost MRR while off therapy, all achieved a second MMR upon resuming TKI therapy. Based on the average wholesale price, $3,149,576 was saved by cessation of TKI therapy during the observed period. The required follow up and PCR testing accounted for an additional cost of $84,200 for a net savings of $3,065,376. Conclusions: TKI therapy can be safely discontinued in patients with an MMR duration more than two years with close follow up. While this is a small retrospective study, the results are in keeping with those observed in larger trials. With the life expectancy of patients with chronic phase CML now approaching that of the healthy population, lifelong use of TKI has important implications for patients in terms of medical costs and quality of life. Table 1. Comparison of Patient Characteristics and Outcomes Off Treatment Variable Imatinib (n=12) Dastanib (n=7) Nilotinib (n=10) P-Value Age (years) Median (IQR) 55.5 (53.0 - 61.5) 68.0 (50.0 -72.0) 63.5 (51.0 - 72.0) 0.3811 Range 42.0 - 75.0 48.0 - 72.0 42.0 - 76.0 Gender Male n= 6 (50.0) n= 4 (57.1) n= 2 (20.0) 0.2266 Female n= 6 (50.0) n= 3 (42.9) n= 8 (80.0) Time on treatment prior to discontinuation Median (IQR) 98.0 (64.0- 110.5) 49.0 (39.0 - 69.0) 37.5 (27.0 - 60.0) 0.0016 Range 52.0 - 155.0 33.0 - 115.0 6.0 - 92.0 Time in MMR prior to stopping TKI Median (IQR) 52.5 (39.0 - 96.0) 37.0 (30.0 - 92.0) 71.0 (56.0 - 91.0) 0.6707 Minimum - Maximum 8.0 - 126.0 17.0 - 109.0 19.0 - 108.0 Time off treatment Median (IQR) 7.5 (3.0 - 12.0) 5.0 (2.0 - 9.0) 10.0 (6.0 - 12.0) 0.1599 Range 2.0 - 24.0 2.0 - 11.0 2.0 - 16.0 MMR status off treatment Remain in MMR N= 5 (41.7) N= 4 (57.1) N= 4 (40.0) 0.7970 Loss of MMR N= 7 (58.3) N= 3 (42.9) N= 6 (60.0) Time measured in months. Unless specified otherwise, data are presented as counts (percentages). Categorical variables were examined using Pearson's Chi-square test or Fisher's exact test, as appropriate. Continuous variables were examined using Kruskal-Wallis test or Proc mixed for one-way models, as appropriate. Any P Disclosures McCloskey: Novartis: Consultancy; Pfizer: Consultancy. Koprivnikar:Alexion: Consultancy. Goldberg:Novartis: Research Funding, Speakers Bureau; COTA: Employment, Equity Ownership, Other: Leadership, Stock; Pfizer: Research Funding; BMS: Research Funding, Speakers Bureau; Ariad: Research Funding, Speakers Bureau. Howlett:Teva: Speakers Bureau.

Introduction: B cell receptor signal transduction kinase inhibitors (KI) represent a paradigm shift in CLL management; however, there are limited data regarding real world practice patterns of KI discontinuation and response to subsequent therapies. Two centers reported outcomes of ibrutinib (Ibr) failure patients (pts) treated on clinical trials (n=33, n=71) documenting an extremely poor prognosis (Jain 2014, Maddocks 2015). No analogous data in idelalisib (Ide) failure pts are available. Given the impressive activity of KI and the rarity of discontinuation events, 10 large US cancer centers collaborated to capture the experience of 123 CLL pts who discontinued Ibr- or Ide-based regimens focusing on reasons for discontinuation and response to subsequent KI therapies. Methods: We conducted a multicenter, retrospective analysis of CLL pts who discontinued Ibr- or Ide-based therapy for any reason. We examined demographics, reason for discontinuation, responses, survival data, toxicity, and post KI therapies. Primary endpoint was post KI PFS (time from post KI treatment to progression or last f/u) as determined by the Kaplan Meier method. Comparisons were made using log rank test. Each institution received IRB approval. Results: A total of 123 KI discontinuation pts (Ibr=93/Ide=30) were identified. Table 1 describes baseline characteristics at start of KI. Interestingly, 10% and 32% of Ibr (5% 140 mg, 5% 280 mg daily) and Ide pts (32% 100 mg BID), respectively, were initiated at doses less than FDA labeled dose. Further, 23% and 42% of Ibr pts and 30% and 65% Ide pts had doses modified or held, respectively, prior to discontinuation. Overall median time on KI therapy was 5 months (mos) (4.8 Ibr, 5.5 Ide). ORR to KI was 63% (CR 15%, PR 39%, PR-L 9%). Most common reasons for KI discontinuation were toxicity (58% Ibr, 60% Ide), CLL progression (24% Ibr, 30% Ide), and RT DLBCL (8% Ibr, 7% Ide). Table 2 describes the most common toxicities leading to KI discontinuation. Median PFS from KI initiation for the cohort was 9 mos (77 events, median f/u 6 mos, Figure A ). When stratified by discontinuation reason ( Figure B ), PFS was significantly inferior in RT pts (5 mos RT vs 8 mos progression vs 9 mos toxicity, P=0.04). Median OS for the entire cohort has not been reached (34 deaths, med f/u 12 mos). Median OS was inferior in RT pts (10 mos in RT vs. not reached in CLL progression/toxicity pts; P=0.01). At the time of analysis, 66 (54%) pts following KI discontinuation (21 progression, 36 toxicity, 7 RT, 2 SCT) received a first salvage regimen: 20% R-chemotherapy, 18% Ibr-based, 17% Ide-based, 15% anti-CD20 mab, 14% BCL2-inhibitor, 5% cellular therapy, 5% experimental KI, 3% IMID, 3% other. In evaluable pts, ORR to non-KI therapies following Ibr/Ide discontinuation was 40%. ORR to Ide-based therapy (n=12) following Ibr discontinuation was 50% (42% PR, 8% PRL). ORR to Ibr-based therapy following Ide discontinuation (n=13) was 77% (54% PR, 23% PRL). Responses to alternate KI were similar in pts who discontinued KI for toxicity (ORR 60% PR+PRL) and progression (ORR 67% PR + PRL). PFS (median f/u 5 mos, Figure C ) for pts treated with an alternate KI therapy (Ibr → Ide, Ide → Ibr) has not been reached vs 7 mos in non-KI therapies ( Figure D ). Conclusions: We describe the largest combined experience of practice patterns and outcomes post KI discontinuation in CLL. The majority of pts discontinued KI therapy due to toxicity or progression, not RT. For the first time, we demonstrate that the majority of pts who discontinue a KI due to toxicity or progression respond to other therapies, particularly alternate KI therapy. Collectively, these data provide supporting evidence that: (1) reason for KI discontinuation is toxicity in the majority of cases; (2) alternate KI therapy following KI discontinuation is efficacious; (3) non-overlapping toxicity profiles permit utilization of alternate KI following discontinuation due to toxicity; and (4) mechanisms of KI resistance may not overlap. | Median time diagnosis to KI | 84 mos (1-333) | | ------------------------------ | --------------------- | | Median age (range) | 61 yr (33 - 89) | | Median prior Therapies (range) | 2 (0 - 11) | | del17p (n) | 34% (36/107) | | del11q (n) | 31% positive (32/103) | | p53 mut (n) | 27% positive (22/81) | | Complex karyotype (n) | 31% (33/106) | Table 1. Baseline Characteristics | Ibrutinib | Idelalisib | | --------------- | ----------------- | | Afib 27% | Pneumonitis 33% | | Infection 14% | Colitis 28% | | Pneumonitis 10% | Rash 17% | | Cytopenias 10% | Transaminitis 11% | | Bleeding 10% | Infection 5% | Table 2. Reasons for KI Discontinuation ![Figure 1.][1] Figure 1. Disclosures Mato: Gilead: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Genentech: Consultancy; Pronai Pharmaceuticals: Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy; Celgene Corporation: Consultancy, Research Funding; TG Therapeutics: Research Funding. Nabhan: Celgene Corporation: Honoraria, Research Funding. Barr: Abbvie: Consultancy; Gilead: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding. Ujjani: Genentech: Membership on an entity's Board of Directors or advisory committees. Hill: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lamanna: Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding. Skarbnik: Genentech: Honoraria, Speakers Bureau; Gilead Sciences: Honoraria, Speakers Bureau; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Howlett: Teva: Speakers Bureau. Pu: Merck: Research Funding; BMS: Consultancy; Cyclacel: Research Funding; Medimmune: Research Funding; Ambit: Research Funding; Astellas: Research Funding. Rago: AbbVie: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Speakers Bureau. Zent: Genzyme-Sanofi: Research Funding; Biothera: Research Funding; GlaxoSmithKline: Research Funding; Novartis: Research Funding. Feldman: Celgene: Honoraria, Speakers Bureau; Pharmacyclics/JNJ: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau. Goy: Allos, Biogen Idec, Celgene, Genentech, and Millennium. Gilead: Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau. Claxton: Cyclacel: Research Funding; BMS: Consultancy; Merck: Research Funding; Astellas: Research Funding; Ambit: Research Funding; Medimmune: Research Funding. Svoboda: Celgene: Research Funding; Celldex: Research Funding; Immunomedics: Research Funding; Seattle Genetics: Research Funding. Dwivedy Nasta: BMS: Research Funding; Millenium: Research Funding. Porter: Genentech: Other: Spouse employment; Novartis: Other: IP interest, Research Funding. Schuster: Nordic Nanovector: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Novartis: Research Funding; Genentech: Consultancy; Gilead: Research Funding; Hoffman-LaRoche: Research Funding; Celgene: Consultancy, Research Funding; Phamacyclics: Consultancy, Research Funding. Cheson: Celgene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Rochr-Genentech: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Astellas: Consultancy; Acerta: Research Funding. [1]: pending:yes

Introduction: “Double-hit lymphoma” (DHL), characterized by the presence of both c-Myc and BCL-2 rearrangements, is an aggressive B-cell non-Hodgkin's lymphoma (NHL) that is clearly associated with an inferior prognosis compared to standard risk DLBCL. DHL pts do poorly when treated with R-CHOP and typically cannot be salvaged once relapsed. Studies examining the treatment of DHL pts have been small and there is a lack of consensus in the lymphoma community as to whether DHL pts benefit from dose-escalated chemotherapy regimens in the front-line setting. To address this question, we generated pooled, meta-analytic estimates of the effectiveness of dose-escalated approaches vs. standard dose immunochemotherapy in prolonging overall survival (OS) and progression-free survival (PFS) in newly diagnosed DHL pts. Methods: DHL was defined by the presence of c-Myc rearrangement (FISH) in combination with BCL2 rearrangement (FISH) in pts with DLBCL or transformed follicular lymphoma. Treatment regimens included dose intensive (DI; R-Hyper-CVAD, R-CODOX-M/IVAC), intermediate dose [Dose adjusted (DA)-R-EPOCH], or standard dose (R-CHOP). PubMed, Embase, and abstracts at 3 specific congresses from 1/2009 to 6/2014 were searched using terms “lymphoma” with “DHL”, “dual hit”, “dual translocation”, “double-hit”, or “myc” and “bcl2”. Randomized controlled trials and observational studies evaluating treatment of DHL were eligible for inclusion. Studies of ≤ 10 DHL pts were excluded. Data were collected from study authors or extracted from publications as the proportions of pts surviving at specific follow-up times or individual event times. Data were synthesized to estimate the hazard ratios of higher-dose treatments relative to R-CHOP using a Weibull proportional hazards model within a Bayesian meta-analysis framework. Results: The initial search yielded 996 hits and 57 congress abstracts. After independent review by three investigators, 11 studies examining 401 pts were included in the analysis. Pts were treated with either R-CHOP (n=180), DA-R-EPOCH (n=91), or DI regimen (n=130) in the front-line setting. There were no significant differences in baseline characteristics of pts between included studies or across treatment regimens (median age at diagnosis 60 years, median Ki-67 88%, 53% IPI ≥ 3). The estimated median (and 95% credible intervals [CrIs; the Bayesian analog to confidence intervals]) OS and PFS for the entire cohort were 27.8 (15.1-48.5) and 20.5 (10.9-36.0) months. No significant differences in OS (n=374) were observed among any of the treatments (estimated med OS: R-CHOP, DA-R-EPOCH and DI were 24.2, 37.5, and 29.5 months, respectively, Figure A). Estimated hazard ratios (HR) of OS were 0.77 (95% CrI: 0.50-1.11) for DA-R-EPOCH and 0.90 (95% CrI: 0.62-1.25) for DI relative to R-CHOP. The PFS (n=357) among pts receiving DA-R-EPOCH (HR 0.64, 95% CrI: 0.42-0.92) or DI (HR 0.75, 95% CrI: 0.51-1.05) was similar and DA-R-EPOCH demonstrated significant improvement over R-CHOP (estimated med PFS: R-CHOP, DA-R-EPOCH and DI of 13.9, 27.8, and 21.9, respectively, Figure B). Conclusions: In the largest study and first meta-analysis of treatment outcomes in DHL pts, we have demonstrated that dose-escalated chemotherapy was associated with a significant increase in PFS (particularly DA-R-EPOCH) which did not translate into an OS advantage. This suggests DHL is a disease of chemotherapy resistance. One can consider the use of dose-escalated front-line therapies as they can lead to a PFS advantage and that consolidation strategies should be developed to reduce the likelihood of relapse. These results highlight (1) outcomes remain poor for DHL pts regardless of the intensity of R-chemotherapy induction (2) the need for routine screening for MYC and BCL2 by FISH in DLBCL pts with high-risk features and (3) the need for prospective induction and consolidation strategies that incorporate our growing understanding of the biological basis of DHL such as combinations of novel targeted therapies and/or upfront consolidation with CAR-T-cells. Figure. Weibull meta-analysis estimates of OS (A) and PFS (B) with hazard ratios and 95% credible intervals; *in Bayesian analyses, statistically meaningful differences between treatments are not assessed by P-values, but by whether the CrI contains the value 1, indicating the probability of lower risk of event is Disclosures Cohen: Pharmacyclics: Consultancy; Seattle Genetics: Consultancy; BMS: Research Funding; Janssen: Research Funding. Mato:Celgene: Honoraria, Research Funding.

Introduction: Fludarabine, cyclophosphamide, rituximab (FCR) remains the standard of care for the treatment of newly diagnosed, fit CLL pts requiring therapy. However, the FCR side effects profile is non-trivial and CLL pts with poor risk features have inferior outcomes. Strategies aimed at minimizing toxicity without compromising efficacy have been reported including modifications of the optimal dosing and duration of FCR using a dose-reduced approach (Foon et al, “FCR lite”) or reduction in number of FCR cycles based on MRD status (Strati et al). In the era of biological agents, both preclinical and clinical data have shown the efficacy of lenalidomide (Len) in CLL likely through its role as an immunomodulator and interference with interactions between CLL and its microenvironment. In CLL, Len presents a clinical opportunity both in combination with chemotherapy and as maintenance strategy. This was the rationale for our trial using Len in combination with FCR and as maintenance to improve outcomes and shorten therapy. Methods: We conducted a phase 2 cohort study examining the combination of dose-reduced FCR and Len (“FCR2”) followed by Len maintenance for treatment naïve, CLL pts requiring therapy (NCIWG criteria). Eligible pts (age ≥18 yr, ECOG 0-2, CrCl ≥30 ml/min, absence of AIHA) were treated with 4-6 cycles of FCR2 (D1-3 fludarabine 20 mg/m2, D1-3 cyclophosphamide 150 mg/m2, D1&15 rituximab 500 mg/m2 every 28 days). Len was administered on D 8-28 of each cycle (starting dose of 5 mg increasing to 10 mg and 15 mg in cycle ≥ 2 based on toxicity algorithm). Pts who were MRD (-) in PB and BM (multicolor flow cytometry) initiated Len maintenance after cycle 4 FCR2 (otherwise proceeded to 6 cycles). Supportive care included asa 81 mg, pegfilgrastim, and antimicrobial prophylaxis (ciprofloxacin, bactrim, fluconazole, acyclovir). Daily Len maintenance started two months after FCR2 completion in responding pts for a total of 12 months (5-15 mg based on toxicity algorithm). The primary study endpoint was the proportion of CR pts after cycle 4 of FCR2 with ≥ 8/19 (≥ 40%) CR+CRi considered a positive result and worthy of further study (α 0.05, β 90%). Secondary endpoints included MRD status, ORR, OS, PFS and toxicity (CTCAE V. 4.0). We report the primary endpoint and preliminary data on non-survival secondary endpoints. Results: 25 pts met inclusion criteria for enrollment of which 22 pts enrolled and 19 were evaluable (consent was withdrawn on 3 pts after ≤ 4 FCR2 cycles due to pt preference n=1, physician preference n=2, one additional pt withdrew consent after cycle 5 to proceed with Allo SCT.) Baseline characteristics expressed as median (range) were as follows: age 62.5 yr (42-75 yr), ECOG PS 1 (0-2), WBC 115.4 x 109/L (8.7-301.7), Hb 12.2 g/dL (7.8-15.3), Plt 131 x 109/L (60-178), IgG 602 mg/dL (294-1018), β2mg 2.8 μg/mL (1.74-6.69), LDH u/L 471 (132-1022), BM % lymphs 75 (25-100%), baseline SPD 23.4 (2.9-63.5). In addition 30% pts had Rai stage III-IV, 53% unmutated-CLL, 5% del17p and 30% del11q. After 4 cycles of FCR2 (n=19) response rates were as follows CR 47%, CRi 5%, PR 42%, SD 5% (pts were MRD neg in 29% BM and 56% PB samples, 3 pts (16%) were MRD neg in both PB and BM). After 6 cycles of FCR2 (n=16), response rates improved and were as follows: 63% CR, 13% CRi, 19% PR, 5% PD (pts were MRD neg in 50% BM and 72% PB samples). Table 1 shows MRD status following 4 and 6 cycles of FCR2. During induction, 12 pts required a treatment interruption or dose reduction of Len per protocol (median dose of len was 10 mg). The most common grade 3-4 toxicities were as follows (% events): neutropenia (51%), leukopenia (20%), hyperglycemia (5%), NTP fever (5%). Grade 3-4 TLS and tumor flare were not noted. The med follow up for the entire cohort is 13.1 months (7.3-22.5 months). One progression has occurred in a pt who withdrew from study after 2 cycle of FCR2. One death has occurred in a pt with del17p who died on D+255 following allogeneic SCT in CR from the complications of cGVHD. 10 pts have gone on to initiate Len maintenance. Conclusions: FCR-lite in combination with Len is feasible and demonstrates encouraging clinical activity in a high-risk, CLL pt population with an acceptable toxicity profile. A significant proportion of pts are MRD neg in PB and/or BM following FCR2. Addition of Len to FCR may minimize chemotherapy exposure without compromising outcome. Table 1:MRD StatusFollowing Cycle 4 FCR2Following Cycle 6 FCR2Bone Marrow29%50%Peripheral Blood56%72% Disclosures Mato: Celgene : Honoraria, Research Funding, Speakers Bureau.

Introduction There is a growing awareness of the molecular heterogeneity of DLBCL beyond the GC and non-GC well established subtypes. “Double-hit” lymphoma (DHL) harboring rearrangements of c-Myc and BCL2 have been clearly associated with a poor prognosis. It is well recognized that these pts do poorly with R-CHOP and typically cannot be salvaged using ASCT in the relapse setting. Small series suggest that dose-intensive (DI) strategies may lead to better outcomes in the frontline setting and that some pts achieve durable disease control after allogeneic SCT in the relapse setting. We report here one of the largest series of consecutive DHL pts treated with a DI approach followed by allogeneic SCT and compare outcomes to a similar pt population treated with standard dose (SD) chemotherapy. Methods We conducted a retrospective cohort study of DHL pts to evaluate clinical outcomes stratified by chemotherapy intensity ± SCT treated at John Theurer Cancer Center (JTCC) between 4/09-6/13. DHL was defined by the presence of c-Myc rearrangement (FISH) in combination with rearrangement of BCL2 (FISH) or BCL2 over expression (IHC). Primary study endpoints were PFS and OS assessed by chart review and SSDI database. Investigators were blinded to clinical outcomes. A group of hematopathologists reviewed all cases to verify DHL status (also blinded to outcome). Statistical tests included a two-sample t-test to compare baseline characteristics between groups and Kaplan-Meier and Cox regression survival analyses (med follow up 7.9 months, max follow up 46 months). Results Among the 280 pts with either DLBCL or FL treated between 4/09-6/13 at JTCC, 37 pts (12%) were identified as DHL [100% c-Myc + rearrangement by FISH; 86% t(14;18) + rearrangement by FISH and 95% BCL2 over expression by IHC]. These included 68% de novo DHL: 68% DLBCL, 24% FL, 8% transformed FL and 82% were of germinal center cell origin (Hans). Baseline pt characteristics included med age 60 yr (range 23-84), 57% males, 60% aaIPI ≥3, 93% stage III-IV, 29% BM involvement, 76% bulky disease, 61% extra-nodal disease, med LDH 899 (range 419-8276) and med Ki-67 was 85% (range 20-99%). Treatment regimens included a DI regimen in 66% (n=24) [R-hyper-CVAD, R-CODOX-M/IVAC (Magrath Regimen), DA-R-EPOCH] or a SD regimen in 33% (n=12) [mostly R-CHOP, R-EPOCH (not DA), R-ESHAP]. Of the DI group, 42% of pts underwent SCT as consolidation (73% allogeneic, 27% autologous). Allogeneic SCT included: 25% URD, 75% myeloablative conditioning (Flu/Mel, Cy/TBI, BEAM). There were no significant differences between DI vs. SD groups in terms of pt age, stage, LDH, cell of origin, number of cycles of chemotherapy or Ki-67 (p=NS). Med PFS for the entire cohort was 30.2 months. When stratified by chemotherapy intensity, there was a significant difference in PFS for the DI vs. SD treatment group [46 vs. 8 months, HR 0.26, p=0.005]. The added benefit of SCT was demonstrated when pts were stratified by transplantation status (Figure 1): med PFS for DI with SCT, DI without SCT, and SD were 46, 14.8 and 4.9 months, respectively [DI with SCT vs. SD, HR 0.079, p=0.016; DI without HSCT vs. SD, HR 0.53, p=0.237]. Med OS for SD group was 11.1 months, while med OS for the DI ± SCT groups has not been reached (Figure 2) [DI with SCT vs. SD, HR 0.13, p=0.05; DI without HSCT vs. SD, HR 0.73, p=0.6]. Conclusions As previously recognized, DHL do very poorly with SD alone. DI strategies with allogeneic SCT lead to significantly longer PFS and OS. Though our series is a retrospective analysis and numbers remain small, this is a relatively large series of “true DHL” (with 100% c-Myc rearrangement by FISH and 86% t(14;18) translocation), a situation where no treatment has demonstrated long term benefit. The effect of DLI (a few relapses post-SCT converted to CR after DLI) and the durability of PFS support a GVL effect of allogeneic SCT in DHL. Prospective screening for DHL is warranted in high risk B-cell NHL particularly based on high Ki-67. Additional studies are needed to confirm the benefit of allogeneic SCT consolidation after DI induction therapy. Disclosures: No relevant conflicts of interest to declare.

We conducted a clinical trial to determine the feasibility of growth factor mobilization of CD34+ progenitor cells in human immunodeficiency virus type 1 (HIV-1)-infected individuals. Eight asymptomatic, HIV-1-infected adults (median CD4+ T-cell count, 415 cells/microL), received 480 micrograms/d of granulocyte colony-stimulating factor (G-CSF) for 6 days without evidence of viral activation. Despite concerns that HIV-1 might inhibit hematopoiesis, CD34+ cells were successfully mobilized to the periphery of all donors, independent of the baseline CD4+ T-cell count, and the status of antiretroviral therapy. Leukapheresis was performed on day 6, and yielded a median of 194 x 10(6) CD34+ cells per leukapheresis (n = 7). CD34-enriched cells from the leukapheresis were predominantly myeloid-committed, but between 0.2% and 1.7% were primitive CD34+/CD38- progenitors. A median of 21.7% of the mobilized CD34+ cells were dimly positive for CD4. Consequently, CD34(+)-enriched cells were purified on the cell sorter (mean purity, 97.7% +/- 2.4%; n = 7), and examined for HIV-1 DNA. Purified CD34+ cells from two of seven donors were polymerase chain reaction (PCR)-positive for HIV-1, but only from one of three samples from each donor. We conclude that G-CSF can safely mobilize CD34+ progenitor cells in HIV-1-infected subjects, and that these cells are suitable for consideration in gene-transfer strategies.

Several inherited human syndromes have combined platelet, auditory, and/or pigment abnormalities. In the mouse the pallid pigment mutant has abnormalities of the otoliths of the inner ear together with a bleeding abnormality caused by platelet storage pool deficiency (SPD). To determine if this association is common, two other mouse pigment mutants, muted and mocha, which are known to have inner ear abnormalities, were examined for hematologic abnormalities. Both mutants had prolonged bleeding times accompanied by abnormalities of dense granules as determined by whole mount electron microscopy of platelets and by labeling platelets with mepacrine. When mutant platelets were treated with collagen, there was minimal secretion of adenosine triphosphate and aggregation was reduced. Lysosomal enzyme secretion in response to thrombin treatment was partially reduced in muted platelets and markedly reduced in mocha platelets. Similar reductions in constitutive lysosomal enzyme secretion from kidney proximal tubule cells were noted in the two mutants. These studies show that several mutations that cause pigment dilution and platelet SPD are associated with abnormalities of the inner ear. Also, these mutants, like previously described mouse pigment mutants, are models for human Hermansky-Pudlak syndrome and provide additional examples of single genes that simultaneously affect melanosomes, lysosomes, and platelet dense granules.

SNS-595 is a novel naphthyridine analog, a class of compounds not previously used for cancer treatment. SNS-595 is currently in an escalating-dose phase 1 trial in acute leukemia and several phase 2 studies in solid tumors. SNS-595 has a unique mechanism of action; causing double-strand breaks during S phase that are solely repaired through a DNA-PK-dependent pathway. This damage induces DNA damage-repair signals through both p53 and p73 pathways during DNA synthesis and is accompanied by a rapid onset of apoptosis and an irreversible G2 arrest. This mechanism suggests that SNS-595 could interact in combination favorably with other DNA damaging agents that utilize different mechanisms of damage signaling and repair. SNS-595 demonstrates potent anti-proliferative effects on human leukemic cell lines in vitro and is active in LM-3 Jck and CCRF-CEM hematologic xenograft models. Previously, we have shown that administration of SNS-595 results in a dose dependent loss in bone marrow cellularity and reduction in circulating neutrophils in mice (Proc. Amer. Assoc. Cancer. Res.47: 4726, 2006). These data suggest that SNS-595 activity in bone marrow and circulating blood may provide a therapeutic rationale for the treatment of acute leukemias and advanced chronic myelogenous leukemia. In this study we evaluated the effects of SNS-595 on peripheral white blood cells and bone marrow cellularity as a single agent and in combination with cytarabine (Ara-C) and daunorubicin (DNR). SNS-595 dosed once a day at 10 mg/kg IV as a single agent and Ara-C dosed three times a day as a single agent at 20 mg/kg SC, on day 0 and 4, resulted in 44% and 12% reductions in cellularity, respectively. In contrast, combination dosing of SNS-595 once a day at 10 mg/kg IV with Ara-C dosed three times a day at 20 mg/kg SC resulted in a 93% reduction in cellularity. Normal cellularity recovered on Day 12 (8 days post last dose). Furthermore, the SNS-595/Ara-C combination reduced cellularity more than Ara-C dosed at the MTD of 60 mg/kg three times a day SC (42% reduction in cellularity). Circulating leukocyte levels were also reduced including neutrophils that dropped from 1359 cells/ml to 587 cells/ml for SNS-595 dosed at 10 mg/kg IV and 1212 cells/ml for Ara-C dosed three times a day at 20 mg/kg SC on day 8. The co-administration of these two doses resulted in a near elimination of circulating neutrophils (29 cells/ml). Leukocyte counts subsequently returned to normal levels by Day 18 (14 days post last dose). In conclusion, co-administration of SNS-595 and Ara-C reversibly ablates murine bone marrow cells and reversibly depletes circulating neutrophils. These data indicate that SNS-595 has the potential to combine effectively with Ara-C for the treatment of acute leukemias and suggests that additional studies in patients with advanced hematologic malignancies are warranted.