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In this issue of Blood, Gokbuget et al provide strong evidence that immunotherapy with blinatumomab can eliminate residual chemotherapy-resistant B-cell acute lymphoblastic leukemia (B-ALL) cells and that this prevents subsequent relapse and improves survival.1 This addresses the most important unsolved clinical problem in adults with B-ALL: the development of chemotherapy-resistant relapsed disease.

Leukemic myeloblasts expressing E-selectin ligand (E-sel ligand) adhere to E-selectin on bone marrow endothelium resulting in environment-mediated drug resistance (EMDR). Uproleselan, a potent E-selectin inhibitor, disrupts the adhesion of AML cells in the bone marrow, re-sensitizing blasts to the cytotoxic effects of chemotherapy. Retrospective data demonstrated that E-sel ligand expression in AML patients is higher in relapsed disease compared to newly diagnosed AML, is more commonly seen in biologically adverse risk patients, and is present on leukemic stem cells (Chien et al ASH 2018). Preliminary data from a phase 1-2 trial of uproleselan combined with mitoxantrone, etoposide, cytarabine (MEC) chemotherapy in R/R AML demonstrated enhanced survival in patients with E-sel ligand expression on AML cells of > 10% compared to lower levels (DeAngelo et al ASH 2018). In order to more fully understand the relationship of E-sel ligand to the activity of uproleselan, we examined the clinical variables of patients with both high (> 10%) and low E-sel ligand levels in comparison to the total population of patients treated on the phase 1-2 trial. Uproleselan, combined with MEC chemotherapy was studied in 66 patients with relapsed and/or refractory AML. The expression level of E-sel ligand on the surface of AML cells (blasts/leukemic stem cells (LSCs)) in the bone marrow was measured by a flow cytometric assay using the HECA 452 antibody that recognizes a functional trisaccharide domain shared by sialyl Lea and sialyl Lex and known to bind to E-selectin. Data on E-sel ligand was available in 36 patients at study entry in the phase 1-2 study and E-sel ligand was detectable on blasts in all patients. E-sel ligand on LSCs was demonstrated at levels ≥ 10% in 22 patients (61%) and at levels < 10 % in 14 patients (39%). Overall, the clinical characteristics confirmed a highly resistant population of R/R AML patients (see table) with 79% categorized as either poor risk by the European Prognostic Index (EPI) for first salvage therapy or ≥ second salvage, with an expected 1 year survival of less than 20% (Breems et al JCO 2005, Giles et al Cancer 2005). Although the sample size was small (n=36), substantially more patients with high E-sel ligand had achieved an initial remission and were in relapse (68%) whereas low E-sel ligand patients were more likely to be primary refractory (57%) (p=0.17). Patients with high E-sel ligand were more likely to have adverse ELN risk disease (55%) compared to low E-sel ligand patients (28%) (p=0.053). These data are consistent with previous findings demonstrating that higher E-sel ligand expression contributes to clinical chemotherapy resistance, particularly increasing the risk of relapse, whereas alternative resistance mechanisms may more commonly contribute to primary resistance. Importantly, the 45% response rate and 12.7 months median overall survival (OS) in the high E-sel ligand patients suggests that E-selectin inhibition by uproleselan contributed to their significantly improved outcomes when compared to the historically dismal outcomes with standard of care alone in these poor risk R/R AML patients. Table. Disclosures DeAngelo: Incyte Corporation: Consultancy; Celgene Corporation: Consultancy; Pfizer, Inc.: Consultancy; GlycoMimetics: Research Funding; AbbVie, Inc.: Research Funding; Takeda Pharmaceuticals: Consultancy; Shire: Consultancy; Amgen: Consultancy; Blue Print Medicines: Consultancy, Research Funding; Jazz Pharmaceuticals, Inc.: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding. Jonas:AbbVie, Accelerated Medical Diagnostics, AROG, Celgene, Daiichi Sankyo, Esanex, Forma, Genentech/Roche, GlycoMimetics, Incyte, LP Therapeutics, Pharmacyclics: Research Funding; AbbVie, Amgen, Celgene, GlycoMimetics, Jazz, Pharmacyclics, Tolero: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie, Amgen, GlycoMimetics: Other: Travel expenses. Liesveld:Abbvie: Membership on an entity's Board of Directors or advisory committees; Onconova: Other: Data safety monitoring board. Advani:Pfizer: Honoraria, Research Funding; Glycomimetics: Consultancy, Research Funding; Amgen: Research Funding; Kite Pharmaceuticals: Consultancy; Abbvie: Research Funding; Macrogenics: Research Funding. Marlton:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: 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; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. O'Dwyer:Onkimmune: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; GlycoMimetics Inc: Research Funding; BMS: Research Funding. Fogler:GlycoMimetics Inc: Employment, Equity Ownership. Magnani:GlycoMimetics Inc: Employment, Equity Ownership. Chen:GlycoMimetics: Employment. Feldman:GlycoMimetics Inc: Employment. Thackray:GlycoMimetics Inc: Employment. Becker:AbbVie, Amgen, Bristol-Myers Squibb, Glycomimetics, Invivoscribe, JW Pharmaceuticals, Novartis, Trovagene: Research Funding; Accordant Health Services/Caremark: Consultancy; The France Foundation: Honoraria.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive hematologic malignancy with historically poor outcomes and no established standard of care. Nearly 100% of patients with BPDCN overexpress CD123, and targeting CD123 has therefore emerged as an attractive therapeutic target. UCART123v1 is an allogeneic "off the shelf" product composed of genetically modified T-cells expressing an anti-CD123 CAR and a RQR8 depletion ligand, which confers susceptibility to rituximab. The expression of the T-cell receptor αβ (TCRαβ) is abrogated through the inactivation of the TRAC gene, using Cellectis' TALEN® gene-editing technology. We have previously reported the selective in vitro anti-tumor activity of UCART123v1 cells against primary BPDCN samples using cytotoxicity and T-cell degranulation assays, as well as the secretion of IFNγ and other cytokines (IL2, IL5, IL6, IL-13 and TNF-α) by UCART123v1 cells when cultured in the presence of BPDCN cells (Cai et al, 2017 ASH). To evaluate anti-tumor activity of UCART123v1 cells in vivo, we established two relapsed BPDCN patient-derived xenografts (PDX1 and 2) in NSG-SGM3 mice. In PDX-1 model, mice were randomized upon tumour engraftment (D21 after primary BPDCN injection) into 4 groups and received an IV injection of either vehicle, 10×106 TCRαβ KO control T-cells, or UCART123v1 cells (3×106 or 10×106 cells). Mice from vehicle group died by D53 after BPDCN injection with high tumor burden in PB, spleen and BM. 3 out of 9 (33%) mice treated with 3×106 and 6 out of 9 (67%) mice treated with 10×106 UCART123v1 were alive and disease-free at the end of the study (D299 after primary BPDCN injection). In PDX-2 model, which received the same treatment as PDX-1 (at D19 after primary BPDCN cell injection), all vehicle-treated mice died by D49. UCART123v1 therapy extended survival of treated mice to 104-241 days, but tumors relapsed at 90-155 days (Fig. 1A). The relapses in UCART123v1 treated mice were associated with the emergence of CD123-, CD56+CD45+ BPDCN cells infiltrating spleens and BMs (Fig. 1B). To understand the molecular basis for CD123 loss, we isolated RNA from CD123+ cells from two of the vehicle-treated mice and CD123- cells from four of the UCART123v1-treated mice and performed RT-PCR and RNA-sequencing. The cells from all samples were hCD45+ and hCD56+, indicating leukemic origin. These analyses detected the presence of full-length transcripts (exons 2-12) in both CD123+ control samples (Sample 1 and 2in Fig. 1C). In 2 of the 4 CD123- samples, CD123 transcripts were absent, as were transcripts of neighbouring genes (samples 3 and 9 in Fig. 1C). RNA-sequencing reads aligned to Genome Browser tracks for CD123 and housekeeping gene GPI showed no reads present for CD123 but reads present for GPI in the two samples with CD123 loss. The aCGH (Array‐Based Comparative Genomic Hybridization) results showed that samples 3 and 9 (CD123-) had large regional deletions on chromosome X, which includes the CD123 gene. In another sample (sample 5), the splicing analysis algorithm MAJIQ detected CD123 transcripts containing only exons 2-9, indicating premature transcription termination. If translated, this truncated transcript would produce a protein isoform lacking the transmembrane domain in exon 10. Finally, MAJIQ also revealed canonical splicing of exon 2 to exon 3 in all CD123+ samples but a sharp increase in skipping from exon 2 to exon 5 in sample 16 (Fig. 1D). This exon-skipping event preserves the open-reading frame and yields the previously reported transcript variant 2. Per UniProt, the resultant protein will retain the ligand-binding domain but lack several glycosylation sites and two beta sheets in the extracellular domain, potentially compromising recognition by UCART123v1 cells. The aCGH and FISH results further showed that this patient sample harbored TP53 deletion, which could have contributed to DNA instability observed in different mice engrafted with these tumor cells. In summary, allogeneic anti-CD123 CAR T therapy resulted in eradication of BPDCN in vitro and in increased disease-free survival in primary BPDCN PDX models. However, CD123 loss was observed in one PDX model harboring a TP53 deletion. These results provide preclinical proof-of-principle that UCART123v1 cells have potent anti-BPDCN activity, and indicate potential mechanisms leading to antigen loss and disease relapse. Disclosures Galetto: Cellectis Inc: Employment. Gouble:Cellectis: Employment. Zhang:The University of Texas M.D.Anderson Cancer Center: Employment. Kuruvilla:The University of Texas M.D.Anderson Cancer Center: Employment. Neelapu:Cellectis: Research Funding; Celgene: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; BMS: Research Funding; Poseida: Research Funding; Novartis: Consultancy; Karus: Research Funding; Acerta: Research Funding; Incyte: Consultancy; Pfizer: Consultancy; Merck: Consultancy, Research Funding; Unum Therapeutics: Consultancy, Research Funding; Precision Biosciences: Consultancy; Cell Medica: Consultancy; Allogene: Consultancy. Lane:AbbVie: Research Funding; Stemline Therapeutics: Research Funding; N-of-One: Consultancy. Kantarjian:BMS: Research Funding; Amgen: Honoraria, Research Funding; Cyclacel: Research Funding; Agios: Honoraria, Research Funding; Novartis: Research Funding; Immunogen: Research Funding; Jazz Pharma: Research Funding; Pfizer: Honoraria, Research Funding; Ariad: Research Funding; Takeda: Honoraria; Astex: Research Funding; Daiichi-Sankyo: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding. Guzman:Cellectis: Research Funding; Samus Therapeutics: Patents & Royalties: intellectual rights to the PU-FITC assay; SeqRx: Consultancy. Pemmaraju:Stemline Therapeutics: Consultancy, Honoraria, Research Funding; samus: Research Funding; plexxikon: Research Funding; incyte: Consultancy, Research Funding; affymetrix: Research Funding; sagerstrong: Research Funding; Daiichi-Sankyo: Research Funding; cellectis: Research Funding; celgene: Consultancy, Honoraria; abbvie: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding; mustangbio: Consultancy, Research Funding. Konopleva:Genentech: Honoraria, Research Funding; Ablynx: Research Funding; Astra Zeneca: Research Funding; Agios: Research Funding; Eli Lilly: Research Funding; Forty-Seven: Consultancy, Honoraria; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; Ascentage: Research Funding; Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties.

Acute myeloid leukemia (AML) is the most common acute leukemia diagnosed in adults, and the majority of patients with AML die from relapsed disease. Although many studies over the past 4 decades have identified disease alleles in AML, recent genome-wide and candidate gene studies have identified additional recurrent somatic mutations in AML patients with biologic, clinical, and therapeutic importance. Herein we review our current understanding of the molecular pathogenesis of AML and discuss how mutational profiling can be used to refine prognostication in AML and to inform therapeutic approaches. We also review the current challenges in translating genomic studies to the clinical setting, which remains a significant challenge and an urgent priority.

Introduction The multistep progression of multiple myeloma from a normal plasma cell to a system with the features of invasive cancer provides a unique opportunity to understand the co-evolution of the malignant clone within its microenvironment. Understanding these changes is becoming increasingly important as we attempt to design early intervention strategies and to precisely leverage emerging immunotherapeutic modalities to prevent and treat disease progression. In this work, we used mass cytometry (CyTOF) to generate a high-resolution map of the BM microenvironment and how it changes during the transition from health through pre-malignancy to disease. This approach allows us to both understand microenvironmental patterns that correlate with rapid disease progression as well as to generate new hypotheses about permissive and protective immune-phenotypes that might reveal novel immunologic drug targets. Methods To understand the immunologic characteristics of monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), newly diagnosed multiple myeloma (NDMM) and relapsed-refractory multiple myeloma (RRMM), we profiled BM aspirates from 79 patients using mass cytometry by time of flight (CyTOF). Furthermore, we compared the BM compartment of pre-malignant, malignant, and relapsed disease states to the BM of healthy donors using a 37-marker pan-immune panel. In this panel, we used antibodies against several immune lineages, tumor antigens, and functional surface markers, including co-stimulatory and co-inhibitory receptors. Cell clusters defined by Citrus analysis of CyTOF data were combined into an evolutionarily optimized decision tree by evtree to identify cluster interactions that strongly partition patient samples. Results During MGUS, when the tumor plasma cells are Conclusions Immune dysregulation is thought to be a major contributor to the progression and outcome of patients with MGUS, SMM, and MM. Using CyTOF, we have begun to benchmark the content of the immune microenvironment across the myeloma continuum. Based on this cross-sectional analysis we hypothesize that it is important to further interrogate whether the losses in the CD4 memory and effector populations we described correlate with outcomes after therapy with either CAR T or T cell engager trials that are currently ongoing, and whether reconstituting these cell types could provide a meaningful treatment strategy. Disclosures Young: Celgene Corporation: Employment, Equity Ownership. Danziger:Celgene Corporation: Employment, Equity Ownership. Fitch:Celgene Corporation: Employment, Equity Ownership. Schmitz:Celgene Corporation: Employment, Equity Ownership. Gockley:Celgene Corporation: Employment. McConnell:Celgene Corporation: Employment. Reiss:Celgene Corporation: Employment, Equity Ownership. Copeland:Celgene Corporation: Employment, Equity Ownership. Newhall:Celgene Corporation: Employment, Equity Ownership. Hershberg:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties. Foy:Celgene Corporation: Employment, Equity Ownership. Ratushny:Celgene Corporation: Employment, Equity Ownership. Dervan:Celgene Corporation: Employment, Equity Ownership. Morgan:Takeda: Consultancy, Honoraria; Janssen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria.

To the editor: The treatment of classical Hodgkin lymphoma (cHL) patients with refractory/relapsed disease remains a clinical challenge.[1][1] To find a new therapeutic option for cHL, we investigated the preclinical activity of the repurposed drug auranofin (AF).[2][2] AF is an anti-inflammatory

ABL001 (Fig. 1) is a first-in-class allosteric inhibitor of BCR-ABL1 that occupies the vestigial myristoyl pocket, inducing an autoinhibited kinase conformation (Sellers, et al. Proceedings of the 106th Annual Meeting of the AACR; 2015 Apr 18-22; Philadelphia, PA). Phase 1 clinical trials with single-agent ABL001 in relapsed patients with chronic or accelerated phase chronic myeloid leukemia (CML) previously treated with at least two different tyrosine kinase inhibitors (TKIs) are underway. Patients who exhibit relapsed disease associated with the presence of the T315I mutation after at least one TKI are also eligible if no other effective therapy exists. The unexplored possibility of combining an allosteric inhibitor (e.g. ABL001) with a clinically proven BCR-ABL1 TKI such as nilotinib could have important implications for maximum disease control. Given the remote location of the myristoyl allosteric pocket relative to the catalytic site in the kinase domain of BCR-ABL1, a reasonable expectation is that ABL001 should be insulated from point mutations that impart resistance to TKIs such as nilotinib, dasatinib or ponatinib. However, pre-clinical studies demonstrate that the high level of potency exerted on native BCR-ABL1 is not uniformly maintained against a panel of clinically observed point mutations that impart resistance to non-allosteric BCR-ABL1 TKIs (Wylie, et al. Blood (2014) 124, 21, Abstract 398). For example, the T315I and F359V mutations confer substantial in vitro resistance to ABL001 in cell line experiments. The mechanistic reasons for these differences are under investigation. We will report on: (1) Ba/F3 cell line resistance assays predictive of clinical mutation-based escape mechanisms starting from cells expressing native BCR-ABL1 or BCR-ABL1T315I, for ABL001 as a single agent and in combination with a BCR-ABL1 TKI (nilotinib, dasatinib or ponatinib) (2) profiling of ABL001 against T315I-inclusive and non-T315I compound mutations, as a single agent and in combination with a BCR-ABL1 TKI (nilotinib, dasatinib or ponatinib) and (3) Molecular Dynamics studies probing the structural reasons for the selectivity profile of ABL001. In summary, our results to date on ABL001 suggest that single-agent ABL001 retains activity against a subset of non-T315I compound mutants. Preliminary findings indicate that the in vitro resistance profile of ABL001 is non-overlapping with that of TKIs that bind in the catalytic site. In contrast to ABL001, it is known that some myristoyl pocket binders activate rather than induce autoinhibition of BCR-ABL1. Current computational modeling efforts are focused on exploring a similar bifurcation from the perspective of native BCR-ABL1 as compared to ABL001-resistant BCR-ABL1 mutants such as T315I and F359V. Results of ongoing experiments with T315I-inclusive compound mutants will be reported. Our ultimate interest is to identify ABL001-sensitive compound mutants and make this information available to clinicians. Figure 1. ABL001 Chemical Structure Figure 1. ABL001 Chemical Structure Disclosures Druker: Millipore: Patents & Royalties; ARIAD: Research Funding; Fred Hutchinson Cancer Research Center: Research Funding; Aptose Therapeutics, Inc (formerly Lorus): Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Oregon Health & Science University: Patents & Royalties; Henry Stewart Talks: Patents & Royalties; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; McGraw Hill: Patents & Royalties; Cylene Pharmaceuticals: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; CTI Biosciences: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Leukemia & Lymphoma Society: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Oncotide Pharmaceuticals: Research Funding; MolecularMD: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Research Funding; Roche TCRC, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sage Bionetworks: Research Funding; AstraZeneca: Consultancy. Deininger:Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees.

4270 Background Clinical and translational research content in hematologic oncology is increasingly complex as new pathways and novel agents are investigated. Continuing oncology education (COE) for community-based oncologists (CBOs) must prioritize discussion of key new developments and clinical implications in order to optimize patient care. Clinical investigators (CIs) at tertiary academic institutions usually focus on specific areas in their research and practice, and these individuals play an important role in defining medical oncology standards of care and often participate in COE. Many CBOs and their patients turn to CIs for advice, answers and second opinions, and we hypothesized that CIs could provide a unique perspective in prioritizing COE content. This pilot project attempted to quantify and elucidate the experiences of investigators specializing in lymphoma/CLL (L) and multiple myeloma (MM), with the hope of gaining insight into current needs in COE that might directly impact patient care. Methods Between April 11 and May 16, 2012 we recruited 51 CIs (L: 26; MM: 25) to complete tandem questionnaires with about 60 items. Participants were provided a modest honorarium. As part of each survey and in order to document real-world experiences, CIs were asked to quantify how often they consult clinically with patients previously seen by another oncologist and how often they answer by phone or email case-related questions from CBOs. CIs also had the option to briefly describe up to 3 recent second opinion cases in which their recommendation differed significantly from that of a prior oncologist. Finally, CIs were also asked to define their usual nonprotocol treatment approaches to a variety of important clinical scenarios (L: 31; MM: 26) and then provide on a 4-point analog scale their perception of the need for additional COE in each of these specific areas. Results Participating CIs have considerable experience with CBOs and CBO-managed patients, providing clinical second opinions a mean of 4.0 times per week (L: 3.3; MM: 4.7; range 0–13) and responding to email or phone case queries a mean of 8.5 times per week (L: 8.4; MM: 8.6; range 0–40). CIs submitted a total of 89 case descriptions (L: 54; MM: 35) in which their treatment recommendation differed significantly from that of the prior oncologist. Specifically, in 19 of these cases (L: 13; MM: 6) the CI disagreed with the diagnosis, in 50 the choice of initial treatment differed (L: 28; MM: 22) and in 20 treatment for relapsed disease was questioned (L: 13; MM: 7). The top-rated areas of education need are presented in the table below. In many of these issues, recent research developments have resulted in controversy and heterogeneity in treatment approaches. Conclusions This pilot project demonstrates that CIs regularly evaluate patients previously managed by CBOs and also provide long-distance second opinions by email and phone that in some instances result in divergent recommendations. These informative experiences contribute to an overall perception of specific education needs that could be very useful in planning COE and in development of performance improvement programs. Additional research is needed to confirm and expand these findings and determine if this quantitative and targeted approach to COE enhances patient care and measurable clinical outcomes. | NHL/CLL clinical decisions (n = 26) | Mean | % rating 4* | MM clinical decisions (n = 25) | Mean | % rating 4* | |:----------------------------------------:| ---- | ----------- | ----------------------------------- | ---- | ----------- | | Relapsed FL after R-CHOP n maintenance R | 3.6 | 62 | Implications of cytogenetics/FISH | 3.8 | 76 | | Choice of chemo with R in FL | 3.5 | 58 | Post-transplant maintenance | 3.7 | 73 | | Induction in younger patients with MCL | 3.5 | 54 | Subcutaneous bortezomib, neuropathy | 3.6 | 64 | | Induction for CLL, 17p deletion | 3.4 | 46 | Induction with acute renal failure | 3.6 | 60 | | Second-line FL after BR | 3.4 | 46 | Role of transplant | 3.5 | 58 | * * 1–4 ratings of education need for medical oncologists (1 = least need; 4 = greatest) * NHL = non-Hodgkin lymphoma; CLL = chronic lymphocytic leukemia; FL = follicular lymphoma; MCL = mantle-cell lymphoma; BR = bendamustine/rituximab Disclosures: Horwitz: Millennium: The Takeda Oncology Company: Research Funding; Seattle Genetics: Consultancy, Research Funding; Kyowa Hakko Kirin Co Ltd: Consultancy, Research Funding; Bristol-Myers Squibb Company: Consultancy; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Allos Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Spectrum Pharmaceuticals: Consultancy, Research Funding. Lonial: Acetylon Pharmaceuticals Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck and Company Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: The Takeda Oncology Company: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx Pharmaceuticals Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees. Palumbo: Bristol-Myers Squibb Company: Consultancy; Celgene Corporation: Consultancy, Speakers Bureau; Millinnium: The Takeda Oncology Company: Consultancy, Speakers Bureau; Amgen, Inc: Speakers Bureau. Smith: Allos Therapeutics: Speakers Bureau; Cephalon Inc: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millinnium: The Takeda Oncology Company: Speakers Bureau; Spectrum Pharmaceuticals Inc: Speakers Bureau; Genentech BioOncology: Speakers Bureau.

Using data derived from the U133Plus2.0 microarray (U2), we recently constructed a 17-gene model predictive of high-risk multiple myeloma (MM). In the model, 13% of newly diagnosed cases were considered to have high-risk MM with 24 month overall survival estimates of 50% and 90% in the high- and low-risk groups, respectively (p

Introduction: Autologous stem cell transplant (ASCT) as part of initial therapy has been shown to prolong survival of patients with multiple myeloma, with some achieving durable complete remission. However, the majority of patients ultimately relapse after ASCT and require salvage treatment. Options for the treatment of such patients have increased significantly over recent years, including not only novel chemotherapeutic and biological agents but also additional ASCTs. We performed a retrospective analysis of our experience with salvage ASCT for multiple myeloma to determine which clinical variables influence outcome. Methods: Between October 1992 and February 2005, we performed 342 ASCTs for multiple myeloma. Twenty-six of these were salvage transplants for relapsed disease after prior ASCT, and all were included in the analysis. Patients who received two planned (tandem) ASCTs were not included. Results: The median age at diagnosis was 47 (range 25–66), and median ISS and DS stages at diagnosis were 1 and 2, respectively. The initial ASCT was melphalan-based in 21/26; six (23%) achieved a complete response (CR) to the initial transplant, and fifteen (58%) achieved a partial response (PR). The median event-free survival (EFS) after the initial transplant was 19.5 months (range 2–60). The median time between initial and salvage ASCT was 2.6 years (range 0.3–7.6). Twenty-two patients (85%) received non-transplant therapy between ASCTs, and the median number of lines of therapy prior to salvage ASCT was 3. At the time of salvage ASCT, the median age was 52.5 (range 28–69). Fourteen patients received melphalan alone, eight received melphalan/TBI, and four received other regimens. Eleven patients (42%) achieved a response to therapy (1 CR, 10 PR). One patient (4%) died of transplant-related toxicity. The median follow-up after salvage ASCT is 12 months (range 0.2–58). Median EFS is 9 months, and median overall survival (OS) is 36 months. The 2-year EFS is 14%, and 2-year OS is 52%. On univariate analysis, both response to and EFS after initial transplant significantly predict improved EFS after salvage transplant (p=0.0008 and p=0.0065 respectively). Both also predict improved OS (p=0.03 and 0.0005 respectively). A greater than 12 month interval between first and second transplant also correlated with OS (p=0.04). There was no significant difference in EFS or OS by preparative regimen. Interestingly, type of response to the salvage transplant (CR/PR or less than PR) did not predict improved EFS or OS. Conclusion: This study suggests that salvage ASCT after relapse from initial ASCT is a feasible therapy for patients with heavily treated multiple myeloma, particularly those with a prolonged response to the first transplant.

Total Therapy II (TT2), consisting of intensive induction with non-cross resistant VAD, DCEP, CAD (with collection of PBSC) and DCEP.; followed by tandem autotransplants in support of melphalan 200mg/m2; followed by consolidation chemotherapy every 3 months x4 ; followed by interferon maintenance, has complete accrual of 668 patients with upfront randomization to +/− Thalidomide. Collection goal was 20 million CD34+ cells/kg with CAD. This number allows for tandem transplants with support of >5 x 106 CD34 cells/kg, additional cells were stored in case of engraftment problems, additional transplants in the future for relapsed disease and in case of development of MDS. Patient characteristics are outlined in Table 1. 319 patients collected >20 x106 CD 34+ cells/kg with CAD (median 24.9 million, range 20–127), 2 proceeded to second collection with DCEP (median 5.005 million, range 0–10.01. Of this group 310 patients (97%) underwent single and 234 (73%) tandem autotransplant. 135 patients collected 10 – 20 x106 CD 34+ cells/kg with CAD (median 16.35 million, range 10.09–19.93), 13 patients had second collection with DCEP (median 4.92 million, range 1.23–11.68), 5 patients underwent third collection with growth factor (median 2.61million, range 0.12–12.85). Of this group 130 patients (96%) underwent single and 94 (70%) tandem autotransplant. 46 patients collected 5 – 10 x106 CD 34+ cells/kg with CAD (median 7.82 million, range 5.1–9.97), 20 patients had second collection with DCEP (median 9.785 million, range 0.93–27.14), 8 patients underwent third collection with growth factor (median 2.02million, range 0.3–11.8). No patient underwent a fourth collection attempt. Of this group 44 patients (96%) underwent single and 29 (63%) tandem autotransplant. 63 patients collected 70%) to proceed to autologous transplant. Table 1: Patients depending on initial collection result with CAD Overall >20* 10–20* 5–10* 0–5* 0* * (x 106 CD34+ cells collected) N 603 319 (53%) 135 (22%) 46 (8%) 63 (10%) 40 (9% Age >65 19% 14% 17% 30% 30% 28% CA 31% 30% 33% 30% 40% 25% Thal Arm 49% 41% 56% 63% 57% 50% CRP >4 8% 7% 10% 7% 8% 10% B2M >4 31% 26% 36% 33% 37% 43% LDH >190 29% 27% 33% 26% 30% 40% BM >30% PC 64% 62% 67% 63% 67% 60%

High-dose chemotherapy with hematopoietic stem cell transplantation has become a mainstay of treatment for patients with non-Hodgkin lymphoma or Hodgkin lymphoma who either fail to achieve a complete remission or who have relapsed disease. As investigators analyzed the results of this approach, it