ALBERT

Description: Disease type and status at the time of allogeneic hematopoietic stem cell transplantation (HSCT) dominantly influence HSCT outcome. It is therefore important to stratify patients by disease risk in any retrospective or prospective transplantation study that enrolls patients across multiple disease types or status. We previously proposed a Disease Risk Index for this purpose, based on a retrospective study of patients transplanted at 2 institutions (Armand et al, Blood 2012;120:905). Here we present the results of a study designed to validate and refine the DRI in a larger multicenter population. We included 13,131 adult patients who underwent HSCT for hematologic malignancies, excluding very rare diseases, between 2008 and 2010 and were reported to the CIBMTR. Their median age was 52 (range, 18-80) years. The cohort included a broad representation of diseases, disease status, donor types, and graft sources. 53% of patients were conditioned with a myeloablative regimen. The median follow-up for survivors was 24 months. The original DRI stratified patients into 4 groups with 2y OS of 64% in the low-risk, 51% in the intermediate, 34% in the high, and 24% in very high risk group (p

Description: Key Points For patients with acute myelogenous leukemia, post-transplant survival is not determined by donor source (unrelated vs related). However, for patients with myelodysplastic syndromes, donor source remains an important determinant of post-transplantation outcomes.

Description: Abstract 33 Background: Circulating levels of peripheral blood (PB) CD34+ cells/μl are a strong predictor of hematopoietic stem cell (HSC) yields in patients with non-Hodgkin's lymphoma (NHL) undergoing autologous HSC transplantation (auto-HSCT), and are routinely monitored to optimize the timing and success of HSC collection after cytokine ± chemotherapy mobilization. The threshold PB CD34+ cell count to initiate apheresis varies from 5-20 cells/μl, depending on the institution. This analysis compared the efficacy of plerixafor + G-CSF to placebo + G-CSF for HSC mobilization in NHL patients with pre-apheresis PB CD34+ cells/μl

Description: Background. We previously reported data from 103 pts receiving PBSC from HLA-matched unrelated donors after conditioning with 2 Gy total body irradiation (TBI) plus 90 mg/m2 fludarabine. Postgrafting immunosuppression included MMF (administered from day 0 until day +40 with taper through day +96), and CSP (given from day -3 to day +100, with taper through day 180) (historical group). The incidences of grade III–IV acute and chronic extensive GVHD were 14% and 48%, respectively. Several studies have suggested that CSP could prevent activation-induced cell death of T-cells, and thus potentially delay the eradication of donor-versus-host alloreactive T-cells, preventing tolerance induction. Conversely, antimetabolite inhibitors, such as MMF, could delete alloreactive T-cells by induction of activation-induced cell death and apoptosis, and thus might favor tolerance induction Pts and Methods. Here, we investigated whether postgrafting immunosuppression with prolonged MMF (given at 15 mg/kg orally thrice a day from day 0 to day +30, then at 15 mg/kg orally twice a day until day 150, and then tapered at day 150 and discontinued at day 180) and truncated CSP (abruptly discontinued on day 80), would promote tolerance induction and reduce the incidence of GVHD (current protocol, n=71) after unrelated HCT with nonmyeloablative conditioning. Results. Sustained donor engraftment was achieved in 68 pts (96%) in the current protocol, versus in 98 pts (95%) in the historical group. Grades II, III and IV acute GVHD were seen in 36 (50.7%), 11 (15.5%) and 7 (9.9%) pts, respectively, in the current protocol, versus 39 (37.9%), 11 (10.7%) and 4 (3.9%) pts, respectively, in the historical group. The incidences of grade II–IV and grade III–IV acute GVHD were 75% and 23% in the current protocol, versus 52% (P=.05) and 14% (P=.14) in the historical group. The 1-yr incidence of chronic GVHD was 46% in the current protocol, versus 48% in the historical group. Finally, the 1-yr probabilities of relapse, nonrelapse mortality and progression-free survival were 24%, 36% and 40%, respectively, in the current protocol, versus 26% (P=.9), 18% (P=.005) and 56% (P=.04) in the historical group. The increased incidence of nonrelapse mortality in the current protocol was not due only to the increased incidence of grade II–IV acute GVHD, since nonrelapse mortality remained significantly higher in the current protocol than in the historical group after adjusting for occurrence of grade II and grade III–IV acute GVHD (P=.04). Evaluation of pretransplant comorbidities is ongoing. Conclusions. Postgrafting immunosuppression with prolonged MMF and truncated CSP failed to decrease the incidence of GVHD after nonmyeloablative conditioning with URD. Ongoing efforts are directed at reducing the risk of acute GVHD after nonmyeloablative conditioning for unrelated donors by replacing tacrolimus for CSP, and by adding sirolimus to MMF and CSP.

Description: Introduction Extramedullary leukemia (EML) will develop in approximately 3% of the patients with acute leukemia. Only a few retrospective studies, and no prospective or randomized studies, have assessed the effectiveness and toxicity of radiation for EML. Here we review the EML patients treated with radiation therapy at the Oregon Health and Sciences University (OHSU) Radiation Oncology department. Methods and Materials From 1987 to 2005, 17 patients with EML underwent 20 radiation courses at the OHSU Radiation Oncology department. All patients had either biopsy-proven EML or had pre-established diagnoses of leukemia and were treated for EML as presumptive relapse. Patient data and disease history were either extracted from the patient chart or obtained from the cancer tumor registry. Variables used for analysis included patient age, gender, histological diagnosis, tumor location, radiation dose, fraction size, acute toxicities, last follow up or date of death, disease recurrence site after radiation therapy, initial symptom with presenting EML, effect of radiation on symptom(s), and time to EML. Univariate and multivariate analyses were done. Kaplan-Meier survival curves and Cox regression analyses were generated. Results The mean age of our patients was 37.5 years, with a range from 7.4 to 78.5 years. Males made up 76% of the patients population. The most common location for an EML was soft tissue (25%), followed by central nervous system (20%), and mucosal (15%). Surgical intervention was performed in only 5 of the 17 EML patients. The 17 patients received 20 treatment courses. The most frequently used radiation energy was 6 Megavoltage photons (55% of the cases), while the next most common was cobalt 60 (10%) and a mixed energy beam (10%). Radiation therapy was quite effective at relieving symptoms with a 94% response rate and 61% having a complete response. Pain was palliated in 88% of patients, while mass effect was decreased in 100% of patients. The mean radiation dose given was 21.8 Gray (range 10–39.6 Gy). We did not observe a radiation dose response to symptom palliation (Table 1). Leukemia recurrence of any type occurred at a median of 5.8 months from the last day of radiation treatment. There was a low incidence of acute grade 1 or 2 toxicities (39%) and no acute grade 3 or 4 toxicities or late toxicities. Our 17 patients had a mean and median overall survival of 20.7 months and 5.6 months, ranging from less than 1 month to 149 months. Regression and correlation models failed to show any significant prognostic factor (age, gender, quality of radiation, total radiation dose, initial presenting EML symptom, or time from diagnosis of leukemia to diagnosis to EML) influencing overall survival. Conclusions The role of radiation in EML is for symptom relief. Low dose radiation provides excellent palliation with minimal toxicity. A radiation dose response was not seen in our small patient population. Table 1 Radiation Dose response in Extramedullary Leukemia Dose # Patients # Symptoms # symptoms with a response # symptoms with a complete response 10–19.9 Gy 6 7 7 (100%) 4 (57%) 20–29.9 Gy 4 5 5 (100%) 3 (60%) 30 Gy or more 4 6 5 (83%) 4 (80%)

Description: Autologous hematopoietic cell transplantation (HCT) followed by nonmyeloablative allogeneic HCT (auto/alloHCT) provides cytoreduction and graft-versus-myeloma effects. We report on long-term outcomes of 102 patients with multiple myeloma who received auto/alloHCT with a median follow-up of 6.3 years. Treatment consisted of high-dose melphalan and autograft followed by 2-Gy total body irradiation, with or without fludarabine, and alloHCT from human leukocyte antigen-identical siblings. Postgrafting immunosuppressive agent was cyclosporine or tacrolimus and mycophenolate mofetil. Forty-two percent of patients developed grade 2 to 4 acute graft-versus-host disease (GVHD) and 74% extensive chronic GVHD. Five-year nonrelapse mortality after allografting was 18%, 95% related to GVHD or infections. Among 95 patients with detectable disease, 59 achieved complete remissions. Median time to progression was 5 years. Median overall survival (OS) was not reached. Median progression-free survival (PFS) was 3 years. Five-year OS and PFS were 64% and 36%, respectively. Seventy-three patients receiving autoHCT within 10 months from treatment initiation had 5-year OS of 69% and PFS of 37%. In multivariate analysis, β-2-microglobulin of more than 3.5 μg/mL at diagnosis and auto/alloHCT more than 10 months after treatment initiation correlated with shorter OS (P = .03 and P = .02) and PFS (P = .04 and P = .03), whereas Karnofsky scores less than 90% at allotransplantation correlated with shorter PFS only (P = .005). Long-term disease control and GVHD remain key issues.

Description: Introduction: Autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy achieves rapid and durable responses in patients with r/r DLBCL, although unique potential toxicities require specialized management. Cytokine release syndrome (CRS) is the most commonly observed adverse event of special interest associated with CAR T-cell therapy. Two CRS grading scales have been used in different clinical trials of CAR T-cell therapy: the Penn scale (Porter, Sci Transl Med, 2015; Porter, J Hematol & Oncol, 2018) and the Lee scale (Lee, Blood, 2014; Neelapu, Nat Rev Clin Oncol, 2017). To better inform management of CRS and develop best practices, we assessed concordance and differences between the two scales by using the Lee scale to regrade observed CRS events in r/r DLBCL patients treated with tisagenlecleucel, who were previously graded per protocol using the Penn scale. Methods: Individual patient level data from the JULIET trial, a single-arm, open-label, multicenter, global phase 2 trial of tisagenlecleucel in adult patients with r/r DLBCL (NCT02445248), were used in this study. Four medical experts who had managed DLBCL patients using different CAR T-cell therapy protocols and products independently reviewed the data, while blinded to the original Penn grading, and re-graded CRS for JULIET patients using the Lee scale. Re-grading assessments and disagreements in the assigned Lee grade were discussed and reconciled among reviewers during a live meeting. As per the investigational charter, the most conservative final assessment of any expert reviewer determined the final grading for any individual case. For example, if an event was graded as 2, 3, 3 and 4, then grade 4 would be the final grading. Results: As of December. 8, 2017, 111 patients with r/r DLBCL were infused with tisagenlecleucel in the JULIET trial. Sixty-four (58%) patients had CRS graded according to the Penn scale and each case was re-graded using the Lee scale based on JULIET data collected prospectively (e.g., CRS-related symptoms, oxygen supplementation, intervention for hypotension, and organ toxicities). Using the Lee scale, 63 (57%) patients were considered to have any grade CRS by investigators, including grade 1 events in 26 (23%), grade 2 in 18 (16%), grade 3 in 10 (9%), and grade 4 in 9 (8%) (Figure 1). One patient with grade 1 per Penn scale was re-graded to grade 0 due to absence of documented fever or symptoms requiring intervention. Compared to Penn grades, the Lee scale provided the same grade for 39 patients, a lower grade for 20 patients, and a higher grade for 5 patients. Among 64 patients re-graded, 59 (92%) had fever, 27 (42%) had oxygen supplementation (3 with grade 1, 6 grade 2, 9 grade 3, and 9 grade 4 per Lee scale) and 7 (11%) had concurrent infections. Of 29 (45%) patients requiring intervention for hypotension (13 with grade 2, 7 grade 3, and 9 grade 4 per Lee scale), 28 had fluid resuscitation and 10 received high dose/combination vasopressors. In addition, 8 of 9 patients re-graded as Lee grade 4 were intubated. As for anti-cytokine therapy, only 17 patients received tocilizumab (1 for grade 1, 2 for grade 2, 5 for grade 3, and 9 for grade 4 CRS per Lee scale) and 12 patients received corticosteroids (2 for grade 2, 1 for grade 3, and 9 for grade 4 CRS per Lee scale). Conclusions: Different CAR-T studies in DLBCL patients have used different approaches (Lee and Penn scales) for grading CRS and had different thresholds for tocilizumab treatment of CRS. Harmonization of grading CRS between studies permits a more accurate comparison of observations and outcomes. In this analysis, patients with r/r DLBCL receiving tisagenlecleucel in the JULIET trial, which used the Penn scale to grade CRS, were re-graded by expert consensus using the Lee scale. Using the Lee scale, more patients were categorized as grade 1 (Lee vs. Penn: 26 vs. 17), fewer patients as grades 2 and 3 (18 vs. 23, and 10 vs. 15, respectively), and the same number of patients as grade 4 (9 vs. 9) compared to the Penn scale. The re-grading of the JULIET CRS data using the Lee scale makes it possible to perform comparative analyses of CRS outcomes from clinical trials using different CAR-T products and could be used to develop best practice guidelines. Disclosures Schuster: Pfizer: Membership on an entity's Board of Directors or advisory committees; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding; OncLive: Honoraria; Genentech: Honoraria, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Physician's Education Source, LLC: Honoraria; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Maziarz:Athersys, Inc.: Patents & Royalties; Kite Therapeutics: Honoraria; Juno Therapeutics: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ericson:Novartis Pharmaceuticals Corporation: Employment. Rusch:Novartis Pharmaceuticals Corporation: Employment. Romanov:Novartis Pharmaceuticals Corporation: Employment. Locke:Cellular BioMedicine Group Inc.: Consultancy; Novartis Pharmaceuticals: Other: Scientific Advisor; Kite Pharma: Other: Scientific Advisor. Maloney:Janssen Scientific Affairs: Honoraria; Roche/Genentech: Honoraria; Seattle Genetics: Honoraria; GlaxoSmithKline: Research Funding; Juno Therapeutics: Research Funding.

Description: Background: Tisagenlecleucel is an autologous anti-CD19 chimeric antigen receptor (CAR)-T cell therapy that is approved for adult patients (pts) with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). In the phase 2 JULIET trial, pts could receive bridging therapy (BT), when needed, to permit flexibility in scheduling and maintain disease control. Lymphodepleting chemotherapy (LDC) was started 5-14 days prior to CAR-T cell infusion. Here we present baseline characteristics, efficacy/safety outcomes, and cellular kinetics by BT and type of LDC used in the JULIET trial. Methods: Pts were categorized based on BT or no BT, as well as LDC (cyclophosphamide/fludarabine [Cy/Flu; 250 and 25 mg/m2 IV daily for 3 doses, respectively] or bendamustine [90 mg/m2 IV daily for 2 days]) or no LDC, received prior to tisagenlecleucel infusion. Cy/Flu was the proposed regimen for LDC, followed by bendamustine (if the pt experienced previous grade [G] 4 hemorrhagic cystitis with Cy or demonstrated resistance to a previous Cy-containing regimen). LDC was not required if white blood cell count was 8 weeks to ≤1 year post-infusion, 〉1 year post-infusion, and any time after infusion were generally consistent across BT and LDC groups for prolonged cytopenias, neurological events (NE), cytokine release syndrome (CRS), and infection (Table). Of note, among pts who did not receive BT, only 1 G3 CRS and 1 G3 NE were reported, and no G4 CRS or NE were reported. Additionally, the rate of cytopenias not resolved by day 28 post-infusion was lowest among pts who did not receive BT (1/11 pts). However, cytopenias resolved to ≤G2 by month 3 or month 6 in the majority of pts. Cmax, Tmax, and exposure (AUC0-28d) were similar between LDC groups (Table). Cmax and AUC0-28d were also similar between pts who received BT and those who did not. Additional analyses of subgroups will be presented at the congress. Conclusions: The majority of pts enrolled in the JULIET trial received BT and LDC, indicating high tumor burden and aggressive disease in this pt population with r/r DLBCL. Although the sample size is small (n=11), pts not requiring BT appeared to have less aggressive disease, achieved high response rates, and had no G4 CRS or NE. Pts who did not receive LDC (n=8) seemed to have low response rates, suggesting either the impact of prior therapy, the importance of LDC, or both. Further evaluation of the impact of BT and LDC on clinical outcomes on larger patient population will be possible with the availability of registry data. Clinical trial information: NCT02445248 Table Disclosures Andreadis: Genentech: Consultancy, Employment; Merck: Research Funding; Roche: Equity Ownership; Novartis: Research Funding; Celgene: Research Funding; Juno: Research Funding; Pharmacyclics: Research Funding; Gilead: Consultancy; Kite: Consultancy; Jazz Pharmaceuticals: Consultancy. Tam:BeiGene: Honoraria; Roche: Honoraria; Novartis: Honoraria; Janssen: Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie company: Honoraria; AbbVie: Honoraria, Research Funding. Borchmann:Novartis: Honoraria, Research Funding. Jaeger:Novartis, Roche, Sandoz: Consultancy; AbbVie, Celgene, Gilead, Novartis, Roche, Takeda Millennium: Research Funding; Amgen, AbbVie, Celgene, Eisai, Gilead, Janssen, Novartis, Roche, Takeda Millennium, MSD, BMS, Sanofi: Honoraria; Celgene, Roche, Janssen, Gilead, Novartis, MSD, AbbVie, Sanofi: Membership on an entity's Board of Directors or advisory committees. McGuirk:Astellas: Research Funding; Novartis: Research Funding; Fresenius Biotech: Research Funding; Gamida Cell: Research Funding; Pluristem Ltd: Research Funding; ArticulateScience LLC: Other: Assistance with manuscript preparation; Juno Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bellicum Pharmaceuticals: Research Funding. Holte:Novartis: Honoraria, Other: Advisory board. Waller:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Other: Travel expenses, Research Funding; Cerus Corporation: Other: Stock, Patents & Royalties; Chimerix: Other: Stock; Cambium Oncology: Patents & Royalties: Patents, royalties or other intellectual property ; Amgen: Consultancy; Kalytera: Consultancy. Jaglowski:Unum Therapeutics Inc.: Research Funding; Novartis: Consultancy, Other: advisory board, Research Funding; Juno: Consultancy, Other: advisory board; Kite: Consultancy, Other: advisory board, Research Funding. Bishop:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Juno: Consultancy, Membership on an entity's Board of Directors or advisory committees; CRISPR Therapeutics: 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; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Foley:Celgene: Speakers Bureau; Amgen: Speakers Bureau; Janssen: Speakers Bureau. Westin:Curis: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; Celgene: Other: Advisory Board, Research Funding; 47 Inc: Research Funding; Genentech: Other: Advisory Board, Research Funding; Novartis: Other: Advisory Board, Research Funding; MorphoSys: Other: Advisory Board; Unum: Research Funding; Kite: Other: Advisory Board, Research Funding. Fleury:Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; AstraZeneca: Consultancy. Ho:Novartis: Other: Trial Investigator meeting travel costs; La Jolla: Other: Trial Investigator meeting travel costs; Janssen: Other: Trial Investigator meeting travel costs; Celgene: Other: Trial Investigator meeting travel costs. Mielke:DGHO: Other: Travel support; IACH: Other: Travel support; EBMT/EHA: Other: Travel support; Miltenyi: Consultancy, Honoraria, Other: Travel and speakers fee (via institution), Speakers Bureau; GILEAD: Consultancy, Honoraria, Other: travel (via institution), Speakers Bureau; Jazz Pharma: Honoraria, Other: Travel support, Speakers Bureau; Kiadis Pharma: Consultancy, Honoraria, Other: Travel support (via institution), Speakers Bureau; Celgene: Honoraria, Other: Travel support (via institution), Speakers Bureau; ISCT: Other: Travel support; Bellicum: Consultancy, Honoraria, Other: Travel (via institution). Teshima:Novartis: Honoraria, Research Funding. Salles:Epizyme: Consultancy, Honoraria; Amgen: Honoraria, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; BMS: Honoraria; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events. Schuster:Novartis: Patents & Royalties: Combination Therapies of CAR and PD-1 Inhibitors (royalties to Novartis); i3Health, Dava Oncology, Novartis, OncLive, PER Oncology: Speakers Bureau; AbbVie, Acerta, Celgene, DTRM Bio, Genentech, Incyte, Merck, Novartis, Portola, TG therapeutics: Research Funding; AbbVie, Celgene, Novartis, Nordic Nanovector, Pfizer: Other: steering committee; Acerta, AstraZeneca, Celgene, Juno, LoxoOncology, Novartis: Other: advisory board; i3Health, Acerta, AstraZeneca, Celgene, Dava Oncology, Juno, LoxoOncology, Novartis, Nordic Nanovector, OncLive, PER Oncology, Pfizer: Honoraria. Bachanova:Kite: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Gamida Cell: Research Funding; GT Biopharma: Research Funding; Incyte: Research Funding; Celgene: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Maziarz:Novartis: Consultancy, Research Funding; Incyte: Consultancy, Honoraria; Celgene/Juno: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees. Van Besien:Miltenyi Biotec: Research Funding. Izutsu:Eisai, Chugai, Zenyaku: Honoraria; Kyowa Kirin, Eisai, Takeda, MSD, Chugai, Nihon Medi-physics, Janssen, Ono, Abbvie, Dainihon Sumitomo, Bayer, Astra Zeneca, HUYA Japan, Novartis, Bristol-Byers Squibb, Mundi, Otsuka, Daiichi Sankyo, Astellas, Asahi Kasei: Honoraria; Celgene: Consultancy; Eisai, Symbio, Chugai, Zenyaku: Research Funding; Chugai, Celgene, Daiichi Sankyo, Astra Zeneca, Eisai, Symbio, Ono, Bayer, Solasia, Zenyaku, Incyte, Novartis, Sanofi, HUYA Bioscience, MSD, Astellas Amgen, Abbvie, ARIAD, Takeda, Pfizer: Research Funding. Wagner-Johnston:Gilead: Membership on an entity's Board of Directors or advisory committees; Jannsen: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees. Corradini:Amgen: Honoraria; Celgene: Honoraria, Other: Travel Costs; AbbVie: Consultancy, Honoraria, Other: Travel Costs; Daiichi Sankyo: Honoraria; Gilead: Honoraria, Other: Travel Costs; Janssen: Honoraria, Other: Travel Costs; Jazz Pharmaceutics: Honoraria; KiowaKirin: Honoraria; Kite: Honoraria; Novartis: Honoraria, Other: Travel Costs; Roche: Honoraria; Sanofi: Honoraria; Servier: Honoraria; Takeda: Honoraria, Other: Travel Costs; BMS: Other: Travel Costs. Tiwari:Novartis: Employment. Awasthi:Novartis: Employment. Lawniczek:Novartis: Employment. Eldjerou:Novartis Pharmaceuticals Corporation: Employment. Kersten:MSD: Other: Travel grants, honorarium, or advisory boards; Janssen/Cilag: Other: Travel grants, honorarium, or advisory boards; Kite: Consultancy, Other: Travel grants, honorarium, or advisory boards; Roche: Consultancy, Research Funding, Travel grants, honorarium, or advisory boards; Bristol Myers Squibb: Other: Travel grants, honorarium, or advisory boards; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Other: Travel grants, honorarium, or advisory boards; Celgene: Other: Travel grants, honorarium, or advisory boards; Gilead: Other: Travel grants, honorarium, or advisory boards; Amgen: Other: Travel grants, honorarium, or advisory boards; Roche: Other: Travel grants, honorarium, or advisory boards; Celgene: Consultancy, Research Funding.

Description: Translocations involving the immunoglobulin heavy chain gene locus (IgH) are common in B cell malignancies. One common target gene is cyclin D1, which is deregulated in most patients with mantle cell lymphoma (MCL) and approximately 15–20% of patients with multiple myeloma (MM). Cyclin D1 is not expressed in normal lymphocytes; cyclin D1 expression in B cell malignancies is deregulated by IgH translocations and insertions. We have shown that the cyclin D1 locus, including the promoter and upstream regions, are acetylated and DNA hypomethylated in both malignant and nonmalignant B cells (Liu et al, Blood in press). Using chromatin immunoprecipitation (ChIP) assays, we have found that RNA polymerase II (Pol II) is a) present at the cyclin D1 promoter b) located at regions far upstream of the cyclin D1 gene and c) present at 3′ Cα IgH regulatory elements only in cyclin D1 expressing malignant B cells. Pol II is present at the translocation breakpoint in a MCL cell line, but we do not find Pol II present continuously from the IgH regulatory regions to the cyclin D1 promoter. Confirmatory RT-PCR analyses also do not demonstrate continous evidence of RNA transcripts extending from the IgH regulatory elements to the cyclin D1 promoter. Mutants derived from gene targeting experiments that have lost the translocated chromosome show Pol II binding only at the Eu intronic enhancer, consistent with known promoter acivity and sterile transcripts originating at this location. Our data suggest that Pol II may play a important role in initiating long distance cyclin D1 deregulation by translocated IgH sequences. Analogous to the mouse β-globin gene locus, a polymerase transfer (LPT) model may be invoked, where other proteins such as CTCF effect Pol II transfer from 3′ Cα IgH regulatory sequences to the cyclin D1 promoter and initiate cyclin D1 transcription.