Abstract: Hairy cell leukemia (HCL) is a rare B-cell malignancy, and there is a need for novel treatments for patients who do not benefit from purine analogs. Ibrutinib, an oral agent targeting Bruton tyrosine kinase in the B-cell receptor signaling pathway, is highly effective in several malignancies. Its activity in HCL was unknown, so we conducted a multisite phase 2 study of oral ibrutinib in patients with either relapsed classic or variant hairy cell leukemia. The primary outcome measure was the overall response rate (ORR) at 32 weeks, and we also assessed response at 48 weeks and best response during treatment. Key secondary objectives were characterization of toxicity and determination of progression-free survival (PFS) and overall survival (OS). Thirty-seven patients were enrolled at 2 different doses (24 at 420 mg, 13 at 840 mg). The median duration of follow-up was 3.5 years (range, 0-5.9 years). The ORR at 32 weeks was 24%, which increased to 36% at 48 weeks. The best ORR was 54%. The estimated 36-month PFS was 73% and OS was 85%. The most frequent adverse events were diarrhea (59%), fatigue (54%), myalgia (54%), and nausea (51%). Hematologic adverse events were common: anemia (43%), thrombocytopenia (41%), and neutropenia (35%). Ibrutinib can be safely administered to patients with HCL with objective responses and results in prolonged disease control. Although the initial primary outcome objective of the study was not met, the observation of objective responses in heavily pretreated patients coupled with a favorable PFS suggests that ibrutinib may be beneficial in these patients. This trial was registered at www.clinicaltrials.gov as #NCT01841723.

Abstract: Background Cord blood transplantation (CBT) is an increasingly used alternative to bone marrow or peripheral blood stem cell transplantation, but is associated with slower neutrophil and platelet recovery. One strategy to overcome the delayed hematopoietic recovery of CB is to correct the decreased fucosylation of CB cell surface molecules which is thought to impair homing to the bone marrow of the limited numbers of stem and progenitor cells in the CB graft. Our pre-clinical murine xenograft models have demonstrated that human CB-derived progenitor cells treated with recombinant human fucosyltransferase-VI (ASC-101:America Stem Cell Inc.) prior to infusion resulted in more rapid and higher levels of human engraftment as compared to untreated CB progenitors (Robinson et al Exp Hematol, 2012). We therefore sought to study this novel strategy in a clinical trial where recipients with hematologic malignancies receive a double CBT where one CB unit is fucosylated prior to infusion. Objective In an effort to improve engraftment following cord transplant, we tested the ability of a 30-minute ex vivo fucosylation treatment to shorten time to neutrophil and platelet recovery. Methods Cell Processing: The unmanipulated CB unit with the highest total nucleated cell (TNC) dose was thawed, washed on the Sepax device (Biosafe) and infused first. The second CB unit which had the smaller TNC dose was thawed and washed using 10% Dextran-40/5% human serum albumin and the cells treated at 106cells/ml for 30 minutes at room temperature with recombinant human fucosyltransferase VI (ASC-101) and substrate GDP-fucose (America Stem Cell Inc). The fucosylated cells were then washed on the Sepax and infused. After the procedure fucosylated (CD34+ CLA+) CD34+ cells increased from a median of 33% to 99%. Clinical 10 patients with AML (5), MDS (2), NHL (2), or HL (1) have been enrolled to date. Three patients are too early to evaluate engraftment; therefore, first 7 evaluable patients are reported here. Median age was 55 (range 26 -62) years and median weight 87 (range 61-97) kg. All patients were conditioned with fludarabine 160mg/m2, melphalan 140mg/m2, and ATG 3mg/kg. Tacrolimus and MMF were used for GVHD prophylaxis. Results Median time to absolute neutrophil count ≥ 0.5 X 109 /L was 14 (range 12-28) days. Median time to platelet count ≥ 20 X 109/L was 33 (range 18-100) days. One patient had secondary graft failure and was rescued with backup autologous stem cells. Four patients had engraftment of the fucosylated unit and 2 of the unfucosylated unit. Two patients developed grade 2 acute graft versus host disease. No infusion related toxicities were seen. Conclusion Ex vivo fucosylation appears to be a safe, simple and rapid approach to enhancing neutrophil and platelet engraftment in the setting of double cord transplantation. Accrual to the trial continues and updated results will be presented. Disclosures: Miller: America Stem Cell Inc: Equity Ownership. Paradiso:America Stem Cell Inc: Equity Ownership. Koh:America Stem Cell Inc: Equity Ownership.

Abstract: Background: Reduced-intensity induction (RII) with imatinib yields comparable outcomes to HyperCVAD with imatinib with fewer induction deaths and an improved CR rate in Ph+ ALL (Chalandon. Blood. 2015). Dasatinib with steroids also produces excellent responses with little toxicity (Foa. Blood. 2011). Allogeneic bone marrow transplant (AlloBMT) remains the goal of therapy in Ph+ ALL based on contemporary trials with TKIs demonstrating improved survival in patients transplanted in CR1, and we have shown that transplant following induction with dasatinib yields better outcomes than with imatinib. Thus we implemented RII with dasatinib for the treatment of Ph+ ALL and compared to patients who received HyperCVAD with a 2nd generation TKI. Methods: Patients with newly diagnosed Ph+ ALL admitted to Johns Hopkins Hospital from September 2017-June 2020 underwent a 4-week RII with: vincristine 2 mg/d weekly, dexamethasone 40 mg PO weekly on days 1 and 2, and dasatinib 100 mg PO daily. CNS prophylaxis with IT MTX was given on day 8. Dexamethasone and vincristine were reduced by 50% for patients over age 70. Filgrastim was started on day 15 for patients without ANC recovery. Patients who received HyperCVAD with dose adjustments for age (Rausch et al. Cancer. 2020) from July 2011-June 2020 were included for comparison. Dasatinib 100 mg PO daily or nilotinib 400 mg PO BID were given with HyperCVAD at the discretion of the treating physician. Rituximab 375 mg/m^2 on days 1 and 8 was given based on CD20 status. Subsequent therapy after induction was not specifically mandated. Results: 21 patients received RII and 24 received HyperCVAD. The cohorts were comparable in terms of gender (38.1% female vs. 50%, p=0.55), age (median 49.8 vs. 50.3, p=0.33), age & gt;60 (33.3% vs. 29.2%, p & gt;0.99), median WBC at diagnosis (19 vs. 23.5, p=0.56), and the presence of decompensated DIC (fibrinogen & lt;150) prior to treatment initiation (4.8% vs. 8.3%, p & gt;0.99). Among the patients treated with HyperCVAD, 15 received dasatinib (62.5%) and 9 received nilotinib (37.5%). Rituximab use was balanced between the cohorts (61.9% vs. 58.3%, p & gt;0.99). Table 1 compares the time to ANC recovery & gt;500, transfusion requirements within 30 days of chemotherapy initiation, rates of decompensated DIC following treatment initiation, and the duration of inpatient hospitalization for induction. While the rates of decompensated DIC were similar in each cohort, patients treated with RII required fewer platelet and pRBC transfusions. ANC recovery was faster following RII, and only 5 patients (23.8%) received growth factor support. All patients achieved a hematologic response. There was one induction death with HyperCVAD (4.2%). Most patients received a subsequent cycle of high-dose (HD) MTX and Ara-C with TKI (76.2% following RII and 91.7% following HyperCVAD). The remaining patients treated with RII subsequently received HD MTX (14.2%) or blinatumomab (9.5%) with TKI due to co-morbidities. Among those patients treated with HD MTX and Ara-C, blinatumomab was given with TKI to 6 patients (37.5%) who initially received RII and 1 patient (4.5%) after HyperCVAD (p=0.03) due to persistent MRD. As shown in Figure 1, the incidence of MRD-negativity by multi-color flow cytometry (MFC) with a sensitivity of 10-4 at day 120 after treatment initiation was similar for RII (85.4%, 95% CI 64.8-97.1) versus HyperCVAD (86.7%, 95% CI 69.8-96.6). Among patients subsequently treated with HD MTX and Ara-C, 62.5% proceeded to alloBMT after RII with an additional 12.5% currently undergoing transplant evaluation, while 86.4% proceeded to alloBMT after HyperCVAD. The 1-year RFS and OS following RII were 87.9% (95% CI 59.6-96.8) and 100% compared to 87.5% (95% CI 66.1-95.8) and 95.8% (95% CI 73.9-99.4) following HyperCVAD. Conclusion: RII with dasatinib results in fewer transfusions and less myelosuppression compared to HyperCVAD with a 2nd generation TKI. More patients treated with RII received blinatumomab following high-dose MTX and Ara-C, but the rates of MRD-negativity were comparable between the two regimens. Thus RII with dasatinib followed by MRD-guided follow-up therapy facilitates MRD negative remissions with less toxicity than HyperCVAD. The vast majority of fit patients were able to proceed to alloBMT following either regimen. Transplant outcomes following dasatinib with induction are presented in our concurrent abstract demonstrating a 5-year RFS of 83% (95% CI 59.8-93.5). Disclosures Webster: Amgen: Consultancy; Pfizer: Consultancy. Jain:Bristol Myer Squibb: Other: for advisory board participation; CareDx: Other: Advisory Board; Takeda: Consultancy, Honoraria. Dalton:AbbVie: Research Funding; Eli Lilly: Research Funding. DeZern:Abbvie: Consultancy; Astex: Research Funding; Celgene: Consultancy, Honoraria; MEI: Consultancy. Gojo:Genentech: Research Funding; Amphivena: Research Funding; Merck: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Bolanos-Meade:Incyte: Other: DSMB Fees. Luznik:WindMil Therapeutics: Patents & Royalties: Patent holder; AbbVie: Consultancy; Merck: Research Funding, Speakers Bureau; Genentech: Research Funding. Ali:Celgene: Membership on an entity's Board of Directors or advisory committees. Borrello:Celgene: Research Funding; Aduro: Patents & Royalties; WindMIL Therapeutics: Other: Founder , Research Funding. Wagner-Johnston:ADC Therapeutics, Regeneron, CALIB-R, Verastem: Membership on an entity's Board of Directors or advisory committees. Smith:Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: 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. Levis:Menarini: Honoraria; Amgen: Honoraria; Daiichi-Sankyo: Honoraria; FujiFilm: Honoraria, Research Funding; Astellas: Honoraria, Research Funding.

Abstract: Cytotoxic T lymphocytes (CTL) specific for a nine amino acid HLA-A2-restricted peptide, PR1 (derived from proteinase 3, P3), are capable of killing leukemia cells and contribute to the elimination of CML. PR1-specific CTL (PR1-CTL) elicited in vitro from healthy donors also can lyse P3-expressing AML blasts. Here, we examined whether PR1-CTL can be adoptively transferred to NOD-SCID/HLA-A2 transgenic mice to eliminate blasts as a preclinical model for PR1-CTL cell therapy for AML. Human AML blasts isolated from bone marrow were transferred into irradiated (200 rad) NOD-SCID/HLA-A2 mice and engrafted in bone marrow at various doses (107, 106, 105) between 2–8 weeks. Human CD45 Ab and mouse CD45.1 Ab were used to identify cells of human origin by FACS and IHC, and human CD33 and CD34 Abs were used to identify AML cells. PR1-CTL were elicited from healthy donors that specifically lysed P3-expressing leukemia. These PR1-CTL were predominantly CD45RA−/CCR7−/CD28+ and maintained an activated effector phenotype following adoptive transfer. Transferred AML blasts were significantly decreased in the bone marrow of mice receiving co-transferred PR1-CTL compared to those that received only AML: 0.5×106 AML cells plus 1×104 PR1-CTL or 0.5×106 AML cells (control) were infused into irradiated mice respectively. Mice were sacrificed at 2–4 weeks post-transfer and tissues were analyzed by FACS and IHC. Bone marrow aspirate from mice that received AML alone had 72–88% blasts in hypercellular marrow, whereas mice that received AML plus PR1-CTL had normal hematopoietic elements and only 10–11% blasts in hypocellular marrow. PR1-CTL also migrated to the secondary lymphoid organs including spleen, peripheral and mesenteric lymph nodes, and in the liver. Leukemia cells also infiltrated extramedullary organs. In the liver, intrasinuosidal and periportal collections of leukemic blasts were associated with vascular damage, and PR-CTL infiltrated these same regions by 2 weeks post-transfer. The PR1-CTL in the bone marrow and liver maintained an effector phenotype similar to the pre-infusion CTL, whereas PR1-CTL in secondary lymph organs such as blood and spleen also contained some cells expressing CCR7 that either reverted to a naïve phenotype or had expanded from the precursor population. By 4 weeks post-transfer, leukemia was no longer evident in the liver, although PR1-CTL remained. In conclusion, we found that PR1-CTL generated in vitro can eliminate the AML cells in NOD-SCID/HLA-A2 mice. PR1-CTL can migrate to sites of disease and maintain their capacity to eliminate leukemic blasts. Surface phenotype of PR1-CTL were consistent with their trafficking pattern in both vascular and end-organ tissues. Our results justify a clinical trial with adoptively transferred PR1-CTL in patients with AML.

Abstract: Background. Prior studies consistently show that the use of maintenance therapy after completion of combination therapy translates into longer progression-free survival (PFS) in patients with multiple myeloma. Some studies show that maintenance therapy prolongs overall survival (OS). Typically, maintenance therapy is used in the setting of newly diagnosed multiple myeloma; however, emerging data suggest that (at least a subset of) patients in the early relapse setting, for example those who achieve MRD negativity, may also be candidates for maintenance therapy integrated with careful disease monitoring. Currently, lenalidomide is considered the standard of care for maintenance; however, there is only limited published data on long-term use, with respect to the ability to sustain MRD negativity, mechanisms of relapse, and late toxicities. We were motivated to develop a study focusing on long-term lenalidomide maintenance therapy and to study clinical and correlative data. Here, we report on sustained MRD negativity and clinical tolerability. Methods. This single arm, phase 2 was designed to enroll 100 evaluable patients. Per protocol, maintenance therapy with lenalidomide 10 mg is given days 1-21 on a 28-day cycle. The initial study design had a total duration of 36 months; it was subsequently extended with additional 24 months (i.e., total of 60 months). Per standard procedures for protocol amendments, patients were offered to re-consent for the extension. Per protocol, patients underwent bone marrow biopsies and aspirates as well as PET/CT exams at baseline, annually, at progression/end of treatment; blood work was done every 3 months. Bone marrow and blood samples were banked longitudinally per the research protocols. Based on practical considerations, the study was statistically powered for the primary end-point progression-free survival, which provided sufficient numbers of samples for the planned correlative assays focusing on MRD testing, genomic characterization of detectable disease, and profiling of the bone marrow microenvironment. All these assays were conducted in serial samples collected over time and assessed in relation to clinical outcomes. Results. A total of 100 evaluable patients meeting eligibility criteria were enrolled (63% males) between September 2015 and January 2019. Baseline characteristics include median age 63 years (range 38-86 years) and median ECOG score 1 (range 0-1). At the submission of this abstract, the median number of cycles delivered is currently 26 (range 1 to 48); 86 patients have completed 12 or more cycles, 57 patients have completed 24 or more cycles, and 29 patients have completed 36 or more cycles. MRD testing had been completed at least once in all patients. Thirty-four patients were MRD negative at enrollment. At median followup time of 28 months (range 3.4 to 45.6), 15/100 (15%) patients have progressed. Considering the entire follow-up time from initial MRD negativity to last follow-up on study, we found 39 (of 85 tested; 46%) and 25 (of 57 tested; 44%) to have evidence of 1 and 2 years sustained MRD negativity, respectively. Only 19 patients were tested for MRD at 3 years and 16 (84%) had sustained MRD negativity. Toxicities (grade 3) include neutrophil count decrease (N=9), hypertension (N=3), diarrhea (N=2), lung infection (N=2), and rash maculo-papular (N=2), and toxicities (grade 4) include sepsis (N=2) and platelet count decrease (N=1). The most common 1/2 toxicities were diarrhea (N=51), fatigue (N=33), and upper respiratory infection (N=23). Among evaluable patients, dose reductions of lenalidomide due to toxicities and tolerability issues were done in 6 (6%) patient. Conclusions. Among evaluable patients who were treated with lenalidomide 10 mg maintenance therapy days 1-21 on a 28-day cycle on this study, at a median followup of 28 months, we found 46% and 44% to have evidence of 1 and 2 years sustained MRD negativity, respectively. Currently, 19 patients have been tested for MRD at 3 years; 16 (84%) show evidence of 3 years sustained MRD negativity. The toxicity profile was in accord with prior studies and tolerability was quite good reflected in only 6 patients requiring dose reductions due to toxicities. Correlative assays focusing on mechanisms of sustained MRD negativity in this study are presented in a separate abstract at this meeting. Disclosures Landgren: Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Theradex: Other: IDMC; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Other: IDMC. Lesokhin:Genentech: Research Funding; GenMab: Consultancy, Honoraria; Janssen: Research Funding; Serametrix Inc.: Patents & Royalties; Juno: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria. Smith:Celgene: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics and Precision Biosciences: Consultancy. Mailankody:Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria. Hassoun:Janssen: Research Funding; Celgene: Research Funding; Novartis: Consultancy. Landau:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Scordo:Angiocrine Bioscience, Inc.: Consultancy; McKinsey & Company: Consultancy. Arcila:Invivoscribe, Inc.: Consultancy, Honoraria. Ho:Invivoscribe, Inc.: Honoraria. Roshal:Physicians' Education Resource: Other: Provision of services; Celgene: Other: Provision of Services; Auron Therapeutics: Equity Ownership, Other: Provision of services. Dogan:Roche: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Novartis: Consultancy.

Abstract: Background. Consensus from prior studies shows that the use of maintenance therapy after completion of combination therapy leads to longer progression-free survival (PFS) for patients with multiple myeloma with some studies showing an overall survival (OS) benefit. Currently, lenalidomide is the standard of care; however, there are limited published data on long-term use regarding ability to sustain minimal residual disease (MRD)-negativity and late toxicities. We were motivated to develop a study focusing on continuous, induction-agnostic lenalidomide maintenance with integration of clinical and correlative data. Here, we report formal results of this phase II study with focus on MRD dynamics and tolerability. Methods. This single arm, phase II trial enrolled 100 evaluable patients. Lenalidomide 10 mg is given days 1-21 on a 28-day cycle. Per protocol, patients underwent bone marrow biopsies and aspirates as well as PET/CT at baseline, annually, at progression/end of study; blood work was done every 3 months. The study was statistically powered for the primary endpoint of PFS at 36 months. Correlative assays included MRD testing (10-color single-tube flow cytometry and IGHV sequencing; sensitivity ≤10-5), genomic characterization of detectable disease, and profiling of the bone marrow microenvironment performed on serially banked samples. Results. 100 evaluable patients were enrolled (63% males) between September 2015 and January 2019. Baseline characteristics include median age 63 years (range 38-87 years) and median ECOG score 1 (range 0-1). Prior to enrollment, 22 (30%) patients had high-risk FISH/SNP signature defined as one or more of: 1q+, t(4;14), t(14;16), t(14;20), and 17p- and 48 patients had undergone autologous hematopoietic cell transplantation (AHCT). At abstract submission, median cycles delivered is 39 (range 9-62). 74% of patients have completed ³24 cycles and 55% have completed ³36 cycles. Overall PFS at 36 months was 77% (95% CI: 0.69-0.87) and PFS at 60 months was 63% (95% CI: 0.51-0.78). All patients had MRD testing at least once. 46% were MRD-negative at enrollment. 7 patients who were MRD+ at enrollment converted to MRD-negative. At median follow up 39.4 months (range 7-56 months), 20/100 patients (20%) have progressed. In consideration of the entire follow-up time from initial MRD-negativity, 44 (of 95 tested; 46%) and 37 (of 73 tested; 51%) achieved sustained MRD-negativity at 1 and 2 years, respectively. 22 patients were MRD-negative at 3 years (of 51 tested; 43%). Among those who sustained MRD-negativity for 2 years, with median follow-up of 19 months past the 2-year landmark analysis (max 120 months), there were no progression events. Age, induction regimen, and MRD status at enrollment were the only significant variables associated with PFS regardless of cytogenetic risk or transplant status. At 1 and 2-year landmark analysis, MRD-negativity superseded all else as the most significant factor associated with PFS with HR 0.06(p=0.0004) and HR 1/Inf (p=0.015), respectively. Toxicities (grade 3) included neutrophil count decrease (20%), hypertension (3%), diarrhea (3%), lung infection (2%), and maculo-papular rash (2%), and toxicities (grade 4) include sepsis (2%) and platelet count decrease (7%). The most common non-grade 3/4 toxicities were diarrhea (55%), fatigue (36%), and upper respiratory infection (30%). 7% developed a secondary malignancy on study: 3 adenocarcinoma, 1 squamous cell carcinoma, 1 CMML, 1 MDS, 1 ALL, and 1 glioblastoma. One evaluable patient required dose reduction due to toxicities/tolerability. Conclusions. This prospective study of continuous lenalidomide maintenance, agnostic to induction regimen or AHCT usage, was designed to evaluate the dynamics of MRD-negativity in relation to PFS. It expands on the importance of MRD as a predictor of outcome and illustrates how continuous maintenance therapy can deepen and sustain MRD-negative responses achieved with modern combination therapy. For this cohort, MRD-negativity at each landmark profoundly outweighed the impact of all other variates. Among those who had sustained MRD-negativity at 2 years (37% of the cohort), regardless of MRD status at enrollment, none have had progression events at median 43 months. Our results support cross-sectional MRD testing as a surrogate endpoint for drug approval, and the use of longitudinal MRD tracking in clinical management. Disclosures Korde: Amgen: Research Funding; Astra Zeneca: Other: Advisory Board. Lesokhin:Genentech: Research Funding; Janssen: Research Funding; GenMab: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Serametrix Inc.: Patents & Royalties; BMS: Consultancy, Honoraria, Research Funding. Smith:Precision Biosciences: Consultancy; Bristol Myers Squibb: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics: Consultancy. Shah:Physicians Education Resource: Honoraria; Celgene/BMS: Research Funding. Mailankody:Physician Education Resource: Honoraria; PleXus Communications: Honoraria; Takeda Oncology: Research Funding; Janssen Oncology: Research Funding; Allogene Therapeutics: Research Funding; Juno Therapeutics, a Bristol-Myers Squibb Company: Research Funding. Hultcrantz:Intellisphere LLC: Consultancy; Amgen: Research Funding; Daiichi Sankyo: Research Funding; GSK: Research Funding. Hassoun:Takeda: Research Funding; Celgene: Research Funding; Novartis: Consultancy. Scordo:McKinsey & Company: Consultancy; Angiocrine Bioscience, Inc.: Consultancy, Research Funding; Omeros Corporation: Consultancy; Kite - A Gilead Company: Other: Ad-hoc advisory board. Chung:Genentech: Research Funding. Shah:Amgen: Research Funding; Janssen Pharmaceutica: Research Funding. Lahoud:MorphoSys: Other: Advisory Board. Thoren:Sebia: Research Funding; The Binding Site: Research Funding. Ho:Invivoscribe, Inc.: Honoraria. Dogan:AbbVie: Consultancy; EUSA Pharma: Consultancy; Takeda: Consultancy; Seattle Genetics: Consultancy; Corvus Pharmaceuticals: Consultancy; Physicians Education Resource: Consultancy; Roche: Consultancy, Research Funding; National Cancer Institute: Research Funding. Giralt:MILTENYI: Consultancy, Research Funding; ACTINUUM: Consultancy, Research Funding; KITE: Consultancy; OMEROS: Consultancy, Honoraria; NOVARTIS: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding; JAZZ: Consultancy, Honoraria; AMGEN: Consultancy, Research Funding; TAKEDA: Research Funding. Landgren:Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Binding Site: Consultancy, Honoraria; Karyopharma: Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Seattle Genetics: Research Funding; Glenmark: Consultancy, Honoraria, Research Funding; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Pfizer: Consultancy, Honoraria; Merck: Other; Cellectis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Glenmark: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Seattle Genetics: Research Funding; Karyopharma: Research Funding; Merck: Other; Adaptive: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Binding Site: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; Juno: Consultancy, Honoraria.

Abstract: Although generally curable with intensive chemotherapy in resource-rich settings, Burkitt lymphoma (BL) remains a deadly disease in older patients and in sub-Saharan Africa. Epstein-Barr virus (EBV) positivity is a feature in more than 90% of cases in malaria-endemic regions, and up to 30% elsewhere. However, the molecular features of BL have not been comprehensively evaluated when taking into account tumor EBV status or geographic origin. Through an integrative analysis of whole-genome and transcriptome data, we show a striking genome-wide increase in aberrant somatic hypermutation in EBV-positive tumors, supporting a link between EBV and activation-induced cytidine deaminase (AICDA) activity. In addition to identifying novel candidate BL genes such as SIN3A, USP7, and CHD8, we demonstrate that EBV-positive tumors had significantly fewer driver mutations, especially among genes with roles in apoptosis. We also found immunoglobulin variable region genes that were disproportionally used to encode clonal B-cell receptors (BCRs) in the tumors. These include IGHV4-34, known to produce autoreactive antibodies, and IGKV3-20, a feature described in other B-cell malignancies but not yet in BL. Our results suggest that tumor EBV status defines a specific BL phenotype irrespective of geographic origin, with particular molecular properties and distinct pathogenic mechanisms. The novel mutation patterns identified here imply rational use of DNA-damaging chemotherapy in some patients with BL and targeted agents such as the CDK4/6 inhibitor palbociclib in others, whereas the importance of BCR signaling in BL strengthens the potential benefit of inhibitors for PI3K, Syk, and Src family kinases among these patients.

Abstract: Ex vivo fucosylation of cord blood cells improves their homing capacities, leading to faster neutrophil and platelet engraftments. This method is quick, safe, and does not require a GMP laboratory; therefore, it can be used widely.

Abstract: Proteasome inhibition with bortezomib is a validated approach to the treatment of multiple myeloma, but drug resistance often emerges and limits its utility in the retreatment setting. To begin to identify some of the mechanisms involved, we developed bortezomib-resistant myeloma cell lines that, unlike previously reported models, showed no β5 subunit mutations. Instead, up-regulation of the insulin-like growth factor (IGF)–1 axis was identified, with increased autocrine and paracrine secretion of IGF-1, leading to increased activation of the IGF-1 receptor (IGF-1R). Exogenous IGF-1 reduced cellular sensitivity to bortezomib, whereas pharmacologic or small hairpin RNA–mediated IGF-1R suppression enhanced bortezomib sensitivity in cell lines and patient samples. In vitro studies with OSI-906, a clinically relevant dual IGF-1R and insulin receptor inhibitor, showed it acted synergistically with bortezomib, and potently resensitized bortezomib-resistant cell lines and patient samples to bor-tezomib. Importantly, OSI-906 in combination with bortezomib also overcame bor-tezomib resistance in an in vivo model of myeloma. Taken together, these data support the hypothesis that signaling through the IGF-1/IGF-1R axis contributes to acquired bortezomib resistance, and provide a rationale for combining bortezomib with IGF-1R inhibitors like OSI-906 to overcome or possibly prevent the emergence of bortezomib-refractory disease in the clinic.