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Background: Pevonedistat is a first-in-class inhibitor of NEDD8-activating enzyme that catalyzes the rate-limiting step of protein neddylation, a critical step in the degradation of cellular proteins that occurs upstream of the proteasome. The combination of azacitidine plus pevonedistat has resulted in high response rates and durable remissions in both myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), particularly in secondary AML (s-AML). Preclinical studies suggest that pevonedistat synergizes with venetoclax through neutralization of Mcl-1, providing rationale for the triplet combination of azacitidine, venetoclax and pevonedistat. Methods: In this phase I/II study, adult patients (pts) with newly diagnosed s-AML, including pts with therapy-related AML (t-AML) or AML with MDS-related changes, who were unsuitable for intensive chemotherapy were eligible. Pts were required to have a performance status ≤2, total bilirubin ≤ upper limit of normal (ULN), ALT/AST ≤2.5 x ULN, and creatinine clearance ≥30 mL/min. In cycle 1, pts received azacitidine 75 mg/m 2 SC/IV on days 1-7, venetoclax on days 1-28, and pevonedistat 20 mg/m 2 IV on days 1, 3 and 5 on a 28-day schedule. Venetoclax dose ranged from 200mg to 400mg daily during the phase I dose escalation. For cycles 2 and beyond, venetoclax was given on days 1-21. Results: Between 3/2019 and 5/2021, 28 pts were treated (3 pts at venetoclax 200mg daily and 25 pts at 400mg daily). Baseline characteristics are shown in Table 1. The median age was 74 years (range, 61-80), and 12 pts (43%) were ≥75 years of age. The study population was enriched with pts with poor-risk features, including 19 pts (68%) with adverse-risk cytogenetics, 14 (50%) with prior hypomethylating (HMA) or chemotherapy exposure for preceding hematologic malignancy, and 8 (29%) with TP53 mutation. The overall response rate (CR+CRi+MLFS) was 71%, and the CR+CRi rate was 64%. Thirteen pts (46%) achieved CR as best response, 5 (18%) achieved CRi, and 2 (7%) achieved MLFS. Among the 18 pts who achieved CR/CRi, 8 (44%) achieved MRD negativity by multiparameter flow cytometry. Responses were observed across subgroups, including in 8/14 pts (57%) with prior HMA/chemotherapy exposure, 6/8 pts (75%) with TP53 mutation, 12/19 pts (63%) with poor-risk cytogenetics, and 8/9 pts (89%) without non-poor-risk cytogenetics. With a median follow-up of 13.4 months (range 0.4 to 26.3+ months), the median overall survival (OS) was 8.2 months, and the median relapse-free survival was 7.5 months (Figure 1). The median OS for pts with poor-risk and non-poor cytogenetics was 7.9 and 18.0 months, respectively; for pts with and without prior HMA/chemotherapy exposure was 6.2 and 8.9 months, respectively; and for pts with inv(3) AML, TP53-mutated AML, and non-inv(3)/non-TP53-mutated AML was 3.8, 8.9, and 18.0 months, respectively. Four pts (14% of the entire cohort, 20% of responding pts) proceed to hematopoietic stem cell transplantation (HSCT), 3 of whom are still alive and 1 with inv(3) who relapsed post-HSCT and died from progressive AML. The combination was overall well-tolerated with myelosuppression as expected with the combination of HMA plus venetoclax in AML. The median number of cycles received was 2 (range, 1-13 cycles). Non-hematologic grade ≥3 adverse events occurring in ≥2 pts included infection or neutropenic fever in 18 pts (61%), hypophosphatemia in 8 pts (29%), hyperglycemia, hyperbilirubinemia and ALT/AST elevation in 3 pts each (11%), and pneumonitis, acute kidney injury, hypokalemia and vomiting in 2 pts each (7%). One pt developed multiorgan failure on cycle 1, day 1 of therapy, with transaminase elevation, hyperbilirubinemia, renal failure and hyperferritinemia; this pt recovered with holding therapy and supportive care. Hypophosphatemia, which has previously been reported with pevonedistat, was easily managed with oral or intravenous phosphorus supplementation. The 4-week and 8-week mortality rates were 7% and 14%, respectively. Conclusions: The combination of azacitidine, venetoclax and pevonedistat was safe and effective in a very poor-risk population of pts with s-AML, half of whom had prior HMA or chemotherapy exposure for antecedent hematologic malignancy. A randomized study evaluating azacitidine and venetoclax ± pevonedistat (NCT04266795) is ongoing and will help to clarify the potential role of pevonedistat in the frontline treatment of AML. Figure 1 Figure 1. Disclosures Short: AstraZeneca: Consultancy; Jazz Pharmaceuticals: Consultancy; NGMBio: Consultancy; Astellas: Research Funding; Novartis: Honoraria; Takeda Oncology: Consultancy, Research Funding; Amgen: Consultancy, Honoraria. Alvarado: Daiichi-Sankyo: Research Funding; Jazz Pharmaceuticals: Research Funding; FibroGen: Research Funding; BerGenBio: Research Funding; MEI Pharma: Research Funding; Sun Pharma: Consultancy, Research Funding; CytomX Therapeutics: Consultancy; Astex Pharmaceuticals: Research Funding. Konopleva: KisoJi: Research Funding; Ascentage: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; Ablynx: Other: grant support, Research Funding; Cellectis: Other: grant support; Forty Seven: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Calithera: Other: grant support, Research Funding; Sanofi: Other: grant support, Research Funding; Stemline Therapeutics: Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Yilmaz: Pfizer: Research Funding; Daiichi-Sankyo: Research Funding. Jain: Genentech: Honoraria, Research Funding; Cellectis: Honoraria, Research Funding; Precision Biosciences: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; Pfizer: Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Aprea Therapeutics: Research Funding; Janssen: Honoraria; Incyte: Research Funding; Servier: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Fate Therapeutics: Research Funding; Beigene: Honoraria; TG Therapeutics: Honoraria; Pharmacyclics: Research Funding; AbbVie: Honoraria, Research Funding. Borthakur: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ryvu: Research Funding; ArgenX: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; University of Texas MD Anderson Cancer Center: Current Employment; GSK: Consultancy; Protagonist: Consultancy. DiNardo: ImmuneOnc: Honoraria, Research Funding; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Foghorn: Honoraria, Research Funding; Forma: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Novartis: Honoraria; Agios/Servier: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Daver: Astellas: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Glycomimetics: Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Amgen: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Hanmi: Research Funding; Novimmune: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Issa: Syndax Pharmaceuticals: Research Funding; Novartis: Consultancy, Research Funding; Kura Oncology: Consultancy, Research Funding. Pemmaraju: MustangBio: Consultancy, Other; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Aptitude Health: Consultancy; Samus: Other, Research Funding; Plexxicon: Other, Research Funding; Sager Strong Foundation: Other; CareDx, Inc.: Consultancy; Cellectis S.A. ADR: Other, Research Funding; Daiichi Sankyo, Inc.: Other, Research Funding; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Springer Science + Business Media: Other; Pacylex Pharmaceuticals: Consultancy; Celgene Corporation: Consultancy; Roche Diagnostics: Consultancy; DAVA Oncology: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; LFB Biotechnologies: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Incyte: Consultancy; Affymetrix: Consultancy, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy. Sasaki: Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding. Ravandi: AstraZeneca: Honoraria; Jazz: Honoraria, Research Funding; Taiho: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Honoraria, Research Funding; Novartis: Honoraria; Prelude: Research Funding. Kadia: Genfleet: Other; Cure: Speakers Bureau; Genentech: Consultancy, Other: Grant/research support; Amgen: Other: Grant/research support; Dalichi Sankyo: Consultancy; Jazz: Consultancy; Novartis: Consultancy; Liberum: Consultancy; Aglos: Consultancy; Pfizer: Consultancy, Other; AbbVie: Consultancy, Other: Grant/research support; Pulmotech: Other; BMS: Other: Grant/research support; Astellas: Other; Sanofi-Aventis: Consultancy; AstraZeneca: Other; Cellonkos: Other; Ascentage: Other. Andreeff: Breast Cancer Research Foundation: Research Funding; Aptose: Consultancy; Daiichi-Sankyo: Consultancy, Research Funding; Karyopharm: Research Funding; Novartis, Cancer UK; Leukemia & Lymphoma Society (LLS), German Research Council; NCI-RDCRN (Rare Disease Clin Network), CLL Foundation; Novartis: Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Consultancy; Senti-Bio: Consultancy; Oxford Biomedica UK: Research Funding; Syndax: Consultancy; AstraZeneca: Research Funding; ONO Pharmaceuticals: Research Funding; Amgen: Research Funding; Reata, Aptose, Eutropics, SentiBio; Chimerix, Oncolyze: Current holder of individual stocks in a privately-held company; Medicxi: Consultancy. Bose: Pfizer: Research Funding; Constellation Pharmaceuticals: Research Funding; Novartis: Honoraria; Sierra Oncology: Honoraria; Kartos Therapeutics: Honoraria, Research Funding; Blueprint Medicines: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Incyte Corporation: Honoraria, Research Funding; Astellas: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding. Kantarjian: Ipsen Pharmaceuticals: Honoraria; Amgen: Honoraria, Research Funding; Precision Biosciences: Honoraria; Astellas Health: Honoraria; Astra Zeneca: Honoraria; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; KAHR Medical Ltd: Honoraria; Aptitude Health: Honoraria; Pfizer: Honoraria, Research Funding; Ascentage: Research Funding; NOVA Research: Honoraria; BMS: Research Funding; Jazz: Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Taiho Pharmaceutical Canada: Honoraria. Cortes: Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Bio-Path Holdings, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sun Pharma: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Astellas, Novartis, Pfizer, Takeda, BioPath Holdings, Incyte: Consultancy, Research Funding.

Background: Blinatumomab is highly effective therapy for both the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) and persistent or recurrent measurable residual disease (MRD) after initial ALL therapy. We hypothesized that early incorporation of blinatumomab in patients (pts) with newly diagnosed Philadelphia chromosome (Ph)-negative B-cell ALL would lead to deeper and more durable responses, reduce relapses, and improve survival. Methods: Pts 14-59 years of age with newly diagnosed Ph-negative pre-B-cell ALL, including pts who had received no more than 1 prior cycle of chemotherapy, were eligible. Pts were required to have a performance status of ≤3, total bilirubin ≤2 mg/dl, creatinine ≤2 mg/dl, and no significant CNS pathology (with the exception of CNS leukemia). Pts received hyper-CVAD alternating with high-dose methotrexate and cytarabine for up to 4 cycles, followed by 4 cycles of blinatumomab at standard doses. Pts with CD20+ disease (≥1% cells) received 8 doses of ofatumumab (2000 mg) or rituximab (375 mg/m 2). Eight administrations of prophylactic IT chemotherapy were given in the first 4 cycles. Maintenance was with alternating blocks of POMP (given in maintenance cycles 1-3, 5-7, 9-11, and 13-15) and blinatumomab (given in maintenance cycles 4, 8, and 12). Beginning with pt #10, those with high-risk disease features (e.g. CRLF2+ by flow cytometry, complex karyotype, KMT2A rearranged, low-hypodiploidy/near triploidy, TP53 mutation, or persistent MRD) started blinatumomab after 2 cycles of hyper-CVAD. Results: 38 evaluable pts have been treated. 6 pts were in complete remission (CR) at enrollment and unevaluable for morphologic response. Pt characteristics of the 38 evaluable pts are summarized in Table 1. Median age was 37 years (range, 17-59 years). At least one high-risk feature was present in 21 pts (55%), including TP53 mutation in 27%, CRLF2+ in 19%, and an adverse-risk karyotype in 32%. 84% of pts received ofatumumab or rituximab. Among 32 pts with active disease at study entry, 100% achieved CR, with 81% achieving CR after the first cycle (Table 1). MRD negativity by 6-color flow cytometry was achieved in 22/26 responding pts (85%) after 1 cycle and 37/38 pts (97%) overall. The 60-day mortality rate was 0%. With a median follow-up of 27 months (range, 11-55 months), the 3-year continuous remission and OS rates were 80% and 83%, respectively (Figure 1). Overall, 5 pts (13%) relapsed, 13 (34%) underwent allogeneic SCT in first remission (including 2 additional pts who relapsed post-SCT), 1 died in CR (possible pulmonary embolism), and 19 (50%) remain in continuous remission and are currently on treatment or have completed maintenance. All relapses occurred in pts with established poor-risk features and no relapses have occurred beyond 2 years from the start of treatment. OS with hyper-CVAD plus blinatumomab compares favorably to a historical cohort of pts treated with hyper-CVAD plus ofatumumab (3-year OS 83% versus 66%, respectively; P=0.2). Treatment was overall well-tolerated. Four pts developed grade 2-3 cytokine release syndrome (grade 2, n=3; grade 3, n=1) which resolved with corticosteroids and interruption of blinatumomab. Overall, 16 (42%) pts had a neurological adverse event of any grade due to blinatumomab. Four pts (11%) developed grade 3 neurologic toxicity related to blinatumomab, all of which was transient and reversible. Only one pt discontinued blinatumomab due to blinatumomab-related adverse event (grade 2 encephalopathy and dysphasia). Conclusion: Hyper-CVAD with sequential blinatumomab is highly effective as frontline treatment of Ph-negative B-cell ALL, with an overall MRD negativity rate of 97% and a 3-year OS rate of 83%. This study shows the potential benefit of incorporating frontline blinatumomab into the treatment of younger adults with ALL and also shows that reduction of chemotherapy in this context is feasible. Figure 1 Figure 1. Disclosures Short: Novartis: Honoraria; AstraZeneca: Consultancy; Astellas: Research Funding; Jazz Pharmaceuticals: Consultancy; NGMBio: Consultancy; Takeda Oncology: Consultancy, Research Funding; Amgen: Consultancy, Honoraria. Kantarjian: Precision Biosciences: Honoraria; Immunogen: Research Funding; Jazz: Research Funding; Astra Zeneca: Honoraria; KAHR Medical Ltd: Honoraria; Novartis: Honoraria, Research Funding; Aptitude Health: Honoraria; Daiichi-Sankyo: Research Funding; Amgen: Honoraria, Research Funding; Ipsen Pharmaceuticals: Honoraria; Astellas Health: Honoraria; Ascentage: Research Funding; AbbVie: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; NOVA Research: Honoraria; BMS: Research Funding; Taiho Pharmaceutical Canada: Honoraria. Ravandi: Taiho: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Prelude: Research Funding; Xencor: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Research Funding; AstraZeneca: Honoraria; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding; Agios: Honoraria, Research Funding; Novartis: Honoraria; AbbVie: Honoraria, Research Funding. Thompson: Pharmacyclics: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Gilead: Other: Institution: Advisory/Consultancy, Honoraria; AbbVie: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Adaptive Biotechnologies: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding, Expert Testimony; Janssen: Consultancy, Honoraria; Genentech: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Amgen: Other: Institution: Honoraria, Research Grant/Funding. Ferrajoli: BeiGene: Other: Advisory Board, Research Funding; AstraZeneca: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board . Kadia: Astellas: Other; Genentech: Consultancy, Other: Grant/research support; Sanofi-Aventis: Consultancy; Cellonkos: Other; Pfizer: Consultancy, Other; Pulmotech: Other; Amgen: Other: Grant/research support; Cure: Speakers Bureau; Novartis: Consultancy; BMS: Other: Grant/research support; AstraZeneca: Other; Liberum: Consultancy; Ascentage: Other; Genfleet: Other; Jazz: Consultancy; Dalichi Sankyo: Consultancy; Aglos: Consultancy; AbbVie: Consultancy, Other: Grant/research support. Jain: Janssen: Honoraria; Precision Biosciences: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; Incyte: Research Funding; Servier: Honoraria, Research Funding; Beigene: Honoraria; Cellectis: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; Aprea Therapeutics: Research Funding; TG Therapeutics: Honoraria; Pfizer: Research Funding; Fate Therapeutics: Research Funding; Genentech: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Pharmacyclics: Research Funding. Alvarado: Sun Pharma: Consultancy, Research Funding; Astex Pharmaceuticals: Research Funding; Daiichi-Sankyo: Research Funding; CytomX Therapeutics: Consultancy; FibroGen: Research Funding; Jazz Pharmaceuticals: Research Funding; BerGenBio: Research Funding; MEI Pharma: Research Funding. Yilmaz: Daiichi-Sankyo: Research Funding; Pfizer: Research Funding. Khoury: Stemline Therapeutics: Research Funding; Angle: Research Funding; Kiromic: Research Funding. Wang: Stemline Therapeutics: Honoraria. Konopleva: KisoJi: Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; Cellectis: Other: grant support; Calithera: Other: grant support, Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Stemline Therapeutics: Research Funding; Sanofi: Other: grant support, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Forty Seven: Other: grant support, Research Funding; Ascentage: Other: grant support, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Ablynx: Other: grant support, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; AstraZeneca: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. OffLabel Disclosure: Blinatumomab in the frontline setting for B-cell ALL

Introduction: Sickle cell disease (SCD) is a group of inherited hemoglobin diseases (Hb), caused by a point mutation in the b-globin gene, that affects more than 100,00 people in the US and millions worldwide. No organ system is left unaffected by SCD, including the musculoskeletal system; complications which can greatly decrease quality of life and contribute to significant burden for these patients. Orthopedic complications include bone pain, dactylitis, growth retardation and atypical skeletal development, osteomyelitis and septic arthritis, bone demineralization, motor/mobility impairment, osteonecrosis and other causes of arthritis and rheumatologic disease. While surgical repair by arthroplasty is often a definitive solution to joint pain, conservative, non-operative treatments are first-line, including physical therapy and intraarticular corticosteroid injections. Corticosteroid injections can be used as a convenient outpatient solution to reduce inflammation and relieve pain without undergoing surgical measures. The use of steroids for non-orthopedic complications of SCD is not benign for many patients, and may be associated with the development of rebound vaso-occlusive pain events, requiring hospitalization, as well as hemorrhagic stroke. A review of the literature revealed two cases of patients with SCD who received intraarticular steroid injections for rheumatoid arthritis in whom the injections precipitated an acute vaso-occlusive episode that required admission. In view of these findings, we are interested in determining if any adults in our adult SCD clinic who had an intraarticular injection of a steroid developed worsening of pain. Methods: After approval by the UIC IRB, a retrospective chart review was conducted for subjects enrolled in the UIC Adult Sickle Cell Center treated with an intraarticular steroid injection. Data collected included: type of medication used, injection location, indication, pain complication and timeline of symptoms, admission, age, sex, genotype and BMI. Vaso-occlusive events described were unusually severe compared to the pre-corticosteroid clinical course and not reported with other triggers for SCD vaso-occlusive events. Results: Four patients were identified. Characteristics of these patients and injections are listed in table 1. Patients received one or more injections of knees, hips, wrists and fingers before recognizing the associated pain with the injection. Indications for injections included primary osteoarthritis, osteoarthritis secondary to avascular necrosis, tendonitis and tenosynovitis. All injections were a combination of local anesthetic and glucocorticoid. The majority of injections were 2 cc lidocaine 1%, 1 cc triamcinolone acetonide-40mg. Other local anesthetics used were xylocaine and bupivacaine. Discussion: With improvements in medical care, more people with SCD are surviving into adulthood and developing orthopedic complications of SCD, as well as aging, such as osteoarthritis. While the development of acute pain after treatment of the acute chest syndrome with steroids is known, there were only 2 reported cases of SCD patients who developed severe pain associated with intraarticular injections. We report here four additional cases of adults with SCD who received an injection and developed worsening of their pain, often requiring admission. While these numbers are small, we believe that this may be a much more common complication of steroid injections and providers should discuss this with their patients. The observations that are made in this study raise into question the idea that while temporary pain relief is the intended outcome, this is not the result in all patients- the fact of which should be a consideration made by all clinicians when offering steroid injections as opposed to non-steroid joint injections to patients with SCD. The pathophysiology behind this effect of steroid injections is unclear. In the event that a patient with SCD presents with pain symptoms, either worsening pain or pain uncharacteristic of their usual symptoms, a consideration for potential causes should be recent steroid injection for joint pain. These considerations may help guide clinical decision making. Disclosures No relevant conflicts of interest to declare.

Introduction The hypomethylating agents (HMA) decitabine (dec) and azacytidine (aza) are used in acute myeloid leukemia (AML) for induction therapy in patients with either newly diagnosed or relapsed disease and who are above the age of 60 or for those who would not tolerate intensive induction chemotherapy. As a result, HMA have been widely used at our institution, on both inpatient (IP) and outpatient (OP) services. The decision to administer IP-HMA vs OP-HMA is complex, but IP-HMA is recommended at our institution for neutropenic infections, debility, or risk of tumor lysis. The prognostic significance of this decision, if any, has not been widely explored. We hypothesized that because patients who receive their first cycle of HMA as an IP were at higher risk for complications, they would have a worse 100-day survival than their OP counterparts. Methods This was a retrospective observational study of patients treated at Thomas Jefferson University Hospital from January 2016-January 2020. Inclusion criteria were patients who had a diagnosis of AML, were above the age of 18 when treated, were treated with an HMA during the course of their disease, and were treated at our institution where electronic medical records (EMR) were complete and readily accessible. Exclusion criteria were patients who had died as a direct result of their hematopoietic stem cell transplant (HSCT) and whose records were incomplete or who had been treated at an outside institution. Logistic regression models were used to analyze data. Survival was calculated from day one of the first cycle of HMA received. Results A total of 68 patients were evaluated. Twenty-nine patients received IP-HMA while 39 received OP-HMA. Mean overall survival from HMA initiation was 252 days (95% CI 164-340) in the IP-HMA group and 430 days (95% CI 269-591) in the OP-HMA group. Mean 100-day survival in the IP-HMA group was 78 days (95% CI 65-91) and 93 days (95% CI 87-99) in the OP-HMA group. The average age at HMA initiation in the IP group was 69 (95% CI 64-74) and was 66 (95% CI 62-70) in the OP group. Average Charlson co-morbidity index was 5.5 (95% CI 5.0-6.0) in the IP group and 5.6 (95% CI 5.0-6.2) in the OP group. In the IP group, there were 1 low risk, 7 intermediate risk, and 21 high risk patients according to the European LeukemiaNet (ELN) risk stratification scale. In the OP group, there were 3 low risk, 8 intermediate risk, and 28 high risk patients. Nineteen of the 29 patients in the IP group and 11 of the 39 patients in the OP group received venetoclax in addition to an HMA as part of their therapy. Using a logistic regression model, location of HMA induction was found to have a significant effect on 100-day survival with IP induction being associated with worse survival (odds ratio=3.94; p=0.028) (see figure 1). Co-variates for this model included age at HMA initiation as this was the only confounder found in Wilcoxon rank sum testing to be significant. Other confounders which were tested but not included in logistic regression due to non-significance included race, gender, ELN risk, and Charlson co-morbidity indices. Discussion In this retrospective study, we found that IP-HMA induction was associated with a worse 100 day and overall survival than its OP counterpart. Though we found that co-morbidity indices and ELN risk scores were similar between the two groups, we postulate the reason the IP group had a significantly worse 100 day survival was that being admitted for neutropenic fever, risk of tumor lysis, etc. inherently put them at higher risk for complications like septic shock and hypoxic respiratory failure. Additionally, we found that patients who received HMA as an IP were far more likely to die shortly after their induction, within 100 days and often within 20 days. This would indicate they were potentially poor candidates for chemotherapy and that a palliative approach may have been more appropriate.. This study describes the survival differences seen in patients receiving IP-HMA versus OP-HMA. Knowledge of these results could spawn a more palliative approach for future patients requiring IP-HMA induction. Figure Disclosures Kasner: Otsuka Pharmaceutical: Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding. Palmisiano:AbbVie: Research Funding; Genentech: Research Funding.

Background: Diagnosing multiple myeloma (MM) is challenging, because MM can present with a myriad of non-specific signs and symptoms, such as bone pain, fatigue, fractures, infection, within an elderly patient population (median age of MM diagnosis is 70 years). Patients with MM therefore experience significant delays in diagnosis, resulting in increased morbidity and reduced survival. In the primary care setting, the presence of bone pain in combination with laboratory abnormalities, such as hypercalcaemia or unexplained renal impairment, have a critical diagnostic role in MM. However, the occurrence of these clinical features prior to MM diagnosis within a population-based incident cohort of patients with MM has not been previously well described. Aims: To describe the frequency and timing of the initial clinical features among patients with newly diagnosed MM (NDMM) in the UK primary care setting. Methods: We used Clinical Practice Research Datalink (CPRD), an electronic health records database, derived from routinely collected general practitioner (GP) data across the UK primary care, containing approximately 17.1 million patients at the time of analysis. We identified patients with NDMM (2006-2016), aged ≥18 years with no history of solid tumors, and ≥2 years of GP registration prior to MM diagnosis. Baseline clinical characteristics were assessed during the 2-year period before MM diagnosis. We assessed clinical features, including bone pain, skeletal-related events (SREs) and CRAB criteria (hyperCalcemia, Renal failure, Anemia, Bone lesions) for MM during the 2-year period before MM diagnosis and from the time of symptom presentation or relevant diagnostic CRAB criteria to the diagnosis of MM. Results: We identified 2,646 eligible patients with NDMM with a median [Q1, Q3] age of 70 [61, 77]; 53.3% of patients were male. During the 2-year period prior to MM diagnosis, 47.5% of patients had a record of bone pain, mainly affecting the back or other joints, and 4.8% had a record of SRE. The median time between the first record of bone pain and MM diagnosis was 220 days. Regardless of recorded bone pain, laboratory investigations for hypercalcaemia, renal impairment, and anaemia and were conducted in 36.4%, 74.2%, 65.6% and of patients prior to MM diagnosis, respectively. Approximately 5.5% of patients presented with hypercalcemia, 13.5% with renal impairment and 31.3% with anemia. The median time from the first-recorded hypercalcaemia, renal impairment or anaemia event to MM diagnosis was 23, 58 and 73 days, respectively. An imaging investigation or referral for an imaging investigation was recorded for approximately 60% of patients with bone pain/SRE and 32% without bone pain/SRE. One out of five patients with bone pain/SRE and imaging investigations had a record of magnetic resonance imaging or computed tomography scan (Table 1). Conclusions: Nearly half of patients with newly diagnosed MM presented with a bone pain symptom in primary care, approximately 7 months prior to MM diagnosis. Investigations for hypercalcaemia were not frequent in patients presenting with bone pain, and tests to explore CRAB criteria were underutilized. Underuse of targeted imaging in patients presenting with bone pain was observed. Early recognition and testing for clinical features of MM in primary care may potentially expedite the disease diagnosis and lead to timely medical care. Disclosures Seesaghur: Amgen (Europe) GmbH: Current Employment, Current equity holder in publicly-traded company. Petruski-Ivleva:Aetion: Current equity holder in private company, Ended employment in the past 24 months. Banks:Amgen (Europe) GmbH: Ended employment in the past 24 months, Other: Contract worker at Amgen during the conduct of the study. Wang:Aetion: Current Employment, Current equity holder in private company. Mattox:Aetion: Current Employment, Current equity holder in private company. Abbasi:Amgen (Europe) GmbH: Other: Contract worker at Amgen. Maskell:Amgen (Europe) GmbH: Current Employment, Current equity holder in publicly-traded company. Neasham:Amgen (Europe) GmbH: Current Employment, Current equity holder in publicly-traded company. Ramasamy:Takeda: Honoraria; Janssen: Honoraria; Janssen: Research Funding; Takeda: Research Funding; Sanofi: Honoraria; Amgen: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria; Oncopeptides: Honoraria; Takeda: Speakers Bureau; Bristol Myers squibb: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Research Funding; Amgen: Honoraria; GSK: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees.

Introduction The treatment landscape of Hodgkin Lymphoma (HL) has undergone a revolution in recent years, providing multiple options for providers and patients in their shared goal for disease control. However, these successful treatment options (e.g. multi-agent chemotherapy, radiotherapy, or combined modality) come at a high cost in the form of late effects, with little known about long-term toxicity of novel agents (e.g., Brentuximab vedotin, immunotherapy). As part of an international effort to develop tools to enhance treatment decision-making for providers and patients, we developed a survey to learn about what role HL survivors played in their initial treatment decision(s) as well as to understand survivors' knowledge and experience of late effects. Methods The survey titled Understanding of Decision-Making among HL Survivors included three themes: 1) initial treatment plan; 2) role in decision-making about the plan and factors important to the treatment selection; and 3) understanding of late effects. The survey was initially piloted at a cancer conference in Spring 2019 after which modest revisions were made to improve clarity. The revised survey was then distributed nationally in a single push through the Leukemia & Lymphoma Society's voluntary email listserv (Summer 2019). Responses were captured in the HIPAA complaint, web-based application, REDCap®, and then analyzed with descriptive statistics. Results A total of 129 HL survivors responded to the survey. The majority of respondents (n=98, 76%) identified as female. While nearly half (46%) were between 1-5 years from treatment, 27% were 5 years ago. Age distribution at diagnosis ranged from 26 years (n=91, 71%). Two-thirds (n=83, 64%) of patients were treated with chemotherapy alone. Overall, 90% of survivors reported receiving ABVD or a close variant (e.g., AVD). The majority of survivors (n=88, 68%) reported only receiving one treatment option by their oncologist. Half (n=69, 54%) engaged in shared decision-making with their physician, with or without family/friends, 24% (n=31) deferred to their physician, 20% (n=26) decided on their own or with family/friend, and 2% (n=3) followed the plan determined by their physician and family on their behalf. Most respondents were treated in the community (n=77, 60%) with an additional 34% (n=44) reporting having been treated at an academic medical center. For 8 respondents (6%) the treatment site was categorized as other. Survivors were asked to rate the importance of factors in their initial treatment decision-making on a 3-point scale. Results were then dichotomized to important or not important. Health systems factors (e.g., cost, distance) were deemed less important, while patient-level factors (e.g., side effects, late effects) were widely endorsed (Table 1). The majority of survivors (n=107, 83%) were aware they are/may be at risk for late effects. Seventy percent (n=68 of 97) had been told at the time of discussion of treatment option(s) with their oncologist. The remainder (n=29 of 97, 30%) learned after completion of treatment or when transitioning care from their treating oncologist to survivorship or primary care. One third of respondents (n=46, 36%) reported they have been diagnosed with a late effect, which included substantial late effects of secondary malignancy (n=5, 11%) and cardiac toxicity (n=4, 9%). Discussion We report the results of a recent national survey of HL survivors, represented by an activated cohort that elects to participate in cancer advocacy groups. While two-thirds of respondents had little choice in initial treatment options, the majority endorsed the importance of side effects and late effects in treatment selection. Only half of survivors engaged in shared decision-making with their physician, indicating ample room for improvement and the development of tools to facilitate this process. Disclosures No relevant conflicts of interest to declare.

The apoptotic and therapeutic activities of the histone deacetylase inhibitor (HDACi) vorinostat are blocked by overexpresssion of Bcl-2 or Bcl-XL. Herein, we used the small molecule inhibitor ABT-737 to restore sensitivity of Eμ-myc lymphomas overexpressing Bcl-2 or Bcl-XL to vorinostat and valproic acid (VPA). Combining low-dose ABT-737 with vorinostat or VPA resulted in synergistic apoptosis of these cells. ABT-737 was ineffective against Eμ-myc/Mcl-1 and Eμ-myc/A1 cells either as a single agent or in combination with HDACi. However, in contrast to the reported binding specificity data, Eμ-myc/Bcl-w lymphomas were insensitive to ABT-737 used alone or in combination with HDACi, indicating that the regulatory activity of ABT-737 is restricted to Bcl-2 and Bcl-XL. Eμ-myc lymphomas that expressed Bcl-2 throughout the tumorigenesis process were especially sensitive to ABT-737, while those forced to overexpress Mcl-1 were not. This supports the notion that tumor cells “addicted” to ABT-737 target proteins (ie, Bcl-2 or Bcl-XL) are likely to be the most sensitive target cell population. Our studies provide important preclinical data on the binding specificity of ABT-737 and its usefulness against primary hematologic malignancies when used as a single agent and in combination with HDACi.

We describe a collection of 11 families with ≥ 2 generations of family members whose condition has been diagnosed as a hematologic malignancy. In 9 of these families there was a significant decrease in age at diagnosis in each subsequent generation (anticipation). The mean age at diagnosis in the first generation was 67.8 years, 57.1 years in the second, and 41.8 years in the third (P < .0002). This was confirmed in both direct parent-offspring pairs with a mean reduction of 19 years in the age at diagnosis (P = .0087) and when the analysis was repeated only including cases of mature B-cell neoplasm (P = .0007). We believe that these families provide further insight into the nature of the underlying genetic mechanism of predisposition in these families.

Background: Acute traumatic coagulopathy occurs in both pediatric and adult trauma patients and is associated with an increased risk of mortality. Trauma patients not only have increased risk for hemorrhagic complications, but also are at increased risk for thrombosis due to multiple factors including local tissue injury, inflammation, and immobility. The complex underlying pathophysiology of coagulation abnormalities associated with traumatic injury have yet to be fully elucidated. Additionally, there are significant differences in the hemostatic system of pediatric patients compared to adults. Objectives: The purpose of this study was to determine the levels of coagulation parameters including von Willebrand factor (VWF) antigen and ADAMTS13 activity in pediatric trauma patients and evaluate for possible association with injury severity and/or mortality. Methods: This study utilized plasma specimens collected from pediatric trauma patients that presented to our institution over a 2-year time period. The specimens were collected at initial presentation and 24 hours later. The injury severity was estimated using both the Glasgow Coma Scale (GCS) and Injury Severity Score (ISS). A cohort of control samples was obtained from pediatric patients for elective surgical procedures over the same time period. Plasma VWF antigen was determined by a sandwich ELISA; plasma ADAMTS13 activity was determined by FRETS-VWF73. The results were determined by nonparametric tests for the differences in median values. Results: A total of 106 trauma patient samples at initial time point, 78 trauma samples at 24 hour time point, and 54 control samples were obtained and utilized for study. There were statistically significant differences (p Conclusions: This study demonstrates significant differences in plasma ADAMTS13 activity and VWF antigen in pediatric trauma patients compared to controls. In patients with more severe injuries as estimated by GCS and ISS, there was also a significant association with decreased levels of ADAMTS13 activity. These finding may underlie part of the prothrombotic propensity in microcirculation that occurs in patients post-trauma. Further investigation is warranted to better understand the mechanisms of acute traumatic coagulopathy and potential prognostic factors, and to determine the most effective interventions for acute traumatic coagulopathy in the pediatric population. Disclosures Zheng: Ablynx: Consultancy; Alexion: Research Funding.

DNA methylation is one of the major epigenetic mechanisms that control T cell differentiation. The ten-eleven translocation (TET) family of methylcytosine dioxygenases converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and other oxidized methylcytosines, intermediates in active DNA demethylation. Here we demonstrate that TET2 regulates CD8+ T cell differentiation in vivo following acute viral infection. At steady-state, mice with a T-cell specific deletion of TET2 have intact thymic and peripheral T cell populations. However, following acute viral infection with LCMV-Armstrong, TET2 loss promotes early acquisition of a memory CD8+ T cell fate in a cell-intrinsic manner without disrupting antigen-driven cell expansion or effector function. Integration of genome-wide methylation analysis and expression data suggest that TET2 loss leads to hypermethyation of the PRDM1 genomic locus (encoding Blimp-1) and alters the relative expression of Blimp-1 and Bcl-6, two antagonistic transcriptional repressors known to direct CD8+ T cell memory differentiation. Together, our data indicate that TET2 is an important regulator of CD8+ T cell fate decisions. Disclosures No relevant conflicts of interest to declare.

The objectives of this study were (1) to determine the clinical presentation and natural history associated with two newly recognized pathologic entities termed mantle cell lymphoma (MCL) and marginal zone lymphoma (MZL), including the mucosa-associated lymphoid tissue (MALT) and monocytoid B-cell subcategories, and (2) to determine whether these entities differ clinically from the other relatively indolent non- Hodgkin's lymphomas with which they have been previously classified. We reviewed the conventional pathology and clinical course of 376 patients who had no prior therapy; had stage III/IV disease; were classified as Working Formulation categories A, B, C, D, or E; and received cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) on Southwest Oncology Group (SWOG) studies no. 7204, 7426, or 7713. All slides were reviewed by the three pathologists who reached a consensus diagnosis. Age, sex, performance status, bone marrow and/or gastrointestinal involvement, failure-free survival, and overall survival were compared among all the categories. We found that (1) MCL and MZL each represent approximately 10% of stage III or IV patients previously classified as Working Formulation categories A through E and treated with CHOP on SWOG clinical trials; (2) the failure-free survival and overall survival of patients with MZL is the same as that of patients with Working Formulation categories A through E, but the failure-free survival and overall survival of the monocytoid B-cell patients were higher than that of the MALT lymphoma patients (P = .009 and .007, respectively); and (3) the failure-free survival and overall survival of patients with MCL is significantly worse than that of patients with Working Formulation categories A through E (P = .0002 and .0001, respectively). In conclusion, patients with advanced stage MALT lymphomas may have a more aggressive course than previously recognized. Patients with MCL do not have an indolent lymphoma and are candidates for innovative therapy.

DNA methylation is one of the major epigenetic mechanisms that controls cellular differentiation. The ten-eleven translocation (TET) family of methylcytosine dioxygenases mediates active DNA demethylation through the oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and subsequent intermediates. Here we demonstrate that TET2 regulates CD8+ T cell differentiation in vivo following acute and chronic viral infection. At steady-state, mice with a T-cell specific deletion of TET2 have intact thymic and peripheral T cell populations. Following acute viral infection with LCMV-Armstrong, TET2 loss enhances LCMV-specific CD8+ T cell memory differentiation in a cell-intrinsic manner without disrupting antigen-specific cell expansion or cytokine production. However, TET2-deficient memory CD8+ T cells exhibit altered recall responses with blunted re-expansion, retained expression of phenotypic memory markers and restricted re-expression of activation markers. During chronic viral infection with LCMV-clone 13, TET2 controls CD8+ T cell expansion and alters differentiation. Importantly, though mice with T-cell specific loss of TET2 developed similar levels of CD8+ T cell exhaustion as wild-type mice, TET2 loss specifically reduced PD-1 expression suggesting that TET2 may direct DNA demethylation of the PD-1 locus. Together, our data indicate that TET2 is an important regulator of CD8+ T cells following both acute and chronic viral infections and suggest targeting epigenetic regulators have potential for enhancing antiviral immunity. Disclosures No relevant conflicts of interest to declare.

Objective: Peripheral blood stem cell transplant (PBSCT) can now cure SCD in adults, but may result in a loss of future fertility. Little is documented regarding fertility preservation in women with SCD. The aim of this study was to perform fertility preservation for women with SCD scheduled for PBSCT. Design: Prospective cohort of women with SCD undergoing fertility preservation prior to PBSCT at a large research hospital. Materials and Methods: Patients underwent standard controlled ovarian hyperstimulation (COH) using an antagonist protocol cycle with leuprolide trigger under close multidisciplinary (including reproductive endocrinologists and hematologists) monitoring. All patients were continued on therapeutic or started on prophylactic anticoagulation prior to beginning COH, and maintained on hydroxyurea. Results: Nine reproductive aged women were screened; 1 declined participation, 1 was diagnosed with unrecognized premature ovarian insufficiency, 1 had her fertility preservation cycle canceled due to poor response to fertility medications and 2 patients are scheduled for upcoming cycles. The remaining four women (ages 20, 34, 24, 27) successfully underwent COH, transvaginal oocyte retrieval and cryopreservation of mature eggs (n= 8, 13, 15, 21 oocytes, respectively). The third patient underwent two cycles due to low mature oocyte yield from her initial cycle. Headaches were reported by patients 1 and 2 following gonadotropin injections, with a negative neurologic workup including MRI in patient 2. Patient 3 underwent an exchange transfusion on day 10 of stimulation, which did not adversely impact serum reproductive hormone levels. Patients 3 and 4 reported an acute exacerbation of their chronic pain during COH, which responded well to intravenous fluids, IV and oral pain medications. Therefore, despite severe SCD and co-morbid conditions, the side effects were manageable. There were no venous thrombotic events. Conclusion: These results provide support that fertility preservation can be safely performed in women with SCD under the care of a multidisciplinary team. The safest stimulation protocol (i.e. antagonist cycle with leuprolide trigger for final oocyte maturation) was successful in all patients despite multiple risk factors for failed leuprolide trigger. Fertility preservation is important not only before PBSCT to cure their underlying disease, but also because of high rates of premature ovarian insufficiency in the SCD population post-transplant. Support: Intramural NICHD and NHLBI, NIH. Disclosures No relevant conflicts of interest to declare.

The growth fraction of tumors from patients with non-Hodgkin's lymphomas (NHL) has been shown to correlate with survival in retrospective studies. The growth fraction can be evaluated using immunohistochemical techniques employing the Ki-67 monoclonal antibody (MoAb) that marks a nuclear protein present in cycling cells. The purpose of this study was to evaluate the clinical utility of the Ki-67 MoAb for predicting survival. Using a prospective trial design in a multi-institutional cooperative trials group, the proliferative index, clinical outcome, and statistical correlations were independently assessed for previously untreated patients with advanced stages of intermediate- and high-grade histologies of NHL treated on Southwest Oncology Group study (SWOG 8516, Intergroup 0067). The proportion of Ki- 67-positive cells was determined on snap-frozen thin tissue sections. A proliferative index of 80% or greater, as determined from prior retrospective studies, identified a group of patients (18%) who had a poor outcome. Overall survival was significantly reduced in these patients with a high Ki-67-associated proliferative index compared with those with a low proliferative index (P = .001). One-year survival estimates were 82% (low proliferative index) versus 18% (high proliferative index). A multivariate regression analysis incorporating commonly used clinical prognostic features confirmed the independent effect of proliferation on survival (relative risk estimate 5.9; 95% confidence interval, 2.2, 16.1). The Ki-67 MoAb identifies a group of patients with rapidly fatal NHL for whom currently available chemotherapy is inadequate.

One hundred twenty-five cases of Hodgkin's disease from the United States (79), Mexico City (31), and Costa Rica (15) were analyzed for the presence of Epstein-Barr virus (EBV) by in situ hybridization to EBER1 transcripts. EBV was more frequently detected in the Reed- Sternberg (RS) cells of mixed cellularity Hodgkin's disease (37 of 48 [77%]) compared with the nodular sclerosis subtype (19 of 71 [27%], P < .001). The presence of EBV was also associated with Hispanic ethnicity (P < .001). In a multivariate analysis, patient age, gender, and geographic location were less predictive of EBV positivity than were mixed cellularity histology (odds ratio = 8.3) and Hispanic ethnicity (odds ratio = 4.3). Southern blot analysis of EBV terminal repeat fragments using the Xho1a probe showed that the viral DNA was monoclonal in 17 of 17 cases having EBER1-positive RS cells. By comparison, EBV DNA was not detected by Southern analysis in 20 cases lacking EBER1 in RS cells, even when occasional background lymphocytes expressed EBER1. Because clonal viral DNA was so readily detected in EBER1-positive cases, the EBV genome is probably amplified at least 50- fold in the infected RS cells. Monoclonality of EBV DNA implies that the RS cells were infected before malignant transformation.