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Relapse after allogeneic hematopoietic stem cell transplantation (HCT) is the leading cause of death in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Infusion of unselected donor lymphocytes (DLIs) enhances the graft-versus-leukemia (GVL) effect. However, because the infused lymphocytes are not selected for leukemia specificity, the GVL effect is often accompanied by life-threatening graft-versus-host disease (GVHD), related to the concurrent transfer of alloreactive lymphocytes. Thus, to minimize GVHD and maximize GVL, we selectively activated and expanded stem cell donor–derived T cells reactive to multiple antigens expressed by AML/MDS cells (PRAME, WT1, Survivin, and NY-ESO-1). Products that demonstrated leukemia antigen specificity were generated from 29 HCT donors. In contrast to DLIs, leukemia-specific T cells (mLSTs) selectively recognized and killed leukemia antigen–pulsed cells, with no activity against recipient's normal cells in vitro. We administered escalating doses of mLSTs (0.5 to 10 × 107 cells per square meter) to 25 trial enrollees, 17 with high risk of relapse and 8 with relapsed disease. Infusions were well tolerated with no grade >2 acute or extensive chronic GVHD seen. We observed antileukemia effects in vivo that translated into not-yet-reached median leukemia-free and overall survival at 1.9 years of follow-up and objective responses in the active disease cohort (1 complete response and 1 partial response). In summary, mLSTs are safe and promising for the prevention and treatment of AML/MDS after HCT. This trial is registered at www.clinicaltrials.com as #NCT02494167.

A 65-year-old male with a history of ischemic strokes, seizures, and subarachnoid hemorrhage presented with a 4-week history of progressive diplopia, vertigo, nausea, and vomiting. Magnetic resonance imaging (MRI) revealed a 2.5×1.8×1.7 cm posterior fossa mass arising from the roof of the 4th ventricle extending into the cerebellar vermis. Posterior fossa craniotomy with stereotactic biopsy confirmed a locally invasive diffuse large B-cell lymphoma (DLBCL). Primary central nervous system lymphoma (PCNSL) arising from the 4th ventricle is a rare extranodal manifestation of non-Hodgkin lymphoma (NHL), with few cases documented in the literature. Review of available cases lends support that lymphoma arising from the 4th ventricle has a variable clinical presentation, occurs most commonly in immunocompetent males, and should be on the differential of any immunocompetent adult presenting with a posterior fossa mass. Optimal treatment modalities are based largely on phase 2 clinical trials, and recommended guidelines regardless of anatomic location should be adhered to.

Secondary acute myeloid leukaemia complicating the natural disease course of pre-existing Philadelphia chromosome-negative myeloproliferative neoplasms (PN-MPN) is well documented and associated with treatment challenges and significant morbidity. The incidence of a T-cell malignancy developing in patients with pre-existing PN-MPN is uncommon, with one case documented in the literature. We present two cases of angioimmunoblastic T-cell lymphoma (AITL) and one case of T-cell acute lymphoblastic leukaemia (T-ALL) that developed in patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF), respectively. All malignancies were advanced at diagnosis and exhibited disease progression, regardless of the mutational status of the underlying ET/PMF, presence of cytogenetic abnormalities, type of T-cell neoplasm or systemic chemotherapy utilised. The median time to diagnosis of AITL or T-ALL from the onset of MPN was 4.5 years (range: 6 months-10 years). This single institutional case series demonstrates the possibility of an association between T-cell neoplasms and PN-MPNs.

The most common preparative regimen for autologous transplantation (ASCT) in myeloma (MM) consists of melphalan 200 mg/m2 (MEL 200). Higher doses of melphalan 220–260 mg/m2, although relatively well tolerated, have not shown significant improvement in clinical outcomes. Several approaches have been pursued in the past to improve CR rates, including poly-chemotherapy preparative regimens, tandem ASCT, consolidation, and/or maintenance therapy. Since there is a steep dose–response effect for intravenous melphalan, we evaluated an alternative single ASCT strategy using higher-dose melphalan at 280 mg/m2 (MEL 280) with amifostine as a cytoprotectant as the maximum tolerated dose determined in an earlier phase I dose escalation trial. We report the final long-term outcomes of MM patients who underwent conditioning with MEL 280 with amifostine cytoprotection followed by ASCT. Although the complete response rate was quite high in the era pre-dating the routine use of novel therapies (proteasome inhibitors, immunomodulatory agents) (49%), the progression-free survival was a disappointing 22 months. The implications of this dichotomy between the excellent depth of ASCT response and progression-free survival are discussed.

Erlotinib, an epidermal growth factor receptor (EGFR) inhibitor, may have off-target activity inducing acute myeloid leukemia (AML) differentiation, possibly through SYK inhibition. We investigated erlotinib in a pilot phase II study for efficacy in relapsed/refractory AML patients at a dose of 150 mg once daily in 28-day cycles. Twenty-nine patients were treated for a median of 29 days (range 12–142 days). Seven patients (24%) received > 1 cycle of therapy and 12 (41%) discontinued treatment before day 28 due to disease progression. One patient (3%) achieved complete remission and 2 (7%) a > 50% reduction in blasts. The most common toxicities associated with erlotinib were fatigue in 10 patients (34%), diarrhea in 10 (34%), nausea in 8 (28%), and rash in 7 (24%). Only 2 patients (7%) had study drug-related adverse events requiring dose reductions and eventual discontinuation. The main reason for treatment discontinuation was disease progression in 26 patients (90%). All patients had died by the time of the last follow-up. Progression of disease was the primary cause of death in all patients. Median overall survival was 14 weeks (range 2.3–96.9 weeks) and median event-free survival was 5 weeks (range 1.7–21.0 weeks). Erlotinib as a single agent has limited clinical efficacy in patients with relapsed/refractory AML.

Abstract text: Background/Introduction: Chronic Myelomonocytic Leukemia (CMML) is an uncommon MDS/MPN overlap syndrome that has historically been included under the umbrella of myelodysplastic syndromes (MDS) for clinical trial and treatment. As a result, DNA methyltransferase inhibitors (DNMTi) such as decitabine or azacitidine have been the established standard of care for the treatment of CMML. The oral bioavailability of these agents has been limited due to rapid degradation by cytidine deaminase (CDA) in the gut and liver so treatment has required intravenous infusion or subcutaneous injections daily for 5-7 days every month (m) adding significant burden to older cancer patients due to daily time commitment and travel to treatment centers. In the context of pandemic SARS-CoV-2, parenteral therapy also increases contact with medical settings with increased infection risk. Oral decitabine 35 mg/cedazuridine 100 mg (ASTX727) is an oral fixed dose combination of decitabine and the CDA inhibitor cedazuridine that produced equivalent exposure (99%; 90% CI 93% to 106%) to IV decitabine 20 mg/m 2 in a randomized cross-over study (Garcia-Manero et al, ASH 2019), and Median overall survival (mOS) for the entire study population in the ASCERTAIN study was approximately 32 months (Savona, 2021). Here, we present outcome data for this study for the enrolled subpopulation of patients with CMML. Methods: We used a randomized cross over design in which patients were randomized in the first 2 cycles 1:1 to either Sequence A: (decitabine 35 mg/ cedazuridine 100 mg in Cycle 1 followed by IV decitabine at 20 mg/m 2 in Cycle 2), or Sequence B: (IV decitabine in Cycle 1 followed by oral decitabine/cedazuridine in Cycle 2). We conducted an intra-patient comparison of decitabine PK (primary PK endpoint: decitabine AUC equivalence over 5 days of dosing). Cycles were repeated every 28 days (unless delays were needed). All patients received oral decitabine/cedazuridine in Cycles 3 and above until disease progression or unacceptable toxicity. Patients were eligible per the FDA-approved label of IV decitabine (MDS patients by FAB classification including CMML, or MDS IPSS Intermediate-1, 2 or high-risk patients). Clinical endpoints were best response according to International Working Group (IWG) 2006 response criteria, transfusion independence for at least 8 or 16 consecutive weeks, overall survival, and safety. Adverse events (AEs) were graded by Common Terminology Criteria for Adverse Events (CTCAE) v 4.03. Results: Of the 133 patients enrolled and treated in ASCERTAIN, 16 (12%) had a diagnosis of CMML with demographics and as follows: median age 71.5 years, 69% Male/31% Female, median weight 87kg (range 65-124), 25% ECOG 0, 75% ECOG 1. Population disease characteristics were: 19% poor or intermediate risk cytogenetics, with median baseline hemoglobin 90 g/L, neutrophils 1.27 X 10 9/L, platelets 84 x 10 9/L, bone marrow blasts 5%, with 38% RBC transfusion dependent. Patients received a median of 7 cycles of therapy (range 3-24). Treatment-emergent adverse events of CTCAE Grade 3 or higher in > 10% of patients, independent of relationship to ASTX727, were cytopenias (neutropenia [69%], thrombocytopenia [63%], anemia [56%], leukopenia [19%]), febrile neutropenia (31%), fatigue (13%). Two patients (12.5%) had Complete Responses (CR), 8 (50%) had marrow CR ([mCR], including 3 (19%) with hematologic improvement (HI); Overall Response rate (ORR) [CR + PR+ mCR + HI] was 75%. Of six patients with baseline RBC transfusion dependence 3 (50%) became transfusion independent. Leukemia-free survival was 28.2 months and after a median follow up of more than 33 months, median overall survival had not been reached. Two patients (13%) went on to Hematopoietic Stem Cell Transplant (HCT). Conclusions: In the overall study, oral decitabine/cedazuridine delivered equivalent PK exposure to 5 days of IV decitabine 20mg/m 2 with a resultant clinical activity safety and efficacy profile in CMML patients consistent with the published literature (e.g Zeidan, et al 2017) and the Phase 2 experience. The use of oral decitabine/cedazuridine is a reasonable approach in CMML patients. References: Garcia-Manero, et al ASH 2019 Savona, et al, Int. MDS Symposium, 2021 Zeidan, et al, Cancer 2017: 3754-3762. Figure 1 Figure 1. Disclosures Savona: Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; BMS-Celgene: 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; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ALX Oncology: Research Funding; Astex: Research Funding; Incyte: Research Funding. McCloskey: Pfizer: Consultancy; Takeda: Consultancy, Speakers Bureau; Incyte: Speakers Bureau; Novartis: Consultancy; COTA: Other: Equity Ownership; BMS: Honoraria, Speakers Bureau; Amgen: Speakers Bureau; Jazz: Consultancy, Speakers Bureau. Griffiths: Boston Biomedical: Consultancy; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Taiho Oncology: Consultancy, Honoraria; Genentech: Research Funding; Astex Pharmaceuticals: Honoraria, Research Funding; Takeda Oncology: Consultancy, Honoraria; Novartis: Honoraria; Apellis Pharmaceuticals: Research Funding; Alexion Pharmaceuticals: Consultancy, Research Funding. Yee: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forma Therapeutics: Research Funding; Geron: Research Funding; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb/Celgene: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann La Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria; Janssen: Research Funding; Onconova: Research Funding; Genentech: Research Funding; Otsuka: Membership on an entity's Board of Directors or advisory committees; MedImmune: Research Funding; Jazz: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; TaiHo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Paladin: Membership on an entity's Board of Directors or advisory committees. Zeidan: BeyondSpring: Consultancy; Janssen: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; BioCryst: Other: Clinical Trial Committees; AstraZeneca: Consultancy; Pfizer: Other: Travel support, Research Funding; Kura: Consultancy, Other: Clinical Trial Committees; Incyte: Consultancy, Research Funding; Ionis: Consultancy; Daiichi Sankyo: Consultancy; Epizyme: Consultancy; Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Genentech: Consultancy; Geron: Other: Clinical Trial Committees; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; Gilead: Consultancy, Other: Clinical Trial Committees; Aprea: Consultancy, Research Funding; Astellas: Consultancy; Astex: Research Funding; Jazz: Consultancy; Jasper: Consultancy; Amgen: Consultancy, Research Funding; Agios: Consultancy; ADC Therapeutics: Research Funding; Acceleron: Consultancy, Research Funding; AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding. Al-Kali: Novartis: Research Funding; Astex: Other: Research support to institution. Patel: Agios: Membership on an entity's Board of Directors or advisory committees; Celgene-BMS: Membership on an entity's Board of Directors or advisory committees; PVI: Honoraria. Sabloff: Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; TaiHo: Membership on an entity's Board of Directors or advisory committees; Jaxx: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; ROCHE: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Dao: Astex Pharmaceuticals, Inc.: Current Employment. Fazal: Janssen Oncology: Consultancy, Honoraria, Speakers Bureau; Taiho Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Agios: Consultancy, Honoraria, Speakers Bureau; Sanofi Genzyme: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Glaxo Smith Kline: Consultancy, Honoraria, Speakers Bureau; AMGEN: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Stemline Therapeutics: Consultancy, Honoraria, Speakers Bureau; Karyopharm Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau. Odenike: Celgene, Incyte, AstraZeneca, Astex, NS Pharma, AbbVie, Gilead, Janssen, Oncotherapy, Agios, CTI/Baxalta, Aprea: Research Funding; AbbVie, Celgene, Impact Biomedicines, Novartis, Taiho Oncology, Takeda: Consultancy. Kantarjian: Ipsen Pharmaceuticals: Honoraria; Astra Zeneca: Honoraria; Astellas Health: Honoraria; Aptitude Health: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz: Research Funding; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; BMS: Research Funding; Ascentage: Research Funding; Amgen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; KAHR Medical Ltd: Honoraria; NOVA Research: Honoraria; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. DeZern: Bristol-Myers Squibb: 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; Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Roboz: Janssen: Research Funding; AbbVie: Consultancy; Actinium: Consultancy; Agios: Consultancy; Amgen: Consultancy; Astex: Consultancy; Astellas: Consultancy; AstraZeneca: Consultancy; Bayer: Consultancy; Blueprint Medicines: Consultancy; Bristol Myers Squibb: Consultancy; Celgene: Consultancy; Daiichi Sankyo: Consultancy; Glaxo SmithKline: Consultancy; Helsinn: Consultancy; Janssen: Consultancy; Jasper Therapeutics: Consultancy; Jazz: Consultancy; MEI Pharma - IDMC Chair: Consultancy; Mesoblast: Consultancy; Novartis: Consultancy; Otsuka: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy. Busque: Novartis: Consultancy. Leber: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AMGEN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TaiHo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Otsuka: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hao: Astex Pharmaceuticals, Inc.: Current Employment. Keer: Astex Pharmaceuticals, Inc.: Current Employment. Azab: Astex Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees.

Background/Introduction: Lower-risk (IPSS low risk and Int-1) myelodysplastic syndromes (MDS) are typically treated supportively to address cytopenias. DNA methyltransferase inhibitors (DNMTi) such as azacitidine and decitabine (DEC) are FDA-approved for higher risk MDS patients (pts), and while the DEC USPI includes IPSS Int-1 pts, it is not widely used in this population. Approved intravenous (IV) or subcutaneous (SC) regimens require 5-7 days of treatment every month burdening older cancer pts due to daily travel and treatment time and may increase potential risk from pandemic SARS-CoV-2 infection. Because DNMTis are rapidly degraded by cytidine deaminase (CDA) in the gut and liver, oral availability has only been recently possible. A randomized study with CC-486, an oral formulation of azacitidine, in the Int-1 population showed a median overall survival (mOS) of approximately 17 months for both placebo and treated patients (Garcia-Manero, 2021). Oral DEC 35 mg/cedazuridine 100 mg (ASTX727) or DEC-C, is an oral fixed dose combination (FDC) of DEC and the CDA inhibitor cedazuridine (CED) resulting in equivalent exposure (99%; 90% CI 93% to 106%) to standard IV DEC 20 mg/m 2 for 5 days in an intra-patient randomized cross-over study (Garcia-Manero et al, ASH 2019). Here, we present data on patients with lower risk MDS from that study. Methods: We used a randomized cross over design with pts randomized 1:1 in the first 2 cycles to either Sequence A: (DEC 35 mg/ CED 100 mg in Cycle 1 and IV DEC at 20 mg/m 2 in Cycle 2), or Sequence B (IV DEC in Cycle 1 and oral DEC/CED in Cycle 2). Cycles were repeated every 28 days unless delays were needed, and all patients received oral DEC-C in Cycles 3+ until disease progression or unacceptable toxicity. We conducted an intra-patient comparison of DEC PK (DEC AUC equivalence over 5 days of dosing). Pts were eligible as per the FDA-approved label of IV DEC (MDS pts by FAB classification including CMML, or MDS IPSS Intermediate-1, 2 or high-risk pts). Clinical endpoints were best response as assessed by an independent expert panel according to IWG 2006 response criteria, transfusion independence (TI), overall survival (OS), and safety. Results: Of the 133 pts treated in ASCERTAIN, 69 had a diagnosis of lower-risk MDS (93% Int-1, 7% LR). Median age was 70.0 years (range 45-87), 65% were male, median weight was 84 kg (range 50-127), median baseline hematologic parameters were: hemoglobin 89 g/L (range 69.8-146.5), WBCs 1.50 X 10 9/L (range 0.11-7.1), platelets (plt) 86 x 10 9/L (range 5-703), bone marrow blasts 4% (range 0-18), cytogenetics: 7 (10.1%) poor-risk, 21 (30.4%) intermediate risk, 37 (53.6%) better-risk, 4 (5.7%) missing or not evaluable. 27(39%) of the pts were RBC transfusion dependent (TD) and 6 (9%) plt TD. 17 (25%) had received prior MDS treatment, 3% prior DNMTi. Pts received a median of 9 cycles of therapy (range 1-28). Treatment-emergent adverse events of CTCAE Gr 3 or higher in >10% of pts, independent of relationship to ASTX727, included cytopenias (neutropenia [59%], thrombocytopenia [58%], anemia [48%], leukopenia [26%]), febrile neutropenia (32%), and pneumonia (19%). Sixteen pts (23%) achieved Complete Response (CR), 18 (26%) had marrow CR (mCR), including 9 (13%) with hematologic improvement (HI). Overall Response rate (ORR; CR + PR+ mCR + HI) was 57%. Of those RBC or plt TD at baseline, 13 (48%) became RBC TI and 4 (67%) became plt TI. With approximately 32 months of median follow up, neither median leukemia-free survival (mLFS) nor mOS had been reached (Figure 1). Twelve pts (17%) went on to allogeneic stem cell transplant. Conclusions: Oral decitabine/cedazuridine given as a FDC in MDS pts produced equivalent PK exposure to 20 mg/m 2 IV DEC; in lower risk MDS pts with treatment indicated, the agent was generally well-tolerated with prolonged treatment and could result in mLFS and mOS which exceeds 32 months. This FDC and other dosing regimens of oral DEC-C should be further studied in this patient population. References: Garcia-Manero, et al, ASH 2019 Savona, et al, Int. MDS Symp. 2021 Garcia-Manero, et al, Phase III, Randomized, Placebo-Controlled Trial of CC-486 (Oral Azacitidine) in Patients with Lower-Risk Myelodysplastic Syndromes. J.Clin.Onc. 2021 39:13, 1426-1436 Figure 1 Figure 1. Disclosures McCloskey: Pfizer: Consultancy; Jazz: Consultancy, Speakers Bureau; COTA: Other: Equity Ownership; Incyte: Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Novartis: Consultancy; BMS: Honoraria, Speakers Bureau; Amgen: Speakers Bureau. Griffiths: Alexion Pharmaceuticals: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria; Taiho Oncology: Consultancy, Honoraria; Genentech: Research Funding; Novartis: Honoraria; Takeda Oncology: Consultancy, Honoraria; Astex Pharmaceuticals: Honoraria, Research Funding; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Apellis Pharmaceuticals: Research Funding; Boston Biomedical: Consultancy. Yee: Paladin: Membership on an entity's Board of Directors or advisory committees; TaiHo: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Geron: Research Funding; Janssen: Research Funding; Jazz: Research Funding; MedImmune: Research Funding; Onconova: Research Funding; Tolero: Research Funding; AbbVie: Honoraria; Bristol-Myers Squibb/Celgene: Membership on an entity's Board of Directors or advisory committees; Otsuka: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann La Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Forma Therapeutics: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Zeidan: Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; Genentech: Consultancy; Ionis: Consultancy; Astellas: Consultancy; Epizyme: Consultancy; AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding; Jasper: Consultancy; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; BeyondSpring: Consultancy; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Janssen: Consultancy; Acceleron: Consultancy, Research Funding; AstraZeneca: Consultancy; Kura: Consultancy, Other: Clinical Trial Committees; Gilead: Consultancy, Other: Clinical Trial Committees; Agios: Consultancy; Daiichi Sankyo: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; Geron: Other: Clinical Trial Committees; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; BioCryst: Other: Clinical Trial Committees; Pfizer: Other: Travel support, Research Funding; Aprea: Consultancy, Research Funding; ADC Therapeutics: Research Funding; Jazz: Consultancy; Incyte: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Astex: Research Funding. Al-Kali: Astex: Other: Research support to institution; Novartis: Research Funding. Patel: Celgene-BMS: Membership on an entity's Board of Directors or advisory committees; PVI: Honoraria; Agios: Membership on an entity's Board of Directors or advisory committees. Sabloff: Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; ROCHE: Membership on an entity's Board of Directors or advisory committees; TaiHo: Membership on an entity's Board of Directors or advisory committees; Jaxx: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Dao: Astex Pharmaceuticals, Inc.: Current Employment. Fazal: Taiho Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Stemline Therapeutics: Consultancy, Honoraria, Speakers Bureau; Sanofi Genzyme: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Karyopharm Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Janssen Oncology: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Glaxo Smith Kline: Consultancy, Honoraria, Speakers Bureau; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau; AMGEN: Consultancy, Honoraria, Speakers Bureau; Agios: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau. Odenike: AbbVie, Celgene, Impact Biomedicines, Novartis, Taiho Oncology, Takeda: Consultancy; Celgene, Incyte, AstraZeneca, Astex, NS Pharma, AbbVie, Gilead, Janssen, Oncotherapy, Agios, CTI/Baxalta, Aprea: Research Funding. Kantarjian: AbbVie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Ascentage: Research Funding; Pfizer: Honoraria, Research Funding; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Amgen: Honoraria, Research Funding; Ipsen Pharmaceuticals: Honoraria; Jazz: Research Funding; Astellas Health: Honoraria; Immunogen: Research Funding; Astra Zeneca: Honoraria; Aptitude Health: Honoraria; KAHR Medical Ltd: Honoraria; NOVA Research: Honoraria; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. DeZern: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho: 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; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees. Roboz: Novartis: Consultancy; Mesoblast: Consultancy; Jasper Therapeutics: Consultancy; Jazz: Consultancy; MEI Pharma - IDMC Chair: Consultancy; Daiichi Sankyo: Consultancy; Otsuka: Consultancy; Bristol Myers Squibb: Consultancy; Blueprint Medicines: Consultancy; Bayer: Consultancy; AstraZeneca: Consultancy; Astellas: Consultancy; Astex: Consultancy; Amgen: Consultancy; Agios: Consultancy; Actinium: Consultancy; AbbVie: Consultancy; Janssen: Research Funding; Celgene: Consultancy; Glaxo SmithKline: Consultancy; Helsinn: Consultancy; Janssen: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy. Busque: Novartis: Consultancy. Leber: Astellas: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Otsuka: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TaiHo: Honoraria, Membership on an entity's Board of Directors or advisory committees; AMGEN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hao: Astex Pharmaceuticals, Inc.: Current Employment. Keer: Astex Pharmaceuticals, Inc.: Current Employment. Azab: Astex Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Savona: Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; CTI: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS-Celgene: 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; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ALX Oncology: Research Funding; Astex: Research Funding; Incyte: Research Funding.

Myelodysplastic syndromes (MDSs) are characterized by ineffective hematopoiesis and an increased risk of transformation. Few effective therapies are available for lower risk MDS patients, especially after the failure of hypomethylating agents. MDS progenitor cells are dependent on the nuclear factor-κB (NF-κB) for survival, which makes it an attractive therapeutic target. As a proteosomal inhibitor, bortezomib is thought to have inhibitory activity against NF-κB. We designed a proof-of-principle study of subcutaneous (SC) bortezomib in lower risk MDS patients with evidence of NF-κB activation in their bone marrow. Fifteen patients were treated, their median age was 71 (range 56-87), 33% were low and 67% int-1 by IPSS, median number of prior therapies was 2, all patients were transfusion dependent. Baseline median pp65 percentage was 31% and 11 patients had evidence of ring sideroblasts (RS). SC bortezomib was safe, well tolerated with no excess toxicity. Three patients out of the 15 (20%) had evidence of response with hematologic improvement (HI-E). Bortezomib caused a decrease in pp65 levels in 7 out of 13 evaluable patients (54%, P = .025). Of interest, unexpectedly, we observed a significant decrease in RS in 7 out of 10 (70%) evaluable patients during treatment. In conclusion, this study suggests that NF-κB activation, measured by pp65 levels, may be a useful biomarker in MDS. Bortezomib is safe in this patient population but has modest clinical activity. The role of the proteasome in the genesis of RS needs further study.

Introduction: Hypomethylating agents (HMAs) or DNA methyltransferase inhibitors (DNMTi) such as decitabine or azacitidine are established standard of care for the treatment of MDS and CMML. The oral bioavailability of these agents has been limited due to rapid degradation by cytidine deaminase (CDA) in the gut and liver, hence requiring intravenous infusion or subcutaneous injections daily for 5-7 days every month (m). This parenteral administration requirement adds significant burden to older cancer patients due to daily time commitment and travel to treatment centers. It also increases exposure to and infection risk with SARS-CoV-2 during the COVID-19 pandemic. Oral decitabine 35 mg/cedazuridine 100 mg (ASTX727) is an oral fixed dose combination drug of decitabine and the CDA inhibitor cedazuridine that have shown 99% (90% CI 93% to 106%) equivalent exposure to standard dose IV decitabine 20 mg/m2 in a randomized cross-over study (Garcia-Manero et al, ASH 2019). Here, we present the clinical efficacy and safety results of oral decitabine/cedazuridine from 133 patient study in MDS and CMML (ASTX727-02 ASCERTAIN study). Methods: We used a randomized cross over design where patients were randomized in the first 2 cycles 1:1 to either Sequence A: decitabine 35 mg/ cedazuridine 100 mg in Cycle 1 followed by IV decitabine at 20 mg/m2 in Cycle 2, or Sequence B: IV decitabine in Cycle 1 followed by oral decitabine/cedazuridine in Cycle 2 to do an intra-patient comparison of decitabine PK (primary PK endpoint: decitabine AUC equivalence over 5 days of dosing). Cycles were repeated every 28 days. All patients received oral decitabine/cedazuridine in all subsequent cycles from Cycle 3 onwards until disease progression or unacceptable toxicity. Patients were eligible as per the FDA-approved label of IV decitabine (MDS patients by FAB classification including CMML, or MDS IPSS Intermediate-1, 2 or high-risk patients). Clinical endpoints were best response as assessed by an independent expert panel according to International Working Group (IWG) 2006 response criteria, transfusion independence for at least 8 or 16 consecutive weeks, overall survival, and safety. Adverse events (AEs) were graded by Common Terminology Criteria for Adverse Events (CTCAE) v 4.03. Results: 138 subjects were randomized, of whom 133 were treated on study. The median age was 71.0 years (range 44-88), 65% were male, 88% MDS and 12% CMML, 43% were either red blood cells (RBCs) or platelets transfusion-dependent at baseline, 25% had poor-risk cytogenetics, and 42% had baseline bone marrow blasts >5%. At the data cutoff for the response analysis, the median duration of follow up was 12.6 m (range 9.3 to 20.5 m) with median number of treatment cycles of 8 (range 1 to 18). Of the 133 treated patients the best response was complete response (CR) in 28 patients (21%; 95% CI 15-29%), marrow (m)CR with hematological improvement (HI) in 20 patients (15%), mCR without HI in 23 patients (17.3%), and HI in 10 patients (7.5%) for an overall objective response (CR+mCR+HI) in 81 patients (61%; 95% CI 52-69%). Median duration of CR was 7.5 m (range 1.6 to 17.5 m), and median time to CR was 4.3 m (range 2.1 to 15.2 m). Of the 133 treated patients 27 (20%) went on to receive allogeneic hematopoietic cell transplant. Of the 57 patients who were either RBCs or platelets transfusion-dependent at baseline, 30 (53%) became transfusion independent for both RBCs and platelets for at least 8 consecutive weeks, and 19 (33%) were both RBCs and platelets transfusion independent for at least 16 consecutive weeks. Median survival has not been reached. Most common Treatment-Emergent AEs of Grade ≥3 regardless of causality were neutropenia in 51.5%, thrombocytopenia in 50%, anemia in 40%, febrile neutropenia in 26%, leukopenia in 21%, pneumonia in 12%, and sepsis in 7% of patients treated with oral decitabine/cedazuridine (excluding the IV decitabine cycle). Summary/Conclusions: Efficacy and safety from oral decitabine 35 mg/ cedazuridine 100 mg daily for 5 days every 28 days are consistent with clinical data from standard IV decitabine 20 mg/m2 daily for 5 days. Oral decitabine/cedazuridine is the only oral HMA with systemic exposure equivalent to its injectable drug. Further investigation of oral decitabine/cedazuridine in all-oral combination studies is warranted and underway. Disclosures Savona: BMS: Consultancy; AbbVie: Consultancy; Gilead: Consultancy; Karyopharm: Consultancy, Current equity holder in publicly-traded company; Ryvu: Consultancy; Boehringer Ingelheim: Patents & Royalties; Takeda: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding. Griffiths:Celgene/BMS: Honoraria, Research Funding; Genentech Inc: Research Funding; Boston Biomedical: Honoraria; AbbVie Inc: Honoraria; Persimmune: Research Funding; Novartis: Honoraria, Research Funding; Alexion Pharmaceuticals: Honoraria, Research Funding; Astex Pharmceuticals: Research Funding. Zeidan:CCITLA: Other; Seattle Genetics: Consultancy, Honoraria; BeyondSpring: Consultancy, Honoraria; Taiho: Consultancy, Honoraria; Cardinal Health: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Leukemia and Lymphoma Society: Other; Jazz: Consultancy, Honoraria; Trovagene: Consultancy, Honoraria, Research Funding; Ionis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Astex: Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Acceleron: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Celgene / BMS: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; ADC Therapeutics: Research Funding; Aprea: Research Funding; MedImmune/Astrazeneca: Research Funding; Cardiff Oncology: Consultancy, Honoraria, Other; Incyte: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria. Patel:DAVA Pharmaceuticals: Honoraria; France Foundation: Honoraria; Celgene: Consultancy, Speakers Bureau; Agios: Consultancy. Keating:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Hoffman La Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy; Servier: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Taiho: Membership on an entity's Board of Directors or advisory committees. Dao:Astex Pharmaceuticals, Inc.: Current Employment. Fazal:Jansen: Speakers Bureau; Gilead/Kite: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Jazz Pharma: Consultancy, Speakers Bureau; Karyopham: Speakers Bureau; Celgene: Speakers Bureau; Glaxosmith Kline: Consultancy, Speakers Bureau; Incyte Corporation: Consultancy, Honoraria, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Stemline: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Odenike:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals, NS Pharma, Gilead Sciences, Janssen Oncology, Oncotherapy, Agios, CTI/Baxalta, Aprea: Other: Institutional research funding; Astra Zeneca: Research Funding; Incyte: Other: Institutional research funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Impact Biomedicines: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kantarjian:Abbvie: Honoraria, Research Funding; BioAscend: Honoraria; Delta Fly: Honoraria; Ascentage: Research Funding; Janssen: Honoraria; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Sanofi: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immunogen: Research Funding; Aptitute Health: Honoraria; BMS: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Jazz: Research Funding; Oxford Biomedical: Honoraria; Amgen: Honoraria, Research Funding; Adaptive biotechnologies: Honoraria. DeZern:MEI: Consultancy; Celgene: Consultancy, Honoraria; Astex: Research Funding; Abbvie: Consultancy. Roboz:Novartis: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Astex: Consultancy; Amphivena: Consultancy; Agios: Consultancy; Pfizer: Consultancy; Abbvie: Consultancy; Array BioPharma: Consultancy; Bayer: Consultancy; Celltrion: Consultancy; Eisai: Consultancy; Jazz: Consultancy; Roche/Genentech: Consultancy; Sandoz: Consultancy; Actinium: Consultancy; Argenx: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; AstraZeneca: Consultancy; Orsenix: Consultancy; Otsuka: Consultancy; Takeda: Consultancy; Trovagene: Consultancy; Cellectis: Research Funding; Jasper Therapeutics: Consultancy; Epizyme: Consultancy; Helsinn: Consultancy; MEI Pharma: Consultancy. Busque:Pfizer: Honoraria; BMS: Honoraria; Novartis: Honoraria. Wells:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Leber:Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda/Palladin: 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, Speakers Bureau; Treadwell: Honoraria, Membership on an entity's Board of Directors or advisory committees; Lundbeck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hao:Astex Pharmaceuticals, Inc.: Current Employment. Keer:Astex Pharmaceuticals, Inc.: Current Employment. Azab:Astex Pharmaceuticals, Inc.: Current Employment. Garcia-Manero:Acceleron Pharmaceuticals: Consultancy, Honoraria; AbbVie: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; H3 Biomedicine: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Amphivena Therapeutics: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Onconova: Research Funding; Merck: Research Funding; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Research Funding.

Introduction Primary or secondary central nervous system (CNS) lymphoma is a rare and aggressive disease. Prior database analyses have enriched our knowledge of the epidemiology, clinical presentation and prognosis for these patients, although data regarding treatment patterns and long-term survival data is lacking. Ours is the first study investigating epidemiology, clinical characteristics, treatment patterns and potential prognostic factors using the Texas Cancer Registry (TCR). This is a statewide database, population-based registry that serves as the foundation for measuring the cancer burden in Texas and it is one of largest cancer registries in the United States1. Methods We used the TCR database to retrospectively identify patients diagnosed with CNS lymphoma from 1997 to 2017. Data collected included age, race, histology (diffuse large B-cell lymphoma, T-cell lymphoma), location and outcomes (alive/dead). Treatment (chemotherapy, radiation therapy or both) data was collected from 2004 to 2017. Differences in patient-level characteristics between cohorts were compared using a chi-square test and Fisher's exact test as appropriate. Survival was analyzed using the Kaplan-Meier method and log-rank tests were used to compare survival distributions. P < 0.05 was considered statistically significant for all analysis. Results There were 1134 patients with CNS lymphoma identified between 1995 and 2017. Most of them were diffuse large B-cell lymphoma (DLBCL) (97.4%); only 22 patients had T cell lymphoma. The most common locations were brain (73.9%), unspecified (14.1%) and spinal cord (6.7%). Almost 50% of all patients were over 65 years old; male to female ratio was 1.23. Patients were frequently reported to be Caucasian (62.7%) followed by Hispanic (27.0%) and African-american (6.9%). The median follow-up time was 11 months. Treatment data was available for 485 patients. They either received chemotherapy (58.1%), radiation (9.7%) or both (12.8%). Survival was better for patients receiving chemotherapy and radiation than radiation alone (HR 1.8, p=0.02) or no treatment (HR 3.3, p < 0.0001). There was no statistically significant difference when compared with chemotherapy alone (HR 1.4, p= 0.0931) (Figure 1). Overall survival (OS) for patients with DLBCL at 5-years was 27.4 % (95% CI: 24.7%, 30.1%) and 42.0% for T-cell (95% CI: 23.9%, 59.0%). Five-year disease specific survival (DSS) was similar at 39.2% (95% CI: 35.9%, 42.5%) for DLBCL and 51.8% for T-cell lymphoma (95% CI: 30.3%, 69.5%). There was no statistically significant difference between these two cohorts for OS (p = 0.5063) and DSS (p=0.2819). Age over 65 years was associated with poor survival (32 months vs 6 months, p Conclusion CNS lymphoma is a rare lymphoma presentation. Most of them are DLBCL and commonly found in patients older than 65 years old. Spinal cord disease alone was associated with a better prognosis and age over 65 years old was associated with a worse outcome. Treatment with chemotherapy (either with radiation or alone) is associated with better outcomes. 1. Cancer incidence data have been provided by the Texas Cancer Registry, Cancer Epidemiology and Surveillance Branch, Texas Department of State Health Services, 1100 West 49th Street, Austin, TX 78756, https://www.dshs.texas.gov/tcr/. Disclosures No relevant conflicts of interest to declare.

Introduction Primary Central Nervous System Lymphoma (PCNSL) is a rare form of extra-nodal non-Hodgkin Lymphoma (NHL), with diffuse large B-cell Lymphoma (DLBCL) reported in 90% of cases. Secondary CNS lymphoma (SCNSL) may occur as an isolated recurrence of previously diagnosed NHL or occur simultaneously as a manifestation of systemic disease. Comparative data on survival in treated PCNSL and SCNSL in the real-world setting is lacking. We present a retrospective analysis of outcomes in PCNSL and SCNSL patients treated at the Houston Methodist Cancer Center. Methods We retrospectively identified patients with a diagnosis of PCNSL or SCNSL from 2015 to 2020. Data collected included age, race, sex, diagnosis (PCNSL, SCNSL), histology and immunohistochemistry, treatment type (chemotherapy, radiation), transplant rates as well as outcomes (alive/dead). Responses were classified as complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). Survival was analyzed using Kaplan-Meier methodology, and log-rank tests were used to compare survival distributions. P < 0.05 was considered statistically significant. Results There were 50 patients with CNS lymphoma identified between 2015 and 2020; 68% were PCNSL. Out of 43 with available pathology, 2 patients were T-cell lymphomas and 41 DLBCL. Out of the DLBCL cases, 95% of cases expressed CD20 while close to 60% were positive for MUM1, bcl-2 and bcl-6. Less than 15% of cases were positive for CD10. CD30 was positive in 17% of cases. Cerebral hemispheres (76%) was the most common organ involved, followed by ocular (8%), intraventricular space (6%) and cerebellum (6%). Median age at diagnosis was 67 years; male to female ratio was 1.27. Caucasian (62%) and Hispanic (24%) were most common ethnicities. Epstein-Barr Virus was positive in 14% of patients (5 in PCNSL and 2 in SCNSL). One patient with SCNSL had human immunodeficiency virus. The median follow-up time was 9.1 months. Multiagent chemotherapy including high dose methotrexate (MTX), cytarabine and rituximab was given to 48% of the patients while 32% received high dose MTX alone plus rituximab. From the latter group, five out of sixteen patients received temozolomide. Other regimens were used in 6% of the cases. Median dose of MTX in a multiagent chemotherapy regimen was 2.5gr/m2 and 2.25gr/m2 when used alone or with temozolomide. Median number of cycles given was 3. Radiation therapy alone was given to 8% of cases. Three patients did not receive treatment. For patients with PCNSL, overall response rate (ORR) was 82.8% (CR 65.5%, PR 13.8%, SD 3.4%). ORRs were similar between multiagent chemotherapy and methotrexate alone (+/- temozolomide) with 86.7% and 83.3% respectively. ORR for SCNSL was 57.1% (CR 35.7%, PR 21.4%); only 1 patient was treated with MTX alone. Further lines of therapy were required in 9.3% of patients. Consolidation with whole brain radiation was given in 22% of the cases (29.4% for PCNSL and 6.3% for SCNSL). Autologous stem cell transplant was performed in 10% of the patients (2 PCNSL, 3 SCNSL). Overall survival for patients with PCNSL was 74.8 months and 10.1 months for SCNSL (p=0.0444) (Figure 1). Survival was not significant between patients receiving multiagent chemotherapy and MTX alone or in combination with temozolomide (3-year OS 57.3% vs 73.4%, p= 0.5652) (Figure 2). Conclusion Most patients diagnosed with PCNSL are non-germinal center DLBCL. Median MTX dose was lower than 3gr/m2 with excellent ORR of over 80% in PCNSL. Response rates were lower in SCNSL and in general, patients with PCNSL had better outcomes. Survival did not differ significantly between regimens, suggesting that a lower intensity therapy may perform similarly to multiagent chemotherapy. These results need to be confirmed by prospective studies. Disclosures No relevant conflicts of interest to declare.

Context: Relapsed/refractory peripheral T-cell lymphoma (R/R PTCL) has a poor prognosis. Romidepsin (Ro) and brentuximab vedotin (Bv), a CD30 antibody-drug conjugate, has shown response rates ranging from 24–42% when used as monotherapy. Efficacy of these agents when combined with salvage chemotherapy such as ifosfamide, carboplatin, and etoposide (ICE) has been scarcely studied in PTCL. Objective: Report outcomes of Bv-ICE in CD30 (+) and Ro-ICE in CD30 (-) R/R PTCL. Design: We retrospectively identified R/R PTCL patients treated with Bv-ICE or Ro-ICE in Houston Methodist Cancer Center from 2016–2019. We used frequencies and median to analyze the quantitative variables. Setting: Institutional practice. Patients or other participants: All patients with R/R PTCL. Interventions: N/A. Main outcome measures: Response rates, transplant rates, and adverse event rates of Bv-ICE and Ro-ICE Results: There were 13 R/R PTCL patients, 6 treated with Bv-ICE and 7 with Ro-ICE. The median age was 65 years old. The male to female ratio was 5:5. More than 75% had stage IV PTCL. The most common subtype was PTCL, not otherwise specified (46.2%), followed by angioimmunoblastic T-cell lymphoma (30.8%). Bv-ICE had an overall response rate (ORR) of 66.7%, with all the patients achieving complete response (CR). The median duration of response (DOR) was 7.5 months. ORR was 71.4% for Ro-ICE; 57.1% of patients achieved CR. The median DOR was 6 months. Two patients treated with Bv-ICE and three treated with Ro-ICE received transplantation. Grade 3 and 4 cytopenias were seen more frequently with Ro-ICE (85.7%) than with Bv-ICE (66.7%). Abnormal renal and liver function tests were seen at a lower proportion (28.6% in Ro-ICE and 33.3% in Bv-ICE). Neuropathy was seen in a third of patients treated with brentuximab. At last, follow-up almost half of all treated patients were still alive. Conclusions: Treatment with Bv-ICE and Ro-ICE are effective salvage regimens for R/R PTCL. Both can improve remission rates prior to transplant with similar ORRs and CRs over 50%. More than a third of patients were able to receive transplantation. In our experience, a treatment strategy based on CD30 positivity is feasible and effective to treat patients with R/R PTCL.

Introduction Primary cutaneous anaplastic large-cell lymphoma (PCALCL) is a rare T-cell lymphoma that presents as a solitary or grouped nodules. It is characterized by anaplastic-appearing cells that are usually ALK negative but have high expression of CD30. There is paucity of epidemiologic data on PCALCL. A prior analysis of the Surveillance, Epidemiology, and End Results (SEER) database by Yu et al. reported only 157 cases from 1973 to 2004. We are presenting an analysis of the patients diagnosed with PCALCL after 2004. Methods We used the SEER database to retrospectively identify patients diagnosed with PCALCL from 2005 to 2016. The database collects data from cancer registries covering approximately 26% of the US population and was used to estimate frequencies and overall incidence rate. Survival was analyzed using the Kaplan-Meier method and log-rank tests were used to compare survival distributions. We assessed the effect of primary skin site (head and neck) and increasing age on survival as they were suggestive of decreased overall survival on multivariate analysis of the 1973-2004 cohort. P < 0.05 was considered statistically significant for all analysis. Results There were 501 cases of PCALCL recorded from 2005 to 2016. Median follow-up was 52 months. The overall incidence rate was found to be 0.12/1,000,000 age adjusted to the 2000 US standard population. More than 50% of the cases were diagnosed after 2010. The median age at diagnosis was 61 years (2-97 years). It was seen most frequently in White (72.9%) patients followed by Hispanic (10.2%) and Black (9.4%) patients. The male to female ratio was 1.42. The most common primary sites affected were the skin of the lower limbs and hip (26.4%) and head and neck (21.3%). A 33.4% of patients required treatment which was mainly excisional (1 patient required amputation). Notably, PCALCL was diagnosed as a second or third malignancy in 19.2% of cases. Overall survival rates at 5 years and 10 years were found to be 80.6% (95% CI: 76.3%, 84.3%) and 61.5% (95% CI: 54.1%, 68.1%) respectively. Age greater than 60 years old was significantly associated with a lower survival (89.7% vs 54.4%, p Conclusion Our analysis of the SEER database for PCALCL is the largest done to our knowledge. Although the number of cases has almost tripled since 2005, it is still a rare type of cutaneous T-cell lymphoma. Lower extremities and hips are the most frequent primary skin site. Only a third of the patients required treatment with overall survival rates of more than 80% by 5 years. Older age (more than 60 years old) is associated with a worse outcome. Head and neck as the primary skin site does not appear to be associated to lower survival as previously thought. Disclosures No relevant conflicts of interest to declare.

Chronic lymphocytic leukemia (CLL) is the most prevalent type of adult leukemia encountered in the western world. Patients with CLL are typically older, with a median age in the 70s, and are at risk for certain complications due to the disease itself and due to the therapies imparted for this. Patients with CLL are at a higher risk of infections, partly due to disease and partly due to the immune dysfunction induced by treatment, such as purine analogous-based chemoimmunotherapy, which leads to lymphocyte depletion. Infections are a leading cause of complications and death in CLL patients. Also, CLL patients have been shown to have a higher incidence of other malignancies. Despite this knowledge, there are no definite guidelines as to what is the best approach to manage or prevent these associated complications of CLL. In this review, the authors discuss the data available and outline recommendations as to the best way to approach this issue in daily practice.

Introduction MDS has been linked to constitutive activation of genes involved in the nuclear factor-kappaB (NF-κB) pathway [Wei et al. Leukemia 2013; Braun et al. Blood 2006]. Hence, NF-kB is an attractive therapeutic target in this disease. Bortezomib is a proteosome inhibitor with inhibitory activity against NF-κB. We designed a phase II trial of SC bortezomib in patients with low- to intermediate (low/int-1)-risk MDS and evidence of NF-κB activation to determine its therapeutic activity in these patients. Methods In this single-arm phase II study in low/int-1-risk MDS patients, bortezomib was administered at 1.3 mg/m2 SC on days 1, 4, 8, and 11 in a 21-day cycle for a maximum of 2 years of therapy. Eligibility criteria included age ≥18 years, adequate performance status and organ function, and having received at least 1 prior therapy. Patients with grade 2 or greater peripheral neuropathy at baseline were excluded. Patients were prescreened prospectively for enrollment by assessing cellular levels of the phosphorylated NF-κB subunit p65 (pp65) in their marrow. This was performed by immunofluorescence with phospho-Ser276 in bone marrow aspirate smears in the Department of Hematopathology (CLIA regulations). Patients were eligible if at least 5% of all nucleated marrow cells were positive for pp65 staining. pp65 levels were assessed again on day 21 of cycles 1 and 2 and then as clinically indicated. Responses were assessed according to IWG [Cheson et al. Blood 2000; Cheson et al, Blood 2006]. The study could accrue a maximum of 40 patients if there were at least a 95% chance of at least a 15% ORR. Results Beginning 9/2013, we enrolled 15 patients with a median age of 71 years (range 56 - 87). Median marrow blast percentage was 1.9% (range 0 - 5%). Eleven patients (73%) had diploid cytogenetics, 2 had del(20q), 1 had Y-, and 1 had del(5q). All had lower-risk MDS by IPSS (low 33.3%, int-1 66.7%). All were transfusion dependent (6 both platelets and red cells (PRBCs), 1 only platelets, 8 only PRBCs). Hypomethylating agents had failed in 12 of the patients. At a median follow-up interval of 22 weeks, the ORR was 20%; 3 patients had hematologic improvement with a mean duration of response of 14.3 weeks (range 4-21). Eight patients had stable disease, and 4 had progression. No correlation between clinical response and molecular or cytogenetic data was observed. Eventually, all patients were taken off study: 7 due to increasing transfusion requirements, 2 worsening cytopenia, 1 lack of response, 1 increased blasts, and 1 grade 2 neuropathy; 2 withdrew by choice, and 1 patient died from causes unrelated to the study. Four patients experienced ≥ 1 grade 3 toxicity. No grade 4 toxicity was observed. Seven patients experienced grade 1 (n=4) or grade 2 (n=3) neuropathy. Morphologic review (n=14) in the responders group (n=3) showed reduction in ring sideroblasts (RS) in 2 patients (60 to 47% and 43% to 30%). Two patients, including 1 of those with reduced RS, had improvement of dysplasia (from severe trilineage dysplasia to moderate bilineage dysplasia). No changes in cytogenetic studies were found in the responder group. Among nonresponders (n=11), 3 had new acquired cytogenetic abnormalities, 3 had worsening dysplasia, and 2 had increase in blast count (1% to 3% and 1% to 4%). Two had no morphologic changes during treatment. One showed improvement in dysplasia and blast count (2% to 0%) and no changes in cytogenetics. Interestingly, 3 nonresponders showed RS reduction during treatment (18% to 1%, 85% to 45%, and 6% to 0%). The median pp65 level at baseline was 30.87% (range 7 - 70%). The pp65 level decreased in 7 of the 15 patients (46.7%), in 6 of them by the end of cycle 1. Interestingly, the 3 responders were among the 7 patients who had a decrease in pp65 level. Eventual loss of response in these patients was accompanied by return to a higher pp65 level. In nonresponders, the pp65 level increased in 7, decreased in 2, and remained unchanged in 1; for 1, the sample was suboptimal. Conclusions In previously treated lower-risk MDS patients, SC Bortezomib was well tolerated and resulted in hematologic improvement and decrease in RS. NF-κB activation, measured by pp65 level, can be a useful biomarker to select patients with lower-risk MDS who could benefit from therapies that target this pathway. The NF-κB pattern of expression suggests an inverse relationship between treatment response and NF-κB level, with associated improvement in bone marrow morphology. Disclosures Konopleva: Calithera: Research Funding; Cellectis: Research Funding. Cortes:ARIAD: Consultancy, Research Funding; Bristol-Myers Squib: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

Splenomegaly is a common sign of primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post-PV MF), and post-essential thrombocythemia myelofibrosis (post-ET MF) that is associated with bothersome symptoms, which have a significant negative impact on patients’ quality of life. It may also be present in patients with advanced polycythemia vera (PV) or essential thrombocythemia (ET). Until recently, none of the therapies used to treat MF were particularly effective in reducing splenomegaly. The discovery of an activating Janus kinase 2 (JAK2) activating mutation (JAK2V617F) that is present in almost all patients with PV and in about 50-60 % of patients with ET and PMF led to the initiation of several trials investigating the clinical effectiveness of various JAK2 (or JAK1/JAK2) inhibitors for the treatment of patients with ET, PV, and MF. Some of these trials have documented significant clinical benefit of JAK inhibitors, particularly in terms of regression of splenomegaly. In November 2011, the US Food and Drug Administration approved the use of the JAK1- and JAK2-selective inhibitor ruxolitinib for the treatment of patients with intermediate or high-risk myelofibrosis, including PMF, post-PV MF, and post-ET MF. This review discusses current therapeutic options for splenomegaly associated with primary or secondary MF and the treatment potential of the JAK inhibitors in this setting.

Background Erlotinib, a reversible TKI, is currently approved for the treatment of patients with locally advanced or metastatic NSCLC after failure of at least 1 prior chemotherapy. In addition to its EGFR inhibitory activity, erlotinib is a potent Syk inhibitor. Syk is frequently activated in AML and anecdotal reports have suggested that erlotinib can induce complete remission in patients with AML being treated for a concomitant non-small cell lung cancer. We thus assess the efficacy of Erlotinib in patients with relapsed / refractory AML. Patients and Methods This was a phase II, single-arm, open-label study. We enrolled 30 patients with refractory or relapsed AML between May 2013 and July 2014. Patients were >18yr, had ECOG PS £2, and adequate liver (total bilirubin £2x ULN, ALT ≤2.5x ULN) and renal (creatinine £2x ULN) function. They received erlotinib at a dose of 150 mg orally, once daily in 28-day cycles until clinically significant progression of the disease or unacceptable toxicity. Evaluation during treatment consisted of physical exam and assessment of adverse events; complete blood counts once weekly for the first 3 months, then every 2-4 weeks until 6 months of therapy. BM aspiration was performed on day 28 (± 7 days), then every 2-3 months for 1 year. Responders are patients who obtain a complete remission (CR), CR with incomplete hematologic recovery (CRi), or partial remission (PR), with or without cytogenetic response, hematologic improvement (HI), and morphologic leukemia free state (MLF). Results: Out of 30 enrolled patients, 29 (97%) were found eligible for evaluation on response. The median age was 67 yrs (range, 20-83) and patients had received a median of 2 prior chemotherapy regimens (range 1-6). Table 1 demonstrates patient’s characteristics. 1 patient (3%) achieved CR, and 2 patients (7%) had blast response (B; >50% reduction in blasts). Baseline blasts in BM decreased from a median of 58% (range 6-94) to a median of 37% (range 1-84) among patients who received 1 or more cycle of Erlotinib. Three (10%) patients had a decrease in bone marrow blasts of 50% or more (from 91% to 23%, 62% to 9% and 6% to 1%). Patients received therapy for a median of 29 days (range 12 to 142). The most common reason for treatment discontinuation was disease progression in 26 patients (90%). Treatment discontinuation before day 28 occurred in 12 patients (41%), in all cases due to disease progression. The most common treatment emergent adverse events were fatigue in 10 patients (32%), diarrhea in 10 (32%), nausea in 8 (26%), and rash in 7 (23%). Thirteen patients (42%) had neutropenic fever, all grade 3. Fourteen (45%) were hospitalized due to pneumonia, 5 of them requiring ICU care. One patient (6%) developed a subdural hematoma not related to study drug. The median Event-free survival (EFS) was 5 weeks (4.2-5.7) and Overall Survival (OS) 14 weeks (9.1-18.8) (Figure 1). 20 patients have died, 19 from progressive disease, and 1 from a cascade of events due to C. Diff infection. Conclusion Erlotinib has limited clinical efficacy in patients with AML. The occasional responses require further investigation (ongoing) to determine potential biomarkers that might identify patients who could benefit from use of erlotinib as part of their treatment. Table 1 PARAMETER Median(Range) Age years, median (range) 67 (20-83) Sex Male/Female, n(%) 17/12 (58.6/41.3) MEDIAN Range White Blood Cell Count (x 109/L) Median(Range) 2.20 (0.5-36) Hemoglobin (g/dL) 9.40 (8.2-12.4) ANC 0.25 (0.0-6.4) Platelets (x 109/L) 27.00 (8-138) Bone marrow blasts (%) 53.50 (6-94) Prior chemo regimens 2.00 (1-6) CYTOGENETICS Characteristic n(%) Diploid 8 (28) Complex 21 (72) Molecular Mutation n(%) FLT3 5 (17) IDH1 4 (13) IDH2 6 (19) NPM1 6 (19) KIT 2 (7) RESPONSE TO ERLOTINIB n % CR 1 3 PR 0 0 HI 2 7 Died on therapy 0 0 PD 19 61 Figure 1 Figure 1. Disclosures Off Label Use: Erlotinib as a treatment for Relapsed / Refractory AML. Cortes:OSI, Genentech: Research Funding.

Introduction: Alterations of innate immunity signaling and activation of NF-κB are known to occur in low/int-1-risk MDS (Braun, 2006, Wei, 2013). These suggest that modulation of NF-κB could be a therapeutic target in this group of patients. Bortezomib is a proteosome inhibitor with potential inhibitory activity against NF-κB. To determine whether bortezomib has therapeutic activity in lower-risk MDS patients, we designed a phase II trial of SC bortezomib in patients with lower-risk MDS and evidence of NF-κB activation. Methods: This was a single-arm phase II study of bortezomib in low/int-1-risk MDS patients. Bortezomib was administered at 1.3 mg/m2 SC on days 1, 4, 8, and 11 in a 21 day cycle for a maximum of 2 years of therapy. Eligibility criteria included age ≥18 years, adequate performance and organ function, and having received at least 1 prior therapy. Patients with grade 2 or greater peripheral neuropathy at baseline were excluded. Patients were then prescreened prospectively for enrollment by assessing cellular levels of the phosphorylated NF-κB subunit p65 (pp65) in their marrows. This was performed in bone marrow aspirate smears stained for immunofluorescence using an antibody against a phosphorylated form of NF-κB p65 (phospho-Ser276). This assay was performed in the Department of Hematopathology following CLIA regulations. Pp65 was considered positive if at least 5% of all the nucleated marrow cells were positive for pp65 staining. Subsequently, pp65 levels were assessed on day 21 of cycles 1 and 2 and then in subsequent marrows as clinically indicated. Responses were assessed according to IWG06. The study could accrue a maximum of 40 patients if there were at least a 95% chance of at least a 15% ORR. Results: Since 9/2013, we have enrolled 12 patients with a median age of 72 years (range 56 - 87). Median marrow blast percentage was 1.5% (range 1 – 5%). Nine patients had diploid cytogenetics, 2 had del 20q, and 1 had trisomy 8. All patients had low (2 patients) or int-1 (10 patients) disease. All were transfusion dependent (6 both platelets and red cells (PRBCs), 1 only platelets and 5 only PRBCs). Ten (83%) of the 12 had received prior hypomethylating agent (HMA) therapy. Thus far, patients have received a median of 3.5 cycles (range 1-12). Baseline median pp65 was 26.5% (range 7 – 70%). Five patients were taken off the study, 2 for disease progression and 3 for no response after a median of 3 cycles. Seven remain on study. No grade 3/4 toxicity and minimal grade 1/2 toxicity have been observed. No peripheral neuropathy has been observed. The median overall survival has not been reached. At a median follow up of 17 weeks, the overall response rate is 33% (3 HI-EP and 1 HI-N). Six patients have stable disease, and 2 had progression. One patient achieved red cell transfusion independence, going from PRBCs every 2 weeks to no transfusions after 2 cycles. All responders had been previously treated with an HMA. At day 21, the median pp65 level was 23% (0-70) and subsequently 22% (5-50) (all NS). Pp65 decreased by at least 50% in 5 patients, but it fell below 5% in only 2 patients. Two of the 5 patients with decreased levels of pp65 had a response to therapy. Of interest, the patient that achieved transfusion independence had a substantial decrease in pp65 (to less than 5%) that was lost (up to 56% pp65) when the patient lost hematological response. We also screened patients with a 28-gene mutation panel and found a MET, JAK2, or TET2 mutation in each of the 3 patients achieving a hematological improvement, a RUNX1 or CEBPA in each of the two patients with progressive disease, and an APC or ASXL1 mutation in each of the patients with stable disease. Conclusions: Bortezomib is well tolerated and results in hematological improvement in pretreated patients with lower-risk MDS. It is feasible to assess pp65 in serial bone marrow samples in this group of patients. Pp65 decreases in 40% of patients, and substantial decreases may be associated with response. This study suggests that it is possible to target patients for therapeutic intent using the NF-κB pathway as a biomarker. Disclosures No relevant conflicts of interest to declare.

Introduction High dose ionizing radiation and chemotherapy, particularly alkylating agents and topoisomerase II inhibitors, are well known causes of secondary acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). Similarly, radiation exposure has been linked to chronic myelogenous leukemia (CML) in large epidemiologic studies of atomic bomb survivors and patients who received high-dose radiation for ankylosing spondylitis and cervical cancer. Patients with secondary AML have poorer survival outcomes compared to de novo AML patients. Little information exists on outcomes of patients with secondary CML. In our study, we investigated treatment responses in patients with secondary CML who have been treated with tyrosine kinase inhibitors (TKIs). Study Design Eight patients who developed CML after receiving chemotherapy, radiation therapy or both were identified between three academic institutions. Retrospective chart review was performed, and information was collected regarding the clinical characteristics and treatment of the patients’ first malignancies. Data about the patients’ CML was also gathered, including time between previous malignancy treatment and diagnosis of CML and type of CML treatment. Finally, hematologic, cytogenetic, and molecular responses to treatment were assessed. Results The mean age of our patients at diagnosis of CML was 58. Three patients were previously diagnosed with breast cancer, two with colorectal cancer, one with peripheral T-cell lymphoma, one with chronic lymphocytic leukemia, and one with Waldenstrom’s macroglobulinemia. One of the patients with colorectal cancer also had a history of cervical cancer, for which she received radiation therapy. Six of eight patients (75%) received radiation therapy prior to onset of CML, and six of eight patients (75%) had previously received chemotherapy, two of whom received alkylating agents. On average, patients developed CML eight years after receiving treatment for the previous malignancy (range 3 to 18 years). All of the patients were diagnosed in chronic-phase CML. Based on the Sokal score, three patients (37.5%) had low risk CML, two (25%) had intermediate risk CML, one (12.5%) had high risk CML, and the Sokal score was unable to be calculated in two (25%) patients due to limited information. Six of the eight patients (75%) received imatinib as initial therapy. Only two of these six patients (33%) achieved a complete cytogenetic response (CCyR). The patient who received up-front nilotinib was the only patient who developed molecularly undetectable leukemia to initial therapy. Seven of the eight patients (87.5%) were alive at a mean four year follow-up. One patient had CML with additional cytogenetic abnormalities at diagnosis and progressed to blast-phase. Discussion This case series is the first study to specifically examine outcomes in secondary CML patients treated with TKIs. The data raise questions regarding the efficacy of imatinib in patients with secondary CML. Only two of the six patients who received imatinib achieved a CCyR. This is a significantly lower response rate than would be expected in de novo CML. This study suggests a role for the newer tyrosine kinase inhibitors as initial therapy in patients with secondary CML. Larger observational studies are needed to confirm these findings. Disclosures: No relevant conflicts of interest to declare.

Abstract 1880 AL is a clonal plasma cell disorder with a reported median survival (OS) of 13 months from diagnosis. Therapy involves suppression of amyloidogenic light chain production from clonal plasma cells. Hematological response (HR) is critical to improve organ function and survival. Autologous transplantation (AHCT) despite its risks, if performed in expert centers leads to rapid HR and organ function improvement. Those with poor Karnofsky performance score (KPS), multisystem disease or cardiac AL are poor candidates for AHCT. We assessed the efficacy of bortezomib (V) based combination therapy in newly diagnosed AL in a population with poor KPS or ineligible for AHCT. Among 35 consecutive newly diagnosed, biopsy proven AL patients (pts) since 2006, 29 pts received at least 2 cycles of V based therapy and were evaluable. Non evaluable pts (n=6) did not complete 2 cycles of therapy: liver function abnormalities (1), neuropathy (1); or early death (4 within 6 weeks of diagnosis). Two treatment protocols were used sequentially over this period. From 2006 – 4/2009, V twice weekly with dexamethasone weekly (VD) for 2 out of 3 weeks (n= 14) and thereafter weekly VD with cyclophosphamide (CVD) x3 on a q 4 week schedule (n=15). For complete or partial responses (CR/PR) after 6 cycles of therapy, V maintenance was administered every 2 weeks. Response evaluation was according to the 10th international AL symposium criteria. Results: Median age was 68 years (range 35–88 years; 55% female). Subtype of AL was lambda in 55%. KPS was less than 80 in more than 50%. Majority had 3 or more organs involved: 62% cardiac, 62% renal, 41% GI, 20% neurologic and 17% liver involvement. Cardiac stage was Mayo III in 50%. Hematological response (HR) was achieved in 86% including 34% CR and 52% PR. Among non-responders (14%), 2 have died after 2 cycles and 1 discontinued therapy. Median number of cycles to achieve a HR was 3 cycles (range, 1 to 9 cycles). CR was achieved after a median of 4 cycles for VD and 3 cycles for CVD. At median follow up of 22 mo (range 2–57 mo), median overall and progression free (PFS) survival have not been reached. Median OS for patients with cardiac involvement (n= 18) was 11 mo (range 2 – 29 mo). Among those with HR, 60% had at least one organ response including 44% renal and 55% cardiac responses. Among those with HR, 2 died following hematological progression; while 6 died of AL related organ failure. Half the deaths due to AL organ dysfunction were within the first 4 cycles. Median duration of response has not been reached. Hematopoietic cell harvest was successful in 41% (n=12) of which 4 pts completed consolidative AHCT. There was no difference in survival between those achieving CR vs. PR (log rank p = 0.5, Fig 1) or between recipients of CVD vs. VD (log rank p= 0.47 and Table 1). Therapy related non-hematologic adverse effects (all grades) included peripheral neuropathy (27%), gastrointestinal events with nausea, vomiting and diarrhea (17%), infections (3%) and blood clots (3%). Grade ≥ 3 toxicities were 3% and discontinuations/dose reductions resulting from toxicities were 10% and 3% respectively. Worsening of preexisting neuropathy was rare (2 pts out of 6). In this cohort of advanced multisystem AL with poor KPS; VD or CVD established rapid responses in 86%. In comparison with upfront AHCT, this approach has the advantages of lower toxicity, wider applicability and similar response time although durability of response is unknown at this time. Stem cell harvest was feasible when attempted. Addition of cyclophosphamide was well tolerated with the benefit of rapid onset of CR and allowed once weekly V without compromising efficacy. In good risk pts, AHCT should be compared against CVD in prospective randomized fashion. Disclosures: No relevant conflicts of interest to declare.

Abstract 1867 Poster Board I-892 Bortezomib has been shown to have significant activity in the suppression of light chain production and induction of responses in patients with relapsed refractory AL Amyloidosis. We analyzed the outcomes of 16 (9 male) newly diagnosed biopsy proven AL Amyloidosis patients treated with Bortezomib based regimens at our institution. All patients received initial therapy with Bortezomib and dexamethasone (dex). Patients with a Karnofsky performance score ( KPS) >70 received Bortezomib at starting doses of 1.3 mg/m2 along with dexamethasone 40 mg on days 1,4,8, 11 ( with a 10 day rest period). Patients with a lower KPS received Bortezomib/Dex on a weekly schedule as tolerated. Dose adjustments were made based on side effects such as neuropathy, hypotension, GI disturbances or electrolyte imbalances. Patients tolerating Bortezomib/dex with improvement in KPS had cyclophosphamide (4) or lenalidomide (1) added to their initial therapy. Patients: Median age was 64 years (39–88). Nine had kappa light chain involvement. Organ involvement was renal (73%), cardiac (63%), hepatic (25%), tongue or soft tissue (20%), GI (30%). Median KPS was 70 (50 –100). Ten of the 16 patients were treated as in-patients due to multi-organ dysfunction. Five patients required hemodialysis within a month of diagnosis. Cardiac involvement was stage 3 (Mayo risk group) in 25%. Three patients were unevaluable: 2 dying before 2 cycles and 1 discontinued therapy (Grade 3 liver dysfunction). Median follow up was 5 months (range 2–33 mo). Results: Evaluable (receiving at least 2 cycles) patients have all had a free light chain response. The overall hematological response rate was 100% with 55% partial remission (PR) and 45% complete remission (CR). Median cycles to achievement of a light chain response was 2 (range 1–4). Four patients underwent autologous stem cell transplantation with no mortality. Five (40%) of the responders have had an organ response (3 renal, 1 macroglossia, 1 cardiac) with only patients alive for >5 months having any evidence of organ response. Five (40%) of the evaluable patients have died with progressive cardiac involvement (2), relapsed disease (2) or renal failure (1) with refusal of dialysis. In patients receiving at least one dose of bortezomib, non-hematologic toxicity (>grade 2) included -neuropathy (20%), hypotension (20%), severe diarrhea (12%), sepsis (12%), paralytic ileus (6%), liver dysfunction (6%), sudden death (6%). Conclusions: Bortezomib in combination with dexamethasone has a high response rate in newly diagnosed AL amyloidosis. This regimen was well tolerated in a cohort of severe, multisystem amyloidosis patients with low treatment related mortality. Light chain responses were fast whereas organ responses were not seen prior to 5 months of therapy. The regimen also served as a platform for further intensification with the addition of lenalidomide, cyclophosphamide or autologous transplant in responders. Disclosures: Off Label Use: Bortezomib for the therapy of amyloidosis. Hari:Millenium: Honoraria, Research Funding.

Abstract 4157 Introduction Hypomethylating agents (HMAs) are effective in inducing remission in myelodysplastic syndrome (MDS). Limited data suggests that these agents are effective in the therapy of patients with AML. A single center retrospective analysis was done to assess the response to HMAs (azacitidine or decitabine) in patients with AML in our institution. Patients and Methods We retrospectively reviewed all AML patients treated with either azacitidine (AZA) or decitabine (DAC) from 1/1/05 to 7/1/09. Responses were defined according to the 2003 International Working Group criteria into complete remission (CR), partial response (PR) and no response (NR). In addition some patients achieved a hematological improvement (HI) according to the modified IWG criteria for response in MDS without satisfying any of the AML response criteria. We also describe those patients as they did have clinical benefit. The overall survival (OS) was determined using the Kaplan Meier method. Patients were censored at the time of stem cell transplantation (SCT). Of the 24 patients identified, 11 were female, and 12 had not received previous treatment. All 12 previously untreated patients either refused or could not tolerate induction chemotherapy. The median age of all patients was 69. The median follow up time from start of the HMA was 196 days. 5 patients were treated with AZA, 13 with DAC and 5 patients received treatment with both HMAs sequentially. Of the 5 pts who underwent SCT, 1 received the HMA after SCT for relapse, and 4 had the SCT after induction treatment with HMAs. Of those 4 pts, 2 were previously untreated and all 4 patients achieved CR prior to SCT. The cytogenetic risk categories were good (2 patients), intermediate (10 patients) and poor risk (10 patients). The median and range for WBC, hemoglobin and platelets at the time of diagnosis was: 5 × 109/L (0-850), 7 gm/dl (5-12) and 77 × 109/L (13-357) respectively. Of the 21 patients evaluable for response, 7 (33%) achieved CR, 1 (4%) CRp (CR without platelet recovery), and 2 (9.4%) HI. The median number of cycles was 3.5 (range 1-23). Of the 8 patients who achieved CR/CRp, 4 had poor risk cytogenetics and 4 were previously untreated. One patient with inversion 16 was refractory to 2 chemotherapy regimens and achieved CR with DAC. The median overall survival (OS) was 366 days, 542 and 366 days for the whole group, previously treated and previously untreated patients respectively. None of the patients died from treatment related complications. The median OS was not reached for patients achieving a CR (range 206 days to 769 days) and was 149 days (range 43-664) for patients with no response. Of the 5 pts who received both HMAs, one patient achieved CR with the second agent. Conclusions Hypomethylating agents are active in newly diagnosed and refractory AML with no treatment related mortality in our institution. The results compare well with other regimens in the treatment of relapsed/refractory AML (25% response rate). Some patients may benefit despite not achieving the IWG defined response criteria. Randomized studies comparing hypomethylating agents to standard therapy in patients with AML will be open soon. Disclosures: Bredeson: Esai: Honoraria. Atallah:Celgene: Honoraria.