ALBERT

Description: B ackground: Current therapies for CLL/SLL have frequent toxicities, are non-curative, and several trials have demonstrated that early treatment of the disease doesn't result in longer overall survival. In high doses, both curcumin (CM), from turmeric, and vitamin D (VD) have been shown to be safe in multiple clinical trials of solid tumors. Curcumin was shown to disrupt CLL cell interactions with the microenvironment, induce apoptosis independent of DNA damage, and upregulate vitamin D receptor (VDR) in malignant lymphoid cells. We hypothesized that the combination of CM and VD is safe and active in CLL/SLL and would delay disease progression. Methods: This was an open-label phase II trial for previously untreated patients with asymptomatic,Rai stage 0-II CLL/SLL not currently meeting National CancerInstitute Working Group (NCI-WG) Criteria for treatment. All patients received 8 gm of CM and 10,000 IU of vitamin D3 (VD) orally daily. VD was started 1 week after CM and both agents were maintained for up to six 4-week cycles. The primary endpoint was the overall response rate (ORR) based on NCI-WG criteria. Secondary endpoints were event-free (EFS), overall survival (OS), and time to next treatment (TTNT). VD-25-OH and CM major metabolites; CM glucuronide (COG) and CM sulfate (COS), were measured in plasma by liquid chromatography-tandem mass spectrometry. Phosphorylated-NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), a validated pharmacodynamic marker of CM activity, as well as VDR, were measured in CLL cells by flow cytometry. Results: A total of 35 patients (pts), 51% males, were accrued to the trial, 30 (86%) were evaluable for response. Median age was 60 years (range 45-80). Most had CLL (97%); 51% were Rai stage 0 and 49% were Rai stage 1. Cytogenetic abnormalities included del13q14 (37%), trisomy 12 (11%), del 11q22 (11%) and del 17p (3%); 20% had ZAP-70 levels 〉20%. Median number of cycles received was 5 (range 1-6) and treatment was well tolerated overall. The most frequent adverse effects (AE) were diarrhea/gastrointestinal upset in 69% of patients (14% were grade 3). No serious AEs were observed. Eighteen pts (51%) completed all 6 cycles of treatment; 10 (29%) withdrew consent, 4 (11%) discontinued treatment because of diarrhea, and 3 (9%) patients progressed on treatment. Best response was stable disease in 28/30 (93%) evaluable pts. After a median follow up of 29 months, EFS was 72.0% (95% CI 52.1 - 84.7%), 74.1% (95% CI 58.7-89.6%) had not started new CLL treatment, and OS was 100%. Median VD-25-OH levels were 28.75ng/ml (range 12.5-55.6) at baseline and 49.5 ng/ml (24.8-69) at 28 days. Median COG/COS levels were 15.8 (2.73-75)/6.71(0-33.5) and 18 (0-75.9)/7.21(0-35.2) ng/ml at 8 and 28 days, respectively. Flow cytometric analysis of CLL cells showed no significant change in VDR or Phosphorylated-NF-κB with CM-VD treatment. Conclusion: Curcumin and high-dose vitamin D combination is safe and well tolerated in patients with early stage CLL. Although no responses were seen, the majority of patients maintained stable disease on treatment. Longer follow up is planned on this study to determine long - term CLL progression rates of patients treated with CM-VD. Disclosures Afable: Eli Lilly: Employment. Lazarus:Pluristem Ltd.: Consultancy. Nagabhushanam:Sabinsa Corporation: Employment. Grote:BTR Group Inc: Employment. Kunati:Symrise AG: Employment.

Description: Venous thromboembolic events (VTE) are common after the diagnosis of lymphoma. Although various risk factors have been associated with VTE in cancer patients, there is no specific VTE risk prediction score for diffuse large B cell lymphoma (DLBCL) patients. The Khorana score is a prediction-model of VTE in cancer patients receiving chemotherapy that incorporates clinical and laboratory parameters. We evaluated the risk factors for VTE, the effect of VTE on the outcomes of DLBCL patients and the utility of the Khorana score in DLBCL patients. Methods: We searched the Hematologic Malignancies Database of University Hospitals Seidman Cancer Center for newly diagnosed DLBCL patients between 2002 and 2014. Data on patient characteristics including risk factors, disease characteristics, treatment, outcomes and VTE was collected. The Khorana score was calculated using clinical (disease type, body mass index) and laboratory (hemoglobin level, platelet and leukocyte count) parameters. Risk factors identified as having statistical significance on univariate Cox proportional hazards analysis (p 12g/dL), increased white cell count (〉11,000/mcl), hemoglobin (800/mcl) and chromosomal translocations involving MYC presented statistically significant increases in hazard of VTE (Table 2). On multivariate analysis only bone involvement (p=0.017) and anemia (p=0.035) retained statistical significance as risk factors for VTE. Three-year OS for patients presenting with VTE within 1 year of DLBCL diagnosis was 46.7 % (95% CI 30-63.3) vs. 72.3% (95% CI 67.4-77.3) in subjects without early VTE (p=0.05) (Figure 2). Presence of VTE at any time after DLBCL diagnosis was also associated with worse OS rates, with estimated 3-year OS of 52.2 % (95 % CI 39.8-64.7) for subjects experiencing VTE and 74 % (95 % CI 69-79) for those without VTE after DLBCL diagnosis (p

Description: Background: Patients (pts) diagnosed with non-Hodgkin lymphoma (NHL) have increased risk of venous thromboembolic event (VTE). Retrospective studies have observed the risk of VTE is not the same across lymphoma subtypes, with aggressive subtypes having higher risk than indolent lymphomas. Current VTE prediction models such as the Khorana score (K-Score) consider all lymphomas as having equal risk of VTE. We conducted retrospective time - based analyses to develop a VTE prediction model that includes lymphoma subtype as a risk factor. Methods: We accessed the Hematologic Malignancies Database at University Hospitals Seidman Cancer Center and collected records of pts diagnosed with diffuse large B cell lymphoma (DLBCL) or follicular lymphoma (FL) between 2000 and 2016. Pts with CNS involvement or active anticoagulation were excluded. FL grade 3B pts were included in the DLBCL cohort. Information retrieved included demographic characteristics, baseline disease and laboratory parameters, as well as comorbidities and diagnosis of VTE, including radiographic confirmation. Time to VTE was measured from the date of NHL diagnosis to the date of VTE incidence or censored at the date of last follow-up for those without VTE. Cumulative incidence of VTE was estimated using Kaplan-Meier method and its difference among groups was examined by log-rank test. Cumulative incidence of VTE was also calculated considering death as competing risk and comparisons done using the Gray test. Cox proportional hazards model was used to evaluate the effect of continuous and categorical covariates on cumulative incidence of VTE and to identify prognostic factors of VTE. Fifty percent of the study participants were randomly assigned to training cohort or reserved as an independent validation cohort. Performance of multivariate models was evaluated using the Akaike Information Criterion (AIC) and Concordance Index (C-Index). The final models built using the training dataset were further validated using the validation cohort. All tests are two-sided and p-values ≤ 0.05 were considered statistically significant. Results: We identified 627 pts with DLBCL (n=421) or FL (n=206) with available baseline characteristics, (Table 1). After a median follow up of 48 months (range 1-191), 77 pts experienced a VTE after NHL diagnosis. The cumulative incidence of VTE at 4 years for the whole cohort was 10.5% (95% CI 8.3-13.2). DLBCL pts had a significantly higher 4 - year cumulative incidence of VTE: 13.7% (95% CI 10.8-17.5) vs. 4.0% (95% CI 2.0 - 7.9) in FL pts (p

Description: Introduction: CD25 is expressed on the cell surface of many lymphomas, including classical Hodgkin lymphoma (cHL) and non-Hodgkin lymphoma. ADCT-301 (camidanlumab tesirine [Cami-T]) is an antibody drug conjugate comprising a human monoclonal antibody against CD25 conjugated to a potent pyrrolobenzodiazepine dimer (PBD) toxin. We report here a first-in-human clinical trial of Cami-T, focusing on patients (pts) with relapsed/refractory (R/R) cHL treated in dose-escalation and subtype-specific dose-expansion cohorts. Methods: This was a Phase 1, open-label, dose-escalation and dose-expansion multicenter study in pts with R/R cHL. The objectives of the study were to assess the safety and tolerability, determine the recommended dose(s) for expansion, and evaluate pharmacokinetics and pharmacodynamics. The clinical activity of Cami-T was measured by overall response rate (ORR; per 2014 Lugano Classification), duration of response (DoR), progression-free survival (PFS), and overall survival. Pts received Cami-T intravenously every 3 weeks (Q3W; 1 Cycle). Dose escalation was performed according to a continual reassessment method. Results: As of June 15, 2018, 60 pts with cHL have been enrolled. Baseline characteristics include median age: 38.5 years (range 19-80); median number of prior therapies: 5 (range 2-15). Cami-T doses ranged from 5 to 300 µg/kg (median number of cycles: 3 [range 1-15], with a median treatment duration of 43 days [range 1-354]). Treatment-emergent adverse events (TEAEs) were reported in 57/60 (95%) pts; most common TEAEs (≥20%) were fatigue (25, 41.7%), maculopapular rash (20, 33.3%), increased gamma-glutamyltransferase (GGT; 18, 30%), pyrexia (18, 30%); increased alanine aminotransferase (ALT; 14, 23.3%), dyspnea (13, 21.7%), nausea (13, 21.7%), increased aspartate aminotransferase (AST; 12, 20.0%), increased blood alkaline phosphatase (ALP; 12, 20.0%), and cough (12, 20.0%). As part of immune-related AEs, there were 2 (3.3%) cases of Guillain-Barré syndrome (1 each at dose 45 and 60 µg/kg) and 1 (1.7%) case of thyroiditis. Also, there were 16 (26.7%) cases of peripheral edema or effusion, which are AEs thought to be associated with PBDs. Grade ≥3 TEAEs occurred in 37/60 (61.7%) pts; the most common Grade ≥3 TEAEs (≥5% of pts) were liver function abnormalities (increased GGT [16.7%], ALT [10.0%] AST [5.0%], and ALP [5.0%]), maculopapular rash (13.3%), anemia (8.3%), and decreased platelet count (5.0%). TEAEs leading to treatment discontinuation occurred in 17/60 (28.3%) pts. Most pts (72%) tolerated at least 3 cycles before an AE leading to a dose reduction/delay occurred. Exposure to the conjugated antibody was dose-related and at a ≥45 µg/kg dose was sustainable throughout the dosage interval at a mean concentration of 0.0826 µg/mL (coefficient of variation [CV] 49.9%) and mean minimum concentration of 0.0092 µg/mL (CV=81.7%; n=25). The maximum tolerated dose was not reached; however, the recommended dose for expansion was identified as 45 µg/kg Q3W. Response data for 55 evaluable pts with cHL are shown in the Table. The ORR was 69.1% (38/55 pts) and the complete response (CR) rate was 43.6% (24/55 pts). In the 45 µg/kg dose group (dose escalation + expansion), the ORR was 80.8% (21/26 pts) and the CR rate was 50% (13/26 pts) (Table). ORRs by prior treatment were 80.8% (21/26) in pts who previously received brentuximab vedotin (BV), 80.0% (12/15) in those who previously received both a checkpoint inhibitor (CHPi) and BV, 81.8% (9/11) in those who had a prior hematopoietic cell transplant (HCT), and 85.7% (6/7) in those who had a prior CHPi, BV, and HCT. Median DoR and PFS were 7.7 and 6.7 months, respectively (Figure). Conclusions: In pts with R/R cHL, therapy with Cami-T provided impressive ORRs and CR rates in a heavily pretreated pt population. A 45 µg/kg dose of Cami-T was identified as having optimal activity with an acceptable safety profile. Enrollment of pts with HL is now complete and initial response data for all pts with HL will be available later this year. This data supports further investigation in a planned Phase 2 study. Study sponsored by ADC Therapeutics. http://clinicaltrials.gov/show/NCT02432235. Disclosures Hamadani: Celgene Corporation: Consultancy; Cellerant: Consultancy; Janssen: Consultancy; ADC Therapeutics: Research Funding; Ostuka: Research Funding; MedImmune: Consultancy, Research Funding; Merck: Research Funding; Takeda: Research Funding; Sanofi Genzyme: Research Funding, Speakers Bureau. Collins:BMS: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; MSD: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Celgene Corporation: Research Funding; Amgen: Research Funding; Gilead: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau; Celleron: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Samaniego:ADC Therapeutics: Research Funding. Spira:AstraZeneca: Consultancy; AbbVie: Consultancy; BMS: Consultancy; Roche: Consultancy; ADC Therapeutics: Research Funding. Davies:GSK: Research Funding; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ADC Therapeutics: Research Funding; Pfizer: Research Funding; Gilead: Honoraria, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Consultancy. Radford:ADC Therapeutics: Consultancy, Research Funding; Celgene: Research Funding; Pfizer: Research Funding; Takeda: Consultancy, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Speakers Bureau; AstraZeneca: Equity Ownership; Novartis: Consultancy, Speakers Bureau; GlaxoSmithKline: Equity Ownership; BMS: Consultancy, Speakers Bureau. Caimi:Celgene: Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Menne:ADC Therapeutics: Research Funding; Amgen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau. Boni:ADC Therapeutics: Employment, Equity Ownership. Cruz:ADC Therapeutics: Employment, Equity Ownership. Feingold:ADC Therapeutics: Employment, Equity Ownership. He:ADC Therapeutics: Employment, Equity Ownership. Wuerthner:ADC Therapeutics: Employment, Equity Ownership. Horwitz:Portola: Consultancy; Corvus: Consultancy; Mundipharma: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Trillium: Consultancy; Aileron Therapeutics: Consultancy, Research Funding; Spectrum: Research Funding; Kyowa-Hakka-Kirin: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Innate Pharma: Consultancy; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Forty Seven: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding.

Description: Background: BL is associated with a high risk of primary or secondary CNS involvement, warranting intrathecal (IT) and/or systemic therapy that penetrates the blood-brain barrier (BBB). The lower-intensity DA-EPOCH-R regimen has recently shown high survival rates in BL (Dunleavy, NEJM 2013), but it omits drugs traditionally used for CNS prophylaxis (like high-dose methotrexate [HDMTX]). The objective of this multi-institutional retrospective study was to examine treatments, risk factors, and CNS-related outcomes among patients (pts) with BL. Methods: We collected data from 26 US centers on adult BL pts diagnosed (dx) in 6/2009-6/2018. Using institutional expert pathology review and 2016 WHO criteria, we excluded other high-grade lymphomas (including BL-like/unclassifiable), or cases with inadequate clinicopathologic data. We studied factors associated with baseline CNS involvement (CNSinv) using logistic regression reporting odds ratios (OR). Progression-free (PFS), overall survival (OS), and cumulative incidence function of CNS recurrence (in a competing risk analysis) were examined in Cox or Fine-Gray models reporting hazard (HR) or subhazard ratios (SHR), respectively. All estimates report 95% confidence intervals (in square brackets). Results: Among 557 BL pts (median age, 47 years [yr], 24% women, 23% HIV+), 107 (19%) had CNSinv at dx, including 89 (16%) with leptomeningeal, and 15 (3%) with parenchymal CNS disease. In a multivariable model, factors significantly associated with CNSinv at dx included stage 3/4 (OR, 11.2 [1.47-85.9]), poor performance status (PS; OR, 2.12 [1.22-3.69]), ≥2 extranodal sites (OR, 3.77 [2.02-7.03]), or marrow involvement (OR, 2.44 [1.35-4.39]), whereas intestinal involvement conferred low risk of CNSinv (OR, 0.27 [0.11-0.65]). CNSinv at dx was not significantly associated with use of specific chemotherapy regimens (Fig. A,P=.75) or receipt of IT chemotherapy (91% vs 84%, P=.065). Pts with CNSinv were less likely to achieve a complete response (62% vs 76%, P=.005), had worse 3 yr PFS (47% vs 69%; P3x]; see Evens AM et al, ASH 2019 for further details). With median follow up of 3.6 yrs, 33 pts (6%) experienced a CNS recurrence (82% within 1 yr from dx; 79% purely in CNS, and 21% with concurrent systemic BL). The cumulative risk of CNS recurrence was 6% [4-8%] at 3y (Fig. D). Univariate significant predictors of CNS recurrence included baseline CNSinv, HIV+ status, stage 3/4, poor PS, LDH〉3x, involvement of ≥2 extranodal sites, marrow, or testis. However, in a multivariate model only baseline CNSinv (SHR, 3.35 [1.53-7.31]) and poor PS (SHR, 2.24 [1.03-4.90]) retained significance. The 3 yr risk of CNS recurrence varied from 3% for pts with no risk factor, to 10% with one, and 17% with both factors (Fig. E). In addition, the risk of CNS recurrence differed according to chemotherapy regimen, and was significantly higher for pts treated with DA-EPOCH (12% at 3y [8-18%]; Fig. F) compared with CODOX-M/IVAC (4% [2-8%]) or hyperCVAD/MA (3% [1-6%]; SHR for DA-EPOCH vs. others, 3.50 [1.69-7.22]). All pts recurring after DA-EPOCH had received IT chemotherapy. Higher risk of CNS recurrence persisted with DA-EPOCH regardless of baseline CNSinv (Pinteraction=.70), poor PS (Pint=.14), or HIV status (Pint=.89). Baseline CNSinv was the strongest factor associated with CNS recurrence after DA-EPOCH (3 yr risk, 30% vs 8%, P

Description: Background: Autologous hematopoietic cell transplant (HCT) is frequently used to treat plasma cell dyscrasias. High-dose melphalan is the most commonly utilized preparative regimen. Frequently seen non-hematologic adverse effects include oropharyngeal mucositis and GI toxicity. Reported incidence rate of overall and severe (grade 3-4) mucositis is 60-90% and 30-40%, respectively. Amifostine is a thiol derivative, which has been used for protection of normal tissues in radiation and chemotherapy. Amifostine has a relatively safe profile with hypotension, nausea, vomiting and diarrhea (N/V/D) as main side effects. We explored the efficacy of amifostine to reduce overall incidence and severity of mucositis after high-dose melphalan therapy. Methods: We conducted a retrospective study of 126 autologous HCT (110 patients) with high-dose melphalan performed from January 2007 to July 2014 at our center for plasma cell myeloma. Twelve patients underwent tandem transplants and four had second autologous transplants after relapsed disease and were excluded from survival analysis. Patients' characteristics (n=110) as listed in Table 1. All but one patient received two doses of Amifostine given as 740 mg/m2 IV bolus on days T-2 and T-1. Melphalan was administered as IV bolus on T-1 at the dose of 200 mg/m2, except for 4 patients who received 140 mg/m2 due to impaired renal function. All patients received ice chips peri-melphalan infusion. All patients received cryopreserved autologous hematopoietic cell infusion on T-0. We graded mucositis and GI toxicities as per CTCAE v4.0 and recorded patient controlled analgesia (PCA), total parenteral nutrition (TPN), transplant and disease outcomes. Results: Severe (grade 3-4) mucositis and diarrhea rates were 14% and 12%, respectively (Table 2). PCA was used in 10% of transplants at a mean duration of 0.9 days and TPN was utilized in 5% of transplants for a mean duration of 0.45 days. Median length of stay for transplant was 15 days (range 3-44 days). Median time to neutrophil and platelet engraftment was 10 and 19 days, respectively (Table 3). Three patients died within 100 days after transplant (2 due to infections and 1 due to renal amyloidosis). At a median follow up of 39 months, median PFS is 25 months and OS is greater than six years. All patients were able to receive amifostine at prescribed doses except for one patient who received only one dose due to intractable N/V/D. Conclusion: Amifostine is effective in reducing high-dose melphalan-induced severe mucositis. Our data would suggest a decrease in severe mucositis and GI toxicity rates when compared to historically reported incidences. In addition, amifostine does not appear to have a deleterious effect on engraftment and/or survival and response rates (Table 3). Table 1. Patients characteristics Median Age (years) 59 (36-71) Gender (%) Male 54Female 46 Performance status (ECOG) 1 (0-2) Median time to transplant from diagnosis (years) 0.97 Median number of treatment regimens prior to transplant 2 (1-6) Response prior to transplant (%) Partial remission (PR)Very good partial remission (VGPR)Complete remission (CR)Stable disease (SD) 60%21%18%0.8% Table 2. Toxicity Overall (grade 1-4) Severe (grade 3-4) Median grade Median Duration (days) Mucositis 55% 14% 2 2 Diarrhea 92% 12% 2 7 Nausea 89% 4% 1 8 Vomiting 67% 3% 1 2 Table 3. Engraftment and post-HCT disease response Engraftment Median (days) Range (days) Neutrophils 10 6-21 Platelets 19 8-71 Post-HCT disease responses (%) Stringent complete response (sCR) 13% Complete response (CR) 32% Very good partial response (VGPR) 24% Partial response (PR) 25% Not evaluated 6% Disclosures Off Label Use: Amifostine use to prevent mucositis.

Description: Background: Bendamustine plus rituximab (BR) is an effective front-line treatment for chronic lymphocytic leukemia (CLL). Immunosuppression induced from disease- and/or treatment-related factors can frequently result in infectious complications, including varicella zoster virus (VZV) reactivation. Antiviral prophylaxis is not universally prescribed for these patients and the duration of treatment is not well defined. We therefore retrospectively reviewed the incidence of VZV reactivation and the impact of antiviral prophylaxis on this complication in CLL patients treated with front-line BR. Methods: We reviewed charts of 82 consecutive CLL patients with adequate clinical follow-up who were treated a median of 5 cycles with front-line BR at the Cleveland Clinic and University Hospitals of Cleveland from December 2005 to February 2015. Patients were grouped as having received antiviral prophylaxis or not. Baseline characteristics were compared between groups using the Chi-square test or Wilcoxon rank sum test. VZV reactivation from the start of front-line therapy was estimated using the cumulative incidence method and compared using the Gray test. Univariable prognostic factors for VZV reactivation were identified with Fine and Gray regression. The number of patients who reactivated was too small for multivariable analysis. All analyses were done using SAS software (SAS Institute Inc., Cary, NC, USA). All statistical tests were two-sided and P 〈 0.05 was used to indicate statistical significance. Results: The median age of patients at the time of BR treatment was 69 years (range 44-93 years). 71% were male. Median follow-up was 1.5 years. 23 patients (28%) received antiviral prophylaxis, 20 acyclovir and 3 valacyclovir. The median duration of antiviral prophylaxis was 8.8 months. Patients who received antiviral prophylaxis were more likely to have had a history of VZV than those who did not receive prophylaxis (17% vs. 0%, P = 0.001). Additionally, patients who received antiviral prophylaxis were more likely to have received prior Zostavax compared to those who did not receive prophylaxis (22% vs. 5%, P = 0.022). All other baseline demographics including age, gender, ECOG PS, Rai stage, and cytogenetics were similar between the groups. 7 patients (8.5%) reactivated VZV following front-line BR therapy. Of the 7, 4 received antiviral prophylaxis with acyclovir and 3 did not receive prophylaxis (P = 0.20). Only one patient who reactivated VZV did so after receiving second line therapy. None of the patients who reactivated had a prior history of zoster activation. Notably, patients who received antiviral prophylaxis and reactivated VZV did so more than 6 months from the time of BR initiation, with reactivation occurring greater than 3 years after the start of front-line BR. [Figure 1] Conclusions: CLL patients who receive front-line BR are at risk for VZV reactivation regardless of antiviral prophylaxis. History of VZV did not predict the likelihood of viral reactivation. Patients who received prophylaxis and experienced VZV reactivation did so more than 6 months from treatment initiation. These data suggest that when given to CLL patients receiving front-line BR, a standard 6-8 month regimen of VZV prophylaxis is insufficient. Rather, prolonged prophylaxis extending years after treatment completion may be more appropriate to prevent VZV reactivation. Further prospective studies are required to further explore this benefit. Figure 1. Incidence of VZV reactivation over time in CLL patients treated with front-line BR who received antiviral prophylaxis. Figure 1. Incidence of VZV reactivation over time in CLL patients treated with front-line BR who received antiviral prophylaxis. Disclosures Smith: celegene, spectrum, genentech: Honoraria. Hill:Pfizer: Consultancy, 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; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Description: Proteasome inhibitors (PIs) capitalize on the constitutive activation of NF-KB in AML cells and increase chemosensitivity to anthracyclines and cytarabine. We combined the second generation PI, ixazomib, with the standard AML salvage regimen of MEC (mitoxantrone, etoposide, cytarabine). The primary objectives of this study were to determine the dose limiting toxicity (DLT), maximum tolerated dose (MTD), and phase 2 dose of ixazomib in combination with MEC in relapsed/ refractory (R/R) AML. Secondary objectives included evaluating the efficacy of this combination and correlating response to the gene expression profile and CD74 expression, which may identify a subset of leukemias in which NF-KB is operative with increased sensitivity to PI (Attar et al. CCR 2008; 14: 1446-54). Methods: Patients (pts) were treated at Cleveland Clinic and University Hospitals of Cleveland from Oct 2014 to present. An IND was approved by the FDA, and the protocol was approved by each institutional review board. Eligibility: age 18-70 yrs, R/R AML, and cardiac ejection fraction ≥ 45%. The fraction of blasts positive for CD74 was assessed by flow cytometry. Samples were stored for gene expression profiling pre- and post-treatment (at the time of response assessment). Pts received MEC: mitoxantrone (8 mg/ m2), etoposide (80 mg/m2), and cytarabine (1000 mg/m2) intravenous (IV) Days 1-6. Ixazomib, provided by Takeda, was given orally on Days 1, 4, 8, and 11 and was dose escalated using a standard 3x3 design. Dose levels (DLs): 1 (1.0 mg), 2 (2.0 mg), 3 (3.0 mg), 4 (3.7 mg). An additional 18 pts were to be treated at the MTD. One cycle of treatment was administered. Response was assessed by bone marrow aspirate/ biopsy by Day 45 and complete remission (CR) was defined by IWG criteria (Cheson 2006). Toxicities were graded according to NCI CTCAE v 4.03. Toxicities secondary to neutropenia or sepsis were not considered DLTs. DLTs included: (1) ≥ Grade 4 non-hematologic toxicity (NHT) with the exception of nausea, vomiting/ alopecia and drug-related fevers; (2) any ≥ Grade 3 neurologic toxicity; (3) grade 4 platelet or neutrophil count 50 days beyond the start of chemotherapy and not related to leukemia; (4) any Grade 4 NHT 〉 grade 2 by 45 days beyond the start of chemotherapy. Grade 2, 3, and 4 hyperbilirubinemia were redefined as 1.5-〈 10x upper limits of normal (ULN), 10-20 x ULN, and 〉 20 x ULN. Results: Of 23 pts enrolled, 22 are evaluable. The median age was 58 yrs (range 31-70), 12 (52%) were male and the median baseline WBC was 2.56 K/ uL (range 0.1-62.9). The median time from initial diagnosis to registration was 7.1 months (range 1.4-36.8) and 7 pts (30%) had a history of an antecedent hematologic disorder. Thirteen pts were in 1st relapse and 10 pts were refractory to their last therapy. One pt had received a prior allogeneic hematopoietic cell transplant (AHCT), 7 pts had FLT3 ITD mutations and 7/ 21 pts (33%) had adverse cytogenetics per CALGB 8461 criteria at the time of relapse. At DL1, 1 DLT occurred (grade 4 thrombocytopenia), so this DL was expanded to 6 pts. At DL2, 2 pts developed Grade 4 thrombocytopenia; therefore, the MTD of ixazomib was 1.0 mg. The most common grade 3-5 NHTs in the dose escalation phase were febrile neutropenia (100%), hypoalbuminemia (25%), hypokalemia (42%), hypotension (33%), and respiratory failure (33%). No adverse events in the dose escalation phase were attributed to ixazomib alone. The overall response rate was 55% [CR/ CR with incomplete count recovery (CRi)], and 9 pts proceeded to AHCT. Five of these 9 pts remain alive with a median follow-up of 12.8 months. Five pts had CD74 expression performed. Two pts had high levels of CD74 expression (〉 80%); and both achieved CRi. Myeloid mutation panel data was available in 14 pts. Previous data has demonstrated the number of mutations in DNTMT3A, TP53, ASXL1, and NRAS (0, 1, 〉1) is associated with a worse response to salvage therapy (Advani et al, abstract 3825, ASH 2015). Seven pts had at least one of these mutations and 6 of the 7 achieved CR/ CRi. Conclusions: The combination of MEC and ixazomib was well-tolerated and produced an overall response rate of 55% in patients with relapsed/ refractory AML irrespective of molecular mutation status. The combination is safe with a similar toxicity profile to MEC alone. CD74 expression may represent a biomarker for response to this therapy. Results from gene expression profiling will be complete by the time of the meeting and will be presented. Disclosures Mukherjee: Novartis: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Caimi:Genentech: Speakers Bureau; Gilead: Consultancy; Roche: Research Funding; Novartis: Consultancy. Maciejewski:Alexion Pharmaceuticals Inc: Consultancy, Honoraria, Speakers Bureau; Apellis Pharmaceuticals Inc: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Speakers Bureau. Sekeres:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.