Witzig, Thomas E.

8556 Background: In the original PARMA trial it was demonstrated that salvage chemotherapy with DHAP followed by autologous bone marrow transplant resulted in increased overall survival over salvage chemotherapy with DHAP alone in patients with aggressive lymphomas. The current study was designed to assess safety and feasibility of ROAD as a salvage chemotherapy regimen which could be administered as an inpatient or outpatient. Methods: Patients received immunochemotherapy on the following schedule: rituximab 375 mg/m2 weekly × 4, oxaliplatin 130 mg/m2 on day 2, Ara C 2000mg/m2 x 2 doses on day 2 and dexamethasone 40 mg on days 2–5, with OAD repeated at 3 week intervals (up to 6 cycles). Patients were considered for autologous stem cell transplantation after 2 cycles if eligible. Eligible histologies included diffuse large B cell lymphoma, mantle cell lymphoma and transformed lymphoma in first relapse. Results: 50 patients were accrued from Aug 2006 through Jul 2008: 5 patients were deemed ineligible after central pathology review. Baseline characteristics of eligible patients included median age 69 (range 23 - 77), 53% were male, 53% had advanced stage at relapse, LDH was elevated in 58% and all patients had an ECOG PS of 2 or less. Patients received a median of 2 cycles of therapy (range 1–6) with 39/45 receiving treatment in cycle 2, with 12 patients continuing beyond 2 cycles. 31 patients experienced grade III/IV hematologic toxicity and 22 patients had grade III/IV non-hematologic toxicity, primarily febrile neutropenia. One patient developed grade III nephrotoxicity due to disease progression. Twenty patients received their treatments exclusively as outpatients. 26 responses were seen in the 45 eligible patients (58%, 95% CI: 44–74%), with 20 responding patients proceeding to autologous SCT. Conclusions: ROAD is a safe and effective salvage chemotherapy regimen for relapsed aggressive lymphoma, including as a preparatory regimen prior to stem cell transplant. It appears to have similar response rates to R-DHAP in a similar patient population, but without the potential nephrotoxicity (data from prior published study from NCCTG). ROAD can be safely administered as an inpatient or outpatient. No significant financial relationships to disclose.

8508 Background: A prior pilot study of epratuzumab (Immunomedics) and rituximab in combination with CHOP chemotherapy (ER-CHOP) in untreated patients with diffuse large B-cell lymphoma demonstrated feasibility and safety. This multicenter NCCTG phase II study was carried out to assess efficacy. Methods: Patients received immunochemotherapy on the following schedule: epratuzumab 360 mg/m2, rituximab 375 mg/m2, and standard dose CHOP every 3 weeks for 6 cycles. Weekly blood counts were obtained to monitor hematological toxicity. Primary endpoint was 12 month event free survival (EFS12). Secondary endpoints were response rate, progression free survival, functional CR (PET negative) and toxicity. Results: 107 patients were accrued from Feb 2006 to Aug 2007. 29 patients were ineligible resulting in 78 eligible patients. Baseline patient characteristics for the eligible patients included median age 61 (range 21–82); 59% were male. 81% had advanced stage; IPI was 0–1 in 17 pts (22%), 2 in 22 pts (28%), 3 in 29 pts (37%) and 4–5 in 10 pts (13%). Based on the revised IPI (R-IPI) 50% were poor/high risk (IPI 3–5). 71% had an elevated LDH. Performance score was 0–1 in 69 pts and 2–3 in 9 pts. The ORR was 95% (CR/CRu: 73%). For the low risk IPI (0–2), ORR was 95% (CR/CRu: 74%) and for the high risk IPI (3–5), ORR was 95% (CR/CRu: 72%). The EFS at 12 months was 80%. The 12 month progression free survival (PFS12) and overall survival (OS12) is 82% and 88% respectively. EFS12, PFS12 and OS12 by IPI risk category is shown ( Table ). Conclusions: ER-CHOP every 21 days is feasible and safe. The ORR, EFS and PFS compare favorably to studies using R-CHOP especially in the high-intermediate and high risk IPI subgroups. A randomized phase III trial of R-CHOP vs ER-CHOP is needed to prove that dual antibody targeting in combination with CHOP is better. [Table: see text] No significant financial relationships to disclose.

e14640 Background: MicroRNAs (miRNAs) are non-coding RNAs that act as negative regulators of gene expression. They have been described to play roles in solid tumors and hematologic malignancies. However the role of miRNAs in multiple myeloma (MM) has not been yet fully described. Methods: We performed miRNA-profiling of primary bone marrow-derived CD138+ MM cells, compared to their normal cellular counterparts and validated data by qRT-PCR. In vitro and in vivo functional studies were performed on miRNA-15a- and -16–1-precursors-transfected MM cells. Effect of miRNA-15a and -16–1 on signaling cascades have been evaluated by western blot and immunofluorescence. NF-kB activity has been studied using the Active Motif TransAM kit. In vivo MM cell growth has been evaluated by either using an in vivo imaging model or bioluminescence. Angiogenesis has been studied both in vitro and in vivo using the chorioallantoic membrane model. Results: We identified a MM-specific miRNA signature characterized by down-expression of miRNA-15a, -16–1 and over-expression of miRNA-222/-221/-382/-181a/-181b (P<0.01). Data were confirmed by qRT-PCR on matched samples. Predicted targets for the decreased miRNAs in MM patients included pro-angiogenic cytokines, oncogenes, cell cycle regulators, NFkB activators. Conversely, predicted targets for the increased miRNAs included cell cycle inhibitors, suppressors of cytokine signaling, and pro-apoptotic factors. We demonstrated that miRNA-15a and - 16–1 regulate proliferation and growth of MM cells. Indeed, transfected cells showed decreased DNA synthesis; decreased cyclinD1/cyclinD3/CDC25a/pRb protein expression; phase G1 cell cycle arrest. Moreover, transfected cells showed inhibition of NFkB pathway as shown by reduced p65-/p50-/p52-NFkB activities; downregulation of p-p65/p50/p52 nuclear protein level; upregulation of cttosolic phospho-IkB; and inhibited translocation of p-p65 from the cytolplasm to the nucleus. Similarly, inhibition of MM cell growth was confirmed in vivo; and anti-angiogenic properties of miRNA-15a and -16–1 were demonstrated both in vitro and in vivo. Conclusions: These data indicate that miRNAs play a pivotal role in the biology of MM; providing the basis for the development of new miRNA-based targeted therapies in this disease. No significant financial relationships to disclose.

Abstract Purpose: We sought to improve upon frontline bendamustine/rituximab (BR) induction therapy followed by rituximab maintenance in untreated high-risk follicular lymphoma (FL). Patients and Methods: Patients were randomized to BR induction followed by 2-year rituximab maintenance (BR-R), BR with bortezomib and rituximab maintenance (BVR-R), or BR followed by lenalidomide (1 year) with rituximab maintenance (BR-LR). Dual primary objectives were complete remission (CR) rate and 1-year disease-free survival (DFS); 289 patients enrolled (NCT01216683). Results: For induction, 92%, 87%, and 86% of patients randomized to BR-R, BVR-R, or BR-LR received six cycles, respectively. CR rate with BR versus BVR induction was 62% versus 75%, respectively (P = 0.04). One-year DFS rates with BR-R versus BR-LR were 85% versus 67%, respectively (P = 0.0009). This was due to an imbalance in CR rates post-BR induction and discontinuation due to adverse events (AEs). The most common grade 3–4 AEs for BVR versus BR were neutropenia and sensory neuropathy (12% vs &lt;1%); 83% of the latter occurred with intravenous bortezomib. The most common grade 3–4 AEs related to LR versus rituximab maintenance were neutropenia 66% versus 21%, respectively (P &lt; 0.0001), and febrile neutropenia 10% versus 2%, respectively (P = 0.05). The overall treatment-related mortality was 1.4%. With 5-year median follow-up, 3-year PFS rates for BR-R, BVR-R, and BR-LR were 77%, 82%, and 76%, respectively (P = 0.36) with OS rates of 87%, 90%, and 84%, respectively (P = 0.79). For prognostication, CR rate and POD-24 were associated with survival. Conclusions: Altogether, neither bortezomib added to BR induction nor lenalidomide added to rituximab maintenance immediately post-BR induction is recommended in untreated FL.

TPS8073 Background: Response rates to salvage immunochemotherapy in patients with DLBCL relapsing after or refractory (R/R DLBCL) to front line therapy remain unsatisfactory. Lenalidomide (Len) has significant single agent activity in relapsed/refractory DLBCL. The addition of lenalidomide (Len) days 1-7 to rituximab plus ifosfamide-carboplatin-etoposide (RICE) was shown to be feasible with promising efficacy in phase 1b study (Feldman T, et al. BJH, 2014). We developed phase I/II study to evaluate the safety and efficacy of the addition of Len (extended to 14 day schedule) to RICE (R2-ICE) for R/R-DLBCL patients who are candidates for stem cell transplant. Methods: The phase I portion was designed to determine the maximally tolerated dose Len in combination with RICE using the standard cohort 3+3 design. The escalation dose levels were 15 mg and 20 mg daily x 14 days. Prophylactic aspirin and growth factor support is mandatory. After 2 cycles of therapy response is evaluated with a PET/CT scan; the responding patients are eligible for 1-2 additional cycles of R2ICE as a bridging before HDC/SCT. The estimated overall response rate for two cycles of R-ICE in R/R DLBCL to RCHOP was estimated to be approximate 45%. We hypothesize that the addition of lenalidomide in the relapse setting could increase the overall response rate by approximately 20%. The one-stage design with an interim analysis being utilized in phase 2 requires 45 evaluable patients (one sided alpha = 0.09, power 90%). For Phase I, all types of B-cell lymphomas were eligible. For phase II portion only DLBCL patients are eligible per central pathology review. Other eligibility criteria include: received one line of previous anti-lymphoma therapy, ≥ 2 weeks from completion of prior anti-lymphoma therapy, candidate for HDC and SCT, adequate organ (creatinine clearance ≥ 60ml/min by Cockcroft-, total bilirubin ≤ 2 × ULN) and bone marrow function (ANC) ≥1500/mm3; platelet count ≥75,000/mm3). The use of steroids and/or rituximab up to 1 week prior to registration for management of symptoms is allowed. 9 patients cleared phase 1 without DLT and dose of 20 mg days 1 -14 was recommend for phase 2 part (RP2D) of the study. The phase 2 study passed interim futility analysis and accrual continues. Correlatives include cell of origin by Nanostring, Myc/bcl2 expression and by FISH and minimal residual disease. PET scans are centrally reviewed including metabolic tumor volume. Clinical trial information: NCT02628405 .

e20068 Background: FL grade 3B (FL3B) is an aggressive subtype of FL with a distinct morphologic, cytogenetic and immunohistochemical profile that is associated with higher mortality compared to other subtypes of FL. FL3B is a rare disease, and data regarding its prognostication beyond grading is lacking. Recent data suggests that spleen and extranodal (EN) involvement on PET/CT predict early clinical failure in FL grades 1-3A[1]. We aimed to determine the incidence of spleen and EN involvement on PET/CT in FL3B, and whether these can predict EFS. Methods: Patients with untreated FL3B diagnosed between 2003-2016, with available pre-treatment PET/CT, were identified using the Mayo Clinic Lymphoma Database and the University of Iowa/Mayo Clinic Lymphoma SPORE database. 27 patients were included in this analysis. All but two patients received treatment with immunochemotherapy. Associations with outcomes were assessed using EFS, defined as disease progression, relapse, transformation, or death. Results: 11/27 (40.7%) of patients had EN involvement on PET/CT. The most common EN site was bone, in 8/27 (29.5%) of patients. Soft tissue involvement was present in 4/27 (14.8%) of patients. Liver, brain, and endometrial involvement were each noted once. 11/27 (40.7%) of patients had spleen involvement on PET/CT. Presence of bone involvement as detected on PET/CT was associated with lower EFS (p = 0.02). EN involvement was associated with a trend toward a lower EFS but statistical significance was not reached likely secondary to low numbers in this cohort. Results in the table are compared to results obtained from our analysis in patients with FL grade 1-3A[1]. Conclusions: Bone involvement on pre-treatment PET/CT in FL3B was associated with early clinical failure in this small cohort of 27 patients. EN involvement at diagnosis may also be associated with poorer outcomes. These findings are similar to our analysis of a large (n = 613) cohort of patients with FL grade 1-3A. These findings may aid in the prognostication of patients with newly diagnosed FL3B, to guide therapy in select higher risk patients. [Table: see text]

e20048 Background: No literature exists regarding whether hypomagnesemia at the time of diagnosis in Burkitt Lymphoma (BL) is associated with inferior survival. Methods: Patients with new diagnosis of BL who were seen at Mayo Clinic, MN from 2000-2019 with a serum magnesium level available prior to chemotherapy were included. Patients were allocated to two groups; Abnormal Magnesium Group (AMG), defined as a magnesium level < 1.7 mg/dL and Normal Magnesium Group (NMG), defined as ≥ 1.7 – 2.3mg/dL. Two-sided Wilcoxon rank sum test and Chi square/Fischer’s exact test were used to compare the continuous and categorical variables, respectively. Kaplan-Meier and log-rank tests were used to perform all time to event analysis which were done from time of treatment. Hazard ratios (HR) with confidence intervals (CI) were calculated using Cox-proportional hazards. Results: Of 90 patients with a diagnosis of BL, 42 patients had a magnesium level at or before time of diagnosis. The Table lists the baseline characteristics and significant findings of the AMG/NMG groups. The median follow-up was 30 months. Hypomagnesemia was predictive for inferior EFS at 30 months - 34.3% (95% CI: 8.7–74.0) for AMG and 79.3% (95% CI: 60.8-90.4) for NMG (p = 0.038). OS at 30 months for AMG was 42.9% (95% CI: 14.4-77.0) and for NMG was 93.7% (95% CI: 78.1-98.4%) (p = 0.002). Other parameters significant on univariate analysis included the Charlson Comorbidity Index (p = 0.034), creatinine (p = 0.009), and number of treatments (p = 0.048). In the multivariate analysis, creatinine (p = 0.005) and number of treatments (p = 0.004) were significant. Likelihood ratio testing of predictors associated with inferior OS were significant for hypomagnesemia (likelihood ratio 3.99, p = 0.046). Conclusions: Patients with hypomagnesemia at the time of BL diagnosis have inferior outcomes compared to BL patients with a normal magnesium level. Prospective studies are needed to confirm this finding and test Mg replacement strategies to mitigate the effects of hypomagnesemia. [Table: see text]

8052 Background: A significant proportion of patients with FL experience an early relapse and a subsequent poor outcome. While several prognostic indices have been developed, none were designed to predict early failure. Recently, we established that lack of intrafollicular CD4+ T-cell expression predicted risk of early failure, and integrating this microenvironment biomarker with the Follicular Lymphoma International Prognostic Index, termed BioFLIPI, further improved identification of FL patients at risk of early failure ( Blood 2019;134(suppl1):121). However, the microenvironment may be influenced by the genetic composition of tumor. We investigated whether the CD4 biomarker and BioFLIPI were impacted by genetic features of the tumor as assessed by a 23-gene expression prognostic score ( Lancet Oncol 2018;19:549-61). Methods: Of the 186 cases with FL grade 1-3A treated with immunochemotherapy (IC) in our prior study, 152 had digital expression quantification of 23 selected genes (23-GEP score), which used RNA from formalin-fixed, paraffin-embedded samples. Event-free survival (EFS) was defined as time from diagnosis to progression, relapse, retreatment, or death. Early failure was defined as failing to achieve EFS at 24 months. Risk of early failure was estimated using odds ratios (ORs) and 95% confidence intervals from logistic regression models. We also used Cox regression to assess associations with continuous EFS and overall survival (OS). Results: 28% of patients failed to achieve EFS24. Lack of CD4+ intrafollicular expression (38% of patients, OR = 2.33, p = 0.024) and high risk 23-GEP score (26% of patients, OR = 3.52, p = 0.001) each predicted early failure, and in a multivariable model that included FLIPI, both CD4+ (OR = 2.26, p = 0.046) and 23-GEP score (OR = 2.26, p = 0.0.057) remained predictors. Similarly, BioFLIPI modeled as a continuous score (1-4, OR per one point increase = 2.31, p < 0.001) predicted early failure, and the association remained (OR = 2.14, p < 0.001) when the high risk 23-GEP score (OR = 2.79, p = 0.013) was included in the model. When stratified on 23-GEP score, BioFLIPI was a stronger predictor of early failure in low risk (74%, OR = 2.51, p = 0.002) relative to high risk (26%, OR = 1.55, p = 0.27) patients. Similar patterns were observed for EFS and OS. Conclusions: CD4+ T-cell infiltrate and tumor gene expression appear to be independently predictive of early failure in newly diagnosed FL patients treated with IC. Future studies should integrate and validate these measures.

e19112 Background: We sought to study the longitudinal QOL, financial burden and perception of care (PoC) in patients with multiple myeloma (MM) or lymphoma (LYM) enrolled on CTs vs. those receiving standard care (Non-CT). Methods: QOL was evaluated using the FACT-G questionnaire (baseline, 1, 2, 3, 6 & 12 months). Financial burden was evaluated using 10 questions adapted from the MEPS survey and PoC was evaluated using 6 questions adapted from the CAHPS survey (baseline, 3, 6 & 12 months). Results: 35 (28%) of 123 enrolled patients were treated on CTs. Demographics, QOL and financial burden are shown in the Table. Baseline QOL scores were similar in CT vs non-CT groups. Age, gender and self-reported performance status were significantly associated with baseline QOL, while lines of therapy & cancer type were not. There were no significant differences in change in QOL vs. baseline in patients treated on CTs vs. non-CTs at 1, 2, 3, 6 and 12 months from baseline, including the total FACT-G score and the subdomains of functional, physical, emotional and social well-being. Within each group, there was a decline in QOL over the first 3 months, specifically physical WB, which gradually returned to baseline. Baseline answers to financial burden questions were similar, except patients on CTs reported less need for taking extended time-off from work (22% vs. 46%, p = 0.02). The only statistically significant difference in individual Qs over 1 year was ‘worry about having to pay large medical bills’ at the 6-month timepoint (CT: 0%, non-CT: 52%, p = 0.01). Using a composite score from 4 MEPS questions, financial burden over time was lower in the CT group, though the differences were not statistically significant. There were no significant differences in PoC at baseline, 3, 6 and 12 months in the two groups based on answers to each of the six questions adapted from the CAHPS survey. Conclusions: Over 1 year, patients on CTs experienced a similar QOL and perceived their care to be similar as non-CT patients. Financial burden was lower in the CT group, though differences were not statistically significant. [Table: see text]