Habermann, Thomas M.

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 <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 < 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.

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]

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]

e14100 Background: Only 3-5% of adult cancer patients in the US enroll in clinical trials. Patients with organ dysfunction are often excluded from clinical trials, regardless of specific drug metabolism or relative function of the organ. The ASCO and the US FDA recommend modernizing criteria related to baseline organ function and comorbidities. In hematological malignancies, often the disease itself is the reason for organ function derangement. In order to better inform clinical trial eligibility and improve participation in the future, we evaluated the impact of baseline organ function on the potential eligibility for clinical trial enrollment for real world patients with newly diagnosed DLBCL. Methods: Consecutive, newly diagnosed lymphoma patients were offered enrollment from 2002-2015 into the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence. This analysis is based on 1270 DLBCL patients receiving immunochemotherapy. Baseline organ function parameters were identified from the exclusion criteria for hemoglobin, absolute neutrophil count (ANC), platelet count, creatinine, and bilirubin reported in recent frontline trials in DLBCL (Table). Abstracted clinical labs from the MER were used to determine the percent of patients that would be excluded based on the criteria. Results: We determined that 11-23% of MER DLBCL patients receiving standard of care frontline therapy would have been excluded in the various trials utilizing baseline organ function alone (Table). Hemoglobin and renal function had the greatest impact on exclusion. Conclusions: Current national and international (phase II and III) trials are excluding up to 23% of patients from clinical trial participation based on organ function alone in DLBCL. These data will be useful in future clinical trial development to meet ASCO recommendations to increase trial accrual, while balancing the drug toxicities and patient safety. An online tool was developed based on these results to aid future trial development. [Table: see text]

53-year-old male with iMCD developed hematoma at biopsy site. He was diagnosed with acquired hemophilia A and Hashimoto’s both were associated with iMCD. He has been in remission without recurrence of hemophilia after Rituximab 375 mg/M² weekly for 1 month, and 375 mg/M² every 2 months for maintenance.

AbstractBackgroundStandard bone marrow biopsy (BMB) and bone involvement with follicular lymphoma (FL) on positron emission tomography (PET)/computed tomography (CT) both predict early clinical failure in FL. The key clinical question is whether PET/CT findings can obviate the need for BMB. The goal of this study was to determine the value of PET/CT in determining bone involvement in FL, using posterior iliac crest BMB as the gold standard.Materials and MethodsA total of 548 patients with newly diagnosed grade 1–3A FL were included. The presence, pattern, and location of bone involvement, spleen involvement, and standardized uptake values (SUVs) in the L3 vertebral body were recorded for all patients and compared with the BMB report.ResultsExcluding patients with focal bone lesions on PET/CT, the sensitivity and specificity of PET/CT in detecting bone or marrow involvement, compared with BMB, were 53% and 88%, respectively. The sensitivity and specificity of spleen involvement on PET/CT in predicting a positive BMB were 55% and 86%, respectively. An L3 SUVmax of less than 2.0 resulted in a negative predictive value (NPV) of 96% for marrow involvement on BMB; an L3 SUVmean below 1.4 resulted in an NPV of 100%.ConclusionIn newly diagnosed FL, PET/CT-detected bone and splenic involvement is highly specific for a positive BMB, and very low SUV values (&lt;2.0 SUVmax and &lt; 1.4 SUVmean) in the lumbar spine have a high NPV for a negative BMB. Routine BMB may be obviated in these patients. BMB remains necessary to definitively exclude bone marrow involvement in a large majority of patients with a negative PET.Implications for PracticePredicting early clinical failure in follicular lymphoma (FL) is important but difficult. Bone marrow involvement by FL is associated with early clinical failure, and determining this involvement is a key component of the initial staging. This study highlights that in certain patients, positron emission tomography/computed tomography is sufficient in determining bone or marrow involvement, without the need for a confirmatory bone marrow biopsy (BMB). An algorithm is provided based on these findings to help clinicians determine which patients would benefit from BMB and when it can be avoided.

Abstract Background. The strongest established prognostic factors for follicular lymphoma are age and clinical factors. Biologic studies suggest a major role for the host immunologic environment in follicular lymphomagenesis, which is in part determined by host genetic background. Cytokines are key regulators of immune function and regulation, are highly polymorphic, and have been implicated in lymphoma etiology and prognosis. We evaluated the hypothesis that inherited variability in cytokine and related immune genes impact overall survival in follicular lymphoma. Methods. We genotyped 73 single nucleotide polymorphisms (SNPs) from 44 candidate cytokine and immune genes in 278 follicular lymphoma patients who participated in a population-based case-control study conducted from 1998–2000 in the Detroit, Iowa, Los Angeles and Seattle SEER (Surveillance, Epidemiology and End Results) cancer registries. Baseline clinical data and survival through early 2005 were obtained from cancer registry files. Cox proportional hazards analysis was used to estimate hazard ratios (HR) and corresponding 95% confidence intervals for the association between individual SNPs and overall survival, adjusting for age, demographic and clinical factors. We also used parallel modeling strategies to identify the best summary multi-SNP risk score to predict survival, and applied these results in a time-dependent receiver-operator characteristics (ROC) analysis. Results. The median age at diagnosis was 57 years (range, 25–74), and 59 (21%) of the patients died during follow-up, with a median follow-up of 59 months (range, 27 – 78 months) for surviving patients. In multivariate modeling, SNPs in IL8 (rs4073; HRTT=2.14, 1.26–3.63), IL2 (rs2069762; HRGT/TT=1.80, 1.06–3.05), IL12B (rs3212227; HRAA/CC=1.83, 1.06–3.06), and IL1RN (rs454078; HRAA=1.93, 1.11–3.34) were the strongest and most robust predictors of survival. A summary score of the number of deleterious genotypes from these four genes was strongly associated with survival (p=1.4 × 10−5) after accounting for demographic and clinical variables (HR=2.06 per deleterious genotype, 1.52–2.79). A combination of the four SNPs and the demographic and clinical risk scores was strongly associated with survival (p=1.8 × 10−11); the 5-year Kaplan Meier survival estimates were 96% (93%–100%), 72% (62%–83%) and 58% (48%–72%) for low, intermediate, and high risk groups respectively. In a time-dependent ROC analysis the three risk groups had an area under the curve (AUC) of 0.83 at 72 months of follow-up (95% CI 0.72–0.93). Conclusion: Host genetic variability in immune genes, particularly IL8, IL2, IL12B, and IL1RN, individually and particularly in combination, was associated with overall survival in follicular lymphoma after accounting for demographic and clinical factors. Host immunogenetics is a promising class of prognostic factors in follicular lymphoma that warrants further evaluation.

Abstract Absolute lymphocyte count (ALC) recovery post-autologous stem cell transplantation has been documented as an independent predictor for survival in non-Hodgkin lymphoma. The effect of ALC recovery on survival during standard CHOP or R-CHOP chemotherapy for newly diagnosed diffuse large B cell lymphoma (DLBCL) is unknown. To participate in the study, patients required to receive their full treatment with complete blood count determinations at the Mayo Clinic College of Medicine. Of 1633 DLBCL cases seen at the Mayo Clinic College of Medicine between February 1994 through August 2004, 212 consecutive DLBCL patients were eligible for the study. We study ALC recovery as a prognostic factor for progression-free survival (PFS) and overall survival (OS) in DLBCL patients treated with at least 3 cycles of CHOP or R-CHOP. 57% were male and the median age was 66 years (range: 20 – 87); 42% had elevated LDH, only 11% had a PS of 2 or higher; 58% were low stage (I or II); 88% of pts achieved a complete response. ALC was evaluated at the beginning of each treatment cycle, focusing on cycles 1–3 and the 3 month post treatment sample. ALC for each of the cycles were significantly correlated with PFS and OS, with cycle 1 ALC most significantly correlated when accounting for inherent differences based on treatment (Rx) type (i.e. CHOP vs. R-CHOP) as well as high vs. low IPI (PFS: p = 0.0012; OS: p = 0.005). Also, 74 pts achieved an ALC of at least 1,000 during all three cycles, where there was no significant relationship with this incidence and Rx type; this incidence was significantly associated with higher PFS (p = 0.0007) and OS (p = 0.0006), even when accounting for Rx type and high vs. low IPI. In the 179 pts who had 3-month post-Rx ALC data, this was also significantly associated with PFS (p = 0.002) and OS (p = 0.0009), while still accounting for Rx type and IPI status. Achievement of ALC &gt;= 1,000 post-Rx was also significant for PFS (p = 0.0014) and OS (0.003). Also of note, only cycle 1 ALC was significantly different in high vs. low IPI pts (p = 0.008). In summary, these data support the hypothesis that there is a critical role of lymphocyte (immune) recovery during CHOP/R-CHOP chemotherapy in DLBCL.

Abstract Background: Several studies suggest that smoking and obesity may increase the risk of developing NHL, but the impact of these factors on survival is relatively unexplored. One recent population-based Italian study found that smoking may negatively impact overall survival. Methods: We evaluated the association of body mass index (BMI) and cigarette smoking on overall survival in 1,286 patients who participated in a population-based case-control study conducted through the Surveillance, Epidemiology, and End Results (SEER) cancer registries in Detroit, Iowa, Seattle and Los Angeles. BMI (on 1189 participants) and a smoking history (on 471 participants) were obtained through in-person interviews. Histology, stage, presence of B symptoms, first course of therapy, date of last follow-up, and vital status were derived from linkage to registry databases at each study site in the spring of 2005. Hazard Ratios (HRs) and 95% confidence intervals were estimated using Cox proportional hazards models, while adjusting for demographic and clinical factors. Results: The median age at diagnosis was 58 years (range: 16 – 74), and the most common histologies were DLBCL (33%), follicular (25%), SLL/CLL (12%), marginal zone (9%), mantle cell (4%) and Peripheral T-cell (3%). The median BMI was 26.6 (range: 16.2 – 47.3), and 26% of patients were classified as obese (i.e. BMI &gt;30). Of patients with a smoking history, 47% had never smoked, 19% were active smokers at diagnosis, and 34% were former smokers. No significant differences were observed between those with and without tobacco use data in terms of primary lymphoma characteristics. Overall survival (OS) was defined as time from diagnosis to death due to any cause. Median follow-up on all living patients was 58 months (range: 4 – 78), and 333 patients had died. When BMI was assessed as a continuous measure, it was borderline significantly associated with OS (p=0.050). An indicator of whether or not BMI &gt; 30 was also significantly associated with OS (HR=1.30; 95% CI: 1.01 – 1.68; p=0.042). Ever vs. never smokers also exhibited a survival disadvantage (HR=1.66; 95% CI: 1.12 – 2.44; p=0.011). When broken down further, former smokers who had smoked for &gt;10 years (HR=1.61; 95% CI: 1.02 – 2.52; p=0.039) and current smokers (HR=1.79; 95% CI: 1.07 – 3.02; p=0.028) were at a survival disadvantage over those who had never smoked. When both smoking and BMI status were included in the model, only the indicator of being a current smoker remained statistically significant (p=0.031), with a trend toward decreased survival for former smokers who had smoked &gt;10 years (p=0.061) and those with BMI &gt;30 (p=0.058). Conclusions: NHL patients who smoke or are obese had a poorer overall survival. These observations warrant further investigation, including whether interventions for smoking cessation or weight loss can impact NHL survival.