Citations

Objectives: To identify patient characteristics, health concerns, and barriers to care based on overweight or obesity. Methods: A 50-question anonymous survey was administered to patients. Data were compared by body mass index (BMI). Results: Among 3976 distributed surveys, 899 were returned and 682 were analyzed. Most respondents were women (60%), White (94%), and married/partnered (65%) and had some college education (80%). Younger and unmarried persons had higher BMI ( P < .001). Concern for quality of life ( P < .001) and importance of lifestyle changes ( P = .006) increased with BMI, but confidence in making changes decreased as BMI increased ( P < .001). Perceived good health decreased with increasing BMI ( P < .001), whereas depression and other comorbid conditions increased. Self-esteem decreased and stigma increased with higher BMI (both P < .001). Weight discussions with clinicians ( P < .001) and belief that clinicians should be involved in weight management ( P = .002) increased with BMI, yet self-perception of being judged by clinicians also increased ( P < .001). As BMI increased, delays in seeking health care increased ( P < .001). Conclusions: This survey study highlights perceived health concerns and barriers to care among persons with overweight and obesity. With higher BMI, self-esteem decreased, and stigma, self-perception of poor health, perception of being judged by clinicians, and delay in seeking medical care increased.

Background: Positron emission tomography (PET) scan is the imaging modality of choice for initial staging and response assessment of follicular lymphoma (FL). Quantitative parameters such as standardized uptake value (SUV) have been investigated as putative prognosticators in FL, with high baseline SUVmax predicting aggressive disease. To date, there is no data to guide treatment choices in patients (pts) with high SUVmax but with no documented evidence of histologic transformation (HT). Specifically, it remains unclear whether anthracycline-containing regimens, such as R-CHOP, are more beneficial than R-Bendamustine (BR) in these pts. Therefore, we aimed to compare the efficacy of frontline R-CHOP and BR in newly diagnosed FL pts based on the SUVmax at baseline PET (bPET). Patients and Methods: Pts with newly diagnosed, biopsy-proven FL1-2 and FL3A who had a bPET scan and who received either first-line R-CHOP or BR within 6 months of diagnosis between 2002 and 2022 were evaluated. Analysis was restricted to pts with age &lt; 70 years to reduce confounding of age with treatment selection. Cohorts included were the FOLL12 (n=562, Luminari et al JCO 2022) and the R-chemotherapy arm of the RELEVANCE (n=216, Morschhauser et al NEJM 2018) clinical trials, the prospectively enrolled Molecular Epidemiology Resource (MER) and the Lymphoma Epidemiology of Outcomes (LEO) cohorts (n=288) and a retrospective cohort from 13 Australian centers (n=219). Choice of chemotherapy regimen was per treating physician. Maintenance was per protocol (FOLL12/RELEVANCE) or per treating physician (MER/LEO/Australia). Event-free survival (EFS) and overall survival (OS) were defined as time from treatment initiation to progression, relapse, retreatment or death; both were censored at 72 months due to varying follow-up across cohorts. SUVmax was grouped by tertile within each cohort to account for potential differences in SUVmax distributions and patient populations across cohorts. Kaplan Meier curves and multivariable Cox models cohort-stratified and adjusted for clinical factors (FLIPI, ECOG PS, age, grade 3A) were used to evaluate outcomes. Results: The median age at diagnosis was 57 years (IQR 49-64). 651 (51%) pts were treated with R-CHOP and 634 (49%) with BR. Within the study cohorts, there was a prevalence of cases receiving BR compared to R-CHOP in the Australian (90% vs 10%) and MER/LEO (68% vs 32%) cohorts, while the opposite was observed in the RELEVANCE (16% vs 84%) and FOLL12 (37% vs 63; p&lt;0.001) trials. Pts receiving R-CHOP were slightly younger (median 56 vs 58 years, p=0.005), more frequently had grade 3A (17% vs 7%, p&lt;0.001), elevated LDH (27% vs 22%, p=0.029), bulky disease &gt; 7 cm (44% vs 37%, p=0.019), lower ECOG PS (PS &gt;1 7% vs 13%, p&lt;0.001), and higher rate of high risk FLIPI (37% vs 30%, p=0.005). Baseline SUVmax was slightly lower in R-CHOP (median 10.7, IQR 7.9-14.9) vs BR (median 11.0, IQR 8.2-14.2) treated pts (p=0.0045). At a median follow-up of 56 months (range, 1-72 months), 415 pts (32%) had an event and 103 (8%) died. Higher SUVmax was not associated with EFS (middle tertile HR=0.96, 95% CI 0.76-1.22; upper tertile HR=0.86, 95% CI 0.68-1.09; p=0.45) or OS (middle tertile HR=1.28, 95% CI 0.80-2.05; upper tertile HR=0.97, 95% CI 0.59-1.59; p=0.44) in multivariable models stratified on cohort and adjusted for treatment and clinical factors. We then compared outcomes by treatment within tertiles of SUVmax. In multivariable models, R-CHOP had modestly inferior EFS to BR in low (HR=1.27, 95% CI 0.84-1.93) and middle tertiles (HR=1.49, 95% CI 0.99-2.25), and modestly superior OS to BR in low (HR=0.59, 95% CI 0.23-1.47) and middle (HR=0.79, 95% CI 0.37-1.71) tertiles. Both EFS (HR=1.06, 95% CI 0.71-1.58) and OS (HR=1.02, 95% CI 0.45-2.30) for R-CHOP were similar to BR in the highest tertile. No comparisons identified a statistically significant benefit for either therapy in multivariable models when evaluating SUVmax tertile subsets. Conclusions: In this large multicenter study of newly diagnosed FL pts with bPET who received frontline immunochemotherapy, higher baseline SUVmax was not associated with inferior outcomes after adjusting for treatment and clinical factors. Within the caveats of retrospective studies and confounding of treatment selection, these data provide no clear insights for SUVmax-based therapy selection in first-line follicular lymphoma pts treated with immunochemotherapy.

Introduction: There are discrepant definitions of both iron deficiency and anemia in pregnancy. It is recognized that iron requirements increase during pregnancy, particularly in the third trimester, and that deficiencies should be corrected to avoid adverse maternal-fetal outcomes. While low dose iron supplementation is recommended for all pregnant persons (ACOG Bulletin 233), dosing through prenatal vitamins varies widely. Additionally, despite the epidemic of iron deficiency in reproductive-age females globally and availability of high-value biomarkers (e.g., ferritin), current guidelines only recommend screening for iron deficiency during pregnancy in the presence of anemia. As anemia is the terminal manifestation of iron deficiency and reference ranges vary by organization, these guidelines and practices warrant further investigation and discussion. Methods: Retrospective review and analysis of the electronic health record at Mayo Clinic (Rochester, MN) was performed for obstetric deliveries between June 2022 and May 2023. Iron deficiency was defined as a ferritin &lt;50 mcg/L and anemia was defined as a hemoglobin &lt;11 g/dL. Results: A total of 2,141 unique deliveries were identified. The median age at delivery was 31 years old (range: 15 - 45) with 82% identifying as white. Anemia was documented in 42% (n=904) of pregnancies at least once throughout gestation, with an increasing frequency of 2% (n=43) in the first trimester, 11% (n=230) in the second trimester, 17% (n=361) in the third trimester, and 38% (n=803) from admission for delivery through the peri-partum period. There were five documented pRBC transfusions prior to admission for delivery; however, from admission for delivery through the peri-partum period, there were a total of 102 documented pRBC transfusions. In total, 15% (n=318) of pregnancies were screened for iron deficiency through ferritin testing. Ferritin levels were measured 415 times with 23% (n=96) occurring between the last menstrual period and 12 weeks gestational age (WGA), 24% (n=100) occurring between 13-27 WGA, 40% (n=164) occurring between 28-40 WGA, and 13% (n=55) occurring post-partum. Iron deficiency was found in 70% (n=67), 79% (n=79), 80% (n=164), and 78% (n=43) of measured ferritin levels, respectively. Despite the paucity of screening, prescriptions for oral iron increased throughout gestation with supplementation in pregnancy for 8% (n=170) prior to 12 WGA, 14% (n=290) for those 13-27 WGA, and 23% (n=489) for those 28-40 WGA. Similarly, intravenous iron infusions increased throughout gestation with supplementation in pregnancy for 0.3% (n=7) prior to 12 WGA, 0.7% (n=16) for those 13-27 WGA, and 4% (n=95) for those 28-40 WGA. Prenatal vitamins were documented in over 90% of pregnancies throughout gestation, although the majority were non-prescription and contained variable amounts of elemental iron. Conclusions: Iron deficiency in pregnancy is underrecognized and undertreated. It follows that the accuracy of current reference ranges for anemia in pregnancy are suspect without rigorous verification of replete iron stores in the reference population. Given potential implications for blood product utilization and prenatal care, additional studies are warranted to better characterize iron deficiency in pregnancy as well as clinical sequelae for both mothers and infants. Simultaneously, discussions are needed around current guidelines and recommendations for both screening and treating iron deficiency in pregnancy. Providers, institutions, and professional societies should pursue pragmatic quality improvement initiatives and equitable healthcare delivery efforts to optimize care for this vulnerable patient population at high risk of iron deficiency.

Background: Rituximab, gemcitabine, and oxaliplatin (R-GemOx) is a commonly utilized chemoimmunotherapy regimen for relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL), especially for patients ineligible for autologous stem cell transplant (ASCT) or chimeric antigen receptor T cell therapy (CAR T). R-GemOx is used as a comparator arm in several active phase III clinical trials for R/R DLBCL, including the POLARGO (polatuzumab vedotion and R-GemOx), STARGLO (glofitamab and GemOx), SUNMO (mosunetuzumab and polatuzumab vedotin), LOTIS-5 (loncastuximab tesirine and rituximab), and EPCORE DLBCL-1 (epcoritamab) studies. However, real-world data are limited to understand the patterns of use and outcomes of R-GemOx in the US. Methods: We developed a retrospective multicenter US cohort (known as LEO CReWE) of patients with R/R DLBCL and other aggressive B-cell lymphomas at the eight US academic centers participating in the LEO Cohort Study (NCT02736357). Patients first diagnosed with DLBCL (including transformed and high-grade B-cell lymphoma) from 2007 - 2022 who received second line (2L) or later therapy for R/R DLBCL with R-GemOx were included. Baseline characteristics, treatment, and follow-up data were abstracted by chart review. Index line of therapy was defined as the first receipt of R-GemOx therapy in the 2L or later setting. Intent for CAR T and/or ASCT was evaluated at each line of therapy based on medical records at the time of treatment initiation. Subgroup analyses were pre-planned in groups of special interest, including those treated with R-GemOx without intent for ASCT or CAR T, those treated as a bridge to CAR T, and those aged 70 and older. Results: 183 patients with R/R DLBCL treated with R-GemOx were included. At time of initiation of R-GemOx, median age was 68 years (range 21-88), with 71 patients (39%) aged 70+ and 18 (10%) aged 80+. Many patients had high risk features including 13% with high grade B-cell lymphoma and 56% with IPI 3 or greater. 21% had an ECOG performance status of 2 or greater. Patients received a median of 2 lines of therapy prior to the index line of R-GemOx (range 1-7). 52% of patients did not achieve a complete response (CR) to first-line therapy, and 20% relapsed &lt;12 months from an initial CR. In all patients receiving R-GemOx, the overall response rate (ORR) was 45% (29% CR). At a median follow-up of 39 months, median EFS was 2.3 months (95% CI: 1.8-3.2), with 12-month EFS of 21% and a 24-month EFS of 15%. Median OS was 13.5 months (95% CI: 9.6-18.1), with a 12-month OS of 52% and a 24-month OS of 38%. In patients treated without intent for ASCT or CAR T, ORR was 33% (18% CR). Median EFS was 2.0 months (95% CI: 1.6-2.5) with 12- and 24-month EFS of 14% and 9%, respectively. Median OS was 9.5 months (95% CI: 6.6-16.1) with 12- and 24-month OS of 45% and 29%, respectively. In patients receiving R-GemOx as bridging to ASCT or CAR T, ORR was 57% (35% CR). 35% received CAR T and 14% received ASCT, while the remainder did not receive the intended therapy as part of this line. Median EFS was 3.6 months (95% CI: 1.8-5.2) with 12- and 24-month EFS of 28% and 25%, respectively. Median OS was 17.4 months (95% CI: 13.4-NR); 12- and 24-month OS were 61% and 50%, respectively. In patients aged 70+, ORR was 53% (33% CR). Median EFS was 2.3 months (95% CI: 1.6-5.2), with 12- and 24-month EFS of 20% and 18%, respectively. Median OS was 13.9 months (95% CI: 8.6-30.2); 12- and 24-month OS were 57% and 39%, respectively. Conclusion: This study represents the largest reported cohort of patients treated with R-GemOx in US academic centers to date. The ORR of 45% and CR rate of 29% CR, as well as median EFS and OS of 2.3 and 13.5 months, respectively, are consistent with findings from previous phase II studies; these results highlight that responses to R-GemOx are not durable and the vast majority of patients require additional therapy. This study demonstrates real-world evidence of the efficacy of R-GemOx in a large cohort of patients with R/R DLBCL from the US over a long period, including both transplant-eligible and -ineligible patients, and patients treated in the CAR T era. These data aid in providing a benchmark for active clinical trials in the rapidly evolving landscape of R/R DLBCL therapies and allow potential comparison to a real-world cohort of patients with a broad range of clinical characteristics.

Background Follicular lymphoma (FL) is a generally indolent disease where a watch and wait strategy is standard in asymptomatic patients (pts) with a low tumor-burden. Harnessing antitumor immunity through an anti-tumor immunization strategy at this stage may delay or avoid the subsequent need for more toxic and complex therapies. EO2463 is a therapeutic vaccine designed from non-self protein sequences, derived from gut bacteria, including 4 HLA-A2 synthetically produced 9-mer CD8 cytotoxic T cell epitopes, exhibiting molecular mimicry with specific epitopes on the B cell markers CD20, CD22, CD37, and CD268 (BAFF-receptor). Additionally, EO2463 contains a CD4 helper epitope UCP2 derived from hTERT. The compound expands pre-existing memory CD8 T cells recognizing the non-self protein sequences from gut bacteria which can then cross-react with the selected B cell antigens on tumor cells. EO2463 is being used to drive anti-tumor immunity against B cell malignancies, and has demonstrated long-lasting, specific CD8-memory T cell responses and clinical activity in relapsed/refractory FL and marginal zone lymphoma (MZL) [J Clinical Oncol 2024, 42 (S16), 7058]. Furthermore, CD8 T cells expanded from samples of patients treated with EO2463 can kill HLA-A2 expressing lymphoblastoid cell lines presenting the B cell targets [Hematological Oncol 2023, 41 (S2), 581-582]. Methods The current report describes Cohort 2 of trial EONHL1-20/SIDNEY (NCT04669171) and includes pts with newly diagnosed, previously untreated FL, grade 1-3A, HLA-A2, and not in need of treatment. Pts receive EO2463 (300μg/peptide) SC with adjuvant Montanide ISA 51 VG, q2 weeks (w) x 4, then q4w, for a total of 12 doses (39w; PET-CTs at w6, w19, and w42). Planned accrual for this cohort is 25 pts. Immune responses were assayed on thawed pt peripheral blood mononuclear cells by flow cytometry and EO2463 peptide specific tetramers or by IFN-γ ELISPOT (assaying responses against 9-mer peptides from CD20, CD22, CD37, and CD268; and from peptides of EO2463) without any proceeding in vitro stimulation (ex vivo). Results As of June 2024, 15 pts had started study treatment. Median age was 62 (range 55-66) year, 7 male and 6 female, 2 pts Ann Arbor stage I/II, 5 stage III, and 8 stage IV. Ten of 15 pts were still on treatment; median treatment duration was 18.4 weeks (range 5-39 w) for all pts. Among 13 evaluable pts, best responses by PET-CT using Lugano criteria were 1 pt CR, 5 pts PR (46% objective responses (OR)), 3 pts SD, and 4 pts PD. Of those with PD per Lugano, 2 had isolated increases in FDG-uptake without increase in lesion size/number at w6 and both remain on treatment (per protocol based on LYRIC criteria). OR was first noted w6 in 3 pts and w19 in 3 pts; duration of response is not evaluable at this time due to short follow-up. The pt with CR had isolated increases in FDG-uptake at w6, PR at w19, and CR at w35. Anti-EO2463 immune responses were observed in 4 of 5 tested pts at the 1st testing timepoint (w5) and onwards (currently longest tested up until w31). In an exploratory analysis, the percentage of EO2463 peptide specific CD8 T cells measured by tetramers seemed linked to clinical response (OR 3 pts vs non-OR 2 pts; 2-sided T-test, p=0.02; range of percentages in pts with OR 0.85%-1.39% of all CD8 T cells in peripheral blood, range in pts with non-OR 0.17%-0.27%). Functionality and cross-reactivity of responses were shown by IFN-γ ELISPOT using 9-mer peptides corresponding to the B cell targets in 4 tested pts. Expanded antigen-specific CD8 T cells displayed a memory phenotype; effector/memory (TEM), and terminally differentiated effector memory CD8 T cells (TEMRA). The most common related AEs were grade 1 (7 pts) and grade 2 (5 pts) local administration site reactions (mainly erythema, pruritus, and induration). Other related AEs in &gt; 1 pt were grade 1 headache (2 pts) and grade 1-3 fatigue/asthenia (3 pts). Asthenia lasting 2 days was the only related grade 3 adverse event (AE). Conclusions EO2463 monotherapy is associated with a very manageable safety profile and appears to demonstrate meaningful single-agent efficacy in FL. Consistent with the preclinical hypothesis, expansion of specific CD8 memory T cells may be associated with response. Results will be expanded at the meeting. Study EONHL1-20/SIDNEY also includes cohorts, not covered in this abstract, exploring EO2463 plus rituximab for 1st line FL/MZL, and EO2463 plus lenalidomide/rituximab in relapsed FL/MZL.

Background Follicular and marginal zone B cell lymphoma (FL; MZL) demonstrate an indolent course with heterogeneous outcomes and a potential for spontaneous remissions indicating immune system intervention. T cell-based therapeutic approaches are therefore an attractive proposition in FL and MZL. EO2463 peptide immunotherapy expands pre-existing memory CD8 T cells recognizing non-self-protein sequences from gut bacteria which cross-react with B cell antigens. The compound includes 4 HLA-A2 synthetically produced epitopes which exhibit molecular mimicry with the B cell markers CD20, CD22, CD37, and CD268 (BAFF-receptor), as well as a the CD4 helper-epitope UCP2 derived from hTERT. EO2463 is being used to drive anti-tumor immunity against B cell malignancies, and has demonstrated long-lasting, specific CD8-memory T cell responses and clinical activity in relapsed/refractory FL and MZL [J Clinical Oncol 2024, 42 (S16), 7058]. Furthermore, CD8 T cells expanded from samples of patients (pts) treated with EO2463 can kill HLA-A2 expressing lymphoblastoid cell lines presenting the B cell targets [Hematological Oncol 2023, 41 (S2), 581-582]. Methods The current report describes testing of a possible biomarker in the phase 1 portion of the ongoing EONHL1-20/SIDNEY trial (NCT04669171).This part of the trial (“Cohort 1”) included pts (n=9) with relapsed (at least 1, no limit, prior treatments) FL and MZL, stage 1-3A, confirmed to be positive for HLA-A2. Pts received EO2463 (150 [n=3] or 300μg/peptide [n=6]) SC with adjuvant Montanide ISA 51 VG q2 weeks (w) x 4, then q4w, for a max of 12 months; at w7 lenalidomide (20 mg/day for 21/28 days up to 12 cycles) was added (EL), and if no complete remission (CR) at w19, rituximab (375 mg/m IV, q1w x 4, then q4w x 4) was also added (ER2). Immune responses and clinical outcomes of Cohort 1 were previously reported [J Clinical Oncol 2024, 42 (S16), 7058]. To assess a possible biomarker, tetramers were used to specifically detect CD8 T cells recognizing the 4 epitopes in the EO2463 compound (derived from gut bacterial proteins exhibiting molecular mimicry with the B cell markers CD20, CD22, CD37, and CD268). The tetramers were all marked with phycoerythrin. Thawed samples of peripheral blood mononuclear cells taken at start of w5 (after 2 administrations of EO2463 monotherapy, each followed by 2w observation) were stained ex vivo (without any in vitro stimulation) with the tetramers and assayed by flow cytometry. Results are presented as percentage of EO2463 specific CD8 T cells among all CD8 T cells in the peripheral blood of the pt. Results Among the 9 treated pts, PET-CT at w6 (after 3 administrations of EO2463 monotherapy) suggested possible clinical activity in 4/9 pts (1 PR, 1 pt size reduction 15%, 1 pt 20% reduced tracer uptake, 1 pt 5/6 target lesions reduced metabolic activity). By PET-CT at w42 (after 12 administrations of EO2463 monotherapy, 11 cycles of lenalidomide, and rituximab treatment) the Lugano response assessment was complete response in 6/9 pts. A positive biomarker response was assessed in 5/9 pts (percentage of specific CD8 T cells ranged from 0.2-2.1%). EO2463 monotherapy PET-CT activity at w6 (n=4/9 pts): 4 of 4 pts with clinical activity were biomarker positive and 1/5 of the other pts was also positive; this pt had an isolated increase in FDG-uptake at w6, followed by a CR at w19. Four further other pts were biomarker negative. In this limited sample, the biomarker had sensitivity 100% and specificity 80%. EO2463 in combination with lenalidomide/rituximab PET-CT CR at w42 (n=6/9): 5 of 6 pts with CR were biomarker positive and 1 pt with CR was negative; the pt with a negative test had no objective tumor response until after rituximab. In this limited sample, the biomarker showed sensitivity 83% and specificity 100%. Conclusions The current preliminary assessment indicates that direct ex vivo tetramer staining for specific CD8 T cells after short term (5 w) treatment with EO2463 monotherapy could be a possible biomarker for clinical response, both for EO2463 monotherapy response, and for response to EO2463 in combination with lenalidomide/rituximab. We plan to validate these findings in the ongoing study cohorts of the trial; expansion phase 2 cohorts, exploring EO2463 monotherapy in the “watch & wait” setting, EO2463 plus rituximab for 1st line FL/MZL, and EO2463/lenalidomide +/- rituximab in relapsed FL/MZL.

Background: FL3B is the least common among FL subtypes, accounting for 5-10% of cases. Almost half of FL3B tumors have concurrent diffuse large B cell lymphoma (DLBCL) in the diagnostic tissue biopsy, while FL3B rarely coexists with FL1-2 or FL3A. Several lines of evidence suggest that FL3B displays distinct biological and clinical characteristics resembling aggressive DLBCL rather than the indolent FL1-3A. Accordingly, DLBCL anthracycline-containing regimens, such as R-CHOP, are the mainstay of therapy for FL3B with or without coexisting DLBCL. However, while some studies show that R-CHOP therapy in FL3B was associated with 5-year overall survival (OS) rate of 54%, others report outcomes comparable to FL3A with 79-90% survival. Additional controversy involves the clinical implication of pure FL3B (FL3Bp) vs FL3B with concurrent DLBCL (FL3Bc). Thus, it remains unclear if FL3B clinically resembles DLBCL or lower-grade FL and whether FL3Bp has a different prognosis from FL3Bc. To address these questions, we performed a pooled study of two large prospective multicenter study cohorts to compare the clinical characteristics and outcomes of newly diagnosed FL3B with FL1-2, FL3A and DLBCL patients, all of whom were uniformly treated with frontline R-CHOP. Patients and Methods: Weevaluated 469 newly diagnosed patients with FL1-2 (n=216), FL3A (n=170) and FL3B (n=83) who received R-CHOP within 6 months of diagnosis and 739 de novo DLBCL (GCB n=455 and non-GCB n=284) who were prospectively enrolled into the Molecular Epidemiology Resource (MER) and the Lymphoma Epidemiology of Outcomes (LEO) cohorts between 2002 and 2021. FL3B cases were designated as FL3Bc and FL3Bp based on the presence or absence of coexisting DLBCL, respectively. Histologic diagnosis was determined by an expert pathologist at each participating center and centrally reviewed. Event free survival (EFS) and OS were defined as time from diagnosis to progression, relapse, retreatment or death, and early progression defined as failing to achieve EFS at 24 months (EFS24). Associations between clinical features and EFS or OS were evaluated using Kaplan Meier curves and Cox proportional hazards models unadjusted and adjusted for age and FLIPI (comparisons with FL1-2 and FL3A) or IPI (comparisons with DLBCL). Results: The median age was 61 years (range, 18-94 years). Among FL3B patients, 21 (25%) had FL3Bc and 62 (75%) FL3Bp. Baseline characteristics and outcomes were broadly similar between the two FL3B subtypes. We then compared all FL3B patients to those with lower-grade FL. Patients with FL3B showed similar clinical features to those with FL1-2 and FL3A, with exception for a lower tumor burden. After R-CHOP, FL1-2 patients had an inferior EFS (HR 2.13 95%CI 1.31-3.46) than those with FL3B, whereas there was no difference compared to FL3A. OS was similar across all FL grades. Although FL1-2 patients failed to achieve EFS24 more frequently than FL3B and FL3A (34% vs 18% and 15%, p&lt;0.001), FL3B patients who did fail EFS24 had almost three folds higher risk of subsequent mortality (HR 2.84 95%CI 1.35-6.01) than other FLs. At 5-year follow-up, FL3B patients had twice the risk of relapse with an aggressive subtype (i.e., DLBCL, high-grade B-cell lymphoma) than those with FL1-2 and FL3A, who instead often recurred with indolent disease (i.e., FL1-2, FL3A; p&lt;0.001). We further compared FL3B patients to those with DLBCL classified based on cell-of-origin into GCB and non-GCB subtypes. At diagnosis, patients with FL3B had more favorable clinical features than those with GCB and non-GCB DLBCL. Compared to FL3B, patients with non-GCB DLBCL had an inferior EFS (HR 1.73 95%CI 1.07-2.79) and OS (HR 2.04 95%CI 1.11-3.75), while those with GCB DLBCL did not show a significant difference in EFS (HR 1.41 95%CI 0.88-2.25) or OS (HR 1.69, 95%CI 0.93-3.06) likely due to insufficient statistical power. Patients with FL3B failed EFS24 less frequently than patients with GCB or non-GCB DLBCL (17% vs 25% and 32%; p=0.01). Among patients who failed EFS24, those with FL3B had a similar subsequent OS as both GCB (HR 1.41 95%CI 0.73-2.72) and non-GCB DLBCL (HR 1.27 95%CI 0.65-2.47). Conclusions: We report that FL3Bp and FL3Bc appear clinically similar. While most FL3B patients have a prognosis comparable to FL1-2 and FL3A, 18% exhibit aggressive behavior with poor outcome reminiscent of DLBCL. Future studies with a larger population will be needed to confirm our findings.

Introduction: High-risk smoldering multiple myeloma (SMM) is an asymptomatic precursor disorder to active multiple myeloma (MM) without approved treatment options. However, recent evidence suggests patients at high risk of progression to MM may benefit from early treatment. Daratumumab (DARA) is a human IgGκ monoclonal antibody targeting CD38 with direct on-tumor and immunomodulatory mechanisms of action. DARA is approved as monotherapy for relapsed/refractory MM (RRMM) and in combination with standard-of-care regimens for RRMM and newly diagnosed MM. Based on the encouraging activity and tolerability observed with DARA monotherapy in patients with intermediate- or high-risk SMM in the phase 2 CENTAURUS study, the phase 3 AQUILA study sought to determine if DARA could delay progression to MM versus active monitoring. Here we report the primary analysis from the AQUILA study. Methods: Eligible patients had a confirmed diagnosis of high-risk SMM for ≤5 years, defined as clonal bone marrow plasma cells (BMPCs) ≥10% and ≥1 risk factor (serum M protein ≥30 g/L, IgA SMM, immunoparesis with reduction of 2 uninvolved Ig isotypes, serum involved:uninvolved free light chain ratio ≥8 and &lt;100, and/or clonal BMPCs &gt;50% to &lt;60%). Focal and lytic lesion assessment was performed in screening by CT and MRI and centrally reviewed prior to study enrollment. Patients were randomized 1:1 to receive DARA SC versus active monitoring. DARA (QW in Cycles 1 and 2, Q2W in Cycles 3-6, and Q4W thereafter) was given in 28-day cycles until cycle 39, 36 months, or disease progression, whichever came first. The primary endpoint was progression-free survival (PFS), defined as progression to active MM as assessed by an independent review committee and according to IMWG diagnostic criteria for MM (SLiM-CRAB) or death. Major secondary endpoints included overall response rate (ORR), PFS on first-line MM treatment (PFS2), and overall survival (OS). Results: A total of 390 patients (DARA, n = 194; active monitoring, n = 196) were randomized. Median (range) age (64 [31-86] years) and time from initial SMM diagnosis to randomization (0.72 [0-5.0] years) were balanced between treatment groups. Median treatment duration in the DARA group was 38 cycles (35.0 months). At a median (range) follow-up of 65.2 (0-76.6) months, PFS was significantly improved with DARA versus active monitoring (HR, 0.49; 95% CI, 0.36-0.67; P &lt;0.0001). Median PFS was not reached in the DARA group versus 41.5 months for active monitoring; estimated 60-month PFS rates were 63.1% versus 40.8%, respectively. Prespecified analyses showed generally consistent PFS improvement with DARA versus active monitoring across subgroups. ORR was 63.4% with DARA versus 2.0% with active monitoring (P &lt;0.0001). As of the clinical cutoff, 64 (33.0%) patients in the DARA group and 102 (52.0%) patients in the active monitoring group had started first-line MM treatment. Median time from randomization to the date of first-line MM treatment was not reached with DARA versus 50.2 months with active monitoring (HR, 0.46; 95% CI, 0.33-0.62; nominal P &lt;0.0001). There was a positive trend in favor of DARA for PFS2 (HR, 0.58; 95% CI, 0.35-0.96) and OS (60-month OS rates: DARA, 93.0%; active monitoring, 86.9%; HR, 0.52; 95% CI, 0.27-0.98). A total of 41 deaths were observed, 15 for the DARA group and 26 for the active monitoring group. Grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 40.4% and 30.1% of patients in the DARA and active monitoring groups, respectively. The most common (≥5% in either group) grade 3/4 TEAE was hypertension (DARA, 5.7%; active monitoring, 4.6%). The frequency of TEAEs leading to DARA discontinuation was low (5.7%), as was the incidence of fatal TEAEs in both groups (DARA, 1.0%; active monitoring, 2.0%). Conclusions: DARA monotherapy was well tolerated and demonstrated a clinically meaningful and significant benefit in preventing or delaying progression to active MM compared with active monitoring in patients with high-risk SMM. ORR was significantly higher and time to first-line MM treatment was prolonged with DARA compared with active monitoring. This was accompanied by positive trends for PFS2 and OS in favor of DARA. These results strongly support the benefit of early intervention with DARA monotherapy versus active monitoring, the current standard of care, in patients with high-risk SMM.

Background: Monoclonal B-cell lymphocytosis (MBL) is a common premalignant condition that can be classified into chronic lymphocytic leukemia (CLL)-type (CD5, CD23, and CD20 co-expression), and non-CLL-type (CD5-negative) based on flow cytometry immunophenotypes. CLL-type MBL is relatively well characterized with increased risk of hematologic (especially lymphoid) malignancies, serious infections, and decreased response to vaccinations. However, the prevalence, genetic predispositions, and clinical consequences of non-CLL-type MBL remain to be fully elucidated. Herein, we report findings in non-CLL-type MBL in a large screening cohort. Methods: We screened 10,330 individuals (40 years or older with no prior history of hematologic cancers) for MBL with highly sensitive flow cytometry, in the Mayo Clinic Biobank, with patients recruited from primary care-based clinics. Individuals were genotyped by Regeneron Genetics. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Among those individuals residing in the 27 counties surrounding Rochester, Minnesota, we identified incident hematologic malignancies and melanomas using ICD codes and the Rochester Epidemiology Project, a population based medical records linkage system. All diagnoses were manually reviewed for confirmation. Cox regression was used to calculate hazard ratios (HR) and 95% CIs, adjusted for age and sex. Results: We identified 1,736 individuals with MBL and 8,341 individuals without MBL. Among those with MBL, 246 (14.2%) had non-CLL-type MBL as the major clone. The median age of non-CLL-type MBL was 77 years (range, 47-95). The prevalence of non-CLL-type MBL significantly increased with age, with 0.5% prevalence among those between 40 to 59 years of age, 2.3% prevalence among those between 60 and 79 years, and 7.8% prevalence in those 80 years of age or older. The prevalence of non-CLL-type MBL was significantly higher (P &lt; .001) among males (3.1%) than females (2.0%). Using the genome-wide complex trait analysis tool, the heritability of non-CLL-type MBL was estimated to be ~26%, suggesting inherited genetics plays a role in etiology. To identify common inherited variants, we first evaluated the known CLL susceptibility variants, many of which also associated with CLL-type MBL. Among the 42 variants, none were statistically associated (all P &gt; .05) with non-CLL-type MBL. We next conducted a genome-wide association study to identify novel variants, and the most significant variant resided in 10q26.3 (minor allele frequency [MAF]control = 0.7%, MAFMBL = 3.5%, OR = 6.4, 95% CI 3.6-11.3, P = 5.7 * 10-8). Among the 6,478 individuals (192 with non-CLL-type MBL and 6,286 without MBL) followed for incident hematologic malignancies, 36 developed lymphoid and 23 developed myeloid malignancies after a median of 4.2 years of follow up. Similar to CLL-type MBL, non-CLL-type MBL was associated with a 5.2-fold risk for lymphoid malignancies (95% CI 2.0-13.0, P &lt; .001). Elevated but not significant risks were observed for myeloid malignancies (HR = 2.3, 95% CI 0.5-10.3, P = 0.27). The lymphoid malignancies developed by individuals with non-CLL-type MBL included diffuse large B-cell lymphoma, multiple myeloma, marginal zone lymphoma, and other low-grade lymphomas. We recently reported that individuals with CLL-type MBL are at higher risk for developing melanoma (HR = 1.9, 95% CI 1.3-2.8). Interestingly, non-CLL-type MBL had no evidence of an association with melanoma risk (HR = 0.4, 95% CI 0.1-1.8). We did not observe a significant difference in overall survival between individuals with non-CLL-type MBL vs those without MBL. Conclusions: In the largest screening cohort to date, we evaluated the etiology and clinical outcomes of non-CLL-type MBL, an understudied yet common condition that occurs in ~4 million adults in the United States. Non-CLL-type MBL is more common in men and older individuals, and evidence supports that inherited genetics plays an etiological role with 10q26.3 locus identified as a novel susceptibility locus. Individuals with non-CLL-type MBL had significantly increased risk of lymphoid malignancies, similar to CLL-type MBL, but, distinct from CLL-type MBL, no evidence of an increased risk of melanoma. Our study provides insights into the prevalence, genetic predispositions and clinical consequences of non-CLL-type MBL and how it differs from the classic CLL-type MBL.