Low-grade Follicular Lymphoma Research Articles

Case report: Mutation evolution in a patient with TdT positive high grade B cell lymphoma with MYC and BCL2 rearrangements following the treatment of concurrent follicular lymphoma and diffuse large B-cell lymphoma

BackgroundConcurrent follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL)was reported in some studies, while the diagnosis of TdT (terminal deoxynucleotydil transferase) positive high grade B cell lymphoma (HGBL) with MYC and BCL2 rearrangements (“double hit”) transformed from FL/DLBCL has been rarely reported. Herein, we described the clinical features and mutation profiles of a case diagnosed with TdT positive “double hit” HGBL following the treatment of FL/DLBCL.Case presentationThis is a 43-year-old Chinese man who was diagnosed with low grade FL (account for 80%) combined with DLBCL (20%) at a stage of IVB. The patient presented with BCL2/IGH translocation without MYC rearrangement, as well as the expressions of CD20, CD19, CD10 and BCL2 at the initial diagnosis of FL/DLBCL. MYC rearrangement and TdT expression occurred after the treatment. The targeted sequencing revealed mutations in KMT2D, FOXO1, CREBBP, ATM, STAT6, BCL7A, DDX3X, MUC4, FGFR3, ARID5B, DDX11 and PRKCSH genes were the co-mutations shared by the FL/DLBCL and TdT positive “double hit” HGBL, while CCND3, BIRC6, ROBO1 and CHEK2 mutations specifically occurred after the treatment. The overall survival time was 37.8 and 17.8 months after the initial diagnosis of FL/DLBCL and TdT positive “double hit” HGBL, respectively.ConclusionThis study reports a rare case of TdT positive “double hit” HGBL following the treatment of concurrent FL/DLBCL and highlights the mutation characteristics. Collectively, this study will help enrich the knowledge of TdT positive “double hit” HGBL transformed from FL/DLBCL.

Ovarian tissue biopsy for cryopreservation by vaginal natural orifice transluminal endoscopic surgery: a new approach for a minimal invasive ovarian biopsy

Vaginal natural orifice transluminal endoscopic surgery (vNOTES) is an emerging surgical procedure that combines the advantages of the vaginal approach with laparoscopic vision and instrumentation [1]. Shorter hospitalization and lower postoperative pain associated to vNOTES [2] may be explained by the advantages of this innovative surgical approach (such as absence of abdominal incisions, shorter operating time, lower insufflation pressure) [2;3]. Ovarian tissue cryopreservation allows to preserve reproductive and endocrine functions in young women with oncological disease at risk of premature ovarian insufficiency (POI) caused by gonadotoxic treatments [4]. Ovarian tissue biopsy for cryopreservation consists of a large biopsy of one or both ovaries [4] that is usually performed by laparoscopy. Then, the removed ovarian tissue is cryopreserved for the future transplant after cancer remission. Volume of ovarian biopsy ranges from 50% of the ovary for women at moderate risk of POI to 70 % or whole ovary for women at high risk [5]. Inclusion criteria for ovarian tissue cryopreservation are women aged less than 35 who cannot delay start of oncological treatments for follicles cryopreservation, with a moderate or high risk of POI and good chance of 5-year survival [6]. Ovarian tissue cryopreservation cannot be performed if tumor treatments include uterine irradiation or for tumors at risk of ovarian metastases (as in case of ovarian cancer, leukemia, neuroblastoma, Burkitt lymphoma) [7]. Despite widespread adoption of vNOTES in gynecology, ovarian biopsy for cryopreservation has never been performed using this route. Step-by-step explanation of the procedure with descriptive text and narrated video footage. Tertiary level referral academic center. A 27-years-old patient recently diagnosed with low grade follicular non-hodgkin lymphoma was referred to our center for ovarian tissue cryopreservation before chemotherapy. The patient included in this study gave informed consent for publication of the video and posting of the video online including social media, the journal website, scientific literature websites (such as PubMed, ScienceDirect, Scopus, etc.) and other applicable sites. Due to the nature of the study, IRB approval was not required. Access to peritoneal cavity was created by a 3 cm posterior colpotomy. Peritoneum was then opened using cold scissors and temporarily fixed to the posterior vaginal wall. The Gelpoint Mini Advanced Access Platform (Applied Medical, Rancho Santa Margarita, CA, USA), with one 10 mm and two 5 mm trocars, was used as vNOTES port. The inner Alexis ring of the Gelpoint was inserted through the colpotomy into the pouch of Douglas. An hysterometer was placed into the uterine cavity to keep the uterus anteverted during the surgery. A pneumoperitoneum was created to a pressure of 8 mmHg and the operating table was tilted to 20° Trendelenburg position. A 10-mm rigid 30° camera was inserted in the inferior and larger trocar and both the ovaries were visualized. 70 % of the left ovary was removed with cold scissors, in order to minimize trauma on the surgical specimen. After removal of the Gelpoint cap, ovarian biopsy was immediately picked-up by the biologist of our fertility center. The ovary was coagulated with bipolar instrument. Hysterometer was then replaced by a uterine manipulator to perform tubal patency test and blue dye passage through both the salpinges was observed. Finally, the Alexis retractor and the stich on the posterior peritoneum were removed and the vagina was sutured using interrupted stiches. Total operative time was 25 minutes. Ovarian tissue biopsy for cryopreservation by vNOTES. No intraoperative and postoperative complications were reported and the patient was discharged after 24 hours from surgery. VNOTES may be a feasible alternative approach to laparoscopy for ovarian tissue cryopreservation: it allows an easy access to the ovaries and removal of different tissue volumes. Patients undergoing ovarian cryopreservation may benefit of vNOTES approach since a rapid post-operative recovery is crucial to start chemotherapy in a short time. As for other vNOTES surgical procedures, accurate selection of patients seems to be crucial for a successful ovarian tissue cryopreservation [8]. We think that inclusion and exclusion criteria reported for other gynecologic procedures performed through vNOTES may also be valid for ovarian tissue cryopreservation by vNOTES [9]. Women at high risk of pelvic adhesions (such as coexistent endometriosis, previous pelvic surgery or inflammatory pelvic disease), with elevated Body Mass Index or enlarged uterus as well as women with cervical, vaginal or uterine cancer cannot be considered for this approach since all these factors are associated to failure of vNOTES. On the other hand, women with no history of surgery, endometriosis and large myomas may benefit from vNOTES approach and these women represent most of patients who undergo ovarian tissue cryopreservation.

Case Report: Primary follicular lymphoma of the colon presenting as an incidental finding on endoscopy

We present a previously healthy 63-year-old female with incidental polyps in the colon that were detected during a surveillance endoscopy. Clinical examination and imaging studies did not detect any lymphadenopathy or organomegaly. Histopathologic evaluation of polyps showed a low-grade primary follicular lymphoma. We suggest that follicular lymphoma should be considered as a differential diagnosis of polypoid lesions of the colon.

Digital and manual interfollicular Ki-67 are associated with a progression-free survival in patients with low-grade follicular lymphoma.

Novel histopathologic prognostic factors are needed to identify patients with follicular lymphoma (FL) at risk of inferior outcomes. Our primary objective was to evaluate the Ki-67 proliferative index in follicular and interfollicular areas in tissue biopsy specimens from patients with newly diagnosed FL and correlate with clinical outcomes. Our secondary objective was to correlate PD-L1 and LAG-3 with clinical outcomes. Seventy cases of low-grade FL from the University of Minnesota were evaluated with Ki-67 immunohistochemical stain. Ki-67 expression as a continuous variable was interpreted digitally and manually in follicular and interfollicular areas. Progression-free survival (PFS) and overall survival (OS) were analyzed by Cox regression, and hazard ratios (HRs) per 10-point increase in Ki-67 were calculated. Progression-free survival at 4 years was 28% (95% CI, 19%-41%). Interfollicular, but not follicular, Ki-67 was associated with PFS by manual (HR, 1.33; P = .01) and digital (HR, 1.38; P = .02) analysis. Digital and manual Ki-67 were only moderately correlated but demonstrated similar effects on PFS. At 4 years, OS was 90% with no association with follicular or interfollicular Ki-67 proliferation. Higher interfollicular Ki-67 by either digital or manual analysis is associated with a poorer PFS in patients with low-grade FL. These results suggest further validation of this marker is warranted to improve pathologic risk stratification at FL diagnosis. PD-L1 and LAG-3 were not associated with PFS or OS.

Concurrent metastatic melanoma and follicular lymphoma diagnosis on liver fine needle aspiration and biopsy

Abstract Introduction/Objective The liver is commonly involved in metastatic neoplasms, such as colorectal, breast, esophageal, stomach, pancreatic, lung, and kidney. Fine needle aspiration (FNA) and core needle biopsy (CNB) are frequently used to establish an accurate diagnosis of liver masses. Here we report the coexistence of metastatic malignant melanoma (MM) and follicular lymphoma (FL) involving the liver. To our knowledge, This is the first reported case, and we hope to add to the literature. Methods/Case Report The patient is a 75 -year-old woman diagnosed with stage I skin melanoma in 2004, and systemic low-grade FL in 2009. She presented with fatigue, weight loss, and difficulty swallowing. CT scan showed new pulmonary, hepatic, and splenic nodules with stable abdominal lymphadenopathy. Smears from the liver nodule FNA showed numerous single tumor cells with moderate cytoplasm and eccentrically located hyperchromatic nuclei. CNB showed fragments of liver parenchyma infiltrated by metastatic melanoma and a focal portal area with expansile lymphoid aggregates of small lymphocytes. The lymphoid cells were positive for CD10, CD20, PAX5, and BCL2 and negative for CD3, CD5, BCL6 and BCL1, with a low Ki-67 proliferative index (<5%). Although not characteristic of an FL, this immunophenotype was most consistent with FL given her clinical history. The metastatic MM was positive for SOX10 and Melan-A, while negative for CD45 and CK AE1/AE3. Despite neoadjuvant therapy, the patient died just two months after diagnosis. Results (if a Case Study enter NA) NA Conclusion A tremendous variety of neoplasms can occur in the liver. Different morphologies under a microscope should broaden the list of differential diagnoses. Familiarizing with morphological features and using ancillary studies are essential for accurate diagnosis and proper patient management. FNA and CNB combined with ancillary studies can successfully establish the diagnosis of malignancies involving the liver.

A Rare Case of Incidental Primary Follicular Lymphoma Co-Existing With Grade Group 5 Prostatic Adenocarcinoma

Abstract Introduction/Objective Primary lymphoma of the prostate is an exceedingly rare entity comprising less than 0.1% of all prostatic cancers with follicular lymphoma making up only 12% of primary prostatic lymphomas. There is very limited literature owing to their rarity and underdiagnosis. To the best of our knowledge, prostatic adenocarcinoma with an incidental follicular lymphoma presenting as a prostate imaging reporting and data system 4 (PI-RADS 4) lesion on multiparametric magnetic resonance imaging (mpMRI) with mildly elevated serum prostate specific antigen (PSA) has not been previously described. Methods/Case Report A 73 year old male presented to Danbury Hospital for follow up on benign prostatic hyperplasia (BPH) diagnosed in 2020. The patient was experiencing nocturia and had a serum PSA of 4.8. Multiparametric MRI revealed an enlarged, 5.5 x 4.1 x 3.3 cm, prostate gland (estimate weight of 45.5 grams) with a 1.2 cm PI-RADS 4 lesion in the right anterior mid gland. There was no evidence of metastatic disease on his most recent body imaging. He was subsequently scheduled for prostate needle biopsy. Histopathology showed a high grade prostatic adenocarcinoma, with a Gleason score 4 + 5=9, along with a focally prominent dense lymphoid infiltrate in four of four cores from the same area of abnormality that was detected on mpMRI. The latter comprised of ill defined follicles and sheets of small cleaved atypical lymphoid cells consistent with centrocytes and very few centroblasts. By immunohistochemical staining, the atypical cells in lymphoid follicles and interfollicular areas were positive for CD20, CD10 and BCL2 and negative for cyclin D1. CD21 stain highlighted the follicular dendritic cell meshwork in the germinal centers with a low Ki67 proliferation index. A final diagnosis of low grade follicular lymphoma (grade1-2) coexisting with the prostatic adenocarcinoma was rendered. The patient is currently undergoing lymphoma staging as the treatment for adenocarcinoma is planned. Results (if a Case Study enter NA) NA Conclusion Primary lymphoma of the prostate usually presents with non specific obstructive voiding symptoms and normal or near normal PSA levels which makes it challenging for physicians to suspect lymphomas. The lymphocytic infiltrate, originally thought to be prostatitis, underwent further evaluation with immunohistochemistry due to its monotonous appearance, which clinched the final diagnosis. Careful evaluation of prostate core needle biopsies is necessary even after spotting carcinoma in order to rule out low grade lymphomas.

Increased Frequency of Low-Grade Follicular Lymphoma with a High Proliferative Index: A First Step Towards Histological Transformation? a Retrospective Analysis of 25 Follicular Lymphoma Cases

Background: The most common form of indolent non-Hodgkin's lymphoma (NHL) is follicular lymphoma (FL). Although the overall survival of patients is currently over 20 years, 2-3% per year will suffer from histologic transformation. Patients with low-grade (WHO 1-2) FL with high proliferative index (PI), defined as Ki-67 expression ≥30%, have a shorter time to first treatment and worse disease-specific survival. Low-grade high-proliferative index (LG-HPI) is reported to account for 20% of low-grade FL cases. A specific clinical approach for LG-HPI is still controversial. Here, we report an increased frequency of LG-HPI cases in our institution and their associated clinical characteristics. Methods: We retrospectively analyzed a cohort of adult patients with a confirmed diagnosis of FL. Included patients had a tissue biopsy with defined Ki-67 by immunohistochemistry (IHC) and were categorized according to the WHO classification. A high proliferative index (PI) was defined as Ki-67 ≥30%. To compare their characteristics, patients were divided into three different categories: those with low grade and high proliferative index (LG-HPI), those with low grade and low proliferative index (LG-LPI), those with high grade (HG) including 2 cases with histologic transformation. All clinical and laboratory data were retrieved from the electronic clinical database. Frequencies of categorical variables were described as percentages, while continuous variables were described as medians. Comparisons were made using ANOVA. Results: A total of 25 patients were evaluated. The median age at diagnosis was 66 years and 40% were female (10). 17 patients had low-grade FL (68%), six had WHO 3a high-grade FL (24%), and two had transformed high-grade FL (8%). 14 patients (56%) were diagnosed at a localized stage (I - II) and eleven at an advanced stage (44%). After diagnosis, five patients were initially observed (20%), three received radiotherapy as a single treatment (12%), and 17 received chemoimmunotherapy (68%). For actively treated patients, the median time from diagnosis to treatment was 18 days (range 2 - 392 days). Overall, the median Ki-67 expression was 40% (range 3 - 90). Of the low grade FL patients, nine were LG-LPI (53%) and eight were LG-HPI (47%). Patients with LG-LPI had lower LDH levels and baseline SUVmax, which reached significance when compared to HG ( Figures 1 & 2). All patients initially observed at diagnosis were LG-LPI. We found no differences in hemoglobin, stage, albumin, beta-2 microglobulin, IgG and response to treatment between these groups. Data on progression or overall survival are yet immature. Discussion: Our data suggest that patients with LG-HPI may represent a higher proportion of FL cases than previously reported. Consistent with previous reports, LG-HPI is clinically more aggressive than LG-LPI and may represent an intermediate step toward transformation. Further improvements in quantitative Ki-67 standardization are needed to define its prognostic and clinical role.

Real-World Treatment Patterns and Outcomes of Patients (Pts) with Follicular Lymphoma (FL) Who Experienced Progression of Disease within 24 Months (POD24)

Introduction: Follicular lymphoma (FL) accounts for about 35% of all non-Hodgkin lymphomas and 70% of indolent lymphomas in the United States. Despite relatively high 1L remission rates, a clinically high-risk subgroup experiences early disease progression within 24 months of 1L initiation (POD24). As the understanding of this population evolves, a treatment paradigm is yet to be established. This study aimed to describe the characteristics of patients who experienced POD24 to 1L therapy and their outcomes following receipt of select 2L treatment sequences using a contemporary real-world (rw) dataset. Methods: Pts meeting the study criteria were identified in the COTA rw database. Eligible pts were aged ≥ 18 years at diagnosis (dx) with grade I-IIIA FL and had no documented grade IIIB or transformation anytime from dx until index date. Pts were treated with 1L CD20+chemotherapy (CHOP/CVP or Benda) and initiated 2L therapy with one of the following treatment categories between January 1, 2010 and December 31, 2019: Benda-CD20, CHOP/CVP-CD20, chemosalvage (e.g., R-ICE), or other novel therapy (e.g., lenalidomide-CD20). Pts were excluded if they were not treated with the specified 1L or 2L therapies, had missing or imprecise key study dates, multiple concurrent primary malignancies at dx, evidence of histologic transformation prior to 2L,1L or 2L clinical trial participation, or documentation of 1L maintenance therapy that did not contain CD20. Characteristics, treatment patterns, and outcomes were analyzed among pts who experienced POD24, defined as documented progression/relapse event within 24 months of 1L initiation. The index date was the date of 2L therapy initiation, and the observation period was defined as the duration of time from index date to the date of death or last visit date (if date of death was not available). Characteristics and treatment patterns were summarized as appropriate using means, medians, and/or counts and percentages. The following rw time to event outcomes were evaluated using the Kaplan-Meier method: time to next treatment (rwTTNT), progression-free survival (rwPFS), and overall survival (rwOS). Rw complete response rate (rwCRR) was calculated as the proportion of pts who achieved a complete response (CR) as the best response to 2L among all POD24 pts. Results: The study included 149 pts who experienced POD24 and met the remaining study criteria. An additional 170 pts (53.3%) qualified for the study but did not experience POD24. The median age at dx for POD24 pts was 61 years. This population was mostly male (57.0%), White (87.9%), and treated in the community practice setting (86.6%). More than 85% of pts had low grade FL at their last assessment at index. Following 1L therapy, 47.0%, 1.3%, 39.6%, and 0.7% of pts had a documented CR, near CR, partial response, or stable disease, respectively. About 11% of pts had progression as their best documented response to 1L. The most common 2L treatment category was Benda+CD20 (47.0%), followed by CHOP/CVP-CD20 (25.5%), chemosalvage (17.4%), and other novel therapies (10.0%). The CD20 received most commonly in 2L was rituximab (87.2%). Of 68 pts who received 3L, 11 (16.2%) received stem cell transplant. Median rwOS from 2L initiation overall was 64.8 months (95% CI: 54.0, 99.6). For pts who received Benda-CD20, CHOP/CVP-CD20, chemosalvage, and other novel therapies in 2L, 5-year rwOS rate from 2L initiation was 49.9%, 52.3%, 57.2%, and 86.2%, respectively. (Table 1) Median rwPFS from 2L initiation overall was 11.3 months, and pts who received Benda-CD20 or other novel therapies in 2L experienced median rwPFS of 25.6 and 18.0 months, respectively, while pts who received CHOP/CVP-CD20 or chemosalvage in 2L experienced median rwPFS of 8.3 and 4.6 months, respectively. (Figure 1) A similar trend was seen in rwTTNT from 2L initiation (overall: 19.6, Benda-CD20: 38.0, CHOP/CVP-CD20: 12.0, chemosalvage: 5.4, and other novel therapies: 19.6 months) and rwCRR for pts who received 2L (overall: 47.7%, Benda-CD20: 57.1%, CHOP/CVP-CD20: 34.2%, chemosalvage: 34.6%, and other novel therapies: 60.0%). Conclusions: Among pts who experienced POD24 and received qualified therapies, 2L outcomes highlight continued unmet need despite recent improvements. Future research is required to identify this subset of high-risk pts at diagnosis and to investigate prospectively the effect of novel therapeutic approaches on their treatment outcomes.

Response to Mosunetuzumab in Patients with B-Cell Lymphomas Relapsed or Refractory after CAR-T Cell Therapy Is Associated with Changes in Lymphocyte Counts

Introduction: Mosunetuzumab is a CD20/CD3 bispecific antibody that redirects endogenous T cells to kill malignant B cells by concomitantly binding to CD3 on T cells and CD20 on B cells. A multicenter phase I/II study evaluating mosunetuzumab in relapsed/refractory (r/r) non-Hodgkin lymphomas, including patients r/r after chimeric antigen receptor-modified T-cell therapies (CAR-T), was the basis for FDA approval for mosunetuzumab in follicular lymphoma (NCT02500407; Budde et al. Lancet Oncol 2022). We retrospectively assessed the impact of mosunetuzumab on lymphocyte counts and CAR T cells in responding and non-responding patients. Methods: Samples were collected prospectively from participants enrolled on NCT02500407 and exploratory post hoc analyses were performed on a subset of patients who had received prior CAR-T. P-values unadjusted for multiple comparisons are reported. We examined changes in absolute lymphocyte counts (ALC) and CAR-T transgene levels, as well as CD4 counts and CD8 counts, at baseline (C1D1) and prior to cycle 2 day 1 (C2D1) of mosunetuzumab. We also examined length of time from CAR-T to mosunetuzumab. CAR transgene levels were assessed by quantitative PCR. Results: 30 patients had cycle 1 day 1 (C1D1) and C2D1 paired samples available for analysis. 27 patients had large B-cell lymphoma (90%) and 3 patients had low-grade follicular lymphoma (10%). The doses of mosunetuzumab received ranged from 6mg - 60mg IV or 1.6mg - 20mg SC. The median time from CAR-T infusion to mosunetuzumab was 161 days (range: 35-1071); 40% of patients (12/30) received mosunetuzumab within 100 days of CAR-T, 43% of patients (13/30) received mosunetuzumab > 100-days to 1 year after CAR-T, and 17% (5/30) of patients received mosunetuzumab > 1 year after CAR-T infusion. We found that patients who responded to mosunetuzumab had a longer time from CAR-T infusion than non-responders (mean 342 days [range: 98-587] vs 110 days [range: 70-150], respectively, p = 0.02). Although there was no difference in baseline ALC, we found that responding patients had higher ALCs on C2D1 (p=0.005). For 15 patients with available T-cell subsets, CD4 counts were higher on C2D1 for responders (p=0.05). We also investigated changes in CAR transgene levels. 14/20 patients who received commercially available standard of care CAR-T products had detectable CAR transgene levels vs only 1/10 patients who received an investigational CAR-T due to assay limitations. Thus, we examined changes in CAR transgene levels in those patients who had received commercially available standard of care CAR-T (n=20). No difference was observed between responders and non-responders in CAR transgene copy numbers at baseline; however, on C2D1 after one cycle of mosunetuzumab, non-responding patients had a trend toward decrease in CAR transgene levels while responding patients had persistence or increase in CAR transgene levels (p=0.07). Conclusions: We observed higher peripheral blood lymphocytes after one cycle of mosunetuzumab in responding patients. Of interest, an increase in lymphocytes in responding patients had previously been described after blinatumomab (Klinger et al. Blood 2012). These findings may indicate a class effect of bispecific antibodies in general. We also found that patients who were r/r to CAR-T and responding to mosunetuzumab had a trend towards an increase in CAR transgene levels compared with patients not responding to mosunetuzumab. This suggests an interaction between CAR-T cells and bispecific antibodies. Finally, it is notable that post-CAR patients responding to mosunetuzumab had a longer time from CAR-T infusion, perhaps reflecting recovery from lymphodepletion. Further investigations are needed to understand the mechanism(s) behind these observations.

Treatment Outcomes of Limited Stage Grade 3A Follicular Lymphoma

Introduction While radiotherapy is the established standard of care for limited stage, grade 1-2 follicular lymphoma (FL), the management of localized grade 3A (FL3A) disease remains controversial. We reviewed the outcomes of grade 3A patients treated with definitive RT, systemic therapy (ST) alone or combined modality therapy (CMT) of RT plus ST. Methods We analyzed a single institution database to identify newly-diagnosed, FL3A patients with Ann Arbor stage I/II disease treated between 2000-2021. All cases were reviewed by the Hematopathology staff at the time of diagnosis. Patients were stratified by definitive treatment modality including RT monotherapy, CMT, or ST. Best post-RT imaging response was evaluated using Lugano criteria for all by CT, and by PET if available. Rate of complete response (CR), overall survival (OS), progression-free survival (PFS) and time to out-of-field progression were compared between the three treatment modalities. Progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan Meier from first day of treatment. Time to out-of-field progression was estimated via cumulative incidence function from treatment start date with competing events death without out-of-field progression of disease (PD) and in-field PD. Univariable Cox regression was used to assess possible clinicodemographic associations with PFS. Results 84 patients (median age 62, 38% male) were analyzed with median follow-up of 6.9 years from treatment. Patients were stage I (73%) or II (27%) and 92% were initially PET staged at diagnosis. 29 (35%) had extranodal disease. The most common site of extranodal disease was the head and neck (13% of patients). The median (IQR) baseline maximum SUV and maximum lesion size prior to treatment were 9.8 (5.4, 14.0) and 3.2 (2.0, 4.5) cm respectively, and did not differ between treatment groups. RT was the most commonly utilized treatment modality (n=48, 57%), followed by CMT (n=21, 25%), then ST (n=15, 18%). For RT/CMT patients the planned RT dose was most commonly 36 Gy (32%, range 4-40Gy). 2 patients (3%) received a very low dose program beginning with 4 Gy. Of the CMT/ST patients the most common regimen was 3-4 cycles of R-CHOP (53%). 3 patients (8%) received Rituximab alone. All ST patients were diagnosed after 2010. The ST subset had the highest proportion of patients with stage II disease (p<0.001), while CMT patients had the highest proportion of female patients (p=0.03) and grade 3 disease not further characterized (p=0.002). The rates of CR post-treatment were 88% for RT, 100% for CMT, and 87% for ST. Of the 22 patients who relapsed, only 1 suffered an infield relapse alone (4.5%) with the rest experiencing distant relapse (95.5%). The 5-year cumulative incidence of out-of-field progression was 32% (95%CI 18-46%) for RT, 11% (95%CI 1.7-30%) for CMT, and 17% (95%CI 2.3-43%) for ST. There were factors significantly associated with PFS univariably including the treatment modality (CMT vs. RT HR 0.30, 95% CI 0.10-0.91, p=0.03), and presence of low-grade FL component in the biopsy (HR 3.33, 95% CI 1.43-7.78, p=0.005). Age, sex, stage, extranodal status, Ki67 score, max pre-treatment size, and max pre-treatment SUV were not associated with PFS. The probability of transformation to DLBCL was 4.2% (95% CI 1.1-11%) at 5 years after treatment. Overall survival was excellent for all treatment modalities with median OS of 18 years for CMT, and not reached for RT or ST. Conclusion To our knowledge this is the largest study of the outcomes of early stage FL3A after therapy. CMT had the highest rate of CR in our cohort, and was associated with a statistically significantly lower hazard of PFS compared to RT. However, OS is excellent regardless of treatment modality suggesting all may be appropriate options.

Phase I Trial of ‘Re-Priming’ Radiation Therapy for Relapsed/Refractory Non-Hodgkin Lymphoma Patients in Incomplete Response after Chimeric Antigen Receptor T-Cell (CAR-T) Therapy

Inpatients with relapsed/refractory non-Hodgkin lymphoma (R/R NHL) treated with CD19-directed CAR-T, only ∼40% achieve complete response (CR) by day 30 PET/CT evaluation. Of those who do not, the large majority (∼70%) ultimately fail, providing an ideal target for early therapeutic intervention to 're-prime' CAR-T. Preclinical and early clinical studies suggest potential synergy and immune augmentation when combining RT with CAR-T. Here we report the phase I results of a prospective phase I/II clinical trial hypothesizing that early salvage focal RT to poor responding sites of disease after CAR-T in R/R NHL patients is safe (phase I) and will improve conversion to CR by day 90 post-CAR-T PET/CT from 29% (historical control) to 58% (phase II). Weopened a single-arm open-label phase I/II prospective clinical trial at our institution for R/R NHL patients treated with CD19-directed CAR-T with incomplete response on day 30 post-CAR-T PET/CT scan (defined as Lugano > = 4). The phase I component used a 'Rolling 6' design with 6 patients enrolled concurrently at the "definitive" dose level (40-50 Gy EQD2 [i.e., 30 Gy in 5 fractions], with de-escalation to "palliative" dose level (20-32.5 Gy EQD2 [i.e., 20 Gy in 5 fractions]) if >2 dose-limiting toxicities (DLT) observed. Hypofractionated regimens (i.e., 5 fractions) directed only to residual FDG-avid disease were recommended to minimize lymphopenia and potentially result in a more favorable immune microenvironment. DLT rate was defined within 60 days of RT by CTCAE v5.0 grade 4+ hematologic, grade 3+ dermatitis/burn, pneumonitis, enteritis, or other toxicity attributable to RT, as well as new grade 3+ cytokine release syndrome (CRS) per ASTCT consensus guidelines or grade 3+ neurotoxicity per ASTCT ICANS consensus guidelines for adults. BetweenApril 2021 and July 2022, 6 patients were enrolled. All 6 patients had diffuse large B-cell lymphoma (DLBCL), with 3/6 (50%) transformed from low-grade follicular lymphoma. 2/6 had primary refractory DLBL, while the other 4/6 had median 2.5 lines of treatment prior to CAR-T. No patient had prior RT to a site of residual FDG-avid disease on day 30 post-CAR-T PET/CT. 5/6 patients were treated to 30 Gy in 5 fractions, with the remainder patient treated to 36 Gy in 10 fractions. No grade 3+ DLTs related to RT were observed in the 60-day post-RT period. RT related toxicities included grad 1 alopecia, grade 1 radiation pneumonitis, grade 1 nausea & vomiting, and grade 2 skin infection. Early salvage focal "definitive" dose RT to sites of incomplete response on day 30 post-CAR-T PET/CT for R/R/ NHL patients was safe with no de-escalation of dose needed. This dose will used in the subsequent phase II component of the trial.

Theranostics in Hematooncology.

In the early 2000s, major clinical trials provided evidence of a favorable outcome from antibody-mediated radioimmunotherapy for hematologic neoplasms, which then led to Food and Drug Administration approval. For instance, the theranostic armamentarium for the referring hematooncologist now includes 90Y-ibritumomab tiuxetan for refractory low-grade follicular lymphoma or transformed B-cell non-Hodgkin lymphoma, as well as 131I-tositumomab for rituximab-refractory follicular lymphoma. Moreover, the first interim results of the SIERRA phase III trial reported beneficial effects from the use of 131I-anti-CD45 antibodies (Iomab-B) in refractory or relapsed acute myeloid leukemia. During the last decade, the concept of theranostics in hematooncology has been further expanded by C-X-C motif chemokine receptor 4-directed molecular imaging. Beyond improved detection rates of putative sites of disease, C-X-C motif chemokine receptor 4-directed PET/CT also selects candidates for radioligand therapy using β-emitting radioisotopes targeting the identical chemokine receptor on the lymphoma cell surface. Such image-piloted therapeutic strategies provided robust antilymphoma efficacy, along with desired eradication of the bone marrow niche, such as in patients with T- or B-cell lymphoma. As an integral part of the treatment plan, such radioligand therapy-mediated myeloablation also allows one to line up patients for stem cell transplantation, which leads to successful engraftment during the further treatment course. In this continuing education article, we provide an overview of the current advent of theranostics in hematooncology and highlight emerging clinical applications.

Treatment outcomes of Limited Stage Grade 3A Follicular Lymphoma

Introduction: While radiotherapy is an established standard of care for limited stage, low grade follicular lymphoma (FL), the management of localized FL grade 3A (FL3A) disease remains controversial. We reviewed the outcomes of grade 3A patients treated with definitive RT, combined modality therapy (CMT), or systemic therapy (ST) alone. Methods: We retrospectively analyzed a single institution database to identify newly-diagnosed, grade FL3A patients with Ann Arbor stage I/II disease treated between 2000 and 2021. Patients were stratified by definitive treatment modality including RT monotherapy, CMT, or ST. Best post-RT imaging response was evaluated using Lugano criteria for all by CT, and by PET if available. Rate of complete response (CR) was compared between the three treatment modalities. Progression-free survival (PFS) and Overall survival (OS) were calculated using Kaplan Meier from first day of treatment. Univariable Cox regression was used to assess possible clinicodemographic associations with PFS. Results: 84 patients (median age 62, 38% male) were analyzed with median follow-up of 6.9 years from initiation of treatment. Patients were stage I (73%) or II (27%) and 92% were initially PET staged at diagnosis. 29 (35%) had extranodal disease. The median (IQR) maximum SUV and size prior to treatment were 9.8 (5.4, 14.0) and 3.2 (2.0, 4.5) cm respectively. RT was the most common treatment modality (n = 48, 57%), followed by CMT (n = 21, 25%), then ST (n = 15, 18%). For RT/CMT patients the planned RT dose was most commonly 36 Gy (32%, range 4–40 Gy). 2 patients (3%) received very low dose of 4 Gy. Of the CMT/ST patients the most common regimen was 3–4 cycles of R-CHOP (53%). 3 patients (8%) received Rituximab alone. Compared to RT patients, ST patients were most likely to have been diagnosed after 2010 (p = 0.002) and have stage II disease (p < 0.001), while CMT patients were more likely to be female (p = 0.03) and have grade 3 disease not further characterized (p = 0.002). The rates of CR post-treatment were 88% for RT, 100% for CMT, and 87% for ST. Factors significantly associated with PFS univariably included the treatment modality (CMT vs. RT HR 0.30, 95% CI: 0.10–0.91, p = 0.03), and presence of low-grade FL component in the biopsy (HR 3.33, 95% CI: 1.43–7.78, p = 0.005). Age, sex, stage, extranodal status, Ki67 score, size, and SUV were not predictive of PFS. The probability of transformation to DLBCL was 4.2% (95% CI: 1.1%–11%) at 5 years after treatment. Overall survival was excellent for all treatment modalities with median OS of 18 years for CMT, and not reached for RT or ST. Keywords: Combination Therapies, Indolent non-Hodgkin lymphoma, Radiation Therapy Conflicts of interests pertinent to the abstract. A. Zelenetz Consultant or advisory role: ADC Therapeutics, AbbVie, Adaptive Biotechnologies Corp Arvinas, Inc. AstraZeneca BeiGene, Ltd. Bristol-Myers Squibb, Curio Science LLC, Dava Oncology, Genentech, Instituto de Ciencias Integradas, Kyowa Kirin Co., Ltd. MEI Pharma, Inc., Medscape, Oncopeptides, AB Sandoz, Inc., Secura Bio, Inc., Suzhou Liang Yihui Network Science and Technology Company, Limited G. Salles Consultant or advisory role: AbbVie, Aptitude Health, Bayer, BeiGene, Ltd., Bio Ascend, Bristol-Myers Squibb, Celgene, Epizyme, Everest Clinical Research Corporation, GenMab, Genentech, Gilead Pharmaceutical, Incyte, Ipsen, Janssen Pharmaceutical, Nordic Nanovector ASA, s, Inc., Loxo Oncology, Miltenyi Biotec Incorporated, MorphoSys AG, Novartis, Owkin, Inc., Physicians' Education Resource, RAPT Therapeutics, Regeneron Pharmaceuticals, Inc., Roche, Scientific Education Support Ltd., Takeda Millennium J. Yahalom Consultant or advisory role: Convergent R.N.R Ltd. B. Imber Consultant or advisory role: GT Medical Technologies, Inc.

Does low-grade follicular lymphoma with high proliferation index require a different treatment strategy? A single center experience.

e19537 Background: Follicular lymphoma is the most common indolent non-Hodgkin lymphoma (NHL). It accounts for 35% of all NHL. FL is divided into three grades based on the proportion of centroblasts. The clinical aggressiveness increases from grade 1 to 3a, but this does not translate to a different therapeutic approach. Some FL patients have a high proliferation index despite having low grade. We assume patients with high proliferation index FL have a more aggressive disease requiring a different therapeutic approach. Here, we examine this theory in a cohort of 145 patients with follicular lymphoma. Methods: This is a retrospective study of patients diagnosed with FL between 01/01/2011 to 12/31/2021. Patients with histological grade 1-3a and reported proliferation index were included. Low grade is defined as grades 1 and 2. A high grade is defined as grade 3a. A high proliferation index (PI) is defined as Ki67 ≥ 30%. Patients were divided into three groups: low grade/high PI (LG/HP), low grade/low PI (LG/LPI), and high grade (HG). Variables collected included age, gender, race, Ann Arbor staging, PET SUV max, FLIPI score, and treatment details. The primary endpoint is progression-free survival. Secondary endpoints include overall survival (OS) and time to first treatment. Univariate and multivariate Cox regression models were used to analyze predictors of PFS. Survival estimates were calculated using the Kaplan-Meier method and compared using the Log-rank test. Results: We identified 145 patients with follicular lymphoma. The median age was 64. The majority were males (54.5%), whites (94.5%) and had Ann Arbor stage of 3 (42.8%). The median SUV max was 10.6. More than half of the patients were in the LG/LP (60%) compared with LG/HP (22.1%) and HG (17.9%). The median follow-up was 48.7 months. Male gender (HR 1.88, CI 1.04-3.4, p 0.03), Ann Arbor stage 3 (HR 4.3, CI 1.0-18.5, p 0.48) and 4 (HR 8.1, CI 1.9-34.8, p 0.005), PET SUVmax (HR 1.06, CI 1.9-1.1, p 0.001), and grade 3 disease (HR 2.2, CI 1.1-4.2, p 0.02) were associated with increased risk of progression. However, on multivariate analysis, only stage 4 (HR 13.1, 95% CI 1.7-104.0, p 0.02) was associated with an increased risk of progression. Adjusted 4-year PFS was 76% for LG/LP, 71% for LG/HG, and 49% for HG. There was no difference in median OS or time to treatment initiation. Conclusions: Our analysis showed that the median PFS for LG/HP patients is numerically worse than LG/LP, but it did not reach statistical significance. In contrast to previous reports, the trajectory of LG/HG is closer to LG/LP group rather than the HG group. Although outcomes are slightly worse for LG/HP compared with LG/LG, it does not justify a different treatment approach. However, a closer follow-up is warranted. Our study is limited by its retrospective nature and its inherent bias; using cox regression model to adjust for baseline characteristics would help mitigate this bias.

Outcomes in primary gastrointestinal (GI) follicular lymphoma (FL): results from a multicenter analysis

Introduction: GI FL is a rare disease, accounting for less than 5% of GI non-Hodgkin’s lymphomas (NHL). We formed a consortium to clarify baseline features, common practices and survival outcomes in primary GI FL. Methods: A retrospective analysis of 182 patients (pts) with primary GI FL from 8 institutions was conducted. Overall survival (OS) and progression-free survival (PFS) were assessed. Cox regression models were used to estimate hazard ratios (HR) with 95% confidence intervals (CI). Results: Median age at diagnosis (dx) was 60 years (yrs) (IQR: 51–68). 89% (n = 141) of pts had low-grade FL by histology, and most presented with a low-risk score by FLIPI (68%, n = 111) or FLIPI-2 (76%, n = 103). At presentation, 18% (n = 32) of pts were asymptomatic, and 71% (n = 124) had at least one GI symptom, most commonly abdominal pain (40%, n = 70). 5% (n = 9) of pts presented with overt GI bleeding, and 9% (n = 15) with bowel obstruction. The most common first-line strategy was observation (33%, n = 59), of which 36% (n = 21) underwent surgical resection at dx. Other regimens included single-agent rituximab (R) (22%, n = 39), chemoimmunotherapy (CI) with R-bendamustine (18%, n = 32) or R-CHOP (11%, n = 19), and radiation therapy (5%, n = 9). The remainder received other CI combinations or R-lenalidomide. For those observed, median time to first treatment (tx) was 4.6 yrs. For those treated, overall response rate was 83% (95% CI, 76%–89%), and median time to second-line tx was 3.7 yrs. With median follow-up of 5.7 yrs, median OS was not reached. 5-yr PFS and OS were 71% (95% CI, 64%–79%) and 93% (95% CI, 89%–98%), respectively. Relevant factors that did not show a significant effect on PFS/OS included advanced disease by Paris and Ann Arbor staging systems, high-risk disease by FLIPI or FLIPI-2, B symptoms, GI symptoms, location of disease within the GI tract, and bone marrow involvement. Patients who were initially observed had similar OS to those who were treated up-front; PFS/OS did not improve significantly with use of maintenance rituximab. Factors that significantly impacted PFS and/or OS are outlined in Table 1. Conclusion: This multi-institutional analysis describes characteristics of the largest cohort of pts with GI FL to date. Observation or tx with rituximab ± chemotherapy were common initial approaches. Patients in this cohort had a good overall prognosis. While some factors including age, grade and BCL-2 expression by immunohistochemistry (IHC) predicted survival, traditional prognostic indices and staging systems did not. The research was funded by: No funding to disclose. Keyword: Extranodal non-Hodgkin lymphoma Conflicts of interests pertinent to the abstract. T. Alrifai Consultant or advisory role: Previous independent consultancy for MJH Life Sciences; completed in June of 2022. J. Kline Employment or leadership position: Speaker for Kite Pharma, Inc./Gilead. B.A.D Consultant or advisory role: Advisory boards for Merck, Kite Pharma, Inc./Gilead, Seattle Genetics, and Verastem Oncology Honoraria: Has received advisory board fees from Janssen, Sanofi, and consulting fees from COTA Healthcare. Research funding: Research support from Merck, iTeos, and Verastem Oncology R. Karmali Employment or leadership position: Speakers Bureau: AstraZeneca, BeiGene, Morphosys Consultant or advisory role: Advisory Board: BMS, Gilead Sciences/Kite Pharma, Janssen, Pharmacyclics, Morphosys, Epizyme, Genentech/Roche, Calithera, Miltenyi, Lilly Oncology Research funding: Grants/Research Support: BMS, Takeda, BeiGene, Gilead Sciences/Kite, Calithera

Clinicopathological and molecular genetic characteristics of primary gastric follicular lymphoma

Primary gastric follicular lymphomas (FLs) have been rarely reported, and little is known about their characteristics. In the present study, we report 5 cases of primary gastric FL and describe their clinicopathological and molecular genetic features. A total of 7 samples from 5 patients were investigated for clinicopathological characteristics and somatic mutations by the targeted sequencing of 50 lymphoma-related genes. Two cases were identified as slightly elevated submucosal tumors and 3 cases as polypoid tumors. Histologically, all cases were low-grade FLs. The immunoprofile was CD20+/CD10+/BCL2+ in 4 cases and CD20+/CD10+/BCL2- in 1 case. The immunostaining pattern for CD21 was similar to that of classic FL. BCL2 rearrangement was not identified in fluorescence in situ hybridization studies in any of the 5 cases. Next-generation sequencing analysis showed mutations in genes involved in epigenetic modifications (KMT2D, ARID1A, EP300, and CREBBP), NK-kB pathway (CARD11), and JAK-STAT pathway as found in classic FL. All cases presented with clinical I without the involvement of regional or systemic lymph nodes. Four patients were well, whereas 1 patient who received endoscopic mucosal resection of tumor without additional chemotherapy or radiotherapy experienced 3 relapses. In conclusion, primary gastric FL is characterized by a low-grade neoplasm with infrequent BCL2 rearrangement. After resection of the lesion, additional treatment such as radiation therapy or chemotherapy is required as there is a possibility of recurrence.

Yttrium-90 Ibritumomab Tiuxetan is Cost-Effective Compared to Bendamustine+Rituximab in Low-grade Lymphomas.

Yttrium-90 ibritumomab tiuxetan [(90)Y-IT] is a CD20-targeted radio-immunotherapeutic agent. It has shown an excellent therapeutic activity with high tolerability against previously untreated follicular lymphoma (FL) and marginal zone B cell lymphoma (MZL). It is an attractive therapeutic option as the treatment schedule is short and convenient. The aim of our study is to determine the cost-effectiveness of (90)Y-IT in comparison to the standard-of-care bendamustine+rituximab (BR) in the first-line treatment of low-grade FL (LG-FL) and MZL in the real world. We included all patients who were treated with standard-dose (90)Y-IT for previously untreated LG-FL and MZL at the Mayo Clinic Cancer Center (N=51). A comparator arm with a historical cohort of previously untreated LG-FL and MZL patients who received BR was used (N=92). Inverse propensity weighting was utilized to balance the 2 study arms. There were no differences in terms of overall response rate (100% vs. 98%, P=.18), complete response rate (94% vs. 95%, P=.91), or 5 years progression-free survival (76% vs. 75%, P=.63) between patients who received (90)Y-IT and BR, respectively. Within the first year, patients who received (90)Y-IT required an average of 4.5 fewer oncology clinic visits (P < .001), an average of 10 fewer days of therapeutic use (P < .001), and 40% less use of growth factors (P < .001) as compared to the BR group. The direct therapeutic cost of (90)Y-IT treatment was 54% less than that of 6 cycles of BR. The findings suggest that (90) Y-IT is more cost-effective than BR and is a viable alternative in up-front management of LG-FL and MZL.

Low-grade follicular lymphoma with extensive marginal zone differentiation and expression of MUM1 and CD30

Low-grade follicular lymphoma with extensive marginal zone differentiation and expression of MUM1 and CD30

Outcomes in grade 3B follicular lymphoma: an international study led by the Australasian Lymphoma Alliance.

Grade (G) 3B follicular lymphoma (FL) is a rare FL subtype which exists on a histological continuum between 'lowgrade' (Grade 1, 2 and 3A FL) and diffuse large B-cell lymphoma (DLBCL) appearing to share features with each. Clinical characteristics and outcomes are poorly understood due to lack of adequate representation in prospective trials and large-scale analyses. We analyzed 157 G3BFL cases from 18 international centers, and two comparator groups; G3AFL (n=302) and DLBCL (n=548). Composite histology with DLBCL or low-grade FL occurred in approximately half of the G3BFL cases. With a median of 5 years follow-up, the overall survival and progression-free survival of G3BFL patients was better than that of DLBCL patients (P<0.001 and P<0.001, respectively); however, G3BFL patients were younger (P<0.001) with better performance status (P<0.001), less extranodal disease (P<0.001) and more frequently had normal lactate dehydrogenase (P<0.001) at baseline. The overall and progression-free survival of patients with G3BFL and G3AFL were similar (P=0.83 and P=0.80, respectively). After frontline immunochemotherapy, 24% of G3BFL relapsed; relapse rates were 63% in the DLBCL cohort and 19% in the low-grade FL cohort. Eight percent of relapses occurred beyond 5 years. In this G3BFL cohort, the revised International Prognostic Index successfully delineated risk groups, but the Follicular Lymphoma International Prognostic Index did not. We conclude that patients with immunochemotherapy-treated G3BFL have similar survival outcomes to those with G3AFL, yet a favorable baseline profile and distinctly superior prognosis compared to patients with DLBCL.

Efficacy Analysis of Bendamustine-Based Combination Regimen in Treatment of Patients with Relapsed/Refractory Non-Hodgkin Lymphoma

To investigate the efficacy and safety of bendamustine combined with gemcitabine, vinorelbine，glucocorticoids (BeGEV)±X regimen in treatment of patients with relapsed/refractory non-Hodgkin lymphoma. A total of 18 relapsed/ refractory non-Hodgkin lymphoma patients at the age of 18 years or older hospitalized in the First People's Hospital of Changzhou from March 2020 to March 2021 were selected. They received two or more cycles of BeGEV±X regimen. X could be anti-CD20 monoclonal antibody, PD-1-blocking antibodies, lenalidomide, BTK inhibitor, Bcl-2 inhibitor and so on according to patients' disease feature. The clinical efficacy and adverse effects were observed. In total, 18 patients completed two or more cycles of BeGEV±X regimen, including 14 with diffuse large B-cell lymphoma, one with low-grade follicular lymphoma, one with follicular lymphoma grade 3b, one with angioimmunoblastic T-cell lymphoma and one with peripheral T-cell lymphoma, not otherwise specified. 11 patients were male. The median age of the patients was 64 years old. 17 patients had modified Ann Arbor stage Ⅲ/Ⅳ disease. 13 patients had high- intermediate risk or high risk IPI score, while 15 patients had high-intermediate high risk or high risk NCCN-IPI score. 14 cases had extranodal sites of disease. And 6 cases had bulky disease. 12 patients experienced refractory disease, while 8 patients had received 3 line or more prior treatment. After two or three cycles of chemotherapy, the complete response rate was 6/18, the partial response rate was 3/18, and the objective response rate was 9/18. From the beginning of salvage chemotherapy to the end of follow-up, the median progression-free survival time was 130 days, and the median overall survival was 152 days. The most common grade 3 to 4 adverse events were hematologic toxicities, infection and febrile neutropenia. BeGEV±X is an effective salvage regimen in treatment of patients with relapsed/refractory non-Hodgkin lymphoma, while adverse events such as hematologic toxicities and infection should be closely monitored.