Aggressive Large B-cell Lymphoma Research Articles

Economic evaluation of anti-CD19 CAR T-cell pathway for large B-cell lymphomas in the real-life setting: the experience of an Italian hub center in the first three years of activity.

Poor literature report actual and detailed costs of chimeric antigen receptor (CAR) T-cell pathway in a real-life setting. We retrospectively collect data for all patients with relapsed/refractory aggressive large B-cell lymphoma who underwent leukapheresis between August 2019 and August 2022. All costs and medical resource consumption accountability were calculated on an intention-to-treat (ITT) basis, starting from leukapheresis to the time when the patient (infused or not) exited the CAR T-cell pathway for any reason. Eighty patients were addressed to leukapheresis and 59 were finally infused. After excluding CAR-T product cost, the main driver of higher costs were hospitalizations followed by the examinations/procedures and other drugs, respectively 43.9%, 26.3% and 25.4% of the total. Regarding costs of drugs and medications other than CAR T products, the most expensive items are those referred to AEs, both infective and extra-infective within 30days from infusion, that account for 63% of the total. Density plot of cost analyses did not show any statistically significant difference with respect to the years of leukapheresis or infusion. To achieve finally 59/80 infused patients the per capita patients without CAR-T products results 74,000 euros. This analysis covers a growing concern on health systems, the burden of expenses related to CAR T-cell therapy, which appears to provide significant clinical benefit despite its high cost, thus making economic evaluations highly relevant. The relevance of this study should be also viewed in light of continuously evolving indications for this therapy.

Clinicopathological and genetic landscape of plasmablastic lymphoma in Taiwan

Plasmablastic lymphoma (PBL) is an aggressive large B-cell lymphoma with a terminal B-cell differentiation phenotype and is frequently associated with immunodeficiency. We aimed to investigate the clinicopathological and immunophenotypic features, genetic alterations, and mutational landscape of PBL in Taiwan. We retrospectively recruited 26 cases. Five (5/18; 28%) patients were HIV-positive and 21 (81%) presented extranodally. There were two morphological groups: one with purely monomorphic large cells (85%) and the other comprising large cells admixed with plasmacytic cells (15%). Phenotypically, the tumors expressed MYC (8/10; 80%), CD138 (20/26; 77%), and MUM1 (20/20; 100%), but not CD20 (n = 26; 0%). Fourteen (54%) cases were positive for EBV by in situ hybridization; the EBV-positive cases were more frequently HIV infected (p = 0.036), with extranodal presentation (p = 0.012) and CD79a expression (p = 0.012), but less frequent light chain restriction (p = 0.029). Using fluorescence in situ hybridization, we identified 13q14 deletion, MYC rearrangement, and CCND1 rearrangement in 74%, 30%, and 5% cases, respectively, without any cases having rearranged BCL6 or IGH::FGFR3 fusion. In the 15 cases with adequate tissue for whole exome sequencing, the most frequent recurrent mutations were STAT3 (40%), NRAS (27%), and KRAS (20%). In conclusion, most PBL cases in Taiwan were HIV-unrelated. Around half of the cases were positive for EBV, with distinct clinicopathological features. Deletion of chromosome 13q14 was frequent. The PBL cases in Taiwan showed recurrent mutations involving JAK-STAT, RAS-MAPK, epigenetic regulation, and NOTCH signaling pathways, findings similar to that from the West.

Effectiveness of Chemo-Immunotherapy (CIT) and Novel Therapies in Second or Later Line of Therapy (2L+) for Patients with Relapsed/Refractory (R/R) Aggressive Large B-Cell Lymphoma (LBCL)

Aim: Patients with R/R LBCL after first-line treatment have poor prognosis. Multiple novel therapies have been approved for R/R LBCL in recent years, but CIT regimens are still commonly used. This study evaluated the effectiveness of CIT and novel therapies in 2L+ in patients with R/R LBCL and the association between patient clinical characteristics and real-world outcomes. Methods: This was a multi-site retrospective observational study of patients aged ≥18 years with R/R LBCL in the Lymphoma Epidemiology of Outcomes (LEO) Consortium of Real-World Evidence (CReWE) cohort (patients followed from 1/1/2015 to 2/15/2023) who were treated with CIT or novel therapy in 2L+. CIT regimens included salvage/palliative chemotherapy, lenalidomide, rituximab, or obinutuzumab, used alone or in combination. Novel therapies included polatuzumab vedotin plus bendamustine and rituximab or variations thereof (i.e., pola-based regimen), tafasitamab plus lenalidomide or variations thereof (tafa-based regimen), and loncastuximab tesirine (lonca). Patients' demographic and clinical characteristics were assessed from the first confirmed R/R disease diagnosis and initiation of 2L+ therapy. When multiple lines of therapy (LOTs) were eligible for inclusion in the analysis, one was randomly selected as the index LOT. Real-world outcomes, determined by investigators at each clinical site, including overall response rate (ORR), complete response (CR) rate, duration of response (DOR), duration of complete response (DOCR), progression-free survival (PFS), and overall survival (OS) were described for all patients in each treatment group and for the subgroup of patients with prior chimeric antigen receptor (CAR) T-cell therapy. Multivariable Cox Proportional Hazards models were used to assess associations between select patient clinical characteristics and real-world outcomes. Results: The study population included patients treated with CIT (N=653), pola-based regimen (N=116), tafa-based regimen (N=55), and lonca (N=42) ( Figure 1A). The median (m) age at date of index treatment initiation across groups ranged from 63 to 74 years. Across groups, most patients had primary refractory disease-i.e., were refractory to the first LOT (69.5% CIT vs. 73.3% pola vs. 58.2% tafa vs. 71.4% lonca), whereas variable proportions had one prior LOT (65.5% vs. 17.2% vs. 43.6% vs. 7.1%) and prior CAR T-cell therapy (5.1% vs. 43.1% vs. 32.7% vs. 47.6%). In the CIT group, ORR was 33.8%, 15.5% of patients achieved CR, mPFS (95% CI) was 1.9 (1.7, 2.1) months, and mOS was 9.1 (8.1, 10.5) months. In the pola group, ORR was 42.2%, 24.1% of patients achieved CR, mPFS was 2.5 (2, 3.2) months and mOS was 7.8 (6.4, 11.8) months. In the tafa group, ORR was 25.5%, 14.5% of patients achieved CR, mPFS was 2.7 (2.1, 4.2) months, and mOS was 8 (5.3, 12.7) months. In the lonca group, ORR was 40.5%, 21.4% of patients achieved CR, mPFS was 3 (2.1, 5.1) months, and mOS was 4.7 (3.7, 10.8) months. Demographics and outcomes for all patients and those who received prior CAR T-cell therapy are summarized in Figure 1A. In the multivariable Cox regression analysis, International Prognostic Index (IPI) risk score ≥3, CIT as the index treatment type, and primary refractory status were significantly associated with time from response to progression/death (P<0.05; Figure 1B). IPI risk score ≥3, CIT as the index treatment type, and primary refractory status were significantly associated with worse PFS. IPI risk ≥3, ≥3 prior LOTs, and primary refractory status were significantly associated with OS. Conclusion: In this large clinical cohort of patients with R/R LBCL with high proportions having primary refractory disease, all common treatments were associated with modest ORR/CR and poor OS. Receiving CIT treatments, higher IPI score, primary refractory status, and higher number of prior LOTs were significantly associated with poor clinical outcomes. A study with larger sample size and longer follow-up may be warranted to further understand the clinical effectiveness of novel treatments. Thus, despite the availability of novel treatments during the study period, these findings highlight the need for more effective treatment alternatives beyond currently available options to improve outcomes.

Clinical Impact of Neoantigen Burden and HLA Loss in Aggressive B-Cell Lymphomas Treated with CD19 CAR T-Cell

INTRODUCTION: CD19-directed chimeric antigen receptor (CAR-19) T cells have revolutionized clinical outcomes in heavily pretreated patients with aggressive B-cell lymphoma. Notably, emerging evidence suggests that the efficacy of CAR-19 therapy extends beyond direct tumor killing and includes its ability to stimulate and guide the host immune system in the fight against tumor cells. To delve deeper into this crucial aspect, our study utilized whole-genome sequencing (WGS) data to explore the impact of neoantigen burden and HLA loss in patients with aggressive large B-cell lymphoma (rrLBCL) who received CAR-19 therapy (WGS; Jain et al. Blood 2022). METHODS: To characterize the importance of genomic immunogenicity in rrLBCL, we conducted a comprehensive analysis of 61 whole-genome sequencing (WGS) and 54 RNA sequencing samples from 54 rrLBCL patients who underwent CAR-19 therapy. Among these samples, 39 were collected at baseline and 15 at relapse, with samples from 7 patients obtained both before and after treatment. Our analytical workflow defined HLA class I mono- or biallelic loss by integrating copy number variants, structural variants, single nucleotide variants, and small insertion-deletion data with allele-specific HLA loss information obtained from LOHHLA software. pVACseq algorithm was used to predict the number of clonal neoantigens in each sample, along with the corresponding HLA allele presenting each of them. RESULTS: HLA class I loss was detected in 38.9% of the patients, with no impact on progression free survival (PFS). Interestingly 7 patients had biallelic loss of HLA-B, and all of them experienced progression within the first year (p=0.03). To expand our analysis, we explored B2M an essential component of HLA class I complexes. B2M was lost in 33.3% of the patients without showing any association with shorter PFS. However, restricting the analysis to patients with B2M biallelic loss (defined as presence of deletions of both alleles, or deletion and mutation with high impact in the structure and function of the B2M protein) 4/4 patients progressed. Overall, all 11 patients with genomic events leading to biallelic loss of HLA class I progressed (p=0.007). Notably, in one patient (CAR_39), biallelic inactivation of HLA class I was not detected at baseline but emerged with the dominant clone at disease progression. HLA class I biallelic loss was associated with genomic drivers previously identified in our study as significantly associated with CAR-19 failure: APOBEC (3/11) and SBS18 (oxygen radical stress; 2/11) mutational signatures, chromothripsis (4/11), RHOA deletions (6/11), and double minutes (4/11). Next, we analyzed the impact of the neoantigen burden corrected for their HLA affinity and allelic status on the outcome of CAR-19 treatment. Patients with high number of neoantigens had shorter PFS (p=0.0095) and were enriched for genomic drivers associated with poor response after CAR-19 (e.g., APOBEC and SBS18). Interestingly, the neoantigen burden had a bimodal distribution across patients that progressed with two distinct groups: one with high neoantigen burden, biallelic loss of HLA, and high genomic complexity and the other with low genomic complexity and low neoantigen burden. Restricting the analysis to patients with retained HLA and low genomic complexity, high neoantigen burden associated with prolonged and favorable response to CAR-T therapy (p=0.04). CONCLUSION: This study offers evidence that there is a critical relationship between CAR-19 efficacy, LBCL immunogenicity, and the endogenous immune response.

Adding a Gene Expression Profile Test to Aid Differential Diagnosis and Treatment in Aggressive Large B-Cell Lymphoma: An Early Exploratory Economic Evaluation.

Adding gene expression profiles (GEPs) to the current diagnostic work-up of aggressive large B-cell lymphomas may lead to the reclassification of patients, treatment changes and improved outcomes. A GEP test is in development using TempO-Seq® technology to distinguish Burkitt lymphoma (BL) and primary mediastinal large B-cell lymphoma (PMBCL) from diffuse large B-cell lymphoma (DLBCL), and to classify patients with DLBLC and to predict the benefit of (e.g.) adding bortezomib to R-CHOP therapy (RB-CHOP). This study aims to estimate the potential impact of a GEP test on costs and health outcomes to inform pricing and evidence generation strategies. Three decision models were developed comparing diagnostic strategies with and without GEP signatures over a lifetime horizon using a UK health and social care perspective. Inputs were taken from a recent clinical trial, literature and expert opinion. We estimated the maximum price of the test using a threshold of Great Britain Pound (GBP) 30,000 per quality-adjusted life-year (QALY). Sensitivity analyses were conducted. The estimated maximum threshold price for a combined test to be cost effective is GBP 15,352. At base-case values, the BL signature delivers QALY gains of 0.054 at an additional cost of GBP 275. This results in a net monetary benefit at a threshold of GBP 30,000 per QALY of GBP 1345. For PMBCL, the QALY gain was 0.0011 at a cost saving of GBP 406 and the net monetary benefit was GBP 437. The hazard ratio for the impact of treating BL less intensively must be at least 1.2 for a positive net monetary benefit. For identifying patients with the DLBCL subtype responsive to bortezomib, QALY gain was 0.2465 at a cost saving of GBP 6175, resulting in a net monetary benefit of GBP 13,570. In a probabilistic sensitivity analysis using 1000 simulations, a testing strategy was superior to a treat all with R-CHOP strategy in 81% of the simulations and with a cost saving in 92% assuming a cost price of zero. Our estimates show that the combined test has a high probability of being cost effective. There is good quality evidence for the benefit of subtyping DLBCL but the evidence on the number of patients reclassified to or from BL and PMBCL and the impact of a more precise diagnosis and the cost of treatment is weak. The developers can use the price estimate to inform a return on investment calculations. Evidence will be required of how well the TempO-Seq® technology performs compared to the testing GEP technology used for subtyping in the recent clinical trial. For BL and PMBCL elements of the test, evidence would be required of the number of patients reclassified and improved costing information would be useful. The diagnostic and therapeutic environment in haematological malignancies is fast moving, which increases the risk for developers of diagnostic tests.

A Single Center Experience with Using Dose-Adjusted Repoch in Elderly Patients with Large B-Cell Lymphoma

Background: RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) has been the predominant regimen for treatment of aggressive large B-cell lymphomas (LBCL). In the CALGB 50303 trial, REPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) was associated with similar efficacy but increased toxicity compared to RCHOP, however pts with higher risk disease by International Prognostic Index (IPI) had longer progression-free survival (PFS) with REPOCH therapy in the subgroup analysis ( J Clin Oncol, 2019). Providers may be hesitant to use REPOCH therapy in older, frail patients (pts) with high-risk LBCL due to concern for increased toxicity. One study demonstrated that empirically dose-reduced REPOCH (30-50% dose reduction by age group) was effective and well-tolerated in an elderly population ( Ann Hematol, 2018).A separate study showed significantly reduced neuropathy rates without compromised efficacy when vincristine doses in the REPOCH regimen were capped at 0.5 mg/d compared to 0.4 mg/m 2/d ( Leukemia & Lymphoma, 2019). At our institution, vincristine doses are capped at 0.4 mg/d for all pts, and REPOCH dosing is not empirically dose-reduced based for age alone. The aim of this study is to provide additional insights on the safety and efficacy of REPOCH in elderly pts diagnosed with LBCL with a routine vincristine dose cap of 0.4 mg/day (“REPOCH 0.4”). Methods: In this single cohort study, pts with newly diagnosed LBCL that received dose-adjusted REPOCH 0.4 at a single institution from August 2015 to October 2020 were retrospectively reviewed. Pts were excluded if they received fewer than 2 cycles, had CNS disease, transferred to another facility during treatment, or were lost-to-follow-up. Primary endpoints included adverse effects (AEs), overall response rates (ORR) via Lugano staging at end of treatment, 2y PFS, and overall survival (OS). Survival endpoints were estimated via Kaplan-Meier survival analysis. Secondary endpoints included CNS relapse rates and percentage of pts electing for hospice during therapy. Outcomes were descriptively compared to the historical cohort (N=241) in the CALGB 50303 trial receiving R-REPOCH without a vincristine dose cap ( J Clin Oncol, 2019) . Results: Forty-six pts were eligible for analysis (“entire cohort”), 19 of whom were 70 years or older (“70+ cohort”, figure 1). Median age in the entire and 70+ cohort was 67 and 75 years respectively. In the entire cohort, 23.9% of pts were double-hit, 43.5% had a non-germinal center phenotype, and 78.3% had stage III-IV disease. The median number of REPOCH 0.4 cycles received in both the entire and 70+ cohort was 6. In the 70+ cohort, 57.9% of pts were escalated to a dose level (DL) of 2 or 3 with no pts escalated beyond DL 3. Fifty-eight percent of pts in the entire cohort received intrathecal CNS prophylaxis and all pts received pegfilgrastim support. Pts in the entire cohort were older and higher-risk in comparison to the historical cohort as evidenced by IPI risk and double-expressor status. In the entire cohort, REPOCH 0.4 was well-tolerated (figure 2) with grade 3+ neuropathy rates of only 2.2% (5.2% in the 70+ cohort). Febrile neutropenia (all grades) occurred in 19.5% and 15.8% of the entire cohort and 70+ cohort respectively. Only 1 patient in the 70+ cohort experienced acute ejection fraction (EF) decline during therapy. ORR (complete and partial response) in the entire and 70+ cohort were 80% and 74% respectively. Complete response (CR) rates in the entire and 70+ cohort were both 63%. 2y PFS in the entire cohort was 68.3% (median not reached), and the 2y OS in the entire cohort was 82.9% (median not reached) which compares favorably to the 2y OS of 86.5% in the historical cohort. Overall, only 7% of pts elected for hospice and only 4% experienced CNS relapse. Conclusion: Pts with LBCL 70+ years tolerated dose-adjusted REPOCH 0.4 mg/d similarly to the entire cohort of all ages indicating that empiric dose reduction for age alone isn't necessary. CR rates were similar (63%) with pts 70+ years compared to pts in the entire cohort of all ages. REPOCH 0.4 mg/d was observed to have numerically lower rates of grade 3 or higher neuropathy (2.2%) compared to vincristine 0.4 mg/m 2/d (8.4%, J Clin Oncol 2019) and vincristine 0.5 mg/d dosing strategies (4.5%, Leukemia & Lymphoma 2019) . To our knowledge, this is the first report of outcomes with REPOCH using a vincristine dose cap of 0.4 mg/d.

Highly Sensitive Interleukin Score for Intra-Ocular Lymphoma Diagnosis: Evidence from Analysis of 5-Year Real-Life of Use

Introduction Primary vitreoretinal lymphoma (PVRL) is a rare and aggressive subset of large B-cell lymphoma of immune-privileged sites. It can occur independently or concomitantly to primary central nervous system lymphoma. Symptoms are not specific and can easily be confused with other uveitis. Diagnosis of intra-ocular lymphoma (IOL), including PVRL and secondary lymphoma localization, is based on malignant lymphoid cells identification in vitrectomy(cytology, flow cytometry, molecular analysis). Nevertheless, the fragility of lymphoma cells and low cellularity of samples make diagnosis difficult with these cellular tools. The quantification of interleukin (IL) in intraocular fluids is a promising soluble alternative approach. Based on IL-10 and IL-6 levels, an Interleukine Score for intra-Ocular Lymphoma Diagnosis (ISOLD) designed for aqueous humor (AH) and vitreous was published to guide the diagnosis of IOL (Costopoulos et al, Ophtalmology, 2016). The aim of this work was to evaluate ISOLD performances in real-life practice after five-year of use in a hospital laboratory. Material and methods IL-10 and IL-6 were measured in intra-ocular sample in a single laboratory using the cytometric bead array® kit (BD Biosciences TM) on a FACS Canto II cytometer, with a limit of quantification of 2.5 pg/ml. ISOLD is calculated at diagnosis in AH (AH-ISOLD) or vitreous (V-ISOLD) samples and is associated with a probability of having a large B-cell IOL. This score classifies patients according to two groups: i) reliable zone: ISOLD < -4.6 (<1% probability to have IOL) and ISOLD > +4.6 (>99% probability to have IOL) ; ii) doubtful zone: ISOLD ranging from -4.6 to +4.6 for which the probability and the clinical context have to be considered. All calculated ISOLD from January 2017 to December 2021 were collected. Centers with more than 30 intraocular samples with a calculated ISOLD were contacted to retrieve patients' definitive diagnosis and potential treatments. Results During these 5 years, IL-10 and IL-6 levels have been quantified for 2796 intraocular samples from 70 centers. ISOLD was calculated at diagnosis for 2013 ocular samples. Clinical data were obtained for 1449 samples (1220 AH and 229 vitreous) corresponding to 1243 patients from 13 out of the 18 centers contacted. 9.7% of patients had an IOL, 82.2% had another diagnosis than IOL and 8.1% of patients had no established diagnosis (Figure 1). Considering the 1341 samples with an established diagnosis, 92.7% were in the reliable zone and 7.3% were in the doubtful zone. For the 1128 AH samples, 1050 AH-ISOLD (93.1%) were in the reliable interpretation zone, with a concordant result for 98.6% of them (n=1035 samples) and a discordant result for 1.4% of them (n=15) (Table 1). The sensitivity and specificity were respectively estimated at 90.6% and 99.3% with a positive predictive value (PPV) of 91.7% and a negative predictive value (NPV) of 99.2%. Seventy-eight AH-ISOLD were in doubtful zone including 23 LIO and 55 others diagnoses than IOL. For the 213 vitreous samples, 193 V-ISOLD (90.6%) were in the reliable interpretation zone, with a concordant result for 98.4% of them (n=190 samples) and a discordant result for 1.6% of them (n=3) (Table 1). The sensitivity and specificity were estimated at 97.6% and 99.1%, respectively with a PPV of 98.8% and a NPV of 98.2%. Twenty V-ISOLD were in doubtful zone including 5 LIO and 15 others diagnoses than IOL. Three patients of the 8 who had a false-negative AH-ISOLD had a positive V-ISOLD. For the 17 AH-ISOLD in the doubtful zone, 4 of them had a V-ISOLD concordant with the diagnosis and 2 had an AH-ISOLD in the other eye concordant with the diagnosis. Independently of the sample type, the main cause of false-negative results was administration of corticosteroids prior to sampling and the main causes of false-positive results were infectious diseases (varicella and herpes virus, toxoplasmosis, syphilis). Conclusion This study confirmed on a 5-year period of real life practice that ISOLD, based on IL-10 and IL-6 levels, is a powerful tool to guide the diagnosis towards IOL. In more than 90% of intra-ocular samples, ISOLD was in reliable interpretation zone with very high sensitivity and specificity levels. In case of positive or doubtful AH-ISOLD, a vitrectomy is needed to make the diagnosis. Easy to use, not expansive, this score appears very useful to optimize the diagnostic approach of this rare and aggressive large B-cell lymphoma.

POSTER: ABCL-612 Real-World Outcomes in Patients With Relapsed or Refractory (r/r) Aggressive Large B-Cell Lymphoma (LBCL) Treated With Chemo-Immunotherapy

POSTER: ABCL-612 Real-World Outcomes in Patients With Relapsed or Refractory (r/r) Aggressive Large B-Cell Lymphoma (LBCL) Treated With Chemo-Immunotherapy

ABCL-612 Real-World Outcomes in Patients With Relapsed or Refractory (r/r) Aggressive Large B-Cell Lymphoma (LBCL) Treated With Chemo-Immunotherapy

ABCL-612 Real-World Outcomes in Patients With Relapsed or Refractory (r/r) Aggressive Large B-Cell Lymphoma (LBCL) Treated With Chemo-Immunotherapy

Round-robin testing for LMO2 and MYC as immunohistochemical markers to screen MYC rearrangements in aggressive large B-cell lymphoma.

Aggressive large B-cell lymphomas (aLBCL) include a heterogeneous group of lymphomas with diverse biological features. One of the approaches to the diagnosis of aLBCL is based on the identification of MYC rearrangements (MYC-R), in addition to BCL2 and BCL6 rearrangements by genetic techniques, mainly fluorescent in situ hybridization (FISH). Because of the low incidence of MYC-R, the identification of useful immunohistochemistry markers to select cases for MYC FISH testing may be useful in daily practice. In a previous work, we identified a strong association between the profile CD10 positive/LMO2 negative expression and the presence of MYC-R in aLBCL and obtained good intralaboratory reproducibility. In this study, we wanted to evaluate external reproducibility. To evaluate whether LMO2 can be a reproducible marker between observers 50 aLBCL cases were circulated among 7 hematopathologists of 5 hospitals. Fleiss' kappa index for LMO2 and MYC were 0.87 and 0.70, respectively, indicating high agreement between observers. In addition, during 2021-2022, the enrolled centers included LMO2 in their diagnostic panels to evaluate prospectively the utility of the marker, and 213 cases were analyzed. Comparing LMO2 with MYC, the group of CD10 positive cases showed higher specificity (86% vs 79%), positive predictive value (66% vs 58%), likelihood positive value (5.47 vs 3.78), and accuracy (83% vs 79%), whereas the negative predictive values remained similar (90% vs 91%). These findings place LMO2 as a useful and reproducible marker to screen MYC-R in aLBCL.

Real-world Experience of Approved Chimeric Antigen Receptor T-cell Therapies Compared to Clinical Trials Data.

Real-world Experience of Approved Chimeric Antigen Receptor T-cell Therapies Compared to Clinical Trials Data.

Polatuzumab vedotin with infusional chemotherapy for untreated aggressive B-cell non-Hodgkin lymphomas.

The POLARIX trial demonstrated the superiority of polatuzumab vedotin (Pola) over vincristine in the rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone (R-CHOP) regimen for large B-cell lymphomas, but it is unknown whether Pola can be safely incorporated into intensified regimens (eg, dose-adjusted [DA]-EPOCH-R [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab]) typically used for the highest risk histologies. This was a single-center, open-label, prospective clinical trial of 6 cycles of Pola-DA-EPCH-R (vincristine omitted) in aggressive large B-cell lymphomas. The primary end point was to estimate the safety of Pola-DA-EPCH-R as measured by the rate of dose-limiting toxicities (DLTs) in the first 2 cycles with prespecified suspension rules. Secondary and exploratory end points included efficacy and correlation with circulating tumor DNA (ctDNA) levels. We enrolled 18 patients on study, and with only 3 DLTs observed, the study met its primary end point for safety. There were 5 serious adverse events, including grade 3 febrile neutropenia (3, 17%), grade 3 colonic perforation in the setting of diverticulitis, and grade 5 sepsis/typhlitis. Among 17 evaluable patients, the best overall response rate was 100%, and the complete response rate was 76%. With a median follow-up of 12.9 months, 12-month event-free survival was 72%, and 12-month overall survival was 94%. No patient with undetectable ctDNA at the end of treatment has relapsed to date. Using Pola to replace vincristine in the DA-EPOCH-R regimen met its primary safety end point. These data support the further evaluation and use of this approach in histologies where the potential benefit of both an intensified regimen and Pola may be desired. This trial was registered at www.clinicaltrials.gov as #NCT04231877.

Transformation and survival in marginal zone lymphoma: a Finnish nationwide population-based study

Marginal zone lymphoma (MZL) is an indolent B-cell malignancy with heterogeneous anatomical and clinical presentation. While MZLs are generally associated with long survival, some patients experience histological transformation to aggressive large B-cell lymphoma. Population-based long-term data on the transformation of MZL is limited. We conducted a nationwide population-based study to estimate the risk of transformation and relative survival in patients diagnosed with MZL in Finland from 1995–2018. We identified a total of 1454 patients with MZL from the Finnish Cancer Registry (FCR). The cumulative incidence of transformation was 4.7% (95% CI, 3.6−6.2) at 10 years. The highest incidence of transformation was observed in the patients with splenic MZL (14.0%; 95% CI, 8.6−22.7). The transformation was associated with a substantially increased risk of death (HR, 5.18; 95% CI, 3.58–7.50). Ten-year relative survival was 79% (95% CI, 73‒83%). Transformation, nodal MZL subtype, and older age at diagnosis were associated with increased excess mortality, whereas patients diagnosed at a later calendar period had a lower excess risk of death. We conclude that transformation resulted in a substantially increased mortality irrespective of MZL subtype compared with the patients without transformation. Our results also suggest a reduction in excess mortality in recent years.

Baseline circulating tumour DNA and total metabolic tumour volume as early outcome predictors in aggressive large B-cell lymphoma. A real-world 112-patient cohort.

Approximately 20%-50% of patients with large B-cell lymphoma (LBCL) experience poor outcomes. We aimed to evaluate the combined prognostic value of circulating tumour DNA (ctDNA) and total metabolic tumour volume (TMTV) in LBCL. This observational single-centre study included 112 newly diagnosed LBCL patients, receiving R-CHOP/R-CHOP-like chemotherapies. CtDNA load was calculated following next-generation sequencing of cell-free DNA (cfDNA) using a targeted 40-gene lymphopanel. TMTV was measured using a fully automated artificial intelligence-based method for lymphoma lesion segmentation. CtDNA was detected in cfDNA samples from 95 patients with a median concentration of 3.15 log haploid genome equivalents per mL. TMTV measurements were available for 102 patients. The median TMTV was 501 mL. High ctDNA load (>3.57 log hGE/mL) or high TMTV (>200 mL) were associated with shorter 1-year PFS (44% vs. 83%, p < 0.001 and 64% vs. 97%, p = 0.002, respectively). When combined, three prognostic groups were identified. The shortest PFS was observed when both TMTV and ctDNA load were high (p < 0.001). Even with a short follow up, combining ctDNA load with TMTV improved the risk stratification of patients with aggressive LBCL. In the near future, very high-risk patients could benefit from CAR T-cell therapy or bispecific antibodies as first-line treatments.

Beklenmedik bir lokalizasyonda ortaya çıkan primer mediastinal büyük B hücreli lenfoma

Primary mediastinal large B-cell lymphoma (PMLBCL) is a mature aggressive large B-cell lymphoma of putative thymic B-cell origin arising in the mediastinum, with distinctive clinical, immunophenotypic, genotypic, and molecular features. Cases that arise outside the mediastinum are very uncommon. A 27-year-old woman presented with mass which had an extramedullary, extradural component at the right T5-6 foramina indenting to the spinal canal, extending craniocaudally from the middle mediastinum to the level of the aortic hiatus. Pathological examination of the mass revealed atypical lymphoid cells with medium-large size, eosinophilic and clear cytoplasm In our case CD23 and MAL expression with morphological findings supported PMLBCL. PMLBCL may be seen with abnormal localization and clinical presentation. Immunohistochemical profile including MAL is helpful to detect these cases.

Weight Change Trends and Impact of Body Mass Index (BMI) on Outcomes in Patients with Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma, a Retrospective Analysis from the Lymphoma Innovations Orien Network (LION) Consortium

Introduction. Several studies have examined the impact of BMI on outcomes in B-cell non-Hodgkin lymphoma (B-NHL) but most focused on the impact of pretreatment BMI on outcomes in newly diagnosed patients. In addition, data on weight change patterns during treatment in B-NHL are limited. Herein, we report weight change patterns during sequential lines of treatment and the impact of BMI on outcomes in patients with r/r aggressive large B-cell lymphoma (LBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL). Methods. Patients with r/r LBCL, FL or MCL were identified through LION, a consortium of 7 US academic institutions that prospectively collects molecular and clinical data on adult patients with r/r B-NHL. Patients with available weight data at time of initiation of the 2nd (Wt-2) and/or 3rd (Wt-3) line of treatment were included. Changes in weight were categorized into no change (-5% to 5%), decrease (≥-5%), or increase (≥5%) from prior line of therapy. Outcomes were evaluated for the 1st three lines of treatment, with the corresponding event-free survival (EFS) for each line of treatment calculated from treatment initiation until progression, new treatment, or death due to any cause; lymphoma-specific survival (LSS) from treatment initiation until death due to lymphoma; and overall survival (OS) from treatment initiation until death from any cause. Results. Of 614 patients, 413 (67.2%) had available Wt-2 (n=354) and/or Wt-3 (n=245) and were included. LBCL was the most common lymphoma subtype (n=193, 46.7%) followed by FL (n=146, 35.3%) and MCL (n=74, 17.9%) (Table). The baseline characteristics at diagnosis for the overall cohort were: median age 60 years (range 17-86), male 60%, White 89% (available n=400), Black 9%, stage III/IV 85% (available n=377), elevated LDH 48% (available n=179), B symptoms present 30% (available n=339), weight loss as a B symptom 11% (available n=413), and performance status ≥2 10% (available n=219). Most patients (n=327, 80%) received chemoimmunotherapy as their first-line treatment (available n=412) and 43% relapsed within 1 year of first treatment. At time of initiation of 1st, 2nd and 3rd lines of treatment, most patients were either overweight (BMI=25-29.9) (37%, 31%, and 36% respectively) or obese (BMI ≥30) (37%, 42%, and 37%, respectively). Weight changes between sequential lines of treatment were common: between 1st and 2nd line treatments (available n=214): 49 patients (23%) had weight decrease, 104 (49%) no change, and 61 (29%) increase; between 2nd and 3rd line treatments (available n=186): 43 patients (23%) had weight decrease, 113 (61%) no change, and 30 (16%) increase. Higher BMI prior to initiation of 3rd line treatment was associated with LSS with overweight and obese patients having superior LSS compared with patients with normal BMI (hazard ratio (HR): 0.27 (95% confidence interval (CI), 0.08-0.89), p=.031 and HR=0.32 (95%CI 0.11-0.95), p=.04, respectively) (Figure). BMI prior to initiation of 1st, 2nd, or 3rd lines of treatment was not significantly associated with outcomes otherwise. Weight changes between sequential lines of treatment were not significantly associated with EFS, LSS, or OS. Conclusions. Obesity is common among patients with r/r B-NHL. Weight changes during sequential lines of treatment are also common in patients with r/r B-NHL with approximately 40-50% of patients losing or gaining ≥5% of their pretreatment body weight. However, these weight changes were not associated with outcomes in our study. Finally, patients with higher BMI (overweight or obese) prior to initiation of third-line treatment had a significantly lower risk of death from lymphoma compared with patients with normal BMI. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Characterization and Clinical Impact of the Tumor Microenvironment of Post-Transplant Large B-Cell Lymphoma

Post-transplant lymphoproliferative disorders (PTLDs) arise after solid organ or allogeneic hematopoietic stem cell transplantation. They are characterized by abnormal proliferation of lymphoid cells associated with immunosuppression and comprise three histological categories (non-destructive, polymorphic, monomorphic) entailing a heterogeneous clinical behavior. The majority of monomorphic PTLDs fulfill the criteria of aggressive large B-cell lymphomas and are often associated with Epstein-Barr virus (EBV) positivity. The composition and function of the tumor microenvironment (TME) has a major impact on lymphoma development and survival, but to date, only few studies investigating the TME in PTLD have been reported. We used digital gene expression profiling and in silico immunophenotyping to characterize the TME of 75 post-transplant monomorphic aggressive B-cell lymphomas from three Nordic countries and correlated the findings with patient demographics (Table 1) and survival. Unsupervised clustering demonstrated a high degree of heterogeneity and variation in the immune response profile among the PTLDs. EBV+ PTLDs clustered closely together and were enriched for type I interferon signaling and antiviral response genes. In addition, a signature for cytotoxicity associated with EBV-positivity and better overall survival (OS; HR 0.61, 95%CI 0.40-0.92, P=0.019). In silico immunophenotyping utilizing CIBERSORTx suggested that the PTLDs can be divided into two subgroups with distinct immune cell compositions (Figure 1). The patients in the inflamed subgroup with high proportions of T cells and NK cells, as well as high T cell/macrophage ratio, had significantly better OS and PFS compared to the patients in the non-inflamed subgroup (median OS >200.0 vs. 15.2 months, P=0.006; median PFS 89.0 vs. 14.4 months, P=0.049). In multivariable analysis with the EBV-status, International Prognostic Index (IPI) and rituximab-containing treatment, the inflamed TME remained as an independent predictor for favorable OS and PFS. The inflamed subgroup was associated with EBV-positivity (P=0.008) and earlier onset of the disease (P=0.004). We also compared the TME composition between post-transplant and de novo diffuse large B-cell lymphomas (DLBCLs, n=82) and discovered that the PTLD TME was enriched in dendritic cells, NK cells, and activated mast cells, whereas the proportion of T cells, memory B cells and resting mast cells was lower compared to the de novo DLBCL. In conclusion, we provide a comprehensive phenotypic characterization of PTLD, highlighting the importance of TME biology, and in particular T cell infiltration, in the clinical behavior and prognosis of PTLD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

ORAL PLASMABLASTIC LYMPHOMA IN A PATIENT WITH AIDS: A CASE REPORT

Plasmablastic lymphoma is a rare and aggressive large B-cell lymphoma, commonly associated with acquired immunodeficiency syndrome. A 31-year-old man reported a painful and bleeding lesion in the oral cavity that had evolved over 3 weeks. The patient had human immunodeficiency virus infection and was not undergoing antiretroviral therapy. On examination, we observed a swelling on the left side of the face, caused by an exophytic mass in the upper gingiva extending from the anterior region to the tuberosity. The lesion was reddish with areas of necrosis. Radiographic exams showed an extensive osteolytic lesion in the left maxilla with involvement of the maxillary sinus. An incisional biopsy was performed, and the microscopic exam revealed a lymphoid malignant neoplasm with intense pleomorphism and abundant mitosis. Immunohistochemistry showed positivity for CD45, CD10, MUM1, CD38, CD138, and CD30, confirming the diagnosis of plasmablastic lymphoma. Antiretroviral therapy was started, and the patient was referred for cancer treatment. Plasmablastic lymphoma is a rare and aggressive large B-cell lymphoma, commonly associated with acquired immunodeficiency syndrome. A 31-year-old man reported a painful and bleeding lesion in the oral cavity that had evolved over 3 weeks. The patient had human immunodeficiency virus infection and was not undergoing antiretroviral therapy. On examination, we observed a swelling on the left side of the face, caused by an exophytic mass in the upper gingiva extending from the anterior region to the tuberosity. The lesion was reddish with areas of necrosis. Radiographic exams showed an extensive osteolytic lesion in the left maxilla with involvement of the maxillary sinus. An incisional biopsy was performed, and the microscopic exam revealed a lymphoid malignant neoplasm with intense pleomorphism and abundant mitosis. Immunohistochemistry showed positivity for CD45, CD10, MUM1, CD38, CD138, and CD30, confirming the diagnosis of plasmablastic lymphoma. Antiretroviral therapy was started, and the patient was referred for cancer treatment.

Understanding the differences in outcome between CART studies as second-line treatment in aggressive lymphoma.

Patients with refractory/early relapsed aggressive lymphomas belong to the most difficult-to-treat patients with hematological neoplasia. The prognosis of such patients is poor and novel treatment approches are urgently needed. Autologous chimeric antigen receptor T-cell therapy is a promising new therapy option that is approved after the failure of two lines of chemotherapy. Recently, the results of three different CART studies (ZUMA-7, TRANSFORM, and BELINDA) were published. Two of them were positive and one was negative, which created a mix of disappointment, confusion, and irritation. In this article, we are analyzing the data of all three trials and shed light on the differences between the studies which may facilitate an easier understanding of the results and relevance of CART in aggressive large B-cell lymphoma.

P1196: DIFFERENT MUTATIONS IN PATIENTS WITH PRIMARY LARGE B-CELL LYMPHOMA

Background: Primary mediastinal large B-cell lymphoma (PMBCL) is a type of aggressive large B-cell lymphoma which affects mainly young patients and is characterized by a local spread and development of a tumor conglomerate in the mediastinum. One of the most important pathogenetic mechanisms of the development of PMBCLs is their genetic heterogenety. There are a lot of similarities between molecular profiles of diffuse large B-cell lymphoma, Hodgkin’s lymphoma, and gray zone lymphoma, which are described in the literature. However, there is no clear molecular-genetic characteristic of PMBCL. Despite the successful treatment of patients with modern methods of immunochemotherapy, a large number of patients are resistant to the therapy due to the tumor heterogeneity. The aim of this study was the detection of a clinically significant mutation for patients with PMBCL by next-generation sequencing. Aims: To identify significant mutations in the genes in patients with PMBCL for the further studies. Methods: The study included 47 patients diagnosed with different stages of PMBCL who received treatment from 2013 to 2021. NGS was performed using the AVENIO Tumor Expanded Panel, Roche, USA, which includes 77 genes. DNA was isolated using the Gene Read DNA FFPE Kit panel, Qiagen, USA. The data were processed using the AVENIO Oncology Analysis Software to search for clinically significant mutations. The mutations were also confirmed by Sanger sequencing. Results: The genetic material of selected patients was analyzed for the presence of clinically significant mutations among the known databases: COSMIC: v83, TCGA 9.0, ExAC:1.0, dbSNP:150, 1000 Genomes: phase_3_v5b, SnpEff:4.2. A missense variant of clinically significant mutations in the FGFR3, PIK3CA, ALK, EZH2, RNF43, MET genes was identified in patients with refractory PMBCL. For example, an activating driver mutation in the FGFR3 gene was detected in the 9th exon (rs121913479), which is pathogenic. The frequency of alleles was 25.54%. An activating driver mutation in the PIK3CA gene was detected in the 10th exon (rs121913273), which is also pathogenic. The frequency of alleles was 10.88%. The aim of the study was to identify signaling pathways which were related to mutated genes. They were PI3K-AKT, JAK-STAT, RAP1, RAS, MAPK, stem cell regulation signaling pathway, which were also interpreted. According to the bioinformatics analysis, FGF/FGFR3 was the most significant signaling pathway for PMBCL in our study, because it is able to activate all listed pathways via FGFR-receptor activation. Summary/Conclusion: NGS revealed clinically significant mutations in the genes in patients with PMBCL, the therapeutic potential of which requires the further studies.