Transformation in Marginal Zone Lymphoma: Results from a Prospective Cohort and a Meta-Analysis of the Literature.

Marginal zone lymphoma (MZL) includes extranodal (EMZL), splenic (SMZL), and nodal (NMZL) subtypes. Histological transformation (HT) to large B-cell lymphomas is well documented but with a large variability in published cumulative incidence rates. We report results from the Molecular Epidemiology Resource (MER) cohort for the cumulative incidence of HT (with death as competing risk) and associated risk factors and outcomes. We also conduct a meta-analysis of available studies on the cumulative incidence of HT. From 2002-2015, 529 patients with MZL were enrolled in the MER (69% EMZL, 16% SMZL, 15% NMZL). Ten-year overall survival (OS) from diagnosis was 66%. HT occurred in 21 patients, with 5-year and 10-year cumulative incidence of HT of 2.7% (95% confidence interval [CI] 0.02-0.05) and 3.6% (95%CI 0.02-0.06), respectively. HT was associated with an increased risk of death (subdistribution hazard ratio (HR)=3.95; 95%CI 2.06-7.55). Predictors of HT were ≥2 extranodal sites and MALT-IPI score ≥2. OS was 79% at 5 and 55% at 10 years after HT. Age at HT≥70 years was the only predictor of OS after HT (HR=3.57; 95%CI 1.34-9.48). In meta-analysis of 12 studies (6,161 patients), the 5- and 10-year cumulative incidence of HT across all subtypes were 5% (95%CI 0.05-0.06) and 8% (95%CI 0.07-0.09), respectively. Rates were lower in EMZL (3% and 5%) than in SMZL (7% and 13%) and NMZL (9% and 13%). While HT is relatively uncommon in the first decade after MZL diagnosis, it is associated with an inferior outcome and needs new approaches to prevention and management.

Neurologic Clinical, Electrophysiologic, and Pathologic Characteristics of Primary vs Secondary Neurolymphomatosis.

BACKGROUND AND OBJECTIVES: Neurolymphomatosis (NL) is characterized by lymphomatous infiltration of the peripheral nervous system presenting as the initial manifestation of a lymphoma (primary NL [PNL]) or in relapse of a known lymphoma (secondary NL [SNL]). This report details and compares the neurologic clinicopathologic characteristics of these 2 groups. METHODS: This retrospective study was performed on patients diagnosed with pathologically confirmed NL in nerve between January 1, 1992, and June 31, 2020. Patient clinical characteristics, neurologic examination, imaging studies, EMG, and nerve biopsy data were collected, analyzed, and compared between PNL and SNL. RESULTS: A total of 58 patients were identified (34 PNL and 24 SNL). Time from neurologic symptom onset to diagnosis was longer in PNL at 18.5 months compared with 5.5 months in SNL (p = 0.01). Neurologic symptoms were similar in both patient groups and included primarily sensory loss (98%), severe pain (76%), and asymmetric weakness (76%). A wide spectrum of EMG-confirmed different neuropathy patterns were observed, but patients with SNL had increased numbers of mononeuropathies (n = 8) compared with PNL (n = 1, p = 0.01). MRI studies detected NL more frequently (86%) compared with fluorodeoxyglucose (FDG)-PET CT imaging studies (60%) (p = 0.007). Nerve biopsies revealed B-cell lymphoma (PNL n = 32, SNL n = 22), followed by T-cell lymphoma (PNL n = 2, SNL n = 2), with increased demyelination in both groups and increased axonal degeneration (p = 0.01) and multifocal myelinated fiber loss (p = 0.04) significant in SNL vs PNL. Identifying SNL resulted in patient treatment modifications but a worse prognosis compared with PNL (p = 0.025). DISCUSSION: While PNL and SNL are both primarily painful and asymmetric neuropathies with axonal and demyelinating features on EMG and nerve biopsy, SNL presents somewhat differently than PNL with fulminant, asymmetric often mononeuropathies better detected on MRI than FDG-PET/CT. The focal pattern of SNL is likely a result of residual cancer cells that evaded initial chemotherapy, which does not cross the blood-nerve barrier, and these cells can later recur and result in fulminant disease. Although still resulting in a poorer prognosis, identifying SNL is important because this changed treatment and management in every SNL case.

Incidence of Central Nervous System Relapse in Primary Mediastinal Large B-Cell Lymphoma: Implications for Central Nervous System Prophylaxis.

BACKGROUND: Primary mediastinal large B-cell lymphoma (PMBCL) is an uncommon type of aggressive B-cell non-Hodgkin lymphoma. PMBCL shares some clinical and biologic features with nodular sclerosis classic Hodgkin lymphoma (cHL). Central nervous system (CNS) relapse is exceedingly rare in cHL. Therefore, it may be expected that CNS relapse in PMBCL is also uncommon. Herein, we examined the incidence of CNS relapse in patients with PMBCL treated with standard chemoimmunotherapy. PATIENTS AND METHODS: This retrospective single center analysis included 154 patients with newly diagnosed PMBCL seen at Mayo Clinic. The CNS relapse rate was calculated using a competing risk model, with death considered as a competing risk. RESULTS: With a median follow-up of 39 months, 3 patients experienced CNS relapse, all associated with systemic relapse. The cumulative incidence of CNS relapse for the entire cohort was 1.43% (95% CI, 0.3%-4.6%) at 1 year and 2.21% (95% CI, 0.6%-5.8%) at both 2 and 5 years. For those who did not receive CNS prophylaxis (n = 131), the incidence was 0.85% (95% CI, 0.1%-4.2%) at 1 year and 1.80% (95% CI, 0.3%-5.8%) at both 2 and 5 years. All 3 patients who experienced CNS relapse had R-CHOP as frontline therapy; 2 patients did not receive any CNS prophylaxis, while 1 patient received intrathecal CNS prophylaxis. CONCLUSION: The risk of CNS relapse in PMBCL appears to be very low after treatment with standard chemoimmunotherapy, suggesting routine CNS prophylaxis is not necessary.

Transcriptomic classification of diffuse large B-cell lymphoma identifies a high-risk activated B-cell-like subpopulation with targetable MYC dysregulation.

Immunochemotherapy has been the mainstay of treatment for newly diagnosed diffuse large B-cell lymphoma (ndDLBCL) yet is inadequate for many patients. In this work, we perform unsupervised clustering on transcriptomic features from a large cohort of ndDLBCL patients and identify seven clusters, one called A7 with poor prognosis, and develop a classifier to identify these clusters in independent ndDLBCL cohorts. This high-risk cluster is enriched for activated B-cell cell-of-origin, low immune infiltration, high MYC expression, and copy number aberrations. We compare and contrast our methodology with recent DLBCL classifiers to contextualize our clusters and show improved prognostic utility. Finally, using pre-clinical models, we demonstrate a mechanistic rationale for IKZF1/3 degraders such as lenalidomide to overcome the low immune infiltration phenotype of A7 by inducing T-cell trafficking into tumors and upregulating MHC I and II on tumor cells, and demonstrate that TCF4 is an important regulator of MYC-related biology in A7.

Multiomic analysis identifies a high-risk signature that predicts early clinical failure in DLBCL.

Recent genetic and molecular classification of DLBCL has advanced our knowledge of disease biology, yet were not designed to predict early events and guide anticipatory selection of novel therapies. To address this unmet need, we used an integrative multiomic approach to identify a signature at diagnosis that will identify DLBCL at high risk of early clinical failure. Tumor biopsies from 444 newly diagnosed DLBCL were analyzed by WES and RNAseq. A combination of weighted gene correlation network analysis and differential gene expression analysis was used to identify a signature associated with high risk of early clinical failure independent of IPI and COO. Further analysis revealed the signature was associated with metabolic reprogramming and identified cases with a depleted immune microenvironment. Finally, WES data was integrated into the signature and we found that inclusion of ARID1A mutations resulted in identification of 45% of cases with an early clinical failure which was validated in external DLBCL cohorts. This novel and integrative approach is the first to identify a signature at diagnosis, in a real-world cohort of DLBCL, that identifies patients at high risk for early clinical failure and may have significant implications for design of therapeutic options.

Should All Patients With Stage IE Gastric Mucosa-Associated Lymphoid Tissue Lymphoma Receive Antibiotic Eradication Therapy for Helicobacter pylori?

PURPOSE: H. pylori eradication therapy (HPE) can lead to tumor regression in H. pylori-positive (HPP) gastric mucosa-associated lymphoid tissue (MALT) lymphoma. However, some patients do not have detectable H. pylori (HP) infection (H. pylori-negative [HPN]) and the guidelines differ in their initial approach to HPN patients. The National Comprehensive Cancer Network (NCCN) recommends proceeding to radiation therapy, whereas European Society for Medical Oncology suggests HPE for every patient, even those who are HPN. To address this issue, we evaluated the effectiveness of HPE in limited-stage gastric MALT lymphoma. MATERIALS AND METHODS: We retrospectively reviewed patients newly diagnosed with stage IE gastric MALT lymphoma between January 2002 and December 2022. The primary outcome was the complete remission (CR) rate defined as no macroscopic findings of lymphoma and negative gastric biopsy at the follow-up gastric endoscopy. RESULTS: Fifty-two patients were reviewed, and HP infection was detected in 19 (36.5%) patients-14 by immunostaining, three by serology, and one each by stool antigen and urea breath test. All 19 HPP and eight of the 33 HPN patients received HPE treatment. The CR rate was 63% (12/19) in HPP patients and 13% (1/8) in HPN patients (P = .033). After a median follow-up of 89.7 months, only two of the 12 HPP patients achieving CR have relapsed; the one HPN patient who received HPE remains in CR at 12+ months. CONCLUSION: For limited-stage HPP gastric MALT lymphoma, HPE is an effective and durable first-line treatment and should be used. For HPN patients, the CR rate with HPE is very low in our experience and is thus in support of the NCCN guideline.

Cytogenetic and pathologic characterization of MYC-rearranged B-cell lymphomas in pediatric and young adult patients.

MYC-rearranged B-cell lymphoma (BCL) in the pediatric/young adult (YA) age group differs substantially in disease composition from adult cohorts. However, data regarding the partner genes, concurrent rearrangements, and ultimate diagnoses in these patients is scarce compared to that in adult cohorts. We aimed to characterize the spectrum of MYC-rearranged (MYC-R) mature, aggressive BCL in the pediatric/YA population. A retrospective study of morphologic, immunophenotypic, and fluorescence in situ hybridization (FISH) results of patients age ≤ 30 years with suspected Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL) or high-grade B-cell lymphoma (HGBCL), and a MYC-R by FISH between 2013-2022 was performed. Two-hundred fifty-eight cases (129 (50%) pediatric (< 18 years) and 129 (50%) YA (18-30 years)) were included. Most MYC-R BCL in pediatric (89%) and YA (66%) cases were BL. While double-hit (DH) cytogenetics (MYC with BCL2 and/or BCL6-R, HGBCL-DH) was rare in the pediatric population (2/129, 2%), HGBCL-DH increased with age and was identified in 17/129 (13%) of YA cases. Most HGBCL-DH had MYC and BCL6-R, while BCL2-R were rare in both groups (3/258, 1%). MYC-R without an IG partner was more common in the YA group (14/116 (12%) vs 2/128 (2%), p = 0.001). The pediatric to YA transition is characterized by decreasing frequency in BL and increasing genetic heterogeneity of MYC-R BCL, with emergence of DH-BCL with MYC and BCL6-R. FISH to evaluate for BCL2 and BCL6 rearrangements is likely not warranted in the pediatric population but should continue to be applied in YA BCL.

Follicular lymphoma B cells exhibit heterogeneous transcriptional states with associated somatic alterations and tumor microenvironments.

Follicular lymphoma (FL) is an indolent non-Hodgkin lymphoma of germinal center origin, which presents with significant biologic and clinical heterogeneity. Using RNA-seq on B cells sorted from 87 FL biopsies, combined with machine-learning approaches, we identify 3 transcriptional states that divide the biological ontology of FL B cells into inflamed, proliferative, and chromatin-modifying states, with relationship to prior GC B cell phenotypes. When integrated with whole-exome sequencing and immune profiling, we find that each state was associated with a combination of mutations in chromatin modifiers, copy-number alterations to TNFAIP3, and T follicular helper cells (Tfh) cell interactions, or primarily by a microenvironment rich in activated T cells. Altogether, these data define FL B cell transcriptional states across a large cohort of patients, contribute to our understanding of FL heterogeneity at the tumor cell level, and provide a foundation for guiding therapeutic intervention.

Immune Checkpoint Inhibitor-Induced Pure Red Cell Aplasia: A Review of 2 Cases in Metastatic Melanoma.

BACKGROUND Immunotherapy is a novel treatment offering an alternative to traditional chemotherapeutic agents for different malignancies. Hematologic adverse reactions (HARs) related to immune checkpoint inhibitors (ICIs) are uncommon. Pure red cell aplasia (PRCA) is a rare hematologic complication of ICI therapy in metastatic melanoma with significant mortality risk despite treatment with steroids or immunosuppressive therapy. For unexplained acute anemia after exclusion of other causes, performing bone marrow biopsy is imperative to diagnose PRCA and rule out involvement of bone marrow by primary tumor. HARs can occur during ICI therapy or even after ICI therapy is stopped. ICI rechallenge, even after the development of HARs, is considered in some patients with good response to treatment of HARs from ICIs. Recurrence of HARs with the same or different type of reaction is seen in some patients. CASE REPORT Two cases of ICI-induced PRCA were confirmed on bone marrow biopsy after dual ICI treatment with nivolumab and ipilimumab in metastatic melanoma. In case 2, PRCA was successfully treated with steroids and later rechallenged with single-agent nivolumab, causing mild ICI-induced immune thrombocytopenia, which did not require treatment with steroids. CONCLUSIONS It is crucial to increase clinician awareness of the possibility of PRCA development not only during treatment with ICI but also after finishing treatment with ICI; there is high mortality associated with missing an opportunity to diagnose and treat PRCA on time with favorable results. ICI rechallenge can be considered in patients who showed response to immunotherapy, especially those with limited alternative therapeutic options.

Follicular lymphoma and diffuse large B-cell lymphoma with BCL2 and IRF4 rearrangements in adult patients.

Follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) with concurrent BCL2 and IRF4 rearrangements are rare. It is unclear whether such cases should be classified as large B- cell lymphoma with IRF4 rearrangement or FL/DLBCL-not otherwise specified. We identified 5 adult patients (FL, N = 3 and FL/DLBCL, N = 2) with concurrent BCL2 and IRF4 rearrangements. The median age at presentation was 77 years, and three patients presented with advanced stage disease. Both nodal and extranodal sites were involved and involvement was not limited to head and neck region. With a median follow-up of 18 months, 1 patient died and 4 patients were alive, including 3 who received chemotherapy and 1 who was observed. The neoplasms were histologically heterogeneous, including grade 2 and 3 FL and DLBCL. Four cases coexpressed CD10, BCL6, BCL2 and MUM1/IRF4. The Ki67 labelling index ranged from 20% to 95%. In 4 patients, the percentage of cells with BCL2 rearrangement was equal to or slightly greater than the cells harboring IRF4 rearrangement. Two cases underwent next generation sequencing tailored for lymphoid neoplasms. Both lacked mutations involving IRF4 and NF-kB pathway genes that are frequently detected in large B-cell lymphoma with IRF4 rearrangement, and one case showed DLBCL-EZH2 type mutations, including KMT2D and BCL2 mutations, similar to 2 previously reported DLBCL with BCL2 and IRF4 rearrangements. Adults with FL and FL/DLBCL with BCL2 and IRF4 rearrangements display clinicopathologic and mutational features more akin to FL and DLBCL and should not be characterized as large B-cell lymphoma with IRF4 rearrangement.

Multiomic Analysis Identifies a High-Risk Metabolic and TME Depleted Signature that Predicts Early Clinical Failure in DLBCL.

PURPOSE: 60-70% of newly diagnosed diffuse large B-cell lymphoma (DLBCL) patients avoid events within 24 months of diagnosis (EFS24) and the remainder have poor outcomes. Recent genetic and molecular classification of DLBCL has advanced our knowledge of disease biology, yet were not designed to predict early events and guide anticipatory selection of novel therapies. To address this unmet need, we used an integrative multiomic approach to identify a signature at diagnosis that will identify DLBCL at high risk of early clinical failure. PATIENTS AND METHODS: Tumor biopsies from 444 newly diagnosed DLBCL were analyzed by WES and RNAseq. A combination of weighted gene correlation network analysis and differential gene expression analysis followed by integration with clinical and genomic data was used to identify a multiomic signature associated with high risk of early clinical failure. RESULTS: Current DLBCL classifiers are unable to discriminate cases who fail EFS24. We identified a high risk RNA signature that had a hazard ratio (HR, 18.46 [95% CI 6.51-52.31] P < .001) in a univariate model, which did not attenuate after adjustment for age, IPI and COO (HR, 20.8 [95% CI, 7.14-61.09] P < .001). Further analysis revealed the signature was associated with metabolic reprogramming and a depleted immune microenvironment. Finally, WES data was integrated into the signature and we found that inclusion of ARID1A mutations resulted in identification of 45% of cases with an early clinical failure which was validated in external DLBCL cohorts. CONCLUSION: This novel and integrative approach is the first to identify a signature at diagnosis that will identify DLBCL at high risk for early clinical failure and may have significant implications for design of therapeutic options.

Survival trends in young patients with Waldenström macroglobulinemia: Over five decades of experience.

Waldenström macroglobulinemia (WM) is a rare, indolent lymphoma, that predominately affects the elderly. We report the outcomes of young WM patients, evaluated over five decades, compared to their older counterparts, matched for the time of diagnosis. Between January 1, 1960 and October 31, 2013, 140 (11.8%) WM patients were ≤50 years of age at diagnosis in our database, and their estimated 10-year overall survival (OS) was 74%, with death attributable to WM in a higher proportion of patients compared to their older (≥65 years) counterparts (91% vs. 58%, p = .0001). Young patients were grouped into three cohorts based on the timing of the initiation of therapy: Group 1 (1960-1977, n = 12), Group 2 (1978-1995, n = 48), and Group 3 (1996-2013, n = 74). Among young patients, there was no disease-specific survival (DSS) difference across the three periods, [median DSS at 13 years (95% CI 5-23), 16 years (95% CI 14-22), and 15 years (95% CI 10-NR; p = .41), respectively]. However, DSS for the older cohort incrementally improved (Group 1, median 5.2 years, Group 2: 9.6 years, Group 3: 12 years; p = .05) over these periods. The estimated average years-of-life lost for the young cohort was 11.2 years from diagnosis, based on the expected survival for a normal age- and sex-matched population. Despite a protracted disease course, nearly all young patients succumb to their disease. In contrast to the improved survival of the elderly patient population, the evolving treatment strategies in WM have not impacted the outcome of young patients; however, the impact of Bruton tyrosine kinase inhibitors on this unique patient population remains to be determined.

The lymph node transcriptome of unicentric and idiopathic multicentric Castleman disease.

Castleman disease is a polyclonal lymphoproliferative disorder characterized by unicentric or multicentric lymphadenopathy with characteristic histomorphological features, in addition to variable inflammatory symptomatology. The molecular mechanisms and etiologies of unicentric Castleman disease (UCD) and idiopathic multicentric Castleman disease (iMCD) are poorly understood, and identification of targetable disease mediators remains an unmet clinical need. We performed whole exome sequencing on lymph node biopsies from patients with UCD and iMCD and compared the transcriptomic profiles to that of benign control lymph nodes. We identified significantly upregulated genes in UCD (n=443), iMCD (n=316) or both disease subtypes (n=51) and downregulated genes in UCD (n=321), iMCD (n=105) or both (n=10). The transcriptomes of UCD and iMCD showed enrichment and upregulation of elements of the complement cascade. By immunohistochemistry, C4d deposits indicative of complement activation were found to be present in UCD and iMCD, mostly within abnormally regressed germinal centers, but also in association with plasma cell clusters, endothelial cells and stroma cell proliferations. Other enriched gene sets included collagen organization, S1P3 pathway and VEGFR pathway in UCD; and humoral response, oxidative phosphorylation and proteosome in iMCD. Analysis of cytokine transcripts showed upregulation of CXCL13 but not IL6 in UCD and iMCD. Among angiogenic mediators, the VEGFR1 ligand placental growth factor (PGF) was upregulated in both disease subtypes. We hereby report for the first time the whole lymph node transcriptomes of UCD and iMCD, underscoring findings that could aid in the discovery of targetable disease mediators.

Evolution in the definition and diagnosis of the Hodgkin lymphomas and related entities.

Hodgkin lymphoma was the first of the lymphomas to be recognized as a specific disease entity. However, recent studies have highlighted the heterogeneity of the diseases associated with this eponym warranting clarification and refinement of diagnostic terminology. While classic Hodgkin lymphoma (CHL) remains an essentially unchanged diagnostic entity in the 2022 International Consensus Classification of Mature Lymphoid Neoplasms (2022 ICC), nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is now renamed nodular lymphocyte predominant B cell lymphoma (NLPBL) in recognition of the distinct pathologic, biologic, and clinical differences. Fan patterns A, B, and C (sharing the presence of evident follicular structures, and retention of a B cell rich background) will be combined in "typical" or grade 1, while the other "variant" patterns, D, E, and F, are considered grade 2. T-cell/histiocyte-rich large B cell lymphoma (THRBCL) is considered part of the "variant" NLPHL continuum.The entity previously known as "B cell lymphoma, unclassifiable (BCLU), with features intermediate between diffuse large B cell lymphoma (DLBCL) and CHL" has been renamed "mediastinal gray zone lymphoma" (MGZL) in recognition of the importance of the thymic niche in the biology of this tumor. The diagnostic criteria for MGZL have been refined and require both a high tumor cell density and a strongly preserved B cell program.This article will describe updates on CHL, NLPBL, and MGZL in the recently published 2022 ICC and provide some useful differential diagnostic clues in cases with atypical morphology or immunophenotype.

Diagnostic approaches and future directions in Burkitt lymphoma and high-grade B-cell lymphoma.

Since the 2016 WHO update, progress has been made in understanding the biology of Burkitt lymphoma (BL) and the concept of high-grade B-cell lymphomas (HGBCL) that allows some degree of refinement. The summary presented here reviews in detail the discussions of the Clinical Advisory Committee and expands upon the newly published 2022 International Consensus Classification for lymphoid malignancies (Campo et al. Blood, 2022). BL remains the prototypic HGBCL and diagnostic criteria are largely unchanged. HGBCL with MYC and BCL2 and HGBCL with MYC and BCL6 rearrangements are now separated to reflect biologic and pathologic differences. HGBCL, NOS remains a diagnosis of exclusion that should be used only in rare cases. FISH strategies for diffuse large B-cell lymphoma (DLBCL) and HGBCL are discussed in detail for these diseases. Advances in integrative analysis of mutations, structural abnormalities, copy number, and gene expression signatures allow a more nuanced view of the heterogeneity of DLBCL, NOS as well as definitions of HGBCL and point to where the future may be headed for classification of these diseases.

Cell of origin is not associated with outcomes of relapsed or refractory diffuse large B cell lymphoma.

Activated B cell (ABC) type diffuse large B cell lymphoma (DLBCL), double hit lymphoma (DHL) and double expressor lymphoma (DEL) have poor outcomes to frontline R-CHOP but impact of these molecular features on outcomes of relapsed/refractory (R/R) disease is not well-characterized. We evaluated the association of diagnostic cell of origin (COO), double hit and double expressor status with overall survival after first relapse in DLBCL patients who were enrolled into the Molecular Epidemiology Resource (MER) cohort. COO was available from immunohistochemistry (IHC) using Hans criteria or gene expression profiling (GEP) (Nanostring) on the diagnostic FFPE biopsy. Of 373 pts with R/R DLBCL, 278 had COO by IHC: 152 were GCB, 107 were non-GCB. One hundred and fourty had COO by GEP: 44 were ABC, 65 were GCB and 13 were unclassifiable. Nineteen out of 163 (12%) were DHL; 30 out of 135 (22%) had DEL. COO, either by IHC (2 years OS GCB: 45% [CI95 : 38-54] vs. non-GCB: 44% [CI95 :36-55], p > 0.05) or GEP (2 years OS ABC: 42% [CI95 : 29-59] vs. GCB: 40% [CI95 : 30-54], p > 0.05), was not associated with difference in OS. DHL (2 years OS 16 [CI95 :6-45] vs. 45% [CI95 : 34-59], p < 0.01) and DEL (2 years OS 33% [CI95 : 20-56], vs. 50% [CI95 : 41-60], p < 0.05) had lower OS than non-DHL and non-DEL/non-DHL counterparts, respectively. COO by IHC or GEP was not associated with OS in R/R DLBCL while DHL and DEL were adverse prognostic markers in DLBCL at first relapse.