Non-germinal Center Diffuse Large B Cell Lymphoma Research Articles

A first-in-human study of the potent and highly selective BTK degrader ABBV-101 in patients with relapsed/refractory B-cell malignancies.

TPS7091 Background: Bruton tyrosine kinase (BTK) is a clinically validated target with an integral role in the proliferation and survival of neoplastic cells in several B-cell malignancies. Inhibitors of BTK, such as ibrutinib, have revolutionized the treatment landscape for B-cell malignancies. However, long-term use can lead to disease progression and clinical resistance associated with mutations in BTK. ABBV-101 is a reversible BTK degrader. By preclinical kinome profiling, ABBV-101 has demonstrated high selectivity with the potential for best-in-class AE profile. ABBV-101 has also shown potent activity against BTK wildtype and multiple therapy-resistant mutant forms. Degradation eliminates BTK scaffolding and enzymatic functions, which has led to deeper, more durable responses vs covalent and reversible BTKi in animal models (Pan C, et al. ASH 2023). Herein, we describe the first-in-human study of ABBV-101 monotherapy in patients with relapsed/refractory B-cell NHL. Methods: This international phase 1, open-label, multicenter study (NCT05753501) is evaluating the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of ABBV-101. Eligible patients(≥18 years) have measurable disease, received ≥2 prior systemic therapies, and have no available therapies known to provide clinical benefit.Primary objectives are to characterize safety and tolerability of ABBV-101; secondary objectives are to evaluate PK and preliminary efficacy. The study is conducted in 2 parts: dose escalation (part 1) and dose expansion (part 2). Part 1 aims to establish the maximum administered dose and maximum tolerated dose of ABBV-101 guided by a Bayesian optimal interval design; additional patients may be enrolled to a previous dose level to further explore safety, PK, and efficacy. Patients with WHO-defined chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma (including Waldenström macroglobulinemia), and transformed indolent NHL (including Richter’s transformation) are eligible. Part 2 will further characterize the safety and preliminary efficacy of ABBV-101; patients diagnosed with CLL/SLL (up to 3 dose cohorts) and non-germinal center DLBCL (1 cohort) are being enrolled. ABBV-101 is administered orally until disease progression, intolerable toxicity, or other study discontinuation criteria are met. Safety assessments include, but are not limited to, AEs, clinical laboratory parameters, vital signs, and ECG. Response evaluations are performed per disease-specific response criteria at screening and every 8 weeks (1st year), 3 months (2nd year), or 4 months (3rd year onward) until progressive disease. Enrollment is ongoing with active sites in the US and Japan. Clinical trial information: NCT05753501 .

Prognostic Value of Baseline PET/CT Imaging in Diffuse Large B-Cell Lymphoma: Does the Largest Distance between Two Lesions Play a Role in Prognosis?

Background: 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) has become the international standard for diffuse large B-cell lymphoma (DLBCL) staging and is widely used for response assessment. In the past few years, the prognostic value of a variety of imaging-derived quantitative parameters has been investigated. One of these parameters is the distance between the 2 lesions that are farthest apart (Dmax). Dmax is a simple feature that captures lymphoma dissemination and has been reported to be a strong prognosticator of shorter progression-free survival (PFS) and overall survival (OS) in DLBCL patients (pts).Methods: Retrospective analysis of 146 pts with newly diagnosed Ann Arbor stage III-IV DLBCL, NOS, treated with R-CHOP(-like) regimens, between January 2010 and December 2019 in a tertiary center. Dmax was normalized with the body surface area [standardized Dmax (SDmax)]. The receiver operating characteristic curve (ROC) method was applied in resetting the optimal cut-off point for predicting prognosis and treatment outcome. The Kaplan-Meier method was used to describe time-to-event end points. A p-value of 0,05 was used as cut-off for significance.Results: Dmax was available for 40 pts. The median age at diagnosis was 63 years (24-78); 58% of pts were male. Most pts (69%) presented lactate dehydrogenase (LDH) above the upper limit of normal (ULN); 40% presented lymphopenia (lymphocyte count below 1000/μL), and 26% had albumin levels below 3.2 g/dL. Bone marrow (BM) infiltration occurred in 41% of pts, and 5% had central nervous system (CNS) involvement at diagnosis. According to the international prognostic index (IPI), 74% of pts were high-intermediate (HI) and high (H) risk; according to National Comprehensive Cancer Network (NCCN)-IPI, 68% of pts were HI and H risk. According to the cell of origin (COO) 63% of pts presented non-germinal center DLBCL. A complete metabolic response (CMR) on interim PET/CT was observed in 65% of pts, and 71% presented a CMR on end-of-treatment (EOT) PET/CT. At EOT the overall response rate was 80%. Seven percent of pts presented CNS relapse. The 5-year PFS was 58.5% and the 5-year overall survival (OS) was 69.4%.Higher SDmax was significantly associated with BM and CNS involvement at diagnosis (p=0.034 and p=0.049, respectively), as well as with CNS relapse (p=0.048). No statistically significant association was found between SDmax and the following features: lymphocyte count of < 1000/μL (p=0.505), albumin levels < 3.2 g/dL (p=0.140), LDH > ULN (p=0.501), IPI risk ≥ HI risk (p=0.719), NCCN-IPI ≥ HI risk (p=0.239) and COO (p=0.493).There was a tendency, although not significant, towards a lower rate of CMR on interim and EOT PET/CT in pts with higher SDmax (p=0.072 and p=0.077, respectively). A higher SDmax had no statistically significant impact on either PFS (HR 0.456; p=0.500) or OS (HR 0.339; p=0.561).The combination of NCCN-IPI and SDmax allowed to identify a subgroup of pts with low (L) risk and low-intermediate (LI) risk NCCN-IPI and higher (≥ 4.1cm) SDmax with inferior 5-year OS (87.5% vs 50%; HR 4.64; p=0.031) and with a trend towards an inferior 5-year PFS (75% vs 50%; HR 1.92; p=0.166).Conclusions: In our cohort, a higher SDmax was associated with some high-risk features, as well as with a trend towards an inferior response to treatment. Additionally, the combination of SDmax and NCCN-IPI allowed to identify a subgroup of L risk and LI risk pts with inferior OS and a trend towards an inferior PFS. Interpretation of these results may be limited by the small sample size. The role of Dmax in DLBCL prognostication may therefore require further validation before widespread clinical use. DisclosuresGomes: Takeda: Consultancy; Gilead: Consultancy; Janssen: Consultancy.

Primary and Secondary Central Nervous System Lymphoma: Outcomes from Houston Methodist Cancer Center

Introduction Primary Central Nervous System Lymphoma (PCNSL) is a rare form of extra-nodal non-Hodgkin Lymphoma (NHL), with diffuse large B-cell Lymphoma (DLBCL) reported in 90% of cases. Secondary CNS lymphoma (SCNSL) may occur as an isolated recurrence of previously diagnosed NHL or occur simultaneously as a manifestation of systemic disease. Comparative data on survival in treated PCNSL and SCNSL in the real-world setting is lacking. We present a retrospective analysis of outcomes in PCNSL and SCNSL patients treated at the Houston Methodist Cancer Center. Methods We retrospectively identified patients with a diagnosis of PCNSL or SCNSL from 2015 to 2020. Data collected included age, race, sex, diagnosis (PCNSL, SCNSL), histology and immunohistochemistry, treatment type (chemotherapy, radiation), transplant rates as well as outcomes (alive/dead). Responses were classified as complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). Survival was analyzed using Kaplan-Meier methodology, and log-rank tests were used to compare survival distributions. P &amp;lt; 0.05 was considered statistically significant. Results There were 50 patients with CNS lymphoma identified between 2015 and 2020; 68% were PCNSL. Out of 43 with available pathology, 2 patients were T-cell lymphomas and 41 DLBCL. Out of the DLBCL cases, 95% of cases expressed CD20 while close to 60% were positive for MUM1, bcl-2 and bcl-6. Less than 15% of cases were positive for CD10. CD30 was positive in 17% of cases. Cerebral hemispheres (76%) was the most common organ involved, followed by ocular (8%), intraventricular space (6%) and cerebellum (6%). Median age at diagnosis was 67 years; male to female ratio was 1.27. Caucasian (62%) and Hispanic (24%) were most common ethnicities. Epstein-Barr Virus was positive in 14% of patients (5 in PCNSL and 2 in SCNSL). One patient with SCNSL had human immunodeficiency virus. The median follow-up time was 9.1 months. Multiagent chemotherapy including high dose methotrexate (MTX), cytarabine and rituximab was given to 48% of the patients while 32% received high dose MTX alone plus rituximab. From the latter group, five out of sixteen patients received temozolomide. Other regimens were used in 6% of the cases. Median dose of MTX in a multiagent chemotherapy regimen was 2.5gr/m2 and 2.25gr/m2 when used alone or with temozolomide. Median number of cycles given was 3. Radiation therapy alone was given to 8% of cases. Three patients did not receive treatment. For patients with PCNSL, overall response rate (ORR) was 82.8% (CR 65.5%, PR 13.8%, SD 3.4%). ORRs were similar between multiagent chemotherapy and methotrexate alone (+/- temozolomide) with 86.7% and 83.3% respectively. ORR for SCNSL was 57.1% (CR 35.7%, PR 21.4%); only 1 patient was treated with MTX alone. Further lines of therapy were required in 9.3% of patients. Consolidation with whole brain radiation was given in 22% of the cases (29.4% for PCNSL and 6.3% for SCNSL). Autologous stem cell transplant was performed in 10% of the patients (2 PCNSL, 3 SCNSL). Overall survival for patients with PCNSL was 74.8 months and 10.1 months for SCNSL (p=0.0444) (Figure 1). Survival was not significant between patients receiving multiagent chemotherapy and MTX alone or in combination with temozolomide (3-year OS 57.3% vs 73.4%, p= 0.5652) (Figure 2). Conclusion Most patients diagnosed with PCNSL are non-germinal center DLBCL. Median MTX dose was lower than 3gr/m2 with excellent ORR of over 80% in PCNSL. Response rates were lower in SCNSL and in general, patients with PCNSL had better outcomes. Survival did not differ significantly between regimens, suggesting that a lower intensity therapy may perform similarly to multiagent chemotherapy. These results need to be confirmed by prospective studies. Disclosures No relevant conflicts of interest to declare.

An Update on Safety and Preliminary Efficacy of Highly Specific Bruton Tyrosine Kinase (BTK) Inhibitor Zanubrutinib in Combination with PD-1 Inhibitor Tislelizumab in Patients with Previously Treated B-Cell Lymphoid Malignancies

An Update on Safety and Preliminary Efficacy of Highly Specific Bruton Tyrosine Kinase (BTK) Inhibitor Zanubrutinib in Combination with PD-1 Inhibitor Tislelizumab in Patients with Previously Treated B-Cell Lymphoid Malignancies

Osteopontin expression and its relationship with prognostic factors in diffuse large B-cell lymphoma.

The aim of this study is to explore the expression of osteopontin (OPN) and its relationship with prognostic factors and survival in diffuse large B cell lymphoma (DLBCL). A tissue microarray was performed for immunohistochemical evaluation. Contingency tables were analyzed for trends; chi-square test was used to determine differences between groups. Univariate and multivariate Cox proportional hazards-regression analyses were performed to evaluate the impact of prognostic factors on survival. Expression of OPN was observed in 28%. It was different in non-germinal center DLBCL (P=0.04). The mean overall survival (OS) was lower in patients with positive OPN expression (19.762; CI 95% 14.269-25.255) it was not significant (P=0.123). It is not possible to establish a clear relationship between the expression by immunohistochemistry of osteopontin and a poor prognosis but it would be important to complement the analysis with other techniques as PCR or NGS that allow us to assess the influence of the isoforms and post-translational modifications of OPN on the biological behavior of DLBCL. Our findings indicate that OPN expression could be associated with a more aggressive variant of lymphoma: non-germinal center DLBCL.

R-CHOP with or without Lenalidomide/Bortezomib As a First Line Treatment for Patients with Non-Germinal Center Diffuse Large B Cell Lymphoma (DLBCL) Subtype: Son Espases University Hospital Experience

INTRODUCTIONThe standard first line treatment for patients with diffuse large B-cell lymphoma (DLBCL) is rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) independently of cell origin subtype. Retrospective studies have shown that non-germinal center (NGC) subtype is associated with a worse progression free survival (PFS) and overall survival (OS) compared to germinal center subtype. In phase II studies the combination of lenalidomide (lena) or bortezomib (bor) with R-CHOP in this lymphoma subtype has shown better results in comparison to R-CHOP alone. For this reason, the aim of our study is to analyze the efficacy and toxicity of R-CHOP plus lena/bor in comparison with R-CHOP alone in patients with NGC DLBCL.PATIENTS AND METHODSIn order to avoid selection bias, all patients with NGC DLBCL (confirmed by immunohistochemistry with Hans algorithm) who received R-CHOP or R-CHOP-lena/bor (25mg lenalidomide daily from day 1 to 10 / bortezomib 1.3mg/m2 days 1 and 4) were retrospectively selected from the Pharmacy Registry. Patients in our center received R-CHOP from March 2002 to June 2013, R-CHOP-bor from June 2013 to July 2015 and R-CHOP-lena from November 2014 until now. Cheson and Lugano criteria were used to confirm response rates. Toxicity was checked with CTCAE v4-5 criteria.RESULTSFifty-five patients with NGC DLBCL were identified from 2002 to 2018, 18 of whom were treated with R-CHOP-lena/bor and 33 with R-CHOP. Baseline characteristics are specified in Table 1. Overall response rate was similar in both treatment regimens, 94% versus 87%, respectively. 12.5% progression/stable disease cases were identified with R-CHOP alone compared to 5.3% with R-CHOP-lena/bor. With a median follow-up of 45 months (6-126) for R-CHOP and 22 months (6-59) for R-CHOP-lena/bor, the median PFS was 65 months for R-CHOP and was not reached for R-CHOP-lena/bor. 47% versus 9% of progressions were observed in R-CHOP and R-CHOP-lena/bor, respectively (p=0.006). Regarding OS, the death rate in the R-CHOP group was 45% in comparison with 23% in R-CHOP-lena/bor group (p=0.015). Higher hematological toxicity was observed in the R-CHOP-lena/bor group comparing with R-CHOP: neutropenia (95% versus 68%), grade 3-4 neutropenia (81% versus 37%) and anemia (81% vs 56%) (p<0.05) (Table 2) being manageable in all cases.CONCLUSIONSThe addition of lenalidomide or bortezomib to R-CHOP seems to be a good option in NGC DLBCL, with a lower progression rate, refractoriness and less mortality in comparison with R-CHOP alone. R-CHOP-lena/bor is associated to higher rates of hematological toxicity but manageable in all cases. These retrospective data should be confirmed in ongoing phase III clinical trials. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Intussussception and Ileal Ulceration: A Case of Recurrent Near-Tetraploid Diffuse Large B-Cell Lymphoma of the Small Intestine

Diffuse Large B-Cell Lymphoma (DLBCL) presents extranodally in nearly 40% of cases. In patients with polyploidy, however, extranodal presentation is far less common. To date, no primary gastrointestinal cases of polyploid DLBCL have been reported. We present a case of DLBCL with polyploidy diagnosed as intussusception in the terminal ileum with recurrence as an ileal ulcer. A 71-year-old man with history of an inguinal hernia repair and empyema presented to our hospital with two weeks of back pain with periumbilical radiation, non-bilious emesis, inability to tolerate food by mouth, ten pound weight loss, and decreased stool caliber. His last colonoscopy over ten years ago was normal. CT imaging revealed a small bowel obstruction with circumferential wall thickening at the terminal ileum causing 4-cm of intussusception (Figure 1). He underwent exploratory laparotomy and right hemicolectomy with side-to-side ileocolic anastomosis. Pathology revealed a non-germinal center DLBCL with a near-tetraploid karyotype. Resection margins were negative. After positron-emission tomography CT (PET-CT) revealed no evidence of disease, he received six cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. Following treatment, repeat PET-CT revealed normal bowel with adjacent newly avid peritoneal and mesenteric nodules (Figure 2). Given radiographic recurrence, he was treated on a clinical trial with a combination of ibrutinib, lenalidomide and rituximab. During his first cycle, he re-presented with anemia and dark, guaiac-positive stool. Although EGD was unremarkable, colonoscopy revealed a solitary, non-bleeding, 10-mm ulcerated polyp in the neo-terminal ileum with surrounding healthy mucosa proximal to the site of the prior end-to-end ileocolic anastomosis (Figure 3). Pathology revealed recurrent DLBCL and imaging confirmed progressive disease. Treatment with salvage chemotherapy was ineffective. He was transitioned to hospice and died two weeks later. To our knowledge, this is the first reported case of gastrointestinal DLBCL with polyploidy. In addition to reduced infiltration of extranodal sites, these karyotypes carry an unfavorable prognosis and poor overall survival. Early identification and attention to extranodal disease as well as prompt initiation of therapy are imperative to optimize any potential treatment response in these patients.2594_A Figure 1. Coronal CT of Intussusception.2594_B Figure 2. Coronal PET-CT of Recurrent Abdominal Lymphoma.2594_C Figure 3. Endoscopic View of Ileal Ulceration.

Treatment with Chimeric Antigen Receptor Modified T Cells Directed Against CD19 (CTL019) Results in Durable Remissions in Patients with Relapsed or Refractory Diffuse Large B Cell Lymphomas of Germinal Center and Non-Germinal Center Origin, "Double Hit" Diffuse Large B Cell Lymphomas, and Transformed Follicular to Diffuse Large B Cell Lymphomas

Treatment with Chimeric Antigen Receptor Modified T Cells Directed Against CD19 (CTL019) Results in Durable Remissions in Patients with Relapsed or Refractory Diffuse Large B Cell Lymphomas of Germinal Center and Non-Germinal Center Origin, "Double Hit" Diffuse Large B Cell Lymphomas, and Transformed Follicular to Diffuse Large B Cell Lymphomas

Lenalidomide for the treatment of B-cell lymphoma

ABSTRACTIntroduction: Although the combination of an anti-CD20 monoclonal antibody and chemotherapy has widely improved survival of patients with B-cell lymphoma, the disease still relapses. A better understanding of the biology of lymphomas has highlighted the role of the cell of origin in response to treatment and outcome. Lenalidomide represents an attractive therapeutic option due to its original mechanism of action.Areas covered: In this review, the authors describe the pharmacological properties of lenalidomide, and the rational for its use in B-cell lymphomas; focusing on diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL). They discuss the mechanism of action of the drug and its current and future clinical development. They also review the current data in relapsed/refractory situations as well as in first-line treatment.Expert opinion: Lenalidomide is an oral non-chemotherapy immunomodulatory agent with an acceptable toxicity profile and manageable side-effects. Efficacy has widely been demonstrated, especially in MCL, FL and non-Germinal Center DLBCL patients. Further studies are now warranted to better define the strategy for the use of lenalidomide in B-NHL patients, and clarify which subgroup of patients will really benefit of lenalidomide as part of first-line treatment or in a relapsed/refractory setting.

Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

TP53 Mutations, the Most Frequent Genetic Lesion in Richter Syndrome, Represent An Independent Predictor of Survival Post Transformation.

Abstract 670Richter syndrome (RS) represents the transformation of chronic lymphocytic leukemia (CLL) to aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). Knowledge of the genetic lesions associated with RS is scant and represents the aim of this study. The study was based on 47 RS cases (all DLBCL). In 32 cases, paired CLL/RS samples were available (28 clonally related and 4 clonally unrelated). In 15 cases, the sole RS sample was analysed. According to CD10/BCL6/MUM1 immunohistochemistry expression pattern, 43/47 (91.5%) RS were classified as non-germinal center DLBCL. At diagnosis, 37.8% RS showed ECOG PS >1, 77.8% Binet stage B-C, 95.7% Ann Arbor stage III-IV, 44.4% B symptoms, 45.7% tumor size >5 cm, 32.6% involvement of >1 extranodal site, 66.7% LDH elevation, and 28.9% platelets <100 × 10e(9)/l. RS treatment included CHOP-like regimens in 71.1% cases, rituximab-based immunochemotherapy in 44.4%, and allogeneic stem cell transplant in 8.9%. Candidate genetic lesions were selected among those recurrently affecting: i) de novo DLBCL; and ii) CLL. Mutational analysis of the TNFAIP3/A20, CARD11, BLIMP1, and TP53 genes was performed by direct DNA sequencing. Probes used for FISH analysis were: i) LSI13, LSID13S319, CEP12, LSIp53, LSIATM, LSI IGH/BCL2, LSI BCL6, LSI IGH/c-MYC/CEP8, LSI N-MYC (Abbott); BCL3 split signal (Dako): iii) 6q21/alpha-satellite (Kreatech Biotechnology); iv) BAC clones 373L24-rel and 440P05-BCL11A. Clonal relationship between CLL and RS samples was assessed by immunoglobulin gene rearrangement analysis. Among gene mutations that are associated with de novo DLBCL, TP53 mutations (exons 4-8) were identified in 18/46 (39.1%) RS, and CARD11 mutations (exons 5-9) in 3/44 (6.8%). Neither TNFAIP3/A20 (exons 2-9) nor BLIMP1 (exons 2-4) mutations were identified in RS. Among chromosomal abnormalities that are associated with de novo DLBCL, c-MYC translocation was observed in 2/17 (11.8%) RS, c-MYC amplification in 2/17 (11.8%), BCL6 amplification in 2/17 (11.8%), REL amplification in 1/10 (10.0%), and BCL2 amplification in 1/17 (5.9%). Neither BCL6 translocation, nor BCL2 translocation or BLIMP1 deletion were observed in RS. Among chromosomal abnormalities that are associated with CLL, 17p13 deletion (TP53) was observed in 5/17 (29.4%) RS, 11q22-q23 deletion (ATM) in 5/17 (29.4%), +12 in 4/17 (23.5%), 13q14 deletion (MIR15A/16B) in 2/17 (11.8%), BCL11A amplification in 1/10 (10.0%), BCL3 amplification in 2/17 (11.8%), BCL3 translocation in 1/17 (5.9%), and N-MYC amplification in 1/17 (5.9%). Analysis of paired clonally related CLL/RS samples showed that TP53 mutations and CARD11 mutations are acquired at RS transformation. Chromosomal abnormalities acquired at RS transformation included TP53 deletion (3/10, 30.0%), c-MYC translocation (2/10, 20.0%), BCL3 amplification (2/10, 20.0%), c-MYC amplification (1/10, 10.0%), BCL6 amplification (1/10, 10.0%), BCL2 amplification (1/10, 10.0%), and ATM deletion (1/10, 10.0%). To date, the sole tool for predicting RS survival is represented by the RS score, that is based on clinical variables (Tsimberidou et al, J Clin Oncol 2006; 24:2343). The notion that TP53 status predict survival in both CLL (Zenz et al, Blood 2008; 112: 3322; Rossi et al, Clin Cancer Res 2009; 15: 995) and de novo DLBCL (Young et al, Blood 2008; 112: 3088) prompted investigation of the impact of TP53 mutations on survival post RS transformation. Survival post transformation was significantly longer in RS devoid of TP53 mutations (27.0 months) compared to RS with TP53 mutations (9.4 months) (p=.023) (Fig. 1). Other variables associated with RS survival were age (p<.001), ECOG PS (p<.001), tumor size (p=.001), B symptoms (p=.001), platelet count (p=.002), Binet stage (p=.001), Rai stage (p=.001), and IPI (p=.008). Treatment strategy did not affect RS survival. Multivariate analysis selected TP53 mutations (HR:2.34; p=.028) as an independent predictor of RS survival along with variables identified by the RS score, including ECOG PS (p=.008), tumor size (p<.001), and platelet count (p=.004) . The conclusions of our study are multifold: i) the genetic profile of RS differs from that of de novo DLBCL; ii) few lesions are shared by RS and de novo DLBCL, including CARD11 mutations, c-MYC translocation and REL amplification; iii) TP53 mutations are the most frequent genetic lesion in RS; iv) TP53 mutations are an independent prognostic factor in RS. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Coexpression of CD44 variant isoforms and receptor for hyaluronic acid−mediated motility (RHAMM, CD168) is an International Prognostic Index and C-MYC gene status−independent predictor of poor outcome in diffuse large B-cell lymphomas

Expression of CD44 variant (v) isoforms substantiates poor prognosis in patients with hematological malignancies. We have previously shown that CD44v6 expression in diffuse large B-cell lymphoma (DLBCL) correlates with advanced disease stage and is predominantly detected in non-germinal center B-cell-like DLBCL subtypes. With the growing number of associated molecules found to form functional complexes with CD44, we analyzed a larger cohort of cyclophosphamide, doxorubicin, vincristine, prednisone, and equivalently treated DLBCL patients to define the prognostic role of such CD44-associated molecules. Two-hundred and ninety formalin-fixed, paraffin-embedded primary DLBCL tissue samples were analyzed in tissue microarrays. To obtain potential biologically meaningful associations, optimal cutoff values were established by receiver operating characteristic curves. The prognostic significance of every possible multimarker phenotype was also addressed. We showed that coexpression of any of the CD44v with the receptor for hyaluronic acid-mediated motility (RHAMM, CD168) identifies a subgroup of DLBCL patients with a very poor prognosis, independent of the International Prognostic Index. These patients did not show C-MYC translocations or amplifications. CD44v-RHAMM coexpression was most prevalent in non-germinal center DLBCL cases and usually coincided with expression of osteopontin. Evaluation of CD44v-RHAMM coexpression may improve the accuracy of DLBCL prognosis and identify a subgroup of patients who will benefit from therapeutic alternatives to cyclophosphamide, doxorubicin, vincristine, and prednisone.

Activated B-cell immunophenotype might be associated with poor prognosis of primary central nervous system lymphomas

Primary central nervous system (PCNS) diffuse large B-cell lymphoma (DLBCL) is an aggressive form of non-Hodgkin's lymphoma whose growth is restricted to the central nervous system and eye. Primary CNS DLBCL has a poor prognosis relative to other extranodal DLBCL. Recently DLBCL has been subclassified as germinal and non-germinal center B-cell types using microarray. Germinal center B-cell DLBCL is associated with better prognosis compared to non-germinal center B-cell group. The objective of the study was to subcategorize the PCNS DLBCL into germinal center and non-germinal center DLBCL using immunohistochemistry and to correlate its prognostic significance. 21 immunocompetent patients were diagnosed with PCNS DLBCL over last 20 years at William Beaumont Hospital. Clinical data on outcome were collected and their specimens were retrieved. Immunohistochemical staining was done using markers, CD20, CD10, Bcl-6, MUM-1, MIB-1, Bcl-2 and by molecular analysis of the immunoglobulin heavy chain gene (IgH) variable region. Immunohistochemistry showed 1/21 (positive cases/examined cases) for CD10, 19/21 for Bcl-6, 19/21 for MUM-1 and 15/21 for Bcl-2. The expression pattern of CD10(-) MUM-1(+) is corresponded to the non-germinal center DLBCL. The MIB-1 index ranged from 40--80% with a mean of 57%, indicating a high proliferation of lymphoma cells. The IgH gene variable region analysis showed monoclonality in 15 of 21 cases (71%). Primary CNS DLBCL has a non-germinal center B-cell phenotype in majority of cases and has a high Bcl-2 positivity and MIB-1 index. These features might be associated with poor prognosis.

Forkhead Box Protein P1 Expression in Mucosa-Associated Lymphoid Tissue Lymphomas Predicts Poor Prognosis and Transformation to Diffuse Large B-Cell Lymphoma

Gene expression profiling studies have reported upregulated mRNA expression of forkhead box protein P1 (FOXP1) in response to normal B-cell activation and high expression in a poor prognosis subtype of diffuse large B-cell lymphoma (DLBCL). Recently, it was also found that FOXP1 rearrangements and expression of its protein occur in mucosa-associated lymphoid tissue (MALT) lymphomas. In this study, we investigated FOXP1 expression in its relationship to morphology, genetic features, and prognosis in a series of 70 MALT lymphomas. All samples were morphologically reviewed and stained for FOXP1. Presence of structural and/or numeric aberrations of the FOXP1, BCL10, and MALT1 genes was investigated. For all patients, a complete clinical data set was collected. We detected nuclear expression of FOXP1 in 20 of the 70 MALT lymphomas (nine of them featuring structural or numeric aberrations of the FOXP1 locus). FOXP1 positivity was confined to MALT lymphomas with poor clinical outcome (with impact of FOXP1 expression on relapse rate and disease-free survival). It was also found that MALT lymphomas with strong FOXP1 expression are at risk of transforming into an aggressive DLBCL of nongerminal center phenotype if they feature, in addition, a polymorphic histology and the presence of trisomy 3 and 18. The data presented show that FOXP1 expression is an independent prognostic factor in MALT lymphomas. The data also support the hypothesis that a subgroup of nongerminal center DLBCLs (those marked by FOXP1 expression and trisomy 3 and 18) might represent a large-cell variant of MALT lymphomas.