scholarly journals Lymphoplasmacytic lymphoma associated with diffuse large B-cell lymphoma: Progression or divergent evolution?

PLoS ONE ◽  
2020 ◽  
Vol 15 (11) ◽  
pp. e0241634
Author(s):  
Macarena Boiza-Sánchez ◽  
Rebeca Manso ◽  
Olga Balagué ◽  
Cristina Chamizo ◽  
Elham Askari ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Analytical Data ◽  
B Cell Lymphoma ◽  
Lymphoplasmacytic Lymphoma ◽  
Large B Cell Lymphoma ◽  
Clinical Records ◽  
Myd88 L265p ◽  
Large B Cell ◽  
Mutational Study

Aim Lymphoplasmacytic lymphoma (LPL) is an indolent mature B-cell-neoplasm with involvement of the bone marrow. At least 90% of LPLs carry MYD88-L265P mutation and some of them (~10%) transform into diffuse large B-cell-lymphoma (DLBCL). Material and methods Over the past 15 years we have collected 7 cases where the both LPL and DLBCL were diagnosed in the same patient. Clinical records, analytical data and histopathological specimens were reviewed. FISH studies on paraffin-embedded tissue for MYC, BCL2 and BCL6 genes were performed, as well as MYD88-L265P mutation and IGH rearrangement analysis by PCR. A mutational study was done by massive next generation sequencing (NGS). Results There were 4 women and 3 men between 36–91 years of age. Diagnoses were made simultaneously in 4 patients. In two cases the LPL appeared before the DLBCL and in the remaining case the high-grade component was discovered 5 years before the LPL. In 6 cases both samples shared the MYD88-L265P mutation. IGH rearrangement analysis showed overlapping features in two of 6 cases tested. Mutational study was evaluable in three cases for both samples showing shared and divergent mutations. Conclusions These data suggest different mechanisms of DLBCL development in LPL patients.

Clinical Pharmacokinetic (PK) and Safety (Immunogenicity) of Rituximab Biosimilar RTXM83 in Combination with Chemotherapy CHOP in Patients with Diffuse Large B-Cell Lymphoma (DLBCL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5472-5472 ◽  
Author(s):  
Amalia Florez ◽  
Thiago Di Matteo ◽  
Gloria Fresnillo ◽  
Consuelo Tudela ◽  
Mauricio Seigelchifer ◽  
...  
Keyword(s):  
B Cell ◽  
Conflicts Of Interest ◽  
Cell Lymphoma ◽  
Analytical Data ◽  
B Cell Lymphoma ◽  
Assay Sensitivity ◽  
Large B Cell Lymphoma ◽  
Large B Cell ◽  
The Eu

Abstract Background: RTXM83 is a rituximab biosimilar candidate manufactured by MAbxience Company. Full spectrum of physicochemical and preclinical studies showed biosimilarity of RTXM83 and originator drug MabThera®/Rituxan® marketed by Roche. MabThera®/Rituxan® product is approved to treat Non-Hodgkin´s Lymphoma, chronic lymphocytic leukemia and rheumatoid arthritis in the EU and US, plus it is approved to treat Diffuse Large B-cell lymphoma (DLBCL) in the EU. Rituximab is also used for other types of lymphoma (e.g. Mantle cell lymphoma) in certain parts of the word. Objective: To demonstrate comparable pharmacokinetics (PK) and safety profile (immunogenicity) to MabThera®, a clinical PK/immunogenicity analysis was designed to compare RTXM83 and MabThera® when administered with CHOP to patients with DLBCL. Methods: Analysis of an interim PK/Safety report from randomized and blinded study, where 24 patients with newly diagnosed DLBCL treated with R-CHOP as part of a multi-center study undertaken to assess the PK and immunogenicity. R-CHOP (rituximab-375mg/m2; cyclophopsphamide-750mg/m2; adriamycin-50mg/m2; vincristine-1.4mg/m2 on day 1 and prednisolone-60mg/m2 on days 1 to 5) was given every 3 weeks for a total of 6 cycles. The PK analysis were conducted on quality control (QC) checked analytical data for Cycle 1 and Cycle 6 using nominal blood sampling times. PK parameters were determined from the serum Rituximab concentration-time profiles obtained following administration of the first (Cycle 1) and last intravenous infusion of study medication (Cycle 6) using non-compartmental procedures in Phoenix WinNonlin (Version 6.2.1). The immunogenicity assessments were based on a specific and validated method for systematic evaluation of an unwanted immune response against RTXM83 and MabThera®. In fact, a confirmatory assay and specific cut point was established as current described recommendations in white papers and guidance documents. This part assures the assay sensitivity and a “characterization step” in the study sample analysis. A screening assay that picks up 5% positives that are subsequently shown to be due to non-specific binding in a confirmatory (immunodepletion) assay provides assurance that true low positives can be detected. Finally, the clinical immunogenicity measurements were performed on Cycle 5, Cycle 6 and follow-up patient samples. Results: Following the end of infusion of 375 mg/m2 q3w RTXM83 or MabThera® (Rituximab) (3 hours infusion) administered in combination with CHOP in Cycle 1 and Cycle 6, serum concentrations of Rituximab declined steadily in a generally bi-phasic manner. The arithmetic mean ±SD of PK parameters (T1/2(hrs); Cmax (ug/ml); Cmin (ug/ml); AUC0-∞ (ug*hrs/ml) of Rituximab during cycle 1, cycle 6 and follow-up patients were determined. All these data are comparable with values previously reported for rituximab in other conditions. No anti-drug antibody case was reported, so RTXM83 and MabThera® displaying null or undetectable immunogenicity. Conclusions: The data indicate that therapeutic levels of rituximab (RTXM83/Mabthera®) were observed across studied cycles. All data are comparable with values previously reported for rituximab. Therefore, PK profile and immunogenicity profile of RTXM83 is comparable with Mabthera® in treating DLBCL. Disclosures No relevant conflicts of interest to declare.

scholarly journals Prognostic value of MYD88 L265P mutation in diffuse large B cell lymphoma via droplet digital PCR

2020 ◽  
Vol 22 (2) ◽  
pp. 1243-1256 ◽  
Author(s):  
Jing Niu ◽  
Zhiping Ma ◽  
Aijiang Nuerlan ◽  
Sijing Li ◽  
Wenli Cui ◽  
...  
Keyword(s):  
B Cell ◽  
Prognostic Value ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Digital Pcr ◽  
Droplet Digital Pcr ◽  
Large B Cell Lymphoma ◽  
Myd88 L265p Mutation ◽  
Myd88 L265p ◽  
Large B Cell

scholarly journals Ibrutinib Can Induce Complete Remissions and Sustained Responses in Refractory Cutaneous or Leg-Type Diffuse Large B-Cell Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4237-4237
Author(s):  
Johannes Bloehdorn ◽  
Stephanie Ellen Weissinger ◽  
Anca Sindrilaru ◽  
Stefan Schoensteiner ◽  
Thorsten Peters ◽  
...  
Keyword(s):  
B Cell ◽  
Clinical Course ◽  
Cell Lymphoma ◽  
Checkpoint Inhibitors ◽  
B Cell Lymphoma ◽  
Individual Treatment ◽  
Large B Cell Lymphoma ◽  
Sustained Responses ◽  
Myd88 L265p ◽  
Large B Cell

Abstract Background: Primary cutaneous diffuse large B-cell lymphoma, leg-type (LT-DLBCL) is an extremely aggressive DLBCL subtype typically occurring at lower extremities and with very poor prognosis due to early relapses and refractory (R/R) disease. Previous studies have shown increased BCR dependence in DLBCL being observed in association with the mutation status of BCR associated genes and MYD88. Aim: Primary goal was to assess the clinical course in patients with primary cutaneous DLBCL and to elucidate the potential of alternative treatments with regard to molecular characteristics. Methods: We identified 16 patients with cutaneous DLBCL treated at our center of which 8 patients had typical localization and were histologically confirmed as LT-DLBCL. The other 8 patients showed cutaneous DLBCL at other anatomic sites (DLBCL-OS) and were classified as DLBCL/DLBCL NOS. Three R/R patients received ibrutinib as off-label individual treatment attempt (420 mg daily). We extended the clinical and molecular analysis for the ibrutinib exposed DLBCL by 1 R/R oropharyngeal DLBCL. Specimen from R/R ibrutinib exposed and 3 other patients were analyzed for CD79B, MYD88, CARD11 and BTK mutations by targeted resequencing analysis. PD-1/PD-L1 expression was assessed in 2 cases with relapse after ibrutinib. Treatment was initiated after signed informed consent. Results: The median age at diagnosis was 51 years in DLBCL-OS and 80 years in LT-DLBCL (total range 37-91). Patients received a median of 2 (0-7) treatments and response to last chemotherapy was different for DLBCL-OS (6 complete remissions (CR), 2 R/R) and LT-DLBCL (2CR, 5R/R). One LT-DLBCL patient showed stable disease (SD) without treatment. LT-DLBCL patients showed a significantly shorter median overall survival (OS) (21,5 months vs. not reached, p=0.009). After ibrutinib treatment we observed 1 ongoing CR for 10 months till date for a DLBCL-OS with CD79B p.Y197S and MYD88 L273P mutation and 1 CR for 6 months in a LT-DLBCL being WT for all sequenced genes. However, this patient relapsed with a highly proliferative disease and died shortly after. The 3rd patient with LT-DLBCL had an isolated MYD88 L265P mutation and showed a PR for 1 month. Samples from patients with indolent clinical course showed a MYD88 p.S251N and BTK p.P385S mutation (LT-DLBCL with SD) or were WT for all sequenced genes (2 patients with DLBCL-OS and ongoing CR). The patient with R/R oropharyngeal DLBCL had a MYD88 L265P and CD79B c.587A mutation, 4 prior treatment regimen and fulminant progression during the last 2 treatments. Initial response to ibrutinib was rapid with a drop of LDH levels from 2200 U/L to 620 U/L within 7 days and consecutive decrease to 323 U/L. However, this patient relapsed after 30 days of treatment. Immunomodulatory effects of ibrutinib and potential synergistic treatment with checkpoint inhibitors have previously been suggested. We specifically investigated PD-1/PD-L1 expression in tissues obtained from the two patients progressing after ibrutinib treatment. Remarkably, we observed increased expression for PD-1 (moderate) and PD-L1 (strong) in non-tumor bystander cells. Treatment with nivolumab was initiated in 1 patient with early clinical benefit. However, the patient refused the continuation of this treatment. Conclusion: Patients with LT-DLBCL are older and show a poor clinical course compared to cutaneous DLBCL at other anatomic sites. MYD88 L265P mutations were observed only in chemo-refractory cases with extranodal DLBCL. Ibrutinib can induce complete remissions and sustained responses in chemo-refractory extranodal DLBCL but relapses may be more aggressive and disseminated. Mutational patterns and ibrutinib response were in line with previous hypothetical models for sensitivity to BCR inhibition. Combining ibrutinib and checkpoint inhibitors may be considered in future trials for LT-DLBCL patients. Disclosures Weissinger: Bristol-Myers Squibb: Research Funding. Viardot:Roche: Consultancy, Honoraria; Amgen: Consultancy; Gilead Kite: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria.

scholarly journals DLBCL with amplification of JAK2/PD-L2 exhibits PMBCL-like CNA pattern and worse clinical outcome resembling those with MYD88 L265P mutation

2020 ◽  
Author(s):  
Xuemin Xue ◽  
Wenting Huang ◽  
Tian Qiu ◽  
Lei Guo ◽  
Jianming Ying ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Driver Genes ◽  
Large B Cell Lymphoma ◽  
Unfavorable Clinical Outcome ◽  
Myd88 L265p Mutation ◽  
Myd88 L265p ◽  
Large B Cell

Abstract Background: Recently, copy number alteration (CNA) of 9p24.1 were demonstrated in 10% of diffuse large b-cell lymphoma (DLBCL), with gene expression and mutation profiles that were similar to those of primary mediastinal large B-cell lymphoma(PMBCL). However, their CNA-based profile and clinical impact still remain unclear. Methods: Multiplex ligation-dependent probe amplification were employed to investigate the prevalence of JAK2/PD-L2 amplification in DLBCL and their CNA-based pattern of driver genes. The clinical outcome and characteristics were also analyzed. Results: Using unsupervised hierarchical clustering, a small group of DLBCL (10.5%, 8/76) was clustered together with PMBCL as Cluster_2, demonstrating amplification of JAK2 (100%,8/8) and PD-L2 (75.0%,6/8). This subgroups of DLBCL demonstrated significant higher expression of PD-L1 than those with MYD88 L265P mutation(p=0.024). And they exhibited dismal OS and PFS as compared with DLBCL_others(p=0.003 and 0.001, respectively), which is similar to DLBCL with MYD88 L265P mutation. Conclusions: DLBCL with amplification of JAK2/PD-L2 exhibits CNA pattern that is similar to PMBCL, and demonstrates unfavorable clinical outcome that resembles those with MYD88 L265P mutation. It is essential to identify this subgroup of DLBCL who may acquire more benefits from the JAK2 and PD-L1 signaling inhibition.

Bone Marow (BM) Involvement in Diffuse Large B Cell Lymphoma (DLBCL): Clinical Impact of Discordant Disease.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2031-2031
Author(s):  
Mukesh Chhanabhai ◽  
Joseph Connors ◽  
Wayne Seville ◽  
Dan Matso ◽  
Randy Gascoyne
Keyword(s):  
Bone Marrow ◽  
B Cell ◽  
De Novo ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Clinical Impact ◽  
Low Grade ◽  
Large B Cell Lymphoma ◽  
Clinical Records ◽  
Large B Cell

Abstract Background and Methods: Most published studies have suggested that survival of de novo DLBCL with discordant BM involvement by small B cell lymphoma is indistinguishable from patients having a negative staging BM. The aim of the study was to investigate the incidence and clinical impact of BM involvement by concordant and discordant B cell lymphoma in patients with DLBCL seen in a single institution over a 5 year period (1\1\2000 – 31\12\2004). The cases were identified from pathology records and BCCA Lymphoid Cancer Database. Results: The group of interest for this study comprised 652 patients with de novo DLBCL with staging marrow available for review. 60 of 652 (9.2%) of patients with DLBCL had concordant large B-cell lymphoma in their bone marrow. 523 (80.2%) were negative, 16 patients showed what we considered to be atypical lymphoid (ALH) infiltrates lacking definitive features of malignancy. In 50 patients (7.7%) the bone marrow showed discordant histology with predominantly small B-cells, some showing paratrabecular localization. In total there were five cases of TCRBCL in the study, three with marrow involvement. Furthermore, all 54 cases of primary mediastinal B-cell lymphoma (PMBCL) had a negative BM. Of the 652 cases with DLBCL with staging bone marrows available, merging the pathology and clinical databases resulted in 599 patients with complete clinical records. Of these, bone marrows were either not done or deemed inadequate in 101 cases. Therefore, there were 488 patients with DLBCL with an interpretable marrow of which 344 had advanced stage disease. Staging marrows in these patients were negative = 264, positive 41, discordant 28, and ALH 11. The overall survival and progression free survival were strongly affected by the IPI score for these 344 cases (P<0.00001) (see figure). Compared to those without BM involvement patients with concordant large B-cell lymphoma in their BM (n=41) had the worst outcome and those with discordant small B-cell lymphoma in the bone marrow (n=28) had an inferior but intermediate outcome (median survivals (months) = not reached;12 and 20, respectively). Conclusion: Diffuse large B-cell lymphoma is a heterogenous group of lymphomas as demonstrated by gene expression profiling. Our data suggests that discordant low grade B-cell lymphoma in patients who have coincident DLBCL has a poorer prognosis and the presence or absence of BM disease has clinical significance. Though we had very few cases, TCRBCL show a higher incidence of BM involvement in keeping with the reported literature. The absence of marrow disease in PMBCL is consistent with recent data indicating it is a biologically distinct form of DLBCL. Figure Figure

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