Is There a Benefit of Adding Rituximab to CHOP in the Overall Survival of Patients with B-Cell Non-Hodgkin′s Lymphoma in a Developing Country ?

Abstract Abstract 4892 Rituximab ( R ) has changed the prognosis of patients with non-Hodgkin′s lymphoma (NHL) in developed countries, but its role has not been analyzed in underprivileged circumstances. One hundred and two patients with NHL treated in a developing country were analyzed: 28 patients with follicular lymphoma (FL) and 74 diffuse large B cell lymphoma (DLCL). Patients were treated upfront with either CHOP or R-CHOP; the decision to employ R depending solely on the ability of patients to defray it. In DLCL, 42 were given CHOP and 32 R-CHOP, whereas in FL 19 were given CHOP and 9 R-CHOP. The impact of the addition of R was found to be more clear in FL than in DLCL. In patients with DLCL, the overall survival (OS) was 87% at 80 months for those treated with R-CHOP and 84% at 145 months for those treated with CHOP (p NS). In patients with FL, the OS was 89% at 88 months for those treated with R-CHOP and 71% at 92 months for those treated with CHOP (p =.05). In a multivariate analysis, other variables were identified to be associated with the OS were IPI and number of cycles in DLCL. It is concluded that rituximab produced a mild positive impact in the OS of patients with FL, but not in those with DLCL. Since the addition of rituximab results in a 36 fold increase in treatment costs, these observations may be important to decide therapeutic approaches in NHL patients living in underprivileged circumstances. Disclosures: No relevant conflicts of interest to declare.

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Diffuse Large B-Cell Lymphoma Classification System That Associates Normal B-Cell Subset Phenotypes With Prognosis

Journal of Clinical Oncology ◽

10.1200/jco.2014.57.7080 ◽

2015 ◽

Vol 33 (12) ◽

pp. 1379-1388 ◽

Cited By ~ 52

Author(s):

Karen Dybkær ◽

Martin Bøgsted ◽

Steffen Falgreen ◽

Julie S. Bødker ◽

Malene K. Kjeldsen ◽

...

Keyword(s):

B Cell ◽

Classification System ◽

Cell Lymphoma ◽

Positive Impact ◽

Cell Subset ◽

Progression Free Survival ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

The Impact ◽

Large B Cell

Purpose Current diagnostic tests for diffuse large B-cell lymphoma use the updated WHO criteria based on biologic, morphologic, and clinical heterogeneity. We propose a refined classification system based on subset-specific B-cell–associated gene signatures (BAGS) in the normal B-cell hierarchy, hypothesizing that it can provide new biologic insight and diagnostic and prognostic value. Patients and Methods We combined fluorescence-activated cell sorting, gene expression profiling, and statistical modeling to generate BAGS for naive, centrocyte, centroblast, memory, and plasmablast B cells from normal human tonsils. The impact of BAGS-assigned subtyping was analyzed using five clinical cohorts (treated with cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP], n = 270; treated with rituximab plus CHOP [R-CHOP], n = 869) gathered across geographic regions, time eras, and sampling methods. The analysis estimated subtype frequencies and drug-specific resistance and included a prognostic meta-analysis of patients treated with first-line R-CHOP therapy. Results Similar BAGS subtype frequencies were assigned across 1,139 samples from five different cohorts. Among R-CHOP–treated patients, BAGS assignment was significantly associated with overall survival and progression-free survival within the germinal center B-cell–like subclass; the centrocyte subtype had a superior prognosis compared with the centroblast subtype. In agreement with the observed therapeutic outcome, centrocyte subtypes were estimated as being less resistant than the centroblast subtype to doxorubicin and vincristine. The centroblast subtype had a complex genotype, whereas the centrocyte subtype had high TP53 mutation and insertion/deletion frequencies and expressed LMO2, CD58, and stromal-1–signature and major histocompatibility complex class II–signature genes, which are known to have a positive impact on prognosis. Conclusion Further development of a diagnostic platform using BAGS-assigned subtypes may allow pathogenetic studies to improve disease management.

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The Impact of Activated Akt Expression On Clinical Outcome in Diffuse Large B-Cell Lymphoma: A Clinicopathological Study of 99 Cases.

Blood ◽

10.1182/blood.v120.21.2676.2676 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2676-2676

Author(s):

Jung Yong Hong ◽

Moon Ki Choi ◽

Young Saing Kim ◽

Chi Hoon Maeng ◽

Su Jin Lee ◽

...

Keyword(s):

Overall Survival ◽

B Cell ◽

Cell Lymphoma ◽

Progression Free Survival ◽

B Cell Lymphoma ◽

Clinical Impact ◽

Free Survival ◽

Large B Cell Lymphoma ◽

The Impact ◽

Large B Cell

Abstract Abstract 2676 Purpose Akt is a serine/threonine kinase that plays a central role in cell proliferation and growth. To define clinical impact of Akt expression in diffuse large B-cell lymphoma(DLBCL), we investigated the expression of phospho-Akt(p-Akt) in DLBCL and analyzed clinical impact of p-Akt expression on patient survival. Methods We evaluated the p-Akt expression in 99 DLBCL patients using tissue microarray(TMA) technology. Results Positive p-Akt expression was observed in 15.2% of the patients and significantly associated with elevated lactic dehydrogenase level (P = .044). Kaplan-Meier survival analysis showed that the patients with positive p-Akt expression showed substantially poorer overall survival (p-Akt+ vs p-Akt- 25.3 months [95% confidence interval(CI), 14.4–36.2 months] vs 192.6 months [95% CI, 131.3–253.9 months], P < .001) and progression-free survival (p-Akt+ vs p-Akt- 13.6 months[95% CI, 14.4–36.2 months] vs 134.5 months [95% CI, 131.3–253.9 months], P < .001), respectively. Multivariate Cox regression analysis revealed that patients with DLBCL with p-Akt positivity showed poorer overall survival with 3.2 fold (95% CI, 1.6–6.8, P = .002) risk for death compared to patients with DLBCL with p-Akt negativity. Conclusion Positive expression of p-Akt in DLBCL patients is associated with poorer overall and progression-free survival. Expression of p-Akt may act as an independent poor prognostic factor and might be a novel therapeutic target for DLBCL. Disclosures: No relevant conflicts of interest to declare.

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“Double-Hit” Cytogenetic Status Is Not Predicted By Baseline Clinicopathologic Characteristics and Is Highly Associated With Overall Survival In B Cell Lymphoma Patients

Blood ◽

10.1182/blood.v122.21.4338.4338 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4338-4338

Author(s):

Daniel J. Landsburg ◽

Sunita Dwivedy Nasta ◽

Jakub Svoboda ◽

Jennifer JD Morrissette ◽

Stephen J. Schuster

Keyword(s):

Overall Survival ◽

B Cell ◽

Gene Rearrangement ◽

Median Overall Survival ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Gene Rearrangements ◽

Myc Gene ◽

Double Hit ◽

The Impact

Abstract Background “Double-Hit” (DH) lymphomas are most commonly defined as B cell lymphomas demonstrating a MYC gene rearrangement and additional rearrangement(s) involving BCL2 and/or BCL6. DH lymphomas respond poorly to standard immunochemotherapy regimens, often prompting the use of more intensive treatments. DH gene rearrangements can be identified through metaphase cytogenetic testing or more sensitive fluorescence in situ hybridization (FISH) on diagnostic tissue specimens, although these studies are not routinely performed. Here, we analyze a cohort of B cell lymphoma patients to determine whether DH status can be predicted by clinicopathologic features as well as the impact of DH status on survival. Methods Fifty-three patients diagnosed with B cell lymphoma treated at the University of Pennsylvania from 2006-2013 who underwent diagnostic FISH for MYC gene rearrangements using probes to detect either an 8q24 split or t(8;14) were included in this analysis. FISH was performed at request of the interpreting pathologist or treating clinician. Patients with classic Burkitt lymphoma were excluded. Cases of DH lymphoma (DH+) were defined as demonstrating at least one of either 8q24 split, t(8;14), t(2;8) or t(8;22) as well as a BCL2, BCL6 and/or BCL1 rearrangement. Therapy was given at the discretion of the treating clinician. Response was defined using the Revised Response Criteria for Malignant Lymphoma (J Clin Oncol. 2007 Feb 10;25(5):579-86.). Results DH+ was detected in 17 patients (32%) and a sole MYC gene rearrangement was detected in an additional 9 patients (17%). MYC gene rearrangements were detected by metaphase cytogenetics in 4 (15%) and by FISH in 22 (85%) of these patients. No factor, including age, LDH, stage, International Prognostic Index (IPI) or histology was predictive of DH status (Table I). DH+ patients were treated with R-hyperCVAD (41%), R-CHOP (41%) and other regimens (18%). Complete response was less frequent in DH+ compared to non-DH patients (41% vs. 81%, p=0.002). With a median follow-up of 10.4 months (range 1.2-72.4), the median overall survival was significantly shorter for DH+ compared to non-DH patients (8.2 vs. 56.8 months, p<0.001). Median overall survival was not significantly different for non-DH patients with and without a sole MYC gene rearrangement (50.8 months vs. not yet reached, p=0.33). Univariate Cox regression analysis showed that the presence of a MYC gene rearrangement (MYC+) and DH+ had statistically significant associations with overall survival; however, only DH+ retained statistical significance on multivariate analysis (Table II). Conclusions DH status cannot be inferred by baseline disease- or patient-related characteristics and is most predictive of overall survival in this cohort of B cell lymphoma patients. These findings support the practice of routine FISH for DH gene rearrangements in order to better identify DH+ patients who may benefit from risk-adapted and/or targeted therapies. We plan to validate our findings in a larger unselected cohort of diffuse large B cell lymphoma patients. Disclosures: No relevant conflicts of interest to declare.

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Epidemiologic and Clinical Patterns of Lymphoma in Qatar 2013-2017: A Population-Based Cohort Study

Blood ◽

10.1182/blood-2021-144637 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4584-4584

Author(s):

Ahmed A Adel ◽

Aimilia Exarchakou ◽

Anas Hamad ◽

Ruba Yasin ◽

Hafedh Ghazouani ◽

...

Keyword(s):

Overall Survival ◽

B Cell ◽

Conflicts Of Interest ◽

Disease Free Survival ◽

B Cell Lymphoma ◽

Descriptive Statistics ◽

World Health ◽

Treatment Modalities ◽

Epidemiological Characteristics

Abstract Background: Lymphoma: either most common non-Hodgkin (NHL) or less common Hodgkin (HL), are well-known hematological malignancies. With advancement in treatment modalities, the survival in both lymphomas especially the "poor prognosis" non-Hodgkin lymphoma has evolved in the last decades. Hence, patient's outcome may be diverse and quite complicated; with some need extended time for observation, and others having multiple chemotherapy treatments. In this review, we will focus on the clinic-epidemiological patterns of various malignant lymphoma subtypes in Qatar in recent years (2013-2017) Objective: The primary aim is to investigate and compare the overall survival (OS) for both types of lymphoma; HL and NHL at 1, 3 and 5-years of follow up in adult lymphoma patients in Qatar between January 2013 - December 2017. Other objectives include comparing between the most frequent histological varieties, clinical and epidemiological characteristics of HL and NHL lymphoma in Qatar. The secondary objectives included clinical characteristics, treatments used, treatment response, disease-free survival and overall survival. Methods: A retrospective, descriptive study of consecutive cases was carried out at NCCCR, Qatar between 2013-2017. Inclusion criteria included: ≥ 18 years of age, male or female, any clinical stage at diagnosis, who had received any chemotherapy regimen, with a known outcome. Descriptive statistics was performed for all variables, and survival was assessed using Kaplan-Meier curves. Data was abstracted by Qatar National Cancer Registry and the 2008 World Health Organization (WHO) classification of hematopoietic and lymphoid tumors is used as reference for disease staging and pathological classification. We used STATA version 13.0 (StataCorp., College Station, TX) for exploratory data analysis and descriptive statistics. Results: During the period 2013-2017, 414 men and women were diagnosed with lymphoma in the state of Qatar. The median age at diagnosis being 49 years (interquartile range IQR 36-95 years; p<0.001)) for all lymphoma patients combined. Males were more likely to develop both lymphoma types; HL and NHL than females; accounting for 2/3 of cases in each, yet statistically insignificant (74% and 70%, p=0.45). Based on subtypes, mature B-cell neoplasms (61 cases, 60%) were the most common among 13 identifiable NHL-B subtypes. Majority of HL cases belonged to Lymphocyte rich subtype (54 cases, 49%). With a median follow up of 17.3 months, the 1-year, 3-year and 5-year OS for the entire population of lymphoma patients were 99%, 82% and 64% (Figure 12). When stratified by major subtypes; HL and NHL, some trends became evident at 3-years follow-up (94% versus 82%). The 5-year OS were 67% and 60%, respectively. Throughout the study period, the OS in HL group were higher than NHL (p<0.001), yet median OS was not reached. Conclusions: Diffuse large B-cell lymphoma constitutes the most frequent subtype for all lymphomas in Qatar. Overall, the survival was generally better for HL than NHL 67% and 60% respectively. Survival can be slightly deflated than other countries or regions especially HL, this is in part due to higher immigration rate in the country, so changes in survival over time (especially for longer periods) need to be examined alongside trends in incidence rates to interpret improvement in cancer control policies implemented. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Rituximab Does Not Improve Progression Free (PFS) or Overall Survival (OS) in Patients with Limited Stage Diffuse Large B Cell Lymphoma (DLBCL).

Blood ◽

10.1182/blood.v114.22.3755.3755 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3755-3755

Author(s):

Ephraim P. Hochberg ◽

Nicole Birrer ◽

Christiana E. Toomey ◽

Jeffrey A. Barnes ◽

Alfred Ian Lee ◽

...

Keyword(s):

Overall Survival ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Newly Diagnosed ◽

Logrank Test ◽

Limited Stage ◽

Large B Cell Lymphoma ◽

The Impact ◽

Large B Cell

Abstract Abstract 3755 Poster Board III-691 Introduction Diffuse Large B Cell Lymphoma (DLBCL) is the most common lymphoid malignancy accounting for approximately 33% of all newly diagnosed NHLs. Three randomized trials and multiple retrospective analyses have demonstrated both progression-free (PFS) and overall survival (OS) benefit to the addition of the anti-CD20 monoclonal antibody rituximab to anthracycline-containing chemotherapy in older advanced-stage patients, and in young low-risk patients with DLBCL. Approximately half of newly diagnosed patients with DLBCL present in limited stage and the benefit of rituximab containing chemotherapy regimens for these patients remains uncertain. Methods We used an IRB-approved clinicopathologic database, derived from comprehensive tumor registry data at the Massachusetts General Hospital, Dana Farber Cancer Institute and Brigham and Women's Hospital, to identify all patients 18 years or older diagnosed with limited stage DLBCL between 2000 and 2006. We included all patients treated with 3 or more cycles of anthracycline containing chemotherapy with curative intent. We excluded primary DLBCL of the CNS. We determined the impact of the use of rituximab on OS and PFS. PFS and OS were calculated from the date of initial diagnosis. Results A total of 138 patients met eligibility criteria and are included in the analysis. Median age was 51 years (range 18-89 years). 30% of patients were above 60 years of age, and less than 3% had an IPI score of 3 or higher. One hundred and six patients received CHOP + rituximab (RCHOP) and 32 received CHOP alone. Of the 106 patients receiving RCHOP, 48 were irradiated and 58 were not. Of the 32 patients receiving CHOP, 20 received radiation and 12 did not. At a median follow-up of 35 months (range 3-109 months), PFS and OS for the entire cohort are 86.2% and 90.6%, respectively. On univariate analysis of outcome, the addition of rituximab to CHOP did not improve PFS (81.3% vs. 87.7%,p=0.817, Logrank Test) or OS (84.4% vs. 92.5%, p=0.411, Logrank Test). Conclusion The outcome of an unselected series of patients with limited stage DLBCL is excellent. In this retrospective cohort of patients with limited stage DLBCL, the use of rituximab in conjunction with standard chemotherapy did not improve PFS or OS. The results we obtained are very similar to those reported by SWOG (Persky et al. JCO 2008). The overlapping confidence intervals for PFS and OS between SWOG 0014 and 8736 patients and our data suggest that a large multicenter trial will be needed to show a benefit of rituxan in this extremely good prognosis population. Disclosures: Hochberg: Genentech: Speakers Bureau; Biogen-Idec: Speakers Bureau; Enzon: Speakers Bureau; Amgen: Speakers Bureau.

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Review of Primary Mediastinal Large B Cell Lymphomas in Our Hospital

Blood ◽

10.1182/blood.v124.21.5459.5459 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5459-5459

Author(s):

Kati Hurst ◽

Maria Cristina Moragues Martinez ◽

Manuel Espeso de Haro ◽

Manuel Barrios Garcia ◽

Ana Isabel Heiniger Mazo

Keyword(s):

Overall Survival ◽

B Cell ◽

Cell Lymphoma ◽

Survival Rates ◽

B Cell Lymphoma ◽

Bulky Disease ◽

Epidemiological Factors ◽

Consolidation Radiotherapy ◽

The Impact ◽

Large B Cell

Abstract BACKGROUND: Primary mediastinal B-cell lymphoma (PMBCL) are a subtype of diffuse large B cell lymphoma (DLBCL), that represent 2-4% of all non-Hodgkin lymphoma (NHL) and 6-12% of DLBCL. They affect young adults with a median age at diagnosis of 35 years old and are more frequent in females (2:1). Approximately 80% of patients have stage I or II disease at the time of diagnosis, with B symptoms, bulky mass and superior vena cava syndrome (SVCS) in 50 %. There is no standard initial therapy regimen, anthracyclines with Rituximab are the most used. Local consolidation radiotherapy (RT) is reserved for bulky disease and to complete partial remissions (PR) after chemotherapy. AIMS: To analyze prognostic and epidemiological factors, treatment administered and response and survival rates of patients diagnosed with PMBCL in our center. METHODS: Retrospective cohort study between September 2003 and June 2014. The treatment received was 6 to 8 cycles of CHOP-like chemotherapy (Cyclophosphamide, Adriamycin, Vincristine, Prednisone ± methotrexate / Intrathecal triple therapy MTX- TIT ), with or without Rituximab, and subsequent radiotherapy if necessary. The following results were evaluated by univariate analysis: overall survival (OS), disease-free survival (DFS) and incidence of relapse after diagnosis. DFS was defined as the interval of time from complete remission (CR) to relapse or last visit. Response to treatment was assessed by PET-CT. RESULTS: We observed 14 patients diagnosed with PMBCL in our hospital with a median age of 33 years (r, 21-58 years) and female predominance (Š:‰ 10:4). At diagnosis 42.8 % had B symptoms and 42.8% elevated lactic dehydrogenase. Fifty percent of patients presented with SVCS. Central nervous system and bone marrow infiltration was not observed. Early-stage disease at diagnosis (I 30% and II 53%) was observed in 83%, with IPI 1 in 78.5% of patients. The number of cycles received was 6 in 78.5 %, 8 cycles in 14.2 %, and only 1 cycle of CHOP in one patient. Altogether 71.4 % received Rituximab and 71.4 % received MTX-TIT. Ten patients (71.4%) received RT (median 36 Gy) after chemotherapy, 9 of which had initial bulky disease. We observed an overall response rate of 92.8 % after chemotherapy (57.1 % CR, 35.7% PR). After a median follow-up of 60 months (r, 4.4 to 130.8 months) 12 patients had responded to treatment, were alive, without relapse and in complete response, and one patient is currently receiving the 6º cycle of CHOP pending reevaluation (awaiting last MTX-TIT and RT consolidation) and obtained CR after the third cycle of R-CHOP-MTX-TIT. Median overall survival was not reached and median DFS was of 54.8 months. Only one patient died (mortality 7.1 %) due to influenza A in the context of postchemotherapy aplasia after the first cycle of CHOP. CONCLUSIONS: We observed prognostic and epidemiological factors similar to those described in literature, although in our series, CHOP -like chemotherapy ( ± MTX- TIT ) with or without Rituximab and RT has shown improved survival rates and 100% of CR. Consolidation radiotherapy was successfully used to complete treatment in patients that only achieved PR after chemotherapy. Rescue chemotherapy followed by autologous hematopoietic cell transplantation was not required. It is difficult to draw conclusions on the impact of the therapeutic regimen received, we believe multicenter analysis with larger numbers of patients are necessary. Disclosures No relevant conflicts of interest to declare.

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Ibrutinib Sensitizes AML Cells to ROS Inducers Via a BTK-Independent Mechanism

Blood ◽

10.1182/blood.v124.21.2226.2226 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2226-2226 ◽

Cited By ~ 3

Author(s):

Lianne E Rotin ◽

Marcela Gronda ◽

Neil Maclean ◽

Feng-Hsu Lin ◽

Jeff Wrana ◽

...

Keyword(s):

Cell Viability ◽

B Cell ◽

Cell Lines ◽

Conflicts Of Interest ◽

Synergistic Effects ◽

Single Agent ◽

B Cell Lymphoma ◽

Fold Increase ◽

Synergistic Cytotoxicity ◽

Btk Inhibitor

Abstract Ibrutinib is a small-molecule Bruton’s tyrosine kinase (BTK) inhibitor yielding impressive clinical responses in B-cell malignancies, where BTK contributes to disease development and progression. We noted that BTK is expressed and constitutively active in acute myeloid leukemia (AML) cell lines and in a subset of AML patients. We therefore sought to determine BTK’s potential role in AML. Using BTK-pY223 expression on immunoblot as a marker of BTK activity, we demonstrated that ibrutinib doses as low as 1μM were sufficient to inhibit BTK activity in the AML cells TEX and OCI-AML2. Yet, these cell lines were insensitive to ibrutinib compared to the B-cell lymphoma Daudi cell line (IC50 10.4μM and 23.7μM versus 1.1μM, respectively). Although inactive as a single agent, we sought to identify drug combinations that sensitized AML cells to pharmacologically relevant concentrations of ibrutinib by conducting a combination chemical screen with our in-house known drug library in TEX and OCI-AML2 cells. According to excess-over-Bliss additivism criteria, we determined that in both cell lines, the poly(ADP-ribose) glycohydrolase inhibitor ethacridine lactate was the most synergistically cytotoxic, producing an 8-fold reduction in the IC50 of ibrutinib. Synergistic cytotoxicity was also observed in a subset of primary AML cells, but not normal hematopoietic cells. Mechanistically, the combination’s synergistic cytotoxicity resulted from excessive ROS production (>10-fold increase, versus a <2-fold increase with either drug alone in TEX and OCI-AML2), since α-tocopherol addition to combination-treated cells rescued cell viability from 24% to 85% and from 4% to 84% in TEX and OCI-AML2, respectively. Combining ibrutinib with other ROS-inducing agents such as parthenolide and the first-line AML therapy daunorubicin produced similar synergistic effects in AML cells,with α-tocopherol also rescuing cell viability. However, the synergistic effects were likely not related to inhibition of BTK, as knockdown of BTK with shRNA did not sensitize TEX cells to ethacridine or daunorubicin and thus did not recapitulate the effects of ibrutinib. We therefore conclude that the BTK inhibitor ibrutinib lacks single agent anti-AML activity, but synergizes with ROS-inducing agents including daunorubicin by inhibiting targets beyond BTK. Thus, clinical trials of ibrutinib in combination with standard chemotherapy could be warranted in AML. Disclosures No relevant conflicts of interest to declare.

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Efficacy of Yttrium-90 Iburitumomab Tiuxetan for Early Relapsed/Refractory Indolent B-Cell Lymphoma: A Single Institute Retrospective Analysis in the Rituximab Era

Blood ◽

10.1182/blood-2018-99-112782 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5333-5333

Author(s):

Keiichi Nakata ◽

Shigeo Fuji ◽

Ryo Nakata ◽

Kazuhito Tsutsumi ◽

Shuhei Kida ◽

...

Keyword(s):

Follicular Lymphoma ◽

B Cell ◽

Conflicts Of Interest ◽

Cell Lymphoma ◽

Univariate Analysis ◽

B Cell Lymphoma ◽

Significant Prognostic Factor ◽

Hematopoietic Stem ◽

The Impact ◽

Yttrium 90

Abstract Introduction: Indolent B-cell lymphoma is a type of non-Hodgkin's lymphoma that grows slowly and is not a curative disease. Yttrium-90 (90Y) iburitumomab tiuxetan is used in patients with relapsed/refractory indolent B-cell lymphoma, data is still limited in the rituximab era. In addition, previous studies did not assess the impact of early progression of disease within 2 years (POD24) which was reported to be associated with a poor prognosis in follicular lymphoma (Casulo et al, J Clin Oncol 2015) on the efficacy of 90Y iburitumomab tiuxetan. Thus, here we assessed the efficacy of 90Y iburitumomab tiuxetan in relapsed/refractory indolent B-cell lymphoma, and analyzed the impact of POD24 in this setting. Methods: We retrospectively analyzed the clinical outcomes of 51 patients with a relapsed/refractory indolent B-cell lymphoma who received 90Y iburitumomab tiuxetan at our institute from February 2009 to January 2018. POD24 was defined as progression within 24 months from the beginning of induction chemotherapy. Survival outcomes including overall survival (OS) and progression-free survival (PFS) were analyzed by Kaplan-Meier analysis and Cox proportional hazard models. Results: The median age was 64 years (range 37-88 years) at the time of receiving 90Y iburitumomab tiuxetan, and 29 (56.9%) were male. Disease subtypes were as follows: follicular lymphoma (n=44, 86.3%), mantle cell (n=4, 7.8%), marginal zone (n=2, 3.9%), and MALT lymphoma (n=1, 2.0%). The median number of previous regimens was 2 (range 1-9) and included rituximab-based therapy in all patients. Disease status at the time of receiving 90Y iburitumomab tiuxetan were as follows: complete remission (CR n=3, 5.9%), partial remission (PR n=13, 25.5%), stable disease (SD n=3, 5.9%), progression disease (PD n=32, 62.7%). The median follow-up time was 3.7 years (range 0.3-8.8 years) and overall response rate (ORR) was 94.1% (CR 56.9%, PR 37.3%). The ORR in patients with POD 24 was 95.0% (CR 60.0%, PR 35.0%), compared to 93.5% (CR 54.8%, PR 38.7%) with non-POD24. The 3-year OS and PFS rates for all patients receiving 90Y iburitumomab tiuxetan were 83.6% and 41.0%, respectively. POD24 was a significant prognostic factor for PFS in univariate analysis (1.2 years in patients with POD24 vs. 3.3 years in patients with non-POD24, (P=0.02) (Figure1). In multivariate analysis, POD24 was an independent prognostic marker of PFS (hazard ratio (HR) 0.43, 95% confidence interval (CI) 0.22-0.87, P=0.02). Conclusion: 90Y iburitumomab tiuxetan was highly effective in patients with relapsed/refractory indolent B-cell lymphoma patients. However, in patients with POD24, duration of response was short. Thus, another treatment strategy including hematopoietic stem cell transplantation should be considered. Disclosures No relevant conflicts of interest to declare.

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MYD88 L265P Mutation Is a Possible Unfavorable Prognostic Factor in Patients with Diffuse B-Cell Lymphoma

Blood ◽

10.1182/blood.v126.23.5051.5051 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5051-5051 ◽

Cited By ~ 2

Author(s):

Anna A. Sidorova ◽

Eugene E. Zvonkov ◽

Andrey B. Sudarikov ◽

Nataliya A. Severina ◽

Alla M. Kovrigina ◽

...

Keyword(s):

B Cell ◽

Conflicts Of Interest ◽

Cell Lymphoma ◽

International Prognostic Index ◽

B Cell Lymphoma ◽

High Dose ◽

Mutation Status ◽

Myd88 L265p Mutation ◽

The Impact ◽

Myd88 L265p

Abstract INTRODUCTION Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma. Activated B-cell like (ABC) molecular subtype DLBCL is characterized by more aggressive behavior and poor clinical outcomes with standard R-CHOP chemotherapy. Approximately 30% of all patients (pts) with ABC DLBCL have recurrent mutation in the MYD88 gene (a change from leucine to proline at position 256 - L256P). We report the impact of the MYD88 mutation status on the clinical course and outcome of pts with ABC DLBCL. METHODS In present study MYD88 mutation status was investigated in untreated pts with ABC DLBCL. The diagnosis of ABC DLBCL was established according to the WHO 2008 classification. DNA from 41 cryopreserved and 12 formalin-fixed paraffin-embedded tumor samples were tested in our study. Sanger sequencing and real-time allele-specific PCR was used to assess MYD88 L265P mutation status. RESULTS We report data for 53 pts (34 male, 19 female) with a median age of 53 (18-74) years. MYD88 L265P mutation was detected in 26,4% (14/53) of pts. The international prognostic index (IPI) score was 4-5 in 7/14 (50%) of pts with MYD88 mutated DLBCL and 12/39 (30,8%) pts with MYD88 wild type DLBCL, whereas nearly half of all pts presented with Ann Arbor stage IV disease. The majority of pts 13/14 (93%) with MYD88-positive DLBCL had elevated lactate dehydrogenase levels versus 26/39 (66%) pts with MYD88 unmutated DLBCL. Extranodal was more common in pts with MYD88 mutation than in pts with MYD88 unmutated DLBCL (78,5% vs 54%). All pts received high-dose chemotherapy and were followed for 50,5 (11-95) month. Pts with MYD88 mutation had similar complete response rate comparing to pts without MYD88 mutation (78,6% vs 84,6%). The disease relapsed in 45,4% of pts with MYD88 mutation and in 24,2% of pts without MYD88 mutation. Mortality was in 45,4% of pts with MYD88 mutation and in 24,2% of pts without MYD88 mutation. Overall survival (OS) was better in pts with MYD88 unmutated DLBCL than in pts with MYD88 positive DLBCL (5-year OS, 73% vs 31%). CONCLUSION IPI high risk and extranodal involvement is common in ABC DLBCL pts with MYD88 L265P mutation. MYD88 L265P mutation can be a predisposing factor for poor OS probability in pts with ABC DLBCL. Disclosures No relevant conflicts of interest to declare.

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Loss of NR4A1 Accelerates the Development of Aggressive Lymphomas in Myc Induced Cancerogenesis

Blood ◽

10.1182/blood.v126.23.2444.2444 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2444-2444

Author(s):

Kerstin Wenzl ◽

Katharina Troppan ◽

Beata Pursche ◽

Marco Bischof ◽

Christine Beham-Schmid ◽

...

Keyword(s):

B Cell ◽

Median Survival ◽

Conflicts Of Interest ◽

B Cell Lymphoma ◽

Lymphoma Cells ◽

Cancer Specific Survival ◽

Oncogenic Potential ◽

Aggressive Lymphomas ◽

Significant Difference ◽

The Impact

Abstract Introduction and Aim: We recently described a reduced NR4A1 and NR4A3 expression chronic lymphocytic leukemia, follicular lymphoma, and diffuse large B-cell lymphoma compared to normal controls. Our survival analysis of aggressive lymphomas revealed that low NR4A1 expression was associated with poor cancer specific survival. Over-expression of NR4A1 in lymphoma cell lines led to a significantly higher proportion of lymphoma cells undergoing apoptosis and abrogated tumor growth in xenografts1. The aim of this study is to define the role of NR4A1 as a tumor suppressor in the development of lymphoid malignancies in vivo. Methods: To identify, whether the loss of NR4A1 has an impact in Myc driven lymphomagenesis we crossed EµMyc mice with NR4A1-/- mice and performed phenotypical analysis including measurement of tumor development, survival and immunophenotypic determination of the newly developed lymphomas by FACS analysis. To further investigate the impact of NR4A1 loss on the oncogenic potential of EµMyc lymphoma cells we isolated viable tumor cells (B220+ and 7AAD-) and cultured them for 72h with or without lipopolysaccharide (LPS) and determined the number of viable cells and their viability (B220 and 7AAD-staining by flow cytometry analysis) after 24h, 48h and 72h. Finally, expression levels of NR4A1, NR4A3 and Myc with or without NR4A1 loss were evaluated by using RT-qPCR. Results: EµMyc mice with NR4A1 loss (EµMyc NR4A1-/-, n=46) developed visible tumors significantly faster compared to EµMyc mice with NR4A1 (EµMyc NR4A1+/+, n=75) (median = 44 days for EµMyc NR4A1 -/- vs. 107 days for EµMyc NR4A1+/+; p<0.001). Additionally, EµMyc NR4A1-/- mice showed a significantly shorter life span (median survival = 77 days) compared to EµMyc NR4A1 +/+ mice (median survival = 156 days; p<0.001). By comparing the immunophenotype of the newly developed lymphoma between the two groups (EµMyc NR4A1+/+, n=17 and EµMyc NR4A1 /- , n=19), no significant difference was observed. Interestingly, EµMyc NR4A1-/- mice showed an increased frequency of strong CD93 expression (10 of 18, respectively, vs. 2 of 17 EµMyc NR4A1 +/+ mice, p=0.004). Since most of the EµMyc NR4A1-/- lymphoma were IgM negative (7 of 10) it might be speculated that NR4A1 loss leads to a more immature phenotype of the lymphoma. The number of viable B220+ lymphoma cells isolated from EµMyc NR4A1-/- mice was higher compared to B220+ lymphoma cells isolated from EµMyc NR4A1+/+ mice after 72h in culture with or without LPS (p=0.056; p=0,052). This was accompagnied by a higher in vitro proliferation rate as demonstrated by a higher percentage of BrdU positive cells of the EµMyc NR4A1-/- mice compared to B220+ EµMyc NR4A1+/+ cells with and without LPS stimulation (p= 0,064, p=0,038). Interestingly, we detected a 12 fold higher NR4A3 mRNA expression (p=0,038) in EµMyc NR4A1-/- tumors compared to EµMyc NR4A1+/+. Conclusion: Our data demonstrate that NR4A1 possesses tumor suppressive properties and that loss of NR4A1 accelerates Myc driven lymphomagenesis. Furthermore, this study indicates that deletion of NR4A1 confers a more aggressive behavior and increases the oncogenic potential of EµMyc driven lymphoma cells. 1. Deutsch AJ, Rinner B, Wenzl K, et al. NR4A1-mediated apoptosis suppresses lymphomagenesis and is associated with a favorable cancer specific survival in patients with aggressive B-cell lymphomas. Blood. 2014. Disclosures No relevant conflicts of interest to declare.

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