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

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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Intensive Immunochemotherapy In Patients With B-Cell Lymphoma, Unclassifiable (B-UCL), With Features Intermediate Between Diffuse Large B-Cell Lymphoma (DLBCL) and Burkitt Lymphoma (BL): A Comparison With BL Patients Treated With The Same Protocol In The Pethema-Burkimab-04 Trial

Blood ◽

10.1182/blood.v122.21.1793.1793 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1793-1793

Author(s):

Pere Barba ◽

Albert Oriol ◽

Carlos Grande ◽

Pau Abrisqueta ◽

José González-Campos ◽

...

Keyword(s):

Overall Survival ◽

B Cell ◽

Clinical Characteristics ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

World Health ◽

Hiv Positive ◽

Risk Of Death ◽

Grade 3

Abstract B-UCL is a new category of lymphomas that comprises a heterogeneous group of tumors from a morphological, phenotypic and genetic perspective with features intermediate between DLBCL and BL. This entity has been included as a new category in the 2008 World Health Organization (WHO) Classification of Tumors of Hematopoietic and Lymphoid Tissues. The outcome of patients with B-UCL is generally considered very poor. However, the number of series analyzing the prognosis of B-UCL is scarce and they include small number of patients not homogeneously treated. Against this background, herein we present a series of patients diagnosed with B-UCL (WHO 2008) or Burkitt-like variant (WHO 2001) homogeneously treated according to the PETHEMA-Burkimab-04 trial. This trial was designed for the treatment of BL, including both HIV positive and negative patients. Patients with B-UCL were allowed to be treated following the same protocol and were considered separately. The main clinical characteristics and outcome were compared to those obtained from classical BL patients in the same trial (Ribera et al. Cancer 2013). Diagnosis of B-UCL was made in each center based on morphological, phenotypic and genetic characteristics and centrally reviewed by two pathologists. Patients received 6 courses of chemotherapy including continuous methotrexate infusion, cytarabine, vincristine and dexametasone among other drugs. A single dose of rituximab (375mg/m2) before each cycle was administered. Patients with non-bulky stage I-II disease received only 4 courses of treatment, whereas patients with advanced stage (II bulky-IV) received 2 additional doses of rituximab at the end of the chemotherapy. A total of 30 patients with B-UCL were included and were compared with the 118 patients with BL. Median follow-up for survivors was 24 months (range 3-93). Considering B-UCL, 8 (27%) patients were HIV positive and 10 (33%) had an ECOG performance status ≥ 2. Four (13%) and 6 (20%) patients had CNS involvement and bulky (>10 cm) disease, respectively. Serum LDH level was > UNL in 25 (83%) patients. These and other clinical characteristics were similar between patients with B-UCL and BL, except for the median age at diagnosis (57 years in B-UCL vs. 44 years in BL, p=0.001). In B-UCL patients, death during induction occurred in 5 patients (17%) and 2 patients experienced treatment failure. Twenty-three (77%) patients achieved complete remission. Relapse after CR and death in remission were observed in one patient, each. All these outcomes were comparable with BL patients except for a trend to a higher risk of death during induction in patients with B-UCL (17% in B-UCL, vs. 8% in BL, p= 0.1). A total of 104 consolidation cycles were evaluable for patients with B-UCL. Most frequent grade 3-4 toxicities were neutropenia (n=57, 54%), thrombocytopenia (n=44, 42%) and infection (n=21, 20%). Grade 3-4 gastrointestinal, renal and hepatic toxicities were seen in <5% of the cycles. Overall survival at 2 years for patients with B-UCL and BL was 68% (95% CI 59-77) vs. 78% (95% CI 74-82), p=0.2, respectively. Probability of disease-free survival from CR1 for B-UCL and BL patients was 84% (95% CI 76-92) vs. 80% (95% CI 69-91), p=0.6. In conclusion, the Burkitt-type chemotherapy included in the PETHEMA-Burkimab-04 trial was able to achieve an important number of complete and durable responses in patients with B-UCL with an acceptable toxicity. As a consequence, the outcome of patients with B-UCL treated with this intensive immunochemotherapy seems similar to that obtained in the treatment of classical BL.Figure 1Overall survival from diagnosis in patients with B-UCL and BL treated with Burkimab-04.Figure 1. Overall survival from diagnosis in patients with B-UCL and BL treated with Burkimab-04.Table 1Baseline characteristics of all patients according to definitive diagnosis.CharacteristicsBurkitt (n = 118)LDCG-B/Burkitt (n=30)pGender, male n (%)85 (72)21 (70)0.8Age, median [min -max]44 [15 - 83]57 [16-77]0.001Stage, n (%)Non bulky I – II26 (22)10 (33)0.8II (bulky), III - IV92 (78)20 (67)ECOG ≥2, n (%)55 (47)10 (33)0.3HIV infection39 (33)8 (27)0.4Extranodal involvement (≥2 sites), n (%)55 (47)11 (37)0.5CNS involvement, n (%)14 (12)4 (13)0.6Bulky disease, n (%)31 (26)6 (20)0.3LDH level above normal, n (%)106 (90)25 (83)0.5Age-adjusted IPI, n (%)Low6/116 (5)2 (7)1Low-intermediate17/116 (15)6 (20)Intermediate-high46/116 (40)11 (37)High47/116 (40)11 (37)Follow-up [all patients] (months)19 (0-92)16 (0-93)0.9 Disclosures: No relevant conflicts of interest to declare.

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Concurrent Expression Of MYC/BCL2 Protein In Newly Diagnosed DLBCL Is Not Associated With An Inferior Survival Following EPOCH-R Therapy

Blood ◽

10.1182/blood.v122.21.3029.3029 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3029-3029 ◽

Cited By ~ 7

Author(s):

Kieron Dunleavy ◽

Stefania Pittaluga ◽

Margaret Shovlin ◽

Svetlana Pack ◽

Seth M. Steinberg ◽

...

Keyword(s):

Overall Survival ◽

T Cells ◽

Clinical Outcome ◽

B Cell ◽

Conflicts Of Interest ◽

B Cell Lymphoma ◽

Newly Diagnosed ◽

Cell Of Origin ◽

Bcl2 Protein

Abstract Background While several studies have now demonstrated that patients with MYC-rearranged DLBCL have a worse outcome following treatment with CHOP -with or without rituximab - recent reports suggest that concurrent expression of MYC and BCL2 protein by immunohistochemistry (IHC), independent of a MYC rearrangement, is associated with an inferior clinical outcome following R-CHOP (Johnson et al. JCO 2012 Oct 1; 30 (28): 3452-9). We previously reported that DLBCL patients with a MYC rearrangement have a similar outcome to MYC negative cases (4 year EFS of 83% versus 76% respectively: p=0.46) following dose-adjusted (DA)-EPOCH-R (Dunleavy et al. Ann Oncol 2011 (22) Suppl 4 # 71). Methods To assess the prognostic role of MYC and BCL2 protein expression, we performed immunohistochemistry for MYC and BCL2 in patients with newly diagnosed DLBCL who received DA-EPOCH-R or short-course (SC)-EPOCH-RR (if HIV infected). Primary mediastinal B-cell lymphoma (PMBL) cases were excluded as they have a different biology. Tumors were scored positive for MYC if ≥ 40% of cells stained positive. For BCL2, the staining intensity was compared with that in control T cells present in the tumor samples – tumor cells were considered positive if they stained the same or more intensely than T cells. We used the Hans algorithm, as previously described, to predict cell of origin as germinal center B-cell like (GCB) or non-GCB type and correlated this with outcome. Results Of 66 patients enrolled on study, characteristics were median (range) age: 48 (18-76) years; male sex 47 (71%); IPI score low versus intermediate/high 18 (27%) versus 48 (73%); HIV positive 22 (33%). IHC was positive for MYC in 28/48 (58%) cases and positive for BCL2 in 24/51 (47%). 36/51 (71%) and 15/51 (29%) of cases were of GCB and non-GCB origin respectively. At a median follow-up time of greater than 10 years, progression-free survival (PFS) and overall survival (OS) were 67.5% and 75% for all patients. We compared survival in the 4 groups: MYC+/BCL2+, MYC+/BCL2-, MYC-/BCL2+ and MYC-/BCL2-. PFS and OS were not significantly inferior in any group (global p value=0.5 (PFS) and 0.8 (OS)). Cell of origin did however predict outcome and at 10 years follow-up, PFS was 78% (GCB) versus 43% (non-GCB) (p=0.016) and OS 80% (GCB) versus 65% (non-GCB) (p=0.24). There was a significant association between MYC+/BCL2+ cases and non-GCB subtype (p=0.01) but as 42% were of GCB origin, MYC+/BCL2+ status alone did not predict a poor outcome. Conclusions In DLBCL patients treated with DA-EPOCH-R and SC-EPOCH-RR, concurrent expression of MYC and BCL2 protein did not correspond with a worse clinical outcome. However, cell of origin (GCB versus non-GCB) was predictive of outcome. MYC+/BCL2+ cases segregate with the non-GCB subtype. The overall survival of PMBL cases was 97% at 5 years follow-up. We are currently prospectively studying the DA-EPOCH-R regimen in MYC-rearranged DLBCL in a multicenter study (NCT01092182). Disclosures: No relevant conflicts of interest to declare.

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Addition of Rituximab (R) to CHOP Improves Survival in the Non-GCB Subtype of Diffuse Large B Cell Lymphoma (DLBCL).

Blood ◽

10.1182/blood.v108.11.816.816 ◽

2006 ◽

Vol 108 (11) ◽

pp. 816-816 ◽

Cited By ~ 3

Author(s):

Pedro Farinha ◽

Laurie Sehn ◽

Brian Skinnider ◽

Joseph M. Connors ◽

Randy D. Gascoyne

Keyword(s):

Overall Survival ◽

B Cell ◽

De Novo ◽

Univariate Analysis ◽

B Cell Lymphoma ◽

Cell Of Origin ◽

Chop Chemotherapy ◽

Entire Study ◽

Survival Difference

Abstract Background: The cell of origin (COO) distinction provides a prognostic and biologically relevant subclassification of DLBCL. Germinal center B cell (GCB) and non-GCB subtypes were originally characterized by gene expression studies and subsequently validated at the protein level by Hans et al., Blood 193: 275–82 (2004). The addition of R to CHOP chemotherapy has been shown to improve the outcome of patients with DLBCL. The underlying mechanism(s) responsible for this effect is largely unknown. However, it is known that R may preferentially prevent chemotherapy failure in DLBCLs that express Bcl-2 protein or fail to express Bcl-6 (Mounier et al., Blood101: 4279–84 2003, Winter et al., Blood107: 4207–13 2006). Bcl-2 over-expression and absence of Bcl-6 is more common in the non-GCB subtype. Thus, R may benefit mostly non-GCB lymphomas. To test this hypothesis we assessed the clinical impact of CHOP-R vs CHOP in DLBCL distinguished by COO subtypes. Method: We identified 163 patients with DLBCL treated with either CHOP or CHOP-R with available paraffin blocks and interpretable immuno-staining. All were de novo DLBCL cases diagnosed between 1999 and 2002 at the BCCA. The two treatment cohorts represent consecutive eras of therapy (Sehn et al., JCO2005; 23: 5027–33), and thus the median follow-up of living patients was 5.1 and 4.0 y for CHOP and CHOP-R, respectively. HIV+ patients or those with active secondary malignancies were excluded. Tissue microarrays (TMA) were built using duplicate 0.6mm cores from paraffin embedded formalin fixed (FFPE) tissues and stained with antibodies against CD10, Bcl-6, MUM1, and Bcl-2. The COO distinction was determined using the method of Hans. Results: Patients were treated with either CHOP (81) or CHOP-R (82). Their clinical characteristics, including the IPI, were evenly matched. The median follow-up of living patients was 4.4 y. The IPI was predictive of overall survival (OS) (p<0.0001) for the entire study population. Six cases had uninterpretable immunostains resulting in 74 cases with a GCB phenotype and 83 with a non-GCB phenotype (n = 157). Overall, 71% and 75% of the cases over-expressed Bcl-2 and Bcl-6, respectively. Bcl-2 protein was expressed in 70% GCB cases and 73% non-GCB (p= 0.72). Bcl-6 was expressed in 96% GCB cases and 63% non-GCB cases (p<0.0001). In univariate analysis, the addition of R was associated with a better prognosis in the non-GCB cases (p=0.02), but not in the GCB cases (p=0.3). This survival difference was not solely explained by either Bcl-2 or Bcl-6 expression. The addition of R to CHOP chemotherapy and IPI were independent predictors of OS in non-GCB DLBCL (p=0.02; p=0.016, respectively). The addition of R was also of prognostic importance in the lymphomas over-expressing Bcl-2 (p=0.0081). Conclusion: Immuno-chemotherapy using CHOP-R is associated with better OS in DLBCL, due largely to its effect on the non-GCB subgroup. Although Bcl-2 expression does not contribute to the determination of COO distinctions, the OS of Bcl-2-positive DLBCL patients is significantly improved by the addition of R. These results provide insight into the possible mechanisms by which R exerts its beneficial therapeutic effect. Overall Survival for 157 DLBCL Based on Cell of Origin Overall Survival for 157 DLBCL Based on Cell of Origin

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Rates and Outcomes of Follicular Lymphoma Transformation in the Rituximab Era: A Report From the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource

Blood ◽

10.1182/blood.v120.21.1546.1546 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1546-1546

Author(s):

Brian K Link ◽

Matthew J Maurer ◽

Grzegorz S. Nowakowski ◽

Stephen M Ansell ◽

William R Macon ◽

...

Keyword(s):

Overall Survival ◽

B Cell ◽

Mayo Clinic ◽

Cell Lymphoma ◽

Management Strategies ◽

B Cell Lymphoma ◽

Newly Diagnosed ◽

University Of Iowa ◽

The University

Abstract Abstract 1546 Background: Follicular lymphoma (FL) is an incurable disease with an undefined optimal management strategy. Global priorities in goals of care are avoidance of death and transformation to aggressive subtypes. Retrospective series, – most including patients diagnosed before ubiquitous rituximab use, - describe diverse rates of transformation with a common consensus of 3% per year, and with a median survival post transformation of less than 2 years. This study sought to characterize transformation events in a prospective observational series begun after diffusion of early rituximab use in FL. Methods: Newly diagnosed FL patients were prospectively enrolled in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER) from 2002–2009. Clinical data were abstracted from medical records using a standard protocol. Patients were actively followed for retreatment, transformation, and death. Inclusion criteria for this analysis were initial diagnosis of grade I-IIIa FL. Exclusion criteria for this cohort include composite diffuse large B-cell lymphoma (DLBCL), FL grade IIIb, or evidence of clinical or pathological transformation at the time of FL diagnosis. Transformation was defined as refractory/recurrent disease with either a) biopsy confirmed subtype of FLIIIb, DLBCL or higher grade B-cell lymphoma; or b) clinical indication of transformation (sudden rise in LDH, rapid discordant localized nodal growth, new involvement of unusual extranodal sites, new B symptoms or hypercalcemia). Risk of transformation was analyzed via time to transformation using a death as a competing risk. Time to transformation was defined as the date of initial FL diagnosis to date of transformation. Overall survival was defined as the date of initial diagnosis to date of death or last known follow-up for patients still alive. Results: There were 631 newly diagnosed grade I-IIIa FL patients with a median age at enrollment of 60 years (range 23–93). 54% were male. The most common types of initial therapy were observation (33%), rituximab (R) monotherapy (12%), alkylator based chemotherapy +/− R (22%), and anthracycline based chemotherapy +/− R (20%). At a median follow-up of 60 months (range 11–110), 79 patients had died, 311 patients had an event (death, progression, or retreatment), and 60 patients (9.5%) had transformed. Transformation was biopsy proven in 48 of the 60 patients (80%). The overall transformation rate at 5 years (TX5) was 10.7% (95% CI: 8.3%–13.8%) (Figure 1). Time to transformation was associated with a FLIPI score of 3–5 (HR=2.37, 95% CI 1.28–4.39, p=0.006), but was not significantly associated with other standard clinical characteristics. Risk of transformation was different in the common initial treatment groups with the highest rate in patients who were initially observed (TX5=14.4%) and lowest rate in patients who initially received R monotherapy (TX5=3.2%)(p=0.058). Outcome after transformation was inferior to MER subjects with de-novo diagnosed DLBCL (p<0.0001). The median overall survival from date of transformation was 44 months (95% CI: 22-NA). Survival after transformation was superior in patients who transformed greater than 18 months after FL diagnosis compared to patients who transformed earlier (5 yr OS =70% vs 20%) (p=7 ×10−5), and for those initially observed (median unreached) versus those patients who were initially treated with alkylator or anthracycline based chemotherapy (median survival of 11 months)( p=0.016). Conclusions: Follicular transformation rates in this modern large prospective observational study are similar to risk of death without transformation and slightly lower at 5 years than most previous reports. Post-transformation prognosis is substantially better than described in older series. These observed differences may be a function of the prospective nature of the study design, modern management strategies, or patient selection factors. Initial management strategies may influence the risk of transformation. Marked survival differences following early vs. late transformation suggest that these may be different biologic events. Disclosures: Link: Genentech: Consultancy, Research Funding; Celgene: Consultancy; Millenium: Consultancy. Johnston:Novartis: Consultancy.

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Comprehensive Cytokine Profiling in Systemic Mastocytosis: Prognostic Relevance of Increased Plasma IL-2R Levels.

Blood ◽

10.1182/blood.v120.21.2836.2836 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2836-2836 ◽

Cited By ~ 1

Author(s):

Animesh Pardanani ◽

Christy Finke ◽

Terra L Lasho ◽

Ayalew Tefferi

Keyword(s):

Bone Marrow ◽

Overall Survival ◽

Mast Cell ◽

Median Survival ◽

Systemic Mastocytosis ◽

B Cell Lymphoma ◽

World Health ◽

Serum Tryptase ◽

Who Criteria

Abstract Abstract 2836 Background: The clinical phenotype of systemic mastocytosis (SM) is highly variable; establishing prognosis in terms of overall survival or risk of transformation to aggressive disease for those with non-indolent and indolent disease variants, respectively, is not trivial. Similar to other clonal hemopathies, mast cell (MC) activation and/or stromal response to clonal MC expansion likely results in a dysregulated immuno cellular/cytokine profile; analysis of this aspect of SM may provide additional prognostic information within the context of well established parameters such as the World Health Organization (WHO) SM classification system. Here, we conducted a comprehensive analysis of circulating cytokines/chemokines with clinicopathologic and clinical outcome correlations in a cohort of SM patients seen at our institution. Methods: The diagnosis of SM and its subclassification were established according to WHO criteria. Inclusion in this study required availability of archived plasma, bone marrow biopsy, and cytogenetic information at the time of first referral. Follow up information including data on survival and disease progression were updated in July 2012. Concentrations of plasma cytokines were analyzed in duplicate by using Multiplex Bead-Based Luminex technology (Invitrogen, Carlsbad, CA). Results: Forty six SM patients met the above stipulated criteria; 25 (54%) were male and the median age at referral was 61 years (range 21–85). Subclassification of patients per WHO criteria was: indolent SM (ISM) 23 (50%), aggressive SM (ASM) 8 (17%) and SM with associated clonal hematological non-MC lineage disease (SM-AHNMD) 15 (33%). When the distribution of 30 cytokines was considered across the 3 SM sub groups, only interleukin (IL)-8 was significantly different (SM-AHNMD > ISM/ASM; p=0.0002). For ISM patients, increased levels of sIL-2R were associated with presence of B-findings (p=0.0046) including splenomegaly (p=0.001) and serum tryptase levels >200 ng/mL (p=0.0046), and decreased levels of IL-8 and hepatocyte growth factor (HGF) with MC mediator-release symptoms (p <0.05). Increased levels of sIL-2R (r2=0.6; p<0.0001) and RANTES (r2=0.37; p=0.0013) were correlated with bone marrow MC burden, and sIL-2R (r2=0.34; p=0.004) and MIG (r2=0.42; p=0.0012) with serum tryptase levels in ISM patients; similar findings were noted for the overall cohort. At a median follow up of 28 months (range 0–116), 20 (43%) deaths, and 3 (13%) and 1 (2%) transformations to ASM and mast cell leukemia, respectively, were recorded for the overall cohort. In univariate analysis, increased sIL-2R levels were predictive for inferior overall survival (p=0.005); this prognostic significance was maintained in multivariate analysis after adjusting for other known prognostic variables individually (i.e. WHO SM subtypes, age >65 years, hemoglobin <10 g/dL, thrombocytopenia, weight loss or hypoalbuminemia) (all p <0.05). Increased sIL-2R (>75th percentile) effectively stratified patients in the overall cohort into 2 well-delineated risk groups for overall survival (median survival 109 vs. 26 months; p=0.0004) (Figure). This sIL-2R threshold was also able to risk stratify patients within ISM (median survival not reached vs. 38 months) and non-ISM (median survival 31 vs. 5 months) categories (p <0.0001). Conclusions: The current study demonstrates s-IL2R to be a key inflammatory cytokine in SM; it is significantly correlated with a phenotype of high systemic MC burden and in this regard, is an attractive surrogate for treatment response in clinical practice, if validated. The predictive value of sIL-2R for overall survival is akin to similar observations in primary myelofibrosis and diffuse large B-cell lymphoma; in this study, it was noted to be independent of conventional measures of organopathy from MC infiltration, and thus may reflect a novel pathogenetic process in SM, mediated by dysregulated inflammatory and/or immuno cellular pathways. Disclosures: No relevant conflicts of interest to declare.

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Concurrent Follicular Lymphoma At Diagnosis Has a Negative Impact On The Outcome Of Patients With Diffuse Large B Cell Lymphoma

Blood ◽

10.1182/blood.v122.21.4260.4260 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4260-4260 ◽

Cited By ~ 2

Author(s):

David Wrench ◽

Hasan Rizvi ◽

Andrew Wilson ◽

Ciaran O'Riain ◽

Andrew Clear ◽

...

Keyword(s):

Follicular Lymphoma ◽

B Cell ◽

Conflicts Of Interest ◽

Cell Lymphoma ◽

Negative Impact ◽

Tissue Sample ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract In contrast to either de novo diffuse large B cell lymphoma (dnDLBCL) or follicular lymphoma (FL) that transforms to DLBCL, the clinical course of DLBCL and FL presenting simultaneously (DLBCL/FL) is not well characterised. From 1 October 1975 to 31 December 2010, 819 patients were diagnosed with DLBCL at St Bartholomew’s Hospital. Twenty-seven patients with bone marrow (BM) involvement were excluded because of histologies other than FL or DLBCL in the BM (n=2) or unavailable BM samples (n=25). The remaining patients comprised the study population (n=792) which consisted of 45 histologically confirmed DLBCL/FL and 747 dnDLBCL. A pathological review was performed of all DLBCL/FL and all the positive BM samples. Remission duration (RD), progression-free survival (PFS), overall survival (OS) and lymphoma-specific survival (LSS) were compared in DLBCL/FL and dnDLBCL. DLBCL/FL comprised composite (both histologies in the same tissue sample; n=24) and discordant (both histologies in separate tissue samples; n=21) lymphoma. The majority (n=18, 75%) of composite DLBCL/FL were diagnosed on lymph node (LN) sampling with the remainder identified in tonsil (n=3) with single cases in testis, salivary gland and BM. Discordant DLBCL/FL, presented as DLBCL and FL involving LN and BM respectively in 16 cases (76%). Other combinations included DLBCL and FL in separate LNs (n=2) and one each of kidney + BM, mesentery + LN, bone biopsy + BM. At presentation, DLBCL/FL had more advanced stage (p<0.01), higher IPI (p=0.02) and lower Hb (p=0.02) than dnDLBCL in keeping with BM involvement rates of 19/45 (42%) and 32/747 (4%), respectively. Most DLBCL/FL (n=42; 93%) received anthracycline based combination chemotherapy (a single case received HD-MTX and 2 cases palliative / no treatment both of whom died within 3.5 months) and, since 2003, addition of rituximab (24% of cases) to CHOP (n=10) or CODOX-M/IVAC (n=1); with similar rates of anthracycline (82%) and rituximab (29%) use in dnDLBCL. The 44 documented responses in DLCBL/FL included complete response (CR, n=26; 59% similar to 66% in 696 patients with dnDLBCL and assessable responses), partial response (n=7) and stable disease/progression (n=11) with a shorter RD for DLBCL/FL (median 8.7 yrs) compared to dnDLBCL (median not reached), although this was not statistically different (p=0.09). PFS was significantly shorter for DLBCL/FL in comparison with dnDLBCL (2.0 versus 4.6 yrs, respectively; p=0.02) and DLBCL/FL not achieving CR had inferior OS (0.4 yrs) than those achieving CR (11.5 yrs; p<0.01). Relapse after CR occurred in 12/26 (46%) patients with DLBCL/FL and in 142/456 (31%; p=0.13) of those with dnDLBCL; 83% and 87% relapsed cases have died, respectively. With a median follow-up of 10 yrs, 71% patients with DLBCL/FL have died as compared to 65% patients with dnDLBCL, and no differences in median OS were observed (4.0 yrs for DLCBL/FL versus 5.5 yrs for dnDLBCL; p=0.28). Death was most commonly due to lymphoma, the rate being similar in patients with DLBCL/FL (56%) and dnDLBCL (52%). However, LSS was shorter for DLBCL/FL (6.3 yrs) than dnDLBCL (13.8 yrs; p<0.01) and, with the long follow-up, we found no differences in OS between DLBCL with concordant (DLBCL, n=32) or discordant (FL, n=18) BM involvement (p=0.38). This study, to the authors’ knowledge the largest series of concurrent FL and DLBCL, confirms the relative frequency of DLBCL/FL to DLBCL (45:747, 6%) and demonstrates that the simultaneous presence of FL negatively influences the outcome of patients with DLBCL, by shortening PFS and LSS. This data emphasizes the importance of thorough staging at diagnosis, including BM biopsies, and highlights the need for better management of this population, which has a worse prognosis than dnDLBCL and is frequently excluded from clinical trials. Disclosures: No relevant conflicts of interest to declare.

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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 ◽

10.1182/blood.v124.21.5472.5472 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5472-5472 ◽

Cited By ~ 5

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.

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DLBCL with CD30+ Has Not a Better Prognosis in a Brazilian Coorte Population

Blood ◽

10.1182/blood.v126.23.5014.5014 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5014-5014

Author(s):

Talita Rocha ◽

Carlos Sérgio Chiattone ◽

Ana Beatriz Kinupe ◽

Felipe Costa ◽

Jose Vassalo ◽

...

Keyword(s):

Overall Survival ◽

Hodgkin’S Lymphoma ◽

Conflicts Of Interest ◽

Cell Lymphoma ◽

Disease Free Survival ◽

B Cell Lymphoma ◽

Large Cell ◽

Hodgkin's Lymphoma ◽

Anatomic Site ◽

Large Cell Lymphoma

Abstract Background: CD30 is a well-known diagnostic marker in both anaplastic large cell lymphoma (ALCL) and classical Hodgkin's lymphoma (CHL). The chimeric drug brentuximab vedotin that combines an anti-CD30 monoclonal antibody with the anti-tubulin agent monomethyl auristatin E demonstrated activity in patients with relapsed CHL, ALCL and other lymphomas that express CD30+. Previous observational studies have suggested that CD30 may be expressed in 10 to 20% of DLBCLs. It is possible that CD30+ DLBCLs may show different biologic behavior and be amenable to anti-CD30 therapy. The aim of this study was to determine the prevalence of CD30 expression in DLBCL by immunohistochemistry and explore possible relationships with important clinical and biologic variables of DLBCL. Methods: We retrospectively identified cases of DLBCL diagnosed between Jan 2007 and march 2014 at our institution. Eligible cases included patients with diagnosis of DLBCL irrespective of anatomic site or tumor stage. The diagnosis of DLBCL was based on the current WHO 2008 criteria. The following large B cell lymphoma subtypes were excluded from this analysis: post-transplant lymphoproliferative disorders with DLBCL morphology, Primary Mediastinal large cell lymphoma and the unclassifiable lymphomas with features intermediate between either DLBCL and Burkitt's lymphoma or between DLBCL and Hodgkin's lymphoma. Immunohistochemistry was performed with TMA (tissue microarray) in all the cases. We use a cut-off of 0%, 5% (expression between 0 and 10%), 10% and 20%. DLBCLs were classified into germinal center (GC) or non-GC subtypes applying the Hans algorithm. Logistic regression analysis was performed to assess association between selected variables and CD30 expression. Results: A total of 197 cases of DLBCL were eligible for this study and of these 152 cases (77.1%) had paraffin material available to analyse CD30. Clinical and laboratory characteristics of all coorte are shown bellow(table 1). Fifty one patients (33,5%) were positive for CD30, using cut-off>0% and 16 pacients (10,5%) were positives with a cut off ≥ 20%. Nine patients (5,9%) were EBV positives and excluded from the survival analyses. With a follow-up of 34,3 months, according disease free survival, with a cutt off CD30>0%, that was no difference between the groups (71,3% versus 71% p 0,974). According cell origen, no difference was found in the subgroup GC (75% versus 72% p 0,726) nor APC (68,8% versus 64,4% p 0,397). Using cut off CD30 ≥ 20% that was also no difference in DFS between groups (75% versus 70,5% p 0,945). Also ocurred when we analysed cell origen, GC with or without CD30 (75% versus 72,7% p 0,519) and for patients ABC with or without CD30 (75% versus 64,2% p 0,524) . Acoording overall survival, using cutt-off CD30% >0% there was no difference between the groups (86,9% versus 78,2% p 0,257). GC cell origen patients with CD30+ did not have better outcomes than patients CD30- (81,3% versus 77,1% p 0,792). For patients with ABC tumor, there was a slightly better survival for patients with CD30+ (92,3% versus 74,9% p 0,059). Using cut off CD30 ≥ 20% same results were found according CD30 expression. No difference in overall survival (87,1% versus 80,3% p 0,908). Even versus 78,7% p 0,292) nor ABC (90,9% versus 79,8% p 0,384). Conclusion: In this present study, DLBCL with CD30+, using cut-off of 0% or 20% did not shown any difference in DFS or overall survival. Disclosures No relevant conflicts of interest to declare.

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Treatment of Primary Aggressive Gastrointestinal Lymphomas with Intensive Chemotherapy: A 14-Year Experience

Blood ◽

10.1182/blood.v128.22.5388.5388 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5388-5388

Author(s):

Eugene E. Zvonkov ◽

Nelly G. Gabeeva ◽

Anna K. Morozova ◽

Olga A. Gavrilina ◽

Anna A. Sidorova ◽

...

Keyword(s):

Overall Survival ◽

Conflicts Of Interest ◽

Gastric Lymphoma ◽

B Cell Lymphoma ◽

Hematologic Toxicity ◽

Favorable Result ◽

Advanced Stage ◽

Bulky Disease ◽

The Third

Abstract Background. Aggressive lymphomas accounts for about 80% of primary gastrointestinal non-Hodgkin`s lymphomas (PGIAL). In adults the most common type is diffuse large B-cell lymphoma (DLBCL). Burkitt lymphoma (BL) is rare and mainly affects children. R-CHOP chemotherapy can induce favorable result for localized-stage. But the presence of adverse factors (AF) and advanced stage decrease the efficacy of this therapy: 3-year progression-free survival (PFS) and overall survival (OS) are about 50% and 60% respectively. The optimal treatment strategy for this pts still remains unknown. Aim. Efficacy and safety assessment of the modified chemotherapy protocol NHL-BFM-90 (m NHL-BFM-90 and LB-M-04) in the treatment of the PGIAL with advanced stage and AF. Patients. 74 previously untreated pts with PGIAL underwent mNHL-BFM-90 or LB-M-04 treatment between January 2002 and December 2015; out of them, 45 pts - primary gastric lymphoma (PGL), 29 pts - primary intestinal lymphoma (PIL); median age 39 years (range 14-72); age ≥60 years 10 pts (13,5%); M\F=44\30; stage >I 58 pts (78,3%); B-symptoms 30 pts (40,5%); Bulky disease 28 pts (37,8%). Patients characteristics in groups presented in Table 1. In the PIL group compared with the PGL was predominance of male (M\F=20\9 versus 21\24), stage II-IV (89,6% versus 71%), high level of LDH (72% versus 49%), Bulky disease (55% versus 27%). In pts with high Ki-67 (>40%) FISH test on t(8;14) was performed. Burkitt`s lymphoma diagnosed in 5 pts (11%) with PGL and 9 pts (31%) with PIL. In the PIL group more than half (58,6%) pts received surgical treatment before chemotherapy, and only 2 pts (4,4%) - in the PGL group. Of the 74 pts, 60 (81%) were diagnosed with DLBCL, 14 (19%) - BL. All pts with DLBCL received treatment according to the mNHL-BFM-90 program (2 courses A and 2 courses B) that was modified in the following way: doxorubicin (50mg\m2) was added on the third day of course A. All patients with BL received treatment according to the LB-M-04 program (2 courses A and 2 courses C) that was modified in the following way: doxorubicin (50mg\m2) was added on the third day of course A, methotrexate was administered on the 1st day of course C at a dose 1500mg/m2 for 12 hours. No one received consolidation radiotherapy from both groups. Results. In DLBCL group the overall response rate (ORR) was 95%. Complete remission (CR) was achieved in 38 from 40 pts (95%) in PGL, and 17 from 20 pts (85%) PIL. With a median follow-up of 74 months (range, 1-156) disease-free and overall survival of 60 pts with DLBCL constituted 86.7% and 91,7%, respectively. In BL group all pts achieved CR and alive with no signs of progression with a median follow-up of 110 months (range, 62-154). Hematologic toxicity of grade 3 and 4 was observed in 80% of pts. Severe complications became the reason for subsequent switch to CHOP therapy after 2 courses in 6 pts with PGL DLBCL. There was no treatment-related mortality. Conclusions. The mNHL-BFM-90 and LB-M-04 demonstrated acceptable toxicity and high efficacy in patients with PGIAL. Burkett lymphoma is not rare in adults with PGIAL and detection of t(8;14) can improve treatment outcomes. Table 1 Characteristics of the patients with aggressive primary gastrointestinal non-Hodgkin`s lymphomas. Table 1. Characteristics of the patients with aggressive primary gastrointestinal non-Hodgkin`s lymphomas. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Treatment of High Risk Aggressive B Cell Lymphomas with DA EPOCH R- a Retrospective Analysis

Blood ◽

10.1182/blood.v128.22.5413.5413 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5413-5413

Author(s):

Michael Panny ◽

Katharina Troppan ◽

Peter Neumeister ◽

Thomas Nösslinger ◽

Felix Keil

Keyword(s):

High Risk ◽

B Cell ◽

Retrospective Analysis ◽

Dose Escalation ◽

Conflicts Of Interest ◽

Sensory Neuropathy ◽

B Cell Lymphoma ◽

Allogenic Stem Cell Transplantation ◽

Double Hit

Abstract Background: Promising results in patients suffering from high risk DLBCL, Burkitt`s lymphoma (BL), gray-zone lymphoma (GZL) and primary mediastinal B cell lymphoma (PMBCL) treated with DA-EPOCH R have been reported. In our centres high risk DLBCL - defined as double-hit/double hit score 2 or high/ high-intermediate risk NCCN IPI -, BL, MGZL and PMCL are treated with DA EPOCH R. Methods: Retrospective analysis of toxicity and efficacy in DA EPOCH R treated patients. Results: So far 39 previously untreated patients with a median age of 54a (28a - 76a) have been treated with a total of 190 cycles of DA EPOCH R: 16 DLBCL, 9 GZL, 8 PMBCL, 6 BL. 37 Patients have finished treatment, 2 are stilll on treatment. Targeted ANC < 500/l occurred in 46%, thrombocytopenia < 25.000/l in 20% and anemia <8g/dl in 12,5% of all cycles. Dose escalation was possible in 27 (73%) patients - but only in 5 (38%) of 13 patients > 65a. 15 (63%) of 24 patients aged < 65a received at least dose level 3. Due to peripheral sensory neuropathy, Vincristine had to be dose reduced in 52% of all cycles. Other CTCAE grade III/IV non-hematopoietic toxicities were infrequent and manageable. After a median follow up of 10 months (range: 1-25) overall survival (OS) rate is 74%. 2 patients in PR were (1 PMBCL, 1 GZL) bridged to allogenic stem cell transplantation , 1 patient in CR had to be switched to a less toxic regimen due to repeated febrile neutropenia after 3 cycles of treatment. In 16 high risk DLBCL patients (8 DHS2/DHL, 8 high/high intermediate NCCN IPI) OS is 80% after a median follow up of 12 month. As predescribed in literature, prognosis of relapsed or refractory patients is poor: 7 out of 8 (4GZL, 2 DLBCL, 1 BL, 1 PMBCL) relapsed/ refractory died. Causes of death were: 2 infectious complications (1 DLBCL HIV associated, 1 GZL) and 5 progressive disease. Conclusion: Although still preliminary, limited data, DA EPOCH R seems to be a feasible treatment with acceptable toxicity and a promising response rate. Dose escalation is age dependent. Especially in patients with high risk DLBCL DA EPOCH R is an alternative to (insufficient) induction therapy with R CHOP and is challenging more toxic regimens like R ACVBP or R Hyper CVAD. Disclosures No relevant conflicts of interest to declare.

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