Array-CGH Identifies Regions, Including the FOXP1 Locus, Associated with Different Clinical Outcome in Diffuse Large B-Cell Lymphomas (DLBCL) Treated with R-CHOP

Abstract Background. Diffuse large B-cell lymphoma (DLBCL) consists of a heterogeneous group of tumors. More than 30% of cases are not cured with R-CHOP chemotherapy. Aim. To identify genomic aberrations that could affect the response to therapy, we performed an arrayCGH study on uniformly treated DLBCL patients. Materials and Methods. Tumor samples were analyzed with Affymetrix Human Mapping 250K SNP arrays. Eligibility criteria were diagnosis of de novo DLBCL, first line treatment with R-CHOP or R-CHOP-like regimens, availability of frozen biopsy and of clinical baseline and follow-up data. Exclusion criteria were: primary mediastinal DLBCL, primary central nervous system DLBCL, HIV-positivity. Material has been collected according to the local IRB guidelines. Results. Genomic tumor profiles have been obtained in 163 samples from 10 Institutions; 23/163 cases were excluded from this analysis because the information on response was not available; 140/163 cases fulfilled the study requirements. The clinical parameters of the patients reflected the normal DLBLC population, as shown by the IPI score distribution (0–1 in 30%, 2 in 37%, 3 in 23% and 4–5 in 10%). The median follow-up was 23 months (range 1–1251). Complete remission was observed in 108/140 (77%) patients, partial response in 21 (15%), stable disease in 6 (4%) and progression in 5 (2%). Genomic differences were observed between complete responders (108 cases) and the remaining patients, grouped together as poor responders (32 cases). The latter group had more gains of 3p14.1 (FOXP1 locus), 3q29, 11q24.3, and losses of 2p11.2-p13.3, 8p23.1- pter, 10p12.31-p13, 15q11.2-q14, 15q21.1 and copy neutral LOH of chromosome 9p. On the converse, 1q gains were more common among patients achieving complete remission. No differences were observed for other common region of gains (7, 12, 18q/BCL2) or losses (1p, 6q, 17p/TP53). Conclusions. Specific genomic aberrations are associated with the response to R-CHOP in patients with DLBCL. In particular, the gain of the 3p14.1 (FOXP1 locus), which is associated with a lack of response to R-CHOP, suggests that the role of FOXP1 should be further investigated in DLBCL.

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Prevalence and Clinico-Pathological Attributes of c-MYC Rearranged High-Grade B-Cell Non Hodgkin Lymphomas (NHL): Single Centre Experience

Blood ◽

10.1182/blood.v126.23.5031.5031 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5031-5031

Author(s):

Manju Sengar ◽

Sridhar Epari ◽

Hasmukh Jain ◽

Tanuja Shet ◽

Sumeet Gujral ◽

...

Keyword(s):

B Cell ◽

De Novo ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Response To Therapy ◽

High Grade ◽

Ki 67 ◽

Large B Cell ◽

Who 2008

Abstract Introduction: MYC rearrangement in high-grade B-cell NHL(non-burkitt), either as single hit or double hit, has significant prognostic and therapeutic implications. There is remarkable paucity of data on frequency and clinico-pathological features of MYC-rearranged large B-cell lymphomas from developing world. Method: This study included de-novo high grade B-cell NHL cases (>15 years of age) registered at Tata Memorial Centre between January 2013- December 2014. Demography details, clinical features (stage at presentation, bone marrow involvement, presence and extent of extranodal involvement, B-symptoms, international prognostic index),original histopathological diagnosis, chemotherapy and radiotherapy details were recorded from electronic medical or paper case records. Response to therapy, relapses or death if any, status at last follow up, dates of relapse and/or death and last follow up were recorded. All cases were reviewed by expert hematopathologists to categorize the high grade B-cell NHL as per the WHO-2008 classification of hematopoietic malignancies. All cases with adequate formalin-fixed paraffin embedded (FFPE) blocks were evaluated by FISH for c-MYC , BCl-2 and BCl-6 using Vysis dual colour break apart probes. Cases which showed >10% cells with split signal were considered to harbor rearrangement. Result: A total of 114 cases of de-novo high-grade B-cell NHL with adequate FFPE blocks were evaluated. Based on WHO 2008 classification, 112 cases were classified as diffuse large B-cell lymphoma (DLBL)) and 1 each as Burkitt's (BL) and B- cell lymphoma unclassifiable -intermediate between DLBL and BL(BCLU). A total of 9/112 (8%) cases of DLBL showed MYC rearrangement. One of these 9 cases had both MYC and BCl-2 rearrangement. BCLU did not demonstrate MYC or BCl-2 rearrangement. The Ki-67 index was variable (40-95%)in MYC rearranged cases. The median age of the c-MYC rearranged cases was 55 year (range-23-79 years). 88% were males. Advanced stage disease, bulky mass and extranodal disease was seen in 67%, 44% and 55% of cases respectively. All but one patient had high LDH, however none of the patients had elevation more than 2XULN. These patients received rituximab based chemoimmunotherapy (RCHOP-4,RCEOP-4, REPOCH-1) and 77% achieved complete response. At median follow up of 5 months, 1 year-overall survival and progression free survivals were 80% and 75% respectively. There were no significant differences in clinical features (except higher proportion of males in the c-MYC rearranged subset), LDH levels, ki-67 index , response to therapy and survival between DLBL with or without c-MYC rearrangement Conclusion: In our study 8% of all DLBL cases showed c-MYC rearrangement. The frequency of double hit lymphoma was less than 1% (0.8%). Disclosures No relevant conflicts of interest to declare.

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T-cell-rich B-cell lymphomas: diagnosis and response to therapy of 44 patients.

Journal of Clinical Oncology ◽

10.1200/jco.1995.13.7.1742 ◽

1995 ◽

Vol 13 (7) ◽

pp. 1742-1750 ◽

Cited By ~ 47

Author(s):

J P Greer ◽

W R Macon ◽

R E Lamar ◽

S N Wolff ◽

R S Stein ◽

...

Keyword(s):

T Cell ◽

B Cell ◽

Combination Chemotherapy ◽

De Novo ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Response To Therapy ◽

B Cell Lymphomas ◽

Intermediate Grade ◽

Large B Cell

PURPOSE Clinicopathologic features of 44 patients with well-documented T-cell-rich B-cell lymphomas (TCRBCLs) were reviewed to determine if there were distinguishing clinical characteristics and to evaluate the responsiveness to therapy. PATIENTS AND METHODS Forty-one patients had de novo TCRBCL, while three patients had a prior diagnosis of diffuse large B-cell lymphoma. Seventeen TCRBCLs were identified from a retrospective analysis of 176 lymphomas diagnosed before 1988 as peripheral T-cell lymphoma (PTCLs). The initial pathologic diagnosis was incorrect in 36 of 44 cases (82%), usually due to the absence of adequate immunophenotypic and/or genotypic studies at the initial study. RESULTS The median age of patients was 53 years (range, 17 to 92), and the male-to-female ratio was 1.4:1. B symptoms were present in 22 of 41 patients (54%); splenomegaly was detected in 11 patients (25%). Clinical stage at diagnosis was as follows: I (n = 8), II (n = 6), III (n = 15), IV (n = 14), and unstaged (n = 1). Although therapy was heterogeneous, the disease-free survival (DFS) and overall survival (OS) rates at 3 years for patients with de novo TCRBCL were 29% and 46%, respectively. A complete response (CR) to combination chemotherapy for intermediate-grade lymphomas was observed in 16 of 26 patients (62%); 11 of these patients (42%) had a continuous CR, compared with one of 14 patients (7%) who received radiation therapy or therapy for low-grade lymphoma or Hodgkin's disease (HD) (P < .05). However, there was no difference in OS between patients who received chemotherapy for intermediate-grade lymphoma versus other therapies (49% v 48%) due to a high response rate to salvage therapies, including seven patients without disease after marrow transplantation. CONCLUSION TCRBCLs are difficult to recognize without immunoperoxidase studies. Patients with TCRBCL have clinical features similar to patients with other large B-cell lymphomas, except they may have more splenomegaly and advanced-stage disease; they should receive combination chemotherapy directed at large-cell lymphomas.

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Diffuse Large B-Cell Lymphoma (DLBCL) Patients with Composite Histology Have Improved Early Outcome Compared to De Novo DLBCL When Treated with R-CHOP

Blood ◽

10.1182/blood.v112.11.2819.2819 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2819-2819

Author(s):

Matthew J. Maurer ◽

Thomas E. Witzig ◽

William R. Macon ◽

Sergei I. Syrbu ◽

James R. Cerhan ◽

...

Keyword(s):

Bone Marrow ◽

Follicular Lymphoma ◽

B Cell ◽

De Novo ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Indolent Lymphoma ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract Background: A significant percentage of DLBCL patients present with a composite histology, often seen as a node containing both follicular lymphoma and DLBCL or DLBCL in the node and discordant indolent lymphoma in the bone marrow. Literature from the pre-rituximab era suggests DLBCL patients with transformed lymphoma or composite histology have worse outcome than de novo DLBCL. Here we report on early events in a cohort of R-CHOP treated patients. Goal: To determine whether patients with composite lymphoma have an inferior event free survival (EFS) and overall survival (OS) compared to de novo diffuse large B-cell lymphoma when treated with R-CHOP. Methods: Newly diagnosed patients treated with an R-CHOP containing regimen were prospectively enrolled in our Lymphoma SPORE registry from 9/2002 through 6/2007. Pathology was centrally reviewed. All patients were followed for retreatment, disease progression, and death. Results: 401 DLBCL patients were enrolled; 14% (57/401) had a composite histology. 33 patients had DLBCL and another histology, predominantly follicular lymphoma (n=29), in the same node. 20 patients had a non-DLBCL histology in a distinct location from the DLBCL; this was primarily indolent lymphoma in the bone marrow (n=15). 4 patients had both. 19% (75/401) of patients died during follow-up and 30% (121/401) had an event (death due to any cause, progression, or retreatment). Median follow-up for living patients was 34 months (range, 5–73). Composite DLBCL patients had higher event-free (3 year EFS = 79%) and overall (3 year OS = 93%) survival then de novo DLBCL (3 year OS = 66%, 3 year EFS 79%), p=0.05 and p=0.005 respectively. These differences remained statistically significant after adjusting for the International Prognostic Index (IPI): EFS HR = 0.53, 95% CI: 0.29–0.97, p=0.02; OS HR=0.28, 95% CI: 0.10–0.76, p=0.002. OS and EFS for composite DLBCL more closely resembled R-CHOP treated grade III follicular lymphoma (A,B) from the same cohort (3 year EFS = 81%, 3 year OS = 93%). Improved outcome for composite DLBCL was consistent whether the additional histology was in the same node or distinct from the DLBCL. Conclusions: R-CHOP treated DLBCL patients with indolent discordant bone marrow involvement or other composite histology have improved early OS and EFS compared to de novo DLBCL. Further follow-up is needed to assess the long-term prognosis of composite DLBCL in the rituximab era. Histology N Age > 60 Stage III/IV LDH > ULN PS > 1 >2 EN Sites 3 YR EFS 3 YR OS * Denotes statistically significant difference at p=0.05 de novo DLBCL 344 58% 56% 56% 17% 22% 66% 78% Composite DLBCL 57 65% 77%* 34%* 18% 32% 79%* 93%* Figure Figure

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Lymphocyte-to-Monocyte Ratio at Diagnosis and Survival in De Novo Double/Triple Hit Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood.v126.23.3885.3885 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3885-3885

Author(s):

Luis Porrata ◽

Kay Ristow ◽

Ellen D. McPhail ◽

William Macon ◽

Matthew J Maurer ◽

...

Keyword(s):

Prognostic Factor ◽

B Cell ◽

Research Funding ◽

De Novo ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Lymphocyte To Monocyte Ratio ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract The lymphocyte-to-monocyte ratio at diagnosis (LMR-D) has been reported to be a prognostic factor for clinical outcomes in both T-cell and B-cell lymphomas. However, there are no reports testing the prognostic ability of LMR-D in patients diagnosed with de novo double/triple hit diffuse large B cell lymphoma (DLBCL). Thus, we set out to investigate if the LMR-D is a prognostic factor for survival in de novo double/triple hit lymphomas. From 10/5/1998 until 1/16/2015, thirty-four patients with de novo double/triple hit DLBCL were identified for this study. Double and triple hit were defined by interphase FISH evaluating three fusion signals to identify the BCL2 translocation and IGK/MYC D-FISH probe to identify whether the partner is IG or non-IG. Interphase fluorescence in situ hybridization (FISH) was performed on paraffin sections using probes that included 8q24 (5'MYC, 3'MYC); t (2;8), IGK/MYC; t(8,14), MYC/IGH; t(8;22), MYC/IGL; 3q27 (3'BCL6, 5'BCL'6); and 18q21 (3'BCL2, 5'BCL2). The cohort included 14 females and 20 males. The median follow-up for the cohort was 9.0 months (range: 0.4-72.6 months). Using the median for the LMR-D as the cut-off value, patients with a LMR-D ≥ 1.2 experienced superior overall survival (OS) [Hazard ratio (HR) of 0.127, 95% confidence interval (CI) of 0.019-0.530, p < 0.004] and progression-free survival (PFS) [HR of 0.107, 95 CI of 0.024-0.335, p < 0.0001]. The median follow up for OS for patients with a LMR-D ≥ 1.2 was not reached with a 5-year OS rate of 82% (95% CI of 49%-95%) compared with a median follow-up of 10 months for patients with a LMR-D < 1.2 with a 0% 5 year OS rate, p < 0.003 (Figure 1A). The median PFS for patients with a LMR-D ≥ 2 was not reached with a 5 years PFS of 74% (95%CI, of 43%-91%) compared with a median follow-up of 4.7 months for patients with a LMR-D < 1.2 and 0% 5 year PFS rate, p < 0.0001 (Figure 1B). After adjusting for the International Prognostic Index, multivariate analysis showed that the LMR-D remained an independent prognostic factor for OS [HR = 0.180, 95% CI of 0.254-0.784, p < 0.02] and for PFS [HR of 0.127, 95%CI of 0.029-0.409, p < 0.0003]. In spite of the small cohort of de novo double/triple hit DLBCL, the LMR-D was identified as a prognostic factor for clinical outcomes for this specific set of aggressive lymphomas. Further studies are warranted to confirm our findings. Table.LMR-D ≥ 1.2, N = 18Events = 2LMR-D < 1.2, N = 16Events = 8P < 0.003LMR-D ≥ 1.2, N = 18Events = 3LMR-D < 1.2, N = 16Events = 14P < 0.0001Figure 1AB Figure 1. Figure 1. Disclosures Maurer: Kite Pharma: Research Funding. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding. Off Label Use: New agent in a combination regimen..

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Poor Prognostic Effect of CD5 Positivity for Patients with Diffuse Large B-Cell Lymphoma: Results from a Retrospective Single Institution Analysis

Blood ◽

10.1182/blood.v124.21.1700.1700 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1700-1700

Author(s):

Lapo Alinari ◽

Alejandro Gru ◽

Carl Quinion ◽

Ying Huang ◽

Jeffrey A. Jones ◽

...

Keyword(s):

B Cell ◽

Research Funding ◽

Poor Prognosis ◽

De Novo ◽

B Cell Lymphoma ◽

Small Sample ◽

Cell Transplant ◽

Cns Involvement ◽

Large B Cell

Abstract Background. CD5+ diffuse large B-cell lymphomas (DLBCLs) are an uncommon subgroup of DLBCLs representing 5-10% of de novo DLBCLs. Compared with CD5- DLBCLs, de novo CD5+ DLBCLs are associated with a more aggressive clinical course with higher international prognostic index (IPI), more frequent extranodal disease burden including central nervous system (CNS) involvement, and a significantly poorer overall prognosis with conventional anthracycline-based chemotherapy with or without rituximab (Miyazaki K et al. Ann Oncol 2011). Historically, most of these cases belong to the activated B cell (ABC)-type of DLBCLs (Jain P et al., Am J Hematol 2013). The vast majority of the published reports on CD5+ DLBCL are from Asia with limited data on outcomes in US or European patients (pts) in the modern era utilizing rituximab based therapy with no standard guidelines available for the management of this high risk disease. Methods. We reviewed pts with newly diagnosed de novo CD5+ DLBCL treated at the Ohio State University (OSU) from August 2000 to July 2014. Pts did not have an antecedent history of CLL or MCL and diagnosis was confirmed by centralized hematopathology review at OSU. We examined pts' characteristics, treatment response, and survival. Response to treatment was determined by PET/CT. Progression-free survival (PFS) was calculated as the time from diagnosis to the time of progression and/or death, and overall survival (OS) was calculated as time from diagnosis to the time of death. PFS and OS were summarized using Kaplan-Meier methods. Results. Of the 16 CD5+ DLBCL, 11 (70%) were male, and the median age at diagnosis was 58 (range 44-67). Eight pts had CD5+ DLBCL ABC-type, 4 had germinal center (GCB)-type and 4 were non-classifiable by Hans criteria. At diagnosis, 11 pts were stage III/IV; 6 pts had bone marrow involvement, 2 had CNS involvement; and 2 pts had bulky disease (≥10cm). IPI was ≥ 3 in 4 pts (unable to calculate in 6 pts due to unknown LDH) and 2 pts had B symptoms. The median Ki67 was 75% (range 50-95%), EBER was negative in all pts; 3 of 13 evaluable pts were positive for MYC gene rearrangement, and 0 pts had an IGH/BCL2 translocation. Therapies at diagnosis included R-CHOP (12 pts), R-EPOCH (2 pts), R-CHOP with 3 g/m2 of methotrexate (1 pt), and hyperfractionated cytoxan (1 patient). In addition, 2 pts received IT methotrexate prophylaxis and 5 pts received involved field radiation therapy to residual disease sites post frontline chemotherapy. None of the pts underwent autologous stem cell transplant (SCT) in first remission. Thirteen pts (81%) achieved a complete remission (CR) with frontline treatment. Three patients had primary refractory disease, 2 rapidly progressed and died within 1 month from diagnosis. Of the 13 pts in CR, 4 (31%) remain in remission with a median follow up of 28 months (range 10-61). Nine pts in CR relapsed (69%), including 6 pts who proceeded to salvage therapy and autologous SCT, 1 pt who received both autologous and allogeneic SCT, 1 pt who underwent allogeneic SCT, and 1 pt who received multiple lines of salvage chemotherapy with no transplant and eventually died. Five of the 6 pts (84%) that underwent autologous SCT relapsed and both pts that underwent allogeneic SCT relapsed. Ten pts (63%) received ≥ 3 lines of chemotherapy. Of the 16 pts, 5 (31%) have died from disease progression. At a median follow up of 32 months (range 9.4 to 99.4), the 2 year PFS and OS for all pts were 38% and 72%, respectively (Figure 1). The median time to progression (TTP) from frontline therapy was 14 months (95% CI 7-28 months). The median TTP from second line therapy in 10 pts was 17 months (95% CI 7-33 months). Conclusions. To the best of our knowledge,this is the first series of CD5+ DLBCL from Western countries in the PET/rituximab era reported to date. With the recognized limitation of a small sample size and retrospective analysis, our current study confirms that CD5+ DLBCL pts have a poor prognosis which appears to be inferior to CD5- DLBCL despite a multimodality approach. Interestingly, autologous as well as allogeneic SCT at relapse do not seem to improve outcome, raising the question if there is even a role for transplant in these pts outside the context of a clinical trial. Similar to the initial reports about the poor prognosis of MYC translocation and DLBCL (Savage KJ et al. Blood 2009), we suggest that CD5 positivity is a particularly poor prognostic marker and should be used for risk stratification in DLBCL clinical trials. Disclosures Jones: Pharmacyclics: Consultancy, Research Funding. Blum:Janssen, Pharmacyclics: Research Funding.

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Prospective Management of Primary Testicular Lymphoma (PTL) with Doxorubicin-Based Chemotherapy, Prophylactic Intrathecal (IT) Methotrexate and Radiotherapy (RT), but without Rituximab: Results from IELSG.

Blood ◽

10.1182/blood.v108.11.2454.2454 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2454-2454 ◽

Cited By ~ 1

Author(s):

Andreas H. Sarris ◽

Umberto Vitolo ◽

Emanuele Zucca ◽

George Z. Rassidakis ◽

Jeffrey Medeiros ◽

...

Keyword(s):

Complete Remission ◽

B Cell ◽

Cell Lymphoma ◽

Progression Free Survival ◽

B Cell Lymphoma ◽

Contralateral Testis ◽

Large B Cell Lymphoma ◽

Frequent Relapses ◽

Large B Cell

Abstract Introduction: PTL is a rare extranodal lymphoma characterized by a continuous pattern of systemic relapses in spite of doxorubicin-based therapy. There are also frequent relapses in the contralateral testis and the central nervous system (CNS). Therefore we decided to determine whether prophylaxis of the CNS and the contralateral testis would modify the pattern of relapse of PTL. Patients and methods: From 1993 to February 2002 in IELSG member institutions patients with PTL (presenting with testicular enlargement) were managed with doxorubicin-based therapy according to institutional policy, with the addition of four doses of IT methotrexate (15 mg) during the first 6 weeks. At the end of chemotherapy scrotal RT (30 Gy) was given to all patients and 30–36 Gy nodal RT to those with stage II disease. Rituximab was not used in this cohort because it was not yet generally available for patients with diffuse large B-cell lymphoma. Results: There were twenty seven patients; two refused chemotherapy and/or RT/IT therapy and one RT, leaving 24 eligible for analysis. Median age was 60 years (range 31–80). Ann Arbor stage was I in 17, II in four, and four in three patients. B-symptoms were present in one patient. The right testis was involved in 13 and the left in 11 patients. Serum LDH was elevated in four of 21 with available values. No patient had CNS involvement at diagnosis. Pathology was diffuse large B-cell lymphoma in all patients. Treatment was CHOP in 21, alternating triple therapy in two, and hyper-CVAD in one patient. Three patients died during therapy: one from neutropenic sepsis and two from toxicity of systemic methotrexate. The remaining 21 patients achieved a complete remission. With a median follow-up of 57 months (range 8–123) for survivors, seven patients have relapsed, three in the CNS. There were no testicular relapses. Eight patients have died: three from toxicity during induction, three from relapsed lymphoma, one from gastric carcinoma and one from sudden death, both in complete remission. At 5 years the projected progression-free survival was 78%, and survival 66%, but both without an apparent plateau. Freedom from progression in the CNS was 84%, with a plateau. Conclusions: Patients with PTL treated prospectively with doxorubicin-based therapy before the availability of rituximab exhibit the continuous pattern of relapse previously reported. Scrotal RT seems eliminate testicular relapses, and prophylactic IT methotrexate seems to reduce, but not eliminated CNS relapses. These need to be confirmed by longer follow-up. The ongoing IELSG-10 should determine whether the addition of rituximab alters the continuous pattern of systemic relapses. Future studies should determine the molecular basis of the continuous relapses and minimize both systemic and CNS relapses.

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Safety and Efficacy of Rituximab Plus Bendamustine in Relapsed or Refractory Diffuse Large B-Cell Lymphoma Patients

Blood ◽

10.1182/blood.v124.21.3074.3074 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3074-3074 ◽

Cited By ~ 1

Author(s):

Annalisa Arcari ◽

Annalisa Chiappella ◽

Vanessa Valenti ◽

Luca Zanlari ◽

Monica Tani ◽

...

Keyword(s):

Complete Remission ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Extranodal Involvement ◽

Large B Cell Lymphoma ◽

Stage Disease ◽

Poor Functional Status ◽

Large B Cell

Abstract Background: Diffuse large B-cell lymphoma (DLBCL) relapsed or refractory after chemoimmunotherapy have dismal prognosis; the standard salvage treatment is Rituximab plus high dose chemotherapy with autologous stem cell transplantation (R-HDC). However, no standardized treatment is available for patients not eligible for R-HDC because of age and/or comorbidity. The combination Rituximab plus Bendamustine (R-B) has shown to be non-inferior and with a favorable toxicity profile compared to R-CHOP in indolent B-cell lymphoma. The use of R-B in DLBCL is a matter of debate. Purpose: We designed an Italian multicenter retrospective study aimed to evaluate safety and efficacy of R-B as salvage treatment in patients with DLBCL relapsed or refractory after at least one complete course of Rituximab-chemotherapy, who were not eligible for R-HDC because of age and/or comorbidity or in patients with post-HDC recurrence. Patients and Methods: We retrospectively reported 43 unselected consecutive patients with relapsed or refractory DLCBL treated with R-B in 15 Italian haematological centers between October 2008 and January 2014. Schedule of R-B were: 6 courses of Bendamustine at 90 mg/mq or 70 mg/mq on days 1 and 2 of each 28-day cycle and Rituximab 375 mg/mq on day 1 of each cycle. They were analyzed for baseline characteristics (age, IPI, ECOG, comorbidity), outcome (ORR, PFS, OS) and toxicity (CTCAE). Results: The median age was 76 years (range 56-94). Eighty-three % of patients had advanced-stage disease (III-IV stage) and 67% had IPI score of ≥3. An extranodal involvement was present in 65% of cases (bone marrow, lung, stomach, skin, pleura, pericardium). More than half the patients (51%) presented with poor functional status with ECOG score of ≥2. Comorbidity assessment by CIRS-G revelead 30% of patients with ≥1 severely or very severely (level 3 or 4) affected organs and 27% of patients with moderate or severe (level ≥2) cardiopathy. The mean number of prior therapies was 1,7 (range 1-3). All patients were previously treated with Rituximab-chemotherapy and three patients had already received R-HDC. Twelve patients had a refractory disease and 31 experienced relapse after last treatment. Patients received a median of 5 cycles of planned 6 courses of R-B (range 2-6); 24 patients underwent Bendamustine at 90 mg/mq, 19 at 70 mg/mq. All patients received Rituximab 375 mg/mq. In 38% of patients treatment was stopped because of progression; in 4 patients (9%) progression occurred within the first 2 treatment cycles. The overall response rate was 47%, including 28% complete remission and 19% partial remission. One patient in partial remission after R-B achieved a complete remission after local radiotherapy. The median OS was 16 months (95% CI 10-20). The median PFS was 8 months (95% CI 6-11). The median follow up was 10 months (range 2-60). Nine patients are still alive and in complete remission at last follow up; 7 of these patients had a chemosensitive relapse before R-B (in 5 cases a first relapse) and only 2 had a refractory disease with progression after a previous lenalidomide treatment. Toxicity was moderate, mainly grade 1 and 2. Grade 3-4 adverse events were neutropenia in 14 patients (32%), thrombocytopenia in 5 patients (11%), anemia in one patient, infections in 3 patients (6%), skin rash in one patient, nausea in one patient, diarrhea in one patient. One patient died of septic shock after the third R-B cycle. One patient died of miocardial infarction related to underlying cardiac comorbidity. Conclusions: Bendamustine in combination with Rituximab showed promising efficacy results with a low toxicity profile in a poor prognosis population (advanced stage disease and extranodal involvement, high median age, poor functional status, comorbidities), not eligible for R-HDC. The optimal dosage and schedule of Bendamustine and/or combination with novel drugs should be further investigated, in order to improve the duration of response and reduce the rate of early progression. Disclosures Off Label Use: Bendamustine in diffuse large B-cell lymphoma. Marasca:Mundipharma: Honoraria.

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Diffuse Large B-Cell Lymphomas Transformed from or with Concurrent Follicular Lymphoma Demonstrate Similar Clinical Outcomes As De-Novo Diffuse Large B-Cell Lymphomas, Except for Cases Harboring Double Hit Rearrangements

Blood ◽

10.1182/blood.v130.suppl_1.828.828 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 828-828

Author(s):

Amir Behdad ◽

Craig Boddy ◽

Angela Fought ◽

Timothy Taxter ◽

Marissa Falkiewicz ◽

...

Keyword(s):

B Cell ◽

Clinical Outcomes ◽

Burkitt Lymphoma ◽

Research Funding ◽

De Novo ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Double Hit ◽

Large B Cell

Abstract Introduction: Follicular lymphoma (FL) is characterized by an indolent clinical course, but patients with this disease bear a risk of transformation to diffuse large B-cell lymphoma (DLBCL) or high-grade B-cell lymphoma (HGBL). DLBCL transformed from FL (tDLBCL) traditionally has been associated with an aggressive course and a post-transformation survival of 0.6-1.7 years. However, a more recent study showed longer survivals in these patients, challenging the notion that transformation universally portends a poor prognosis in the immunotherapy era. Presence of concurrent FL at the time of diagnosis of DLBCL (cDLBCL/FL) also raises the possibility of transformation, but its clinical significance has not been elucidated in the literature. In this study, we analyzed and compared outcomes of tDLBCL, cDLBCL/FL, and de novo DLBCL. We also characterized the prevalence of MYC/BCL2/BCL6 gene rearrangements in tDLBCL and cDLBCL/FL cohorts and evaluated the impact of dual rearrangements (double hit, DH) on clinical outcomes. Methods: Patients diagnosed with DLBCL or B cell lymphoma unclassifiable with features intermediate between DLBCL and Burkitt lymphoma, also known as HGBL (BCLU/HGBL), treated at Northwestern University or University of Pennsylvania from 1/2010 to 7/2016 were included. Patients with Burkitt lymphoma, primary CNS and HIV-associated lymphoma were excluded. Transformation was defined as presence of DLBCL/ BCLU/HGBL in cases with an antecedent diagnosis of FL by at least 6 months. We divided our cohort into three groups: 1. De novo DLBCL or BCLU/HGBL with no prior history of FL (dDLBCL) 2. Transformed FL (tDLBCL) and 3. DLBCL or BCLU/HGBL with concurrent FL (cDLBCL/FL). Progression free survival (PFS) was defined as time from diagnosis to radiographic progression, regimen change, death or last follow-up. Overall survival (OS) was defined as time from diagnosis to death or last follow-up. Kaplan-Meier (KM) survival analyses, using a log-rank p-values were performed for PFS and OS to compare the three diagnosis groups (dDLBCL, tDLBCL, and cDLBCL; alpha=0.05) and pairwise comparisons of combinations of diagnosis (dDLBCL and tDLBCL+cDLBCL) and double hit status (accounting for multiple comparisons with a Bonferroni corrected alpha=0.013). Fluorescence in situ hybridization for MYC, BCL2 and BCL6 rearrangements was performed using break-apart probes per the policy of each institution. Results: A total of 293 pts, including 233 dDLBCL, 37 tDLBCL, and 23 cDLBCL/FL were included. 50% of the tDLBCL received at cytotoxic chemotherapy before transformation for precedent FL. Age and sex distribution, as well as clinical characteristics including stage, ECOG performance status, IPI score, and primary refractoriness were similar amongst the three groups. LDH was more likely to be elevated in dDLBCL (75%), as compared to tDLBCL(63%) and cDLBCL/FL (47%)( p=0.02%). Additionally, non-bone marrow extra-nodal disease was seen more often in dDLBCL (72%), as compared with tDLBCL (53%) and cDLBCL/FL (43%)( p <0.01). DH were seen more often in tDLBCL(32%) and cDLBCL/FL (30%), compared with the dDLBCL (11%)( p <0.01). The cell of origin was germinal-center type in 92% of the tDLBCL and 91% cDLBCL/FL, compared with 64% of dDLBCL (p <0.01). Intensive chemotherapy regimens (R-EPOCH or R-hyperCVAD) and autologous stem cell transplantation was used more often in tDLBCL (43% and 19%, respectively), compared with dDLBCL (30% and 3%, respectively) and cDLBCL/FL (28% and 8% respectively). For all pts, the median length of follow-up was 13.8 months (range 0.2-59.2). OS and PFS were similar in the three subgroups (p=0.90 and p=0.77, respectively; Figure 1). We then analyzed the survival based on the presence of DH in two separate subgroups: 1) dDLBCL and 2) tDLBCL + cDLBCL/FL (combined as one group given low number of cases). OS was significantly shorter in lymphomas with DH, compared to non-DH in both subgroups (p <0.001 for dDLBCL and p=0.004 for tDLBCL + cDLBCL/FL). Comparison of the OS in DH of dDLBCL versus DH of tDLBCL + cDLBCL/FL showed no statistical difference (p=0.15), similar to the OS of non-DH cases the two groups( p=0.31). Conclusions: DLBCLs transformed from FL or with concurrent diagnosis of FL (composite lymphoma) demonstrated similar clinical outcomes in our study. However, dual rearrangements are more prevalent in these patients and drive inferior survival similar to DH status in de novo DLBCL. Figure 1 Figure 1. Disclosures Landsburg: Curis: Consultancy, Research Funding; Takeda: Research Funding. Winter: Merck: Research Funding; Glaxo-Smith-Kline: Research Funding. Pro: Seattle Genetics: Consultancy; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Gordon: Janssen: Other: Data Monitoring Committee. Karmali: Celgene: Speakers Bureau. Kaplan: Millennium: Research Funding; Takeda: Research Funding; Seattle Genetics: Research Funding; Janssen: Research Funding.

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Treatment of Diffuse Large B Cell Lymphoma with CHOP and Rituximab. Results of a Multicenter Study with 236 Patients.

Blood ◽

10.1182/blood.v106.11.4736.4736 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4736-4736

Author(s):

Javier De la Serna ◽

R. Ayala ◽

M. Canales ◽

P. Giraldo ◽

M. de la Cruz-Mora ◽

...

Keyword(s):

B Cell ◽

Cell Lymphoma ◽

International Prognostic Index ◽

B Cell Lymphoma ◽

Response To Therapy ◽

Chop Regimen ◽

Bulky Disease ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract Introduction: The treatment of diffuse large B cell lymphoma (DLBCL) is based on anthracyclin containing regimens. The CHOP regimen is considered the standard of chemotherapy, although immunochemotherapy regimens appear to be more effective. Rituximab (R), when combined with CHOP or CHOP-like regimens, improve the complete remission (CR) rate and survival in elderly and low risk young patients. Nevertheless, the CR rate and survival continues to be predicted by patient’s international prognostic index (IPI). R-CHOP has been claimed to be a new standard of treatment for DLBCL and adopted in the common practice. Purpose: In this study we aimed to analyze prospectively the results of R-CHOP, used as a standard of care for DLBCL patients irrespectively of age or IPI. Methods: Between 1/2001 and 1/2005, 236 patients with DLBCL recruited from 25 institutions, including community-based and University Hospitals, received upfront therapy with R-CHOP. Patients were required to have no contraindications for antineoplastic therapy and give consent. They were given 3–4 courses for localized, and 6–8 courses for advanced disease. Rituximab was given at 375 mg/m2 the first day of each course. R-CHOP cycles were given every 21 days, except for 5 centres giving cycles every 14 days. Radiation therapy was given for bulky (> 7 cm) areas. Prophylaxis, supportive measures and hematopoietic factors were given according to local policies. Response to therapy was evaluated 3 months after the completion of treatment. Results: There were 109 males and 127 females, median age 62 years (range 18–84). The number of IPI factors at diagnosis were: 0–1 in 32%; 2 in 28%; 3 in 19% and 4–5 in 21% of patients. B-symptoms, bulky disease > 7 cm, high b2-microglobulin and low albumin were present in 47%, 31%, 33% and 31% of patients, respectively. R-CHOP 21 was given to 85%, and R-CHOP 14 to 15% of patients. Dose intensity was maintained in 74% of patients, and 88% completed treatment. Involved-field radiation was given to 17% of cases. The overall CR rate was 82.2%. Failures due to lymphoma resistance or toxicities were 14.1%. According to the IPI score, the CR rate was as follows: 0–1: 90.5%; 2: 85.5%; 3: 72.2%; and 4–5: 73%. After a median follow-up of 15.4 months (range 1 to 53 months), the progression free survival (PFS) and overall survival (OS) are 74.4% and 84%, respectively. The IPI score at diagnosis influenced both PFS and OS. The PFS for patients with an IPI score of 0–1, 2, 3 and 4–5 were 85.5%, 83.0%, 72.2% and 66.7%, respectively. The OS according to the IPI score was 95.2%, 90.9%, 72.2%, and 63.2%, respectively. Patients receiving R-CHOP 14 showed a trend to improved survival. The main causes of death were lymphoma progression (64%), infections (15%), second neoplasms (9%), thrombosis (6%) and cardiac failure (6%). Conclusions: The R-CHOP regimen is well tolerated and achieves improved results and outcome in an unselected population of DLBCL patients. The improved survival in this series require confirmation with longer follow up. The IPI score retains a major prognostic significance for response and survival.

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