Clinicopathological Features and Outcomes of EBV Positive and Negative DLBCL: A Study from the Grupo De Estudio Latinoamericano De Linfoproliferativos (GELL)

Abstract Introduction: Studies conducted in the pre-rituximab era found EBV positive diffuse large B-cell lymphoma (EBV+ DLBCL) as a disctinct entity carrying a dismal prognosis when compared with EBV negative (EBV-) DLBCL cases. However, studies evaluating this disparity in the rituximab era are lacking. Therefore, we aim to investigate the clinicopathological features and outcomes patterns among EBV+ and EBV- DLBCL managed in the modern era. Methods: We retrospectively analyzed patients 18 years and older diagnosed with DLBCL between 2006 to 2020. Seven centers from the Grupo de Estudio Latinoamericano de Linfoproliferativos (GELL) participated in the study. Hematopathologists at each participating institution reviewed the pathological samples to confirm the diagnosis of EBV+ or EBV- DLBCL, not otherwise specified (NOS). EBV infection was confirmed with a positive EBER test ≥1%. The primary endpoint was overall survival (OS), defined as the time from the date of diagnosis until death from any cause or last follow up. The secondary endpoint was progression-free survival (PFS) defined as the time from diagnosis until death, progression, or last follow up. OS and PFS probabilities were computed with the Kaplan-Meier method and compared using the log-rank test. We used Cox regression analysis to evaluate the proportional hazard ratios (HRs) of each score for our study outcomes. Outcomes with a p-value <0.05 were considered statistically significant. Results: A total of 119 patients with EBV+ DLBCL, NOS and 122 patients with EBV- DLBCL, NOS were included in this analysis. The median age at diagnosis was 58 years (range 19-86 years) with an slight female (53%) predominance. Most cases (68%) had advanced stage (III/IV) at diagnosis. EBV+ DLBCL patients had higher-risk clinical features compared with EBV- DBCL: 34% presented ECOG performance status ≥2 (vs 18%, p=0.010), 45% had poor risk R-IPI score (vs 29%, p=0.03), 47% had high and high-intermediate risk NCCN IPI score (vs 40%, p=0.002). Germinal center B-cell was the most common phenotype in both groups (46% each); non-germinal center was more common in EBV+ (44%) than EBV- (34%). All patients received either R-CHOP (95%) or R-EPOCH (5%) as first-line treatment. The overall response rate was 91% for EBV- DLBCL (complete response, CR 81%) compared to 74% for EBV+ DLBCL (CR 65%, p=0.015). With a median follow-up of 60 months, the 5-year OS rates for EBV+ and EBV- DLBCL were 64% and 75% (p=0.062; Fig 1A), respectively; whereas the 5-year PFS rates for EBV+ and EBV- DLBCL were 53% and 68% (p=0.031; Fig 1B), respectively. In the univariate analysis, ECOG ≥2, extranodal involvement >1, elevated serum lactate dehydrogenase (LDH), and serum albumin <3.5 g/dL were statistically significant for OS (Table 1). On the other hand, EBV+ status, ECOG performance status ≥2, extranodal involvement >1, elevated serum LDH, and serum albumin <3.5 g/dL were significant predictors for PFS. In the multivariate analysis, no variable was statistically significant for OS or PFS (Table 1). Conclusions: In this large cohort of Latin American patients with EBV+ DLBCL, we found poor clinical features in EBV+ compared to EBV-DLBCL cases. Although shorter PFS was found in EBV+ DLBCL cases, in the multivariate analysis we could not identify EBV status as an independent risk factor for worse survival. Our results suggest that in the rituximab era, there has been an improvement on the survival outcomes of EBV+ DLBCL, NOS patients managed with chemoimmunotherapy. We are currently validating our findings in a prospective cohort of DLBCL patients and to improve clinical decision-making in those deemed at high-risk for early mortality and relapse. Figure 1 Figure 1. Disclosures Ramirez-Ibarguen: Asofarma: Consultancy; MSD: Consultancy; Abbvie: Speakers Bureau; Astra Zeneca: Speakers Bureau; Janssen: Speakers Bureau; Roche: Speakers Bureau; Takeda: Consultancy, Speakers Bureau. Perini: Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Astra Zeneca: Honoraria, Speakers Bureau; MSD: Honoraria, Speakers Bureau. Oliver: Abbvie: Other: conference support and fees ; Roche: Other: conference support and fees . Castillo: Abbvie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy; Roche: Consultancy; TG Therapeutics: Research Funding.

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A Single-Institution Retrospective Cohort Study of Patients Treated with R-EPOCH for Richter's Transformation of Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood.v126.23.2951.2951 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2951-2951 ◽

Cited By ~ 3

Author(s):

Kerry A. Rogers ◽

Galena Salem ◽

Deborah M. Stephens ◽

Leslie A. Andritsos ◽

Farrukh T. Awan ◽

...

Keyword(s):

B Cell ◽

Research Funding ◽

Performance Status ◽

B Cell Lymphoma ◽

Neutropenic Fever ◽

Lymphocytic Leukemia ◽

Aggressive Lymphoma ◽

First Line ◽

Ecog Performance Status

Abstract Background: Richter's transformation (RT), the occurrence of an aggressive lymphoma in patients with prior chronic lymphocytic leukemia (CLL), occurs in up to 10% of CLL patients. Anthracycline-based chemoimmunotherapy remains standard, but outcomes are poor (median survival approximately 12 months). R-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) has demonstrated superior efficacy to R-CHOP in HIV-associated diffuse large B-cell lymphoma, Burkitt's lymphoma, and primary mediastinal B-cell lymphoma. We conducted a single-institution retrospective cohort study to characterize efficacy and toxicity of R-EPOCH as first-line treatment for RT. Methods: The study included patients treated with R-EPOCH as first-line therapy for histologically confirmed RT at the Ohio State University between January 1st 2006 and May 31st 2014. Characteristics of the CLL and RT, ECOG performance status, and laboratory assessment of bone marrow and organ function were abstracted from medical records. Toxicity of R-EPOCH was assessed by reviewing the frequency of adverse events (AE). R-EPOCH treatment outcomes were assessed as documented by the treating physician and not secondarily verified. Progression free survival (PFS) and overall survival (OS) durations were calculated from date of Richter's biopsy until date of event (PFS: relapse/death; OS: death), censoring patients without event at last follow-up. PFS and OS estimates were obtained using the Kaplan-Meier method. Univariable proportional hazards models were used to model PFS and OS as a function of each clinical variable. Results: The study included 46 patients. Median age at RT diagnosis was 67 (range 38-83). Median number of months from CLL to RT diagnosis was 53 (range 0.4-198). A median of 3 (range 0-13) prior CLL treatments had been given with 10 (22%) patients receiving ibrutinib as the most recent. The majority of patients where CLL risk was evaluable demonstrated poor-risk disease: 24/43 (56%) complex karyotype, 20/41 (49%) del(17)(p13.1), 27/32 (84%) unmutated IGHV. The majority of evaluable patients had an ECOG performance status of 0 or 1 (18/28, 64%). Table 1 shows RT characteristics for these patients. Treatment with R-EPOCH was started a median of 5 days after RT diagnosis (range 0-110). The majority of patients did not complete 6 cycles: 16 (35%) completed 1 cycle, 10 (22%) 2 cycles, 5 (11%) 3 cycles, 4 (9%) 4 cycles, 2 (4%) 5 cycles, and 9 (19%) 6 cycles. Of 131 cycles given, 114 (87%) were fully evaluable for AE with results in table 2. Outcome of R-EPOCH treatment was known for 44 patients: 9 (20%) achieved complete response, 8 (18%) clinical response documented by the treating physician, 14 (32%) progressive disease, and 13 (30%) died without (known) lymphoma progression. With a median follow up of 39 (range 13-54) months, 9 (20%) patients were alive without lymphoma progression. All patients with lymphoma progression died. Median PFS was 3.5 months (95% CI: 2.0-7.6) and median OS was 5.9 months (95% CI: 3.2-10.3) (Figure 1). In univariable analysis, risk of death was higher for patients with complex CLL karyotype (HR 4.38, p=0.0002), del(17)(p13.1) (HR 3.04, p=0.003), higher number of CLL treatments (HR 1.16, p=0.004), higher bilirubin (HR 1.68, p=0.04), and higher serum creatinine (HR 1.65, p=0.05). Conclusions: Patients with RT treated with first-line R-EPOCH had poor PFS (median 3.5 months) and OS (median 5.9 months) with only 20% of patients alive at last follow up. Characteristics of underlying CLL influenced outcomes of R-EPOCH with worse PFS and OS in deletion 17p and complex karyotype patients. Better therapies for RT are urgently needed, especially in patients with poor risk CLL. Table 1. Characteristics of Aggressive Lymphoma n=46 Histology, no. (%)- Large Cell- Early large-cell/Prolymphocytic- Plasmablastic (EBV+)- High-grade B-cell 42 (91) 2 (4) 1 (2) 1 (2) Extranodal Disease- Yes- No 20 (43) 26 (57) Bulky Disease, no. (%)- Yes ≥5, <10 cm- Yes ≥10 cm- No- Unknown 16 (42) 8 (21) 14 (37) 8 Table 2. Adverse Events by Cycle Cycle 1 (n=40) Cycle 2 (n=29) Cycle 3 (n=15) Cycle 4 (n=12) Cycle 5 (n=11) Cycle 6 (n=7) Any AE* Infection Neutropenic Fever Hospitalization ICU Stay 29 (72%) 14 14 14 4 17 (59%) 7 4 7 0 7 (47%) 1 0 1 0 4 (33%) 1 0 1 0 2 (18%) 1 1 1 0 1 (14%) 0 0 1 0 *Hospitalization, infection, neutropenic fever, non-neutropenic fever, ICU stay, transfusion, mucositis, fatigue requiring treatment delay, and ileus. Disclosures Stephens: Immunomedics: Research Funding; Acerta Pharma BV: Research Funding. Byrd:Acerta Pharma BV: Research Funding. Maddocks:Janssen: Research Funding; Novartis: Research Funding; Pharmacyclics: Consultancy, Research Funding. Jones:AbbVie: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding.

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Fludarabine and Mitoxantrone for the Refractory Relapse Treatment of B-Cell Low-Grade Non-Hodgkin Lymphoma (NHL): LACOHG First Interim Report (Latin American Cooperative Oncology Hematology Group).

Blood ◽

10.1182/blood.v108.11.4665.4665 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4665-4665

Author(s):

Severiano Baltazar-Arellano ◽

Patricia Pimentel ◽

Luis Vera ◽

Fernando Bezares ◽

Jose Málaga ◽

...

Keyword(s):

B Cell ◽

Latin American ◽

Progressive Disease ◽

Performance Status ◽

Previous Treatment ◽

Low Grade ◽

Ecog Performance Status ◽

Ann Arbor ◽

Grade 3

Abstract Background: fludarabine (F) is licensed for the management of indolent non Hodgkin’s lymphoma in countries such as Canada and Switzerland. Clinical evidence suggests that fludarabine monotherapy is as least as effective, than conventional therapies such as cyclophosphamide, vincristine, prednisone (CVP) for the first and second line treatment of B-cell low grade NHL achieving objective response rates. Better response rates can be achieved combining F with Mitoxantrone (M) in low grade NHL even in refractory relapsed (RR) patients (pts). The Latin American Cooperative Oncology Hematology Group (LACOHG) proposed a multicenter study in Latin American countries in 2002 to use FM in RR B-cell low grade NHL. Aims: to assess the response rate, safety, disease free survival (DFS) and overall survival (OS) of FM in RR B-cell low grade NHL during (2003–2006). Methods: Forty-eight patients in the period of January 2003 to February 2006 were evaluated. Forty-four pts. had follicular lymphoma and 4 small lymphocytic lymphoma. Median age 63.5 years old (range: 24–83). Gender: female 56% and male 44%. Inclusion criteria for low grade NHL-LG was: any previous treatment excluding autologous transplantation, Ann Arbor stage II to IV, age > 18 years old, ECOG performance status 0–2 and written informed consent. ECOG performance status 0: 2%, 1: 71% and 2: 27%. Ann Arbor staging: II: 2%, III: 29% and IV: 69%. International Prognostic Index (IPI): 0–1: 19%, 2–3: 71% and 4–5: 10%. Median previous treatment was 1 (range: 1–3). FM treatment consisted of F 25 mg/m2 i.v. (day 1–3) and M 10 mg/m m2 i.v. (day 1) each 28 days for 6–8 cycles. Results: on this low grade NHL cohort the overall response rate (ORR was 81%; progressive disease and non-response 19%. With a median follow up of 17 months, OS at 24 months was 86% (DE 5.2%) and DFS at 24 months 57.1% (DE 11.3%). LDH in serum was not an adverse prognostic factor for DFS and OS. Safety: on the 286 cycles in 48 pts, the toxicity was: 18 episodes of grade 3-4 neutropenias, 15 episodes of grade 3-4 thrombocytopenia, 7 episodes of grade 1–2 nausea/vomiting, grade 1–2 diarrhea in 4 pts, 8 pts were admitted to the clinic, 11 fever episodes, 2 allopecia, 4 pts developed grade 1–2 peripheral neuropathy and infections 7%: one case herpes zoster. Mortality rate: 12,5% (6/48 patients), 5 of them because progressive disease. No cardiac toxicity was reported. Conclusions: FM is an effective and safe treatment for RR low grade NHL. A longer follow up and a larger trial, might be needed to confirm these results in a multicenter, randomized study. DFS with FM in RR low grade NHL : LACOHG DFS with FM in RR low grade NHL : LACOHG

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Autologous Stem Cell Transplantation (autoSCT) for HIV-Associated Lymphoma in the Era of Combination Antiretroviral Therapy (cART): A Retrospective Analysis of the EBMT Lymphoma Working Party

Blood ◽

10.1182/blood.v128.22.2257.2257 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2257-2257 ◽

Cited By ~ 1

Author(s):

Kai Huebel ◽

Alessandro Re ◽

Ariane Boumendil ◽

Herve Finel ◽

Marcus Hentrich ◽

...

Keyword(s):

Multivariate Analysis ◽

B Cell ◽

Hodgkin Lymphoma ◽

Dose Regimen ◽

Research Funding ◽

B Cell Lymphoma ◽

High Dose ◽

Hiv Patients ◽

High Dose Regimen

Abstract Introduction: Patients infected with HIV have an increased risk of developing aggressive B-cell non-Hodgkin lymphoma and Hodgkin lymphoma (HL). The continuous development of cART during the last decade has improved the prognosis of HIV-associated lymphoma considerably. However, a significant proportion of these patients will experience lymphoma relapse and may be candidates for autoSCT. The purpose of the present study was to investigate if recent advances in anti-lymphoma therapy and anti-infectious strategies have influenced the outcome of autoSCT for HIV-related lymphoma. Patients and methods: For this retrospective study, all EBMT-registered patients aged 18 years or older with HIV-positive serostatus who were treated with a first autoSCT between 2007 and 2013 were eligible. Baseline patient, disease, and transplant data were collected from MED-A forms. Centers were requested to provide additional HIV and lymphoma treatment and follow-up information. Statistical analysis used log rank test to assess the impact of baseline characteristics on survival endpoints. In multivariate analysis, the relevance of prognostic factors was estimated using Cox regression models. Curves of cumulative incidence of relapse (IR) and non-relapse mortality (NRM) were compared by Gray's test. Results: 138 patients from 25 European centers met the eligibility criteria and had the full data set required for this analysis available. 86% were male, median age was 44 years (range 24-69). Underlying diagnoses were diffuse large B cell lymphoma (DLBCL) in 46%, HL in 21%, Burkitt lymphoma in 14%, plasmablastic lymphoma (PBL) in 10%, and other lymphoma in 9% of the patients. Disease status at autoSCT was complete remission (CR) in 51%, partial remission (PR) in 33%, and less than PR in 16% of the patients, achieved after 1 (28%), 2 (58%), or more than 2 lines of chemotherapy (14%). With HIV load below the threshold of detection in 74% of the patients, the median CD4+ cell count was 187/µl (range 0-800) at transplant. 95% of the patients continued with cART during salvage and high-dose chemotherapy. BEAM was used as high-dose regimen in 77% of the patients. With a median follow-up of 4 years, 2-year NRM, IR, progression-free survival (PFS) and overall survival for the whole series were 9%, 23%, 68% and 70%, respectively. By multivariate analysis, diagnosis DLBCL or PBL (vs HL), increasing number of chemotherapy pretreatment lines, and less than PR at autoSCT were significant predictors of an unfavorable PFS; whilst age, high-dose regimen, performance status, and viral load had no significant impact. 2-year PFS in patients with 1st-line CR, later CR, PR, or less than PR at autoSCT was 91%, 80%, 64%, and 23%, respectively. Conclusions: This series, which is the largest ever on lymphoma transplants in HIV+ patients, suggests that in the cART / chemoimmunotherapy era, the outcome of autoSCT for HIV-related lymphoma is driven by lymphoma-dependent risk factors rather than by characteristics of HIV infection. AutoSCT under ongoing cART therapy remains the treatment of choice for HIV+ patients with PBL or recurrent DLBCL or HL. Disclosures Kröger: Sanofi: Honoraria, Research Funding; Neovii: Honoraria, Research Funding; Riemser: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Montoto:Roche: Honoraria; Gilead: Research Funding. Dreger:Novartis: Consultancy; Gilead: Speakers Bureau; Novartis: Speakers Bureau; Gilead: Consultancy; Janssen: Consultancy; Roche: Consultancy.

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Maintenance Rituximab Following R-CHOP Chemotherapy in Patients with Composite or Discordant, Indolent and Aggressive, B-Cell Non-Hodgkin Lymphomas

Blood ◽

10.1182/blood.v126.23.3950.3950 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3950-3950

Author(s):

Roopesh R. Kansara ◽

Joseph M. Connors ◽

Kerry J. Savage ◽

David W Scott ◽

Randy D. Gascoyne ◽

...

Keyword(s):

B Cell ◽

Research Funding ◽

Cell Lymphoma ◽

Performance Status ◽

B Cell Lymphoma ◽

Advisory Board ◽

Low Grade ◽

Treatment Policy ◽

The Impact

Abstract Background: Patients with follicular lymphoma (FL) who achieve a complete (CR) or partial (PR) response to rituximab-containing chemotherapy followed by maintenance rituximab (MR) experience improved progression-free survival (PFS). In contrast, MR does not improve outcomes in chemo-sensitive patients with diffuse large B-cell lymphoma (DLBCL). There are no published data describing the impact of MR in patients presenting with indolent and aggressive histology lymphoma simultaneously in the same biopsy (composite, COM) or two separate sites (discordant, DIS). Methods: Patients with newly-diagnosed COM/DIS lymphomas composed of an indolent B-cell non-Hodgkin lymphoma (excluding CLL/SLL, mantle cell lymphoma, and grade 3B FL) and DLBCL were identified in the British Columbia Cancer Agency Lymphoid Cancer Database. All patients received first-line chemotherapy with R-CHOP. In early 2006, a treatment policy was introduced recommending MR 375 mg/m2 IV every 3 months for 2 years in patients with COM/DIS lymphomas achieving a CR/PR to R-CHOP induction. PFS, time to progression (TTP) and overall survival (OS) were calculated from the time of diagnosis and compared between treatment groups. Results: 98 patients with COM/DIS lymphomas were identified between January 2001 and December 2013: median age 64 y (range 22 - 86), 56% male, 48% elevated LDH, 30% performance status ≥ 2, 87% stage III/IV, and 51% high-intermediate or high IPI. 58 (59%) and 40 (41%) patients had COM and DIS lymphoma, respectively. FL was the indolent component in 65% of all cases. 35/40 patients with DIS had low-grade histology in the bone marrow. Following R-CHOP, 77 (79%) and 21 (21%) patients achieved CR and PR, respectively. 43 patients were treated with R-CHOP alone before the MR policy introduction, and 55 were treated with R-CHOP+MR; the latter group received a median of 8 (range 1 - 8) MR doses. There were no significant differences in baseline characteristics or response rates between the two groups with the exception of a higher proportion of patients with poor performance status in the group not given MR. With a median follow-up of 10y (range 1.5 - 13.6) in living patients treated with R-CHOP and 6y (range 0.9-9.5) in patients treated with R-CHOP+MR, there were 20 (47%) and 15 (27%) relapses, respectively (p=0.26). Of these, 11 relapsed with indolent histology, 11 relapsed with DLBCL, 3 relapsed in the central nervous system (CNS), and 10 had no biopsy at relapse (8 had aggressive and 2 indolent clinical behavior on review of medical records). There were 6 (30%) indolent and 14 (70%) aggressive relapses in patients treated with R-CHOP, while there were 7 (47%) indolent and 8 (53%) aggressive relapses in patients treated with R-CHOP+MR (p=0.31). 19 patients eventually died from lymphoma (8 with DLBCL relapse, 5 without a biopsy at relapse, and all 3 with CNS recurrence). The 6-y PFS was 60% (standard error [SE] 5%) with no difference between patients treated with or without MR (Hazard ratio (HR) 0.74, 95% CI 0.39 - 1.37, p= 0.33). The 6-year TTP was 64% (SE 5%), again with no differences between the two groups (HR 0.68, 95% CI 0.34 - 1.33, p= 0.25). The 6-year OS was similar between the two groups (p= 0.89). In the subgroup of patients with FL (21 R-CHOP and 43 R-CHOP+MR) the addition of MR did not impact PFS (p= 0.90), TTP (p= 0.99), or OS (p=0.55). An additional 52 patients were diagnosed after the treatment policy introduction in 2006, but did not receive MR for several reasons including physician non-adherence, progressive disease on R-CHOP, toxicity from R-CHOP or patient refusal. In an intent-to-treat analysis (43 pre-policy and 107 post-policy) there were no differences in outcomes. In a per-protocol analysis (95 R-CHOP and 55 R-CHOP+MR), there were no significant differences in outcomes. Conclusion: The addition of MR does not appear to improve PFS, TTP or OS in patients with COM/DIS lymphomas achieving CR/PR to R-CHOP, although comparisons are likely underpowered and 6-year median length of follow-up in the MR group may not be sufficient. However, the majority (63%) of relapses are aggressive and unlikely to be impacted by MR. The role of MR in these uncommon lymphomas requires further exploration. Disclosures Connors: Roche: Research Funding; Seattle Genetics: Research Funding. Savage:Seattle Genetics: Honoraria, Speakers Bureau; BMS: Honoraria; Infinity: Honoraria; Roche: Other: Institutional research funding. Scott:Celgene: Consultancy, Honoraria; NanoString: Patents & Royalties: Inventor on a patent that NanoString has licensed. Gerrie:Roche: Honoraria, Other: Advisory board, Research Funding; Lundbeck: Honoraria, Other: Advisory board, Research Funding; Janssen: Other: Advisory board. Villa:Roche: Research Funding.

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SYK Inhibitor Entospletinib in Combination with Obinutuzumab Demonstrates Efficacy in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)

Blood ◽

10.1182/blood-2019-123586 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4295-4295 ◽

Cited By ~ 1

Author(s):

Adam S. Kittai ◽

Scott R Best ◽

Bria Thurlow ◽

Basak Gokcora ◽

Andrzej Stadnik ◽

...

Keyword(s):

T Cells ◽

Phase I ◽

Research Funding ◽

Performance Status ◽

Data Monitoring Committee ◽

Ecog Performance Status ◽

Bcr Signaling ◽

Syk Inhibitor ◽

Grade 3

B-cell receptor (BCR) signaling kinases are important targets in therapy of CLL. Resistance of lymphoid niche-resident CLL cells to BCR-signaling inhibition is fostered by the tumor microenvironment. We found that stromal B-cell activation factor (BAFF)-mediated activation of spleen tyrosine kinase (SYK) triggered BCR signaling, thereby contributing to apoptosis resistance in CLL cells (Paiva et al, 2017). The SYK inhibitor entospletinib (ENTO) abrogated BAFF-mediated BCR signaling accompanied by a decrease in pSTAT3 and MCL1 in vitro. We designed a Phase I/II investigator-sponsored trial of ENTO in combination with Obinutuzumab (Obin) in patients (pts) with relapsed/refractory CLL and non-Hodgkin lymphoma (NHL). Eligible pts were aged ≥18 years, had CLL/NHL (Phase I) or CLL (Phase II), relapsed and/or refractory to ≥1 prior therapies (no prior SYK inhibitor), ECOG performance status ≤2 and preserved organ function. The Phase I part of the study followed a standard 3+3 design with two dose levels (DL1: ENTO 200 mg PO BID; DL2 - ENTO 400 mg PO BID). ENTO was given for 7 days (run-in). Subsequently, Obin was given IV concurrently with ENTO on days 1, 2, 8, 15 of Cycle 1 and Day 1 of Cycles 2-6 in standard doses. ENTO was given until disease progression. Primary study objectives were toxicity (Phase I) and efficacy (objective response rate (ORR); Phase II). Correlative analysis of samples was performed at baseline, after run-in phase (7 days of entospletinib single agent) and after 6 cycles of combination therapy. Reverse protein phase array was performed at the RPPA core facility at MD Anderson Cancer Center. T cell populations and cytokine production were analyzed by flow cytometry. At DL1 of Phase I, six pts were enrolled (4 - CLL; 2 - follicular lymphoma). One pt experienced a dose-limiting toxicity (DLT: grade 3 asymptomatic LFT abnormalities which failed to resolve within 72 hours) attributed to ENTO. Other grade 3-4 toxicities included 2 grade 3 infusion reactions and one transient grade 4 neutropenia (attributed to Obin). Two pts remain on therapy after a median follow-up of 15 months. Three pts were enrolled at DL2 without DLTs. In Phase 2, 18 pts with CLL received ENTO 400 mg PO BID (in combination with Obin). One pt was deemed ineligible due to Richter's transformation at study entry. Of the 17 evaluable pts, 71% were men. Median age was 66 years (range 47-76), and 76% were aged >65 years. 94% had ECOG performance status ≤1. Six pts (35%) had a complex karyotype, 6 (35%) had a TP53 aberration, 2 - NOTCH1 and 3 - SF3B1 mutation. Median number of prior therapies was 2 (range, 1-6): 47% had received prior fludarabine, 53% - bendamustine, 35% - ibrutinib (5 pts with intolerance, 1 with progression). As of July 1, 2019, with median follow-up of 9.5 months (range, 3-17 months), 71% of pts remain on treatment. Median relative dose intensity of ENTO (ratio of actual to planned cumulative dose during drug exposure period) was 97%. ORR was 82%, 11 (65%) pts with partial response, three (17%) pts had CR (two MRD-negative in the bone marrow). All patients had a reduction in lymphadenopathy. Median duration of response and median progression-free survival (PFS) were not reached. All pts are alive. Five (29%) pts discontinued treatment (1 withdrawal of consent; 1 with recurrent LFT abnormalities; 1 for concomitant comorbidity and 2 with progression of disease). The most frequently occurring adverse events of all grades were infusion-related reactions, neutropenia and fatigue (Table). There were no Grade 5 events. Treatment with ENTO for 7 days during run-in phase led to downmodulation of pSTAT3 and MCL1 in CLL cells (RPPA assay), consistent with our pre-clinical observations. MCL1 has been previously implicated in survival of T cells at multiple stages of development. At the end of cycle 6, we observed a decrease in CD19+ and concomitant increase in CD3+ cells compared with baseline. There was no change in naïve, T-effector memory and T central memory cells within the CD4+ or CD8+ populations. Treatment with ENTO led to decreased PD-1 expression in CD4+ (22.6±3.8 vs. 31.5±5.4%, p=0.02) and CD8+ cells (p=0.05; Figure). Meanwhile, CTLA-4 expression was unchanged. PMA/ionomycin-stimulated CD4+ T cells demonstrated a decrease in IFNγ and IL-4. In summary, a combination of ENTO and Obin was effective and well tolerated in patients with R/R CLL, and was accompanied by downmodulation of MCL1 in CLL cells and PD-1 in T cells. Disclosures Persky: Debiopharm: Other: Member, Independent Data Monitoring Committee; Bayer: Consultancy; Sandoz: Consultancy; Morphosys: Other: Member, Independent Data Monitoring Committee. Spurgeon:Janssen: Research Funding; Astra Zeneca: Research Funding; Bayer: Other: drug support only, Research Funding; Ariad: Other: drug support only, Research Funding; KITE: Other: drug support only, Research Funding; Acerta: Research Funding; Bristol Myers Squibb: Research Funding; Genentech: Honoraria, Research Funding; Novartis: Other: drug support only, Research Funding. Danilov:Gilead Sciences: Consultancy, Research Funding; Abbvie: Consultancy; Takeda Oncology: Research Funding; Bristol-Meyers Squibb: Research Funding; Verastem Oncology: Consultancy, Other: Travel Reimbursement , Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy; Bayer Oncology: Consultancy, Research Funding; Celgene: Consultancy; Curis: Consultancy; Seattle Genetics: Consultancy; Aptose Biosciences: Research Funding; AstraZeneca: Consultancy, Research Funding; MEI: Research Funding; Janssen: Consultancy; Pharmacyclics: Consultancy. OffLabel Disclosure: Entospletinib in CLL

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Cachexia at Diagnosis adversely predicts outcomes in patients with Aggressive B-Cell NHL receiving standard of care treatment: A Prospective Observational Study from India

Blood ◽

10.1182/blood-2019-126295 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2907-2907

Author(s):

Vivek S Radhakrishnan ◽

Reena Nair ◽

Anwesha Patra ◽

Saurabh Jayant Bhave ◽

Jeevan Kumar Garg ◽

...

Keyword(s):

Multivariate Analysis ◽

Observational Study ◽

B Cell ◽

Research Funding ◽

Prospective Observational Study ◽

Univariate Analysis ◽

Standard Of Care ◽

High Grade ◽

Actuarial Survival

Background and Objectives:Cancer associated malnutrition and cachexia is an important determinant of the patient's short and long term outcomes. This prospective study was conducted to determine the association between cachexia at diagnosis and overall survival of patients with aggressive B-cell non-Hodgkin's Lymphoma (ABNHL) Methods:This investigator initiated single centre prospective observational study was conducted at the Tata Medical Center, Kolkata, India between Jan 2015 and Mar 2019 after IRB approval. Patients diagnosed with ABNHL receiving standard of care chemo-immunotherapy were eligible. This study was supported by an educational research grant from Baxter to our institution. All patients who consented to participate were screened for cachexia at entry using a modified Subjective Global Assessment (SGA) tool (1). Baseline clinical factors of prognostic importance including stage, IPI score, etc. were recorded. All statistical analysis was carried out using EpiInfo-ver.7 software. Results:239 patients diagnosed with high grade B-NHL were recruited. The study group included 89 women and 150 men, and 77 (32.1%) were older than 65 years. 130 (54.3%) patients received private care. 88(36.8%) had IPI stage high-intermediate plus high grade; 136 (56.9%) had Ann Arbor stage III plus IV disease; 40 (16.7%) had extra-nodal NHL; 96 (40.1%) had weight loss and 107(44.7%) had reduced food intake. Cachexia scores estimated by the modified SGA tool was SGA-A in 101, SGA-B in 120 and SGA-C in 18 patients. Only 37 (15.4%) had been subjected to screening for malnutrition prior to cancer treatment. 44 (20.5%) patients experienced neutropenic sepsis during treatment. At a median follow up of 457 days, 69% achieved complete remission at the end of initial therapy, 50 (20.9%) patients died during the study period. In univariate analysis, SGA, IPI, Stage and age groups were statistically significant prognostic markers. The 2-year actuarial survival of all patients adjusted for SGA, IPI and Stage was 72%. The two-year actuarial survival in the SGA-A, SGA-B, and SGA-C groups were respectively 80%, 68% and 45% (p<0.001). In a multivariate analysis using cox proportional hazards method the hazard ratio for SGA B was 1.67 (0.94-2.97), and SGA-C was 3.65, after adjusting for IPI and stage groups (p=0.0137).The follow up is continuing and final multivariate analysis will be done when sufficient events have occurred. Conclusions:Cachexia at diagnosis is an important independent prognostic biomarker in patients with ABNHL. The role of routine screening for cachexia before initiating treatments and providing individualized medical nutrition therapy along with physical therapy during chemotherapy to prevent worsening of cachexia and improve survival needs evaluation. References: 1.Shirodkar M etal, Indian J Gastroenterol.2005; 24:246-50 Figure Disclosures Patra: Baxter: Research Funding. Mallath:Otsuka Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Speakers Bureau; GlaxoSmithKline: Research Funding; Baxter: Research Funding; Otsuka Pharmaceuticals: Honoraria; Bristol-Myers Squibb: Honoraria; Bayer-Zydus Pharma: Honoraria; Sayre-Therapeutics: Honoraria.

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Rituximab and dose-adjusted EPOCH (R-EPOCH) for treatment of aggressive B-cell non-Hodgkin lymphomas: A developing country perspective.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e19503 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e19503-e19503

Author(s):

Hasmukh Jain ◽

Tanuja Shet ◽

Epari Sridhar ◽

Hari Menon ◽

Uma Bhaskar Dangi ◽

...

Keyword(s):

B Cell ◽

Germinal Center ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Clinicopathological Features ◽

Hiv Positive ◽

Cd4 Counts ◽

Poor Risk ◽

Grade 3

e19503 Background: Biological heterogeneity of diffuse large B-cell lymphomas (DLBL) is reflected in variable outcomes with R-CHOP. Clinicopathological features like high IPI, underlying acquired immunodeficiency, non-germinal center phenotype, primary mediastinal B-cell histology and Bcl-2 positivity correlate with adverse biology. Effect of adverse biological attributes is also reflected in outcomes B-cell lymphoma intermediate between diffuse large cell B-cell and Burkitt’s lymphomas (BCLU) and Burkitt’s lymphoma in elderly and HIV-positive individuals with low CD4 counts. Given the promising efficacy of R- EPOCH in poor-risk DLBL we used it in therapy of aggressive B-cell NHL. Methods: From May 2010 to December 2012 patients with de-novo aggressive B-cell lymphomas with adverse clinicopathological features (DLBL with multiple extranodal sites, high IPI, primary mediastinal B-cell lymphoma, BCLU, Burkitt’s lymphoma in elderly or in HIV-positive individuals) were treated with R-EPOCH. Demography,stage, bulk of disease, IPI, CD4 counts, grade 3/4 toxicities and death were recorded. Responses were evaluated at mid and end of therapy. Overall and progression-free survivals were calculated. Immunohistochemistry was used to classify the germinal center and non-germinal center phenotype. Results: 33 patients (males-21, female-12) were treated with median of 6 cycles (range 3-6) of R-EPOCH. Histologicalsubtypes distribution was- DLBL-16, BL-8, BCLU-5, and PMBL-4. Sixty percent of DLBL were non-germinal center type and bcl-2 positive. Median age was 33 years (range 15-73 years). More than 2/3 of patients had stage 3/4 bulky disease with high IPI. Twelve patients were HIV positive with median CD4 count of 173/µL (range 43-359/µL). Complete responses were seen in 66.7% at interim evaluation and in 90% at the end of therapy. At a median follow up of 8 months, 1- year overall survival and progression- free survival were 72.5% and 90% respectively. Two patients died due to therapyand grade 3/4 toxicities were seen in 10% patients. Conclusions: R-EPOCH regimen is efficacious in patients with poor-risk aggressive B-cell NHL however longer follow-up is needed.

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Effect of Adding Rituximab to Three Cycles of CHOP Plus Invoved-Field Radiotherapy for Limited-Stage Aggressive Diffuse B-Cell Lymphoma (SWOG-0014).

Blood ◽

10.1182/blood.v104.11.158.158 ◽

2004 ◽

Vol 104 (11) ◽

pp. 158-158 ◽

Cited By ~ 18

Author(s):

Thomas P. Miller ◽

Joseph M. Unger ◽

Catherine Spier ◽

Baldassarre Stea ◽

Emilia Cantu ◽

...

Keyword(s):

Risk Factors ◽

Risk Factor ◽

B Cell ◽

Performance Status ◽

Elevated Serum ◽

Treated Group ◽

Stage Ii ◽

Limited Disease ◽

Involved Field

Abstract The 5-year survival rate of patients with limited disease (LD) and aggressive histologies of non-Hodgkin lymphoma (NHL) who have at least one adverse risk factor is about 70% after treatment with three cycles of CHOP followed by involved-field radiotherapy (CHOP(3) plus RT). We tested the effect of adding four infusions of rituximab to CHOP(3) plus RT in 62 evaluable patients. Patients had an aggressive histology of diffuse B-cell NHL (diffuse large cell or Burkitt’s-like) and had LD. LD is defined as stage I with at least one adverse risk factor (age > 60 years, elevated serum LDH, or a performance status of 2) OR non-bulky stage II disease. Adverse risk factors are defined using a stage-modified IPI system and include: non-bulky stage II, age >60 years, elevated serum LDH and a performance status of 2. Patients with bulky stage II disease were excluded as their prognosis is similar to advanced disease, and patients with stage I disease and no risk factors were excluded as their prognosis exceeds 90% survival at 10 years with CHOP(3) plus RT. Rituximab was infused at 375 mg/m2 on days −7, 1, 22, and 43, and CHOP was given at standard doses on days 3, 24, and 45 (CHOP(3) plus R plus RT). Involved-field RT was given as previously described (N Engl J Med1998;339:21–26). With a median follow-up of 2.4 years, the progression-free survival (PFS) and overall survival (OS) measured at 2 years was 94% and 95%, respectively. In order to estimate whether the addition of rituximab adds benefit to CHOP(3) plus RT, and therefore, would be worth testing in a comparative trial, we identified 68 patients from SWOG study 8736 treated with CHOP(3) plus RT using the same criteria to include LD and aggressive diffuse B-cell histologies. These previously reported patients treated with CHOP(3) plus RT (ref above) have a median follow-up of 12.0 years. The PFS and OS for this group measured at 2 years was 85% and 93%, respectively. Four patients have relapsed in the rituximab-treated group and 10 patients had relapsed in the CHOP(3) plus RT alone treated group within the first 2 years. Three patients have died in the rituximab- treated group and five patients had died on the CHOP(3) plus RT alone treated group within the first 2 years (see Table). Short-term toxicity appeared similar. We conclude that the addition of rituximab to standard treatment with CHOP(3) plus RT results in outcome which compares favorably to our historical experience and merits further study. Effect of Rituximab in Treating Limited Disease MEASUREMENT CHOP(3) + R + RT (0014) CHOP(3) + RT (8736) Results of SWOG study 0014 compared to SWOG study 8736 No. patients 62 68 2-year PFS 94% 85% 2-year OS 95% 93% No. relapses 2 yrs 4 10 No. deaths 2 yrs 3 5

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Prognostic Value of Serum Soluble IL2 Receptor (sIL2R) Level in Patients with Diffuse Large B Cell Lymphoma (DLBCL), Treated with CHOP or R-CHOP Based Therapy.

Blood ◽

10.1182/blood.v110.11.1569.1569 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1569-1569

Author(s):

Yasuhiro Oki ◽

Keitaro Matsuo ◽

Harumi Kato ◽

Kazuhito Yamamoto ◽

Yoshitoyo Kagami ◽

...

Keyword(s):

Multivariate Analysis ◽

Prognostic Factors ◽

B Cell ◽

Cell Lymphoma ◽

Prognostic Significance ◽

B Cell Lymphoma ◽

Entire Group ◽

Extranodal Involvement ◽

The Impact

Abstract Emergence of rituximab (R) has significantly changed the clinical outcome of patients with B-cell lymphoma, which necessitates investigators to reassess the roles of previously determined prognostic factors. We performed a retrospective study to clarify the prognostic significance of serum sIL2R levels among other factors in patients with DLBCL. Study group consisted of 208 consecutive untreated patients with DLBCL who had serum sIL2R levels examined prior to treatment, and were treated in our institution between January 1999 and December 2006. Patients were treated with CHOP based chemotherapy without (R-, n=112) or with (R+, n=96) rituximab. Median follow up duration of each group was 55 and 19 months, respectively. Age (18–92), performance status (PS, ≥2 or <2), B symptoms (present or absent), stage (1–4), number of extranodal involvement (≥2 or <2), bulky diseases (largest diameter of the disease ≥ 10cm, present or absent) serum LDH levels and sIL2R levels were available in all patients. Beta-2 microglobulin levels were available in 130 patients. Serum sIL2R levels ranged from 316 to 35100 U/mL (median 1080), while standard range in healthy individuals was <520 U/mL. Spearman correlation analyses revealed that Log sIL2R level (LsIL2R) was associated with age (p<0.001), PS (p<0.001), B symptoms (p<0.001), stage (p<0.001), number of extranodal involvement ≥2 (p<0.001), Log LDH level (LLDH) (p<0.001) and beta2 microlobulin (p<0.001). The impact of each factor on overall survival (OS) was analyzed by Cox proportional Hazard model. Univariate analyses revealed that age (Hazard ratio [HR]=1.034, p=0.010), stage (HR=1.357, p=0.021), B symptoms (HR=1.152, p<0.001), R− (HR=2.123, p=0.049), PS (HR=4.102, p<0.001), number of extranodal involvement ≥2 (HR=2.592, p<0.001), LsIL2R (HR=3.249, p<0.001), LLDH (HR=4.378, p<0.001) and beta2 microglobulin (HR=1.283, p<0.001) were associated with shorter OS. When analyses was performed separately in R− and R+ groups, HR of LsIL2R was 3.59 (p<0.001) and 2.92 (p=0.071), respectively. Multivariate analysis in the entire group revealed that age (HR=1.030, p=0.041), PS (HR=2.089, p=0.038), B symptoms (HR=2.307, p=0.022), R− (HR=2.721, p=0.038), and LsIL2R (HR=2.140, p=0.018) were independently associated with shorter OS. When multivariate analysis was performed in R− group alone, age (HR=1.035, p=0.035), B symptoms (HR=3.565, p=0.001), and LsIL2R (HR=2.704, p=0.004) independently correlated with shorter OS. In the group of R+, only PS was left as an independent prognostic factor (HR=5.304, p<0.001). When LsIL2R was put back into the multivariate model of R+ group, HR of PS and LsIL2R became 4.308 (p=0.035) and 2.383 (p=0.165), respectively. In conclusion, serum sIL2R levels are frequently elevated in untreated patients with DLBCL and the higher level is significantly associated with shorter OS, independent of other known prognostic factors. When analysis was limited to R+ group, known prognostic factors such as age were not deemed independently associated with OS possibly due to short follow up duration and excellent prognosis in this population (estimated 3-year OS rate of 88%); thus longer follow up of this large cohort is necessary. Updated analyses for OS and various different analyses, such as analyses for correlation with complete response or time to treatment failure will be presented to further clarify the value of sIL2R levels.

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Lenalidomide Plus R-CHOP (R2CHOP) in Patients with DLBCL Is Associated with a Lower Risk of CNS Relapse: Combined Analysis from Two Phase 2 Studies

Blood ◽

10.1182/blood.v128.22.3033.3033 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3033-3033 ◽

Cited By ~ 2

Author(s):

Ayed O. Ayed ◽

Annalisa Chiappella ◽

Grzegorz S. Nowakowski ◽

Federica Cavallo ◽

Angela Giovanna Congiu ◽

...

Keyword(s):

High Risk ◽

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Performance Status ◽

Phase 2 ◽

Cell Of Origin ◽

Ecog Performance Status ◽

Advisory Committees ◽

Cns Relapse

Abstract Background Central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) is a devastating event occurring in approximately 5% of patients treated with standard R-CHOP (Thanarajasingam et al, ASH 2015, abs 1456). Isolated CNS relapse is associated with significant morbidity and mortality. New treatment regimens with agents that cross the blood-brain barrier (BBB) are needed. The combination of lenalidomide with R-CHOP (R2CHOP) has shown promising results in activated B-cell (ABC) type DLBCL in phase 2 studies and is currently being evaluated in randomized trials. Lenalidomide crosses the BBB and has been demonstrated to have single-agent activity in relapsed CNS lymphoma. Accordingly, the addition of lenalidomide to R-CHOP may decrease the risk of CNS relapse. Here we characterize the combined incidence of isolated CNS relapse in a population of DLBCL patients who received R2CHOP for induction therapy in two independent phase 2 studies. Methods We analyzed the incidence of isolated CNS relapse in patients with histologically-confirmed DLBCL enrolled in two R2CHOP phase 2 trials - one conducted by Mayo Clinic (MC) and the other by Italian Lymphoma Foundation (FIL) - in the context of clinical variables that included age, gender, disease stage, cell of origin, and administration of CNS prophylaxis. We assessed CNS-International Prognostic Index (CNS-IPI) factors (age, stage, lactate dehydrogenase level, ECOG performance status, extranodal sites, adrenal/kidney involvement) and classified patients into groups of low, intermediate, and high risk of CNS relapse. The risk of CNS relapse in R2CHOP-treated patients was then estimated and compared against published rates in RCHOP-treated patients based on CNS-IPI score. Results One hundred thirty-six patients with DLBCL from both cohorts (87 MC patients, 49 FIL patients) were included in this analysis. Mean age was 65 and median follow-up in 104 patients still alive was 48.2 months (range: 2.1-88.5). 61.8% of patients were male; 86.0% had stage III disease or higher; 44.1% had ECOG performance status of 0; cell of origin phenotype by immunohistochemistry according to Hans algorithm was germinal center B-cell (GCB), non-GCB (ABC), and not available in 43.4%, 36.8%, and 19.8%, respectively; 14.7% received intrathecal (IT) methotrexate for CNS prophylaxis per local practice. No patients received intravenous methotrexate. 10.3%, 71.3%, and 18.4% of patients were classified into low, intermediate, and high-risk CNS-IPI groups, respectively. Only one of 136 patients developed isolated CNS relapse, corresponding to an estimated incidence of CNS relapse of 0.007 (0.7%). Conclusions Despite a large proportion of patients with intermediate and high risk of CNS relapse treated in both phase 2 studies, induction therapy with R2CHOP in patients with DLBCL is associated with a lower-than-expected rate of isolated CNS relapse. The latter is unlikely to be explained by use of IT chemotherapy, which is considered to be marginally effective in this setting and was implemented only in a small proportion of patients. This suggests that addition of CNS-penetrating small molecules, such as lenalidomide, to R-CHOP may decrease the risk of CNS relapse. Disclosures Chiappella: Celgene: Speakers Bureau; Teva: Speakers Bureau; Roche: Speakers Bureau; Pfizer: Speakers Bureau; Janssen-Cilag: Speakers Bureau; Amgen: Speakers Bureau. Nowakowski:Morphosys: Research Funding; Celgene: Research Funding; Bayer: Consultancy, Research Funding. Cavallo:Janssen-Cilag: Honoraria; Onyx: Honoraria; Celgene: Honoraria. Gaidano:Roche: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Spina:Mundipharma: Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fee; Teva Pharmaceuticals Industries: Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fee. Vitolo:Takeda: Other: Honoraria for lectures; Gilead: Other: Honoraria for lectures; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures.

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