scholarly journals A Multicenter, Open-Label Feasibility Study of Daratumumab with Dose-Adjusted EPOCH in Newly Diagnosed Plasmablastic Lymphoma: AIDS Malignancy Consortium 105

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1595-1595 ◽  
Author(s):  
Carlyn Rose Tan ◽  
Stefan K. Barta ◽  
Shelly Y. Lensing ◽  
Ariela Noy
Keyword(s):  
Clinical Trial ◽  
B Cell ◽  
Board Of Directors ◽  
Peripheral Blood ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Hiv Positive ◽  
Newly Diagnosed ◽  
Advisory Committees

Background: Plasmablastic lymphoma (PBL) is an aggressive large B-cell lymphoma commonly associated with HIV, immunosuppression, old age, and autoimmune disorders, but can be seen in immunocompetent patients. Intensive regimens, including EPOCH, have only a median overall survival between 9 to 15 months. Complete response rates are 40% to 65%. Patients with refractory or relapsed disease typically have a dismal prognosis. Little progress has been made in treating PBL without a single dedicated clinical trial to date. PBL has morphologic and immunophenotypic characteristics overlapping high-grade B-cell lymphoma and multiple myeloma. It is CD20 negative and positive for plasma cell markers, including CD38, CD138, and MUM-1/IRF-4, with a proliferation index typically > 90%. Daratumumab (DARA) is a human IgG1k anti-CD38 monoclonal antibody (mAb). CD38 is a transmembrane receptor with enzymatic activity highly expressed on the surface of plasma cells and plasmablasts. DARA induces directed cell killing of CD38 expressing cells including complement dependent cytotoxicity and antibody-dependent cell cytotoxicity (ADCC). DARA has significant activity as a single agent and part of combination therapy in myeloma. In non-Hodgkin lymphoma (NHL), DARA resulted in synergistic reduction of tumor growth when combined with rituximab and CHOP (R-CHOP) in follicular lymphoma systemic xenograft models and induced dose-dependent ADCC on mantle cell and follicular lymphoma cells lines in the presence of peripheral blood mononuclear cells in vitro (Pérez-Galán P, et al. Hematol Oncol. 2017). In addition, in vivo models using DLBCL (SU-DHL-6) cells injected in SCID mice showed superiority of DARA in combination with CHOP vs DARA alone (63% vs 55%, p <0.01). In a patient-derived DLBCL model with high CD38 expression, DARA with CHOP or R-CHOP showed tumor regression, and tumors did not regrow when treatment with DARA was stopped after 3 doses. (Doshi P, et al. Haematologica. 2014). We designed an innovative approach to treat PBL using a combination of chemotherapy and directed immunotherapy with a mAb. We hypothesize that adding the potent CD38-directed mAb DARA to DA-EPOCH is safe and feasible and results in improved outcomes in PBL similar to the benefit seen with adding rituximab to a CHOP or EPOCH backbone in other DLBCL subtypes. This will be the first clinical trial dedicated to patients with PBL. Study Design and Methods: This is a non-randomized, multicenter study conducted by the AIDS Malignancy Consortium. Both HIV negative and HIV positive PBL patients ≥ 18 years old with Stage II to IV PBL or Stage I with elevated LDH and/or bulky tumor, who have measurable disease and adequate organ function are eligible. HIV positive patients must have CD4 ≥ 100 cells/μL and be on concurrent combination antiretroviral therapy (cART) or agree to start cART. Key exclusion criteria include receiving ≥ 1 prior cycle of combination chemotherapy, hepatitis B seropositivity, and active CNS involvement. DARA will be given in conjunction with DA-EPOCH every 21 days for 6 cycles. DARA 16 mg/kg will be administered intravenously weekly for the first 3 cycles on days 1, 8, and 15, then on day 1 for cycles 4-6. The primary aim is to determine the percentage of newly diagnosed PBL patients who complete ≥ 3 cycles of DARA with DA-EPOCH irrespective of HIV status. We expect that 85% of patients will complete ≥ 5 cycles of DA-EPOCH alone based on the CALGB 50303 study (Bartlett NL, et al. JCO. 2019). Allowing for a lower proportion completing with the addition of DARA, we hypothesize that > 75% of patients will complete ≥ 3 cycles of protocol treatment. An early stopping rule for completing <3 cycles will be employed. The planned enrollment is 15 patients. Correlations with clinical outcomes will include immunohistochemistry on tumor specimens and peripheral blood to study EBV clearance and identify predictive biomarkers. We will study non-invasive monitoring by circulating tumor DNA using plasma DNA mutation panels and clonal immunoglobulin. Disclosures Tan: Merck: Research Funding; Bayer: Research Funding; Takeda: Research Funding; Janssen: Research Funding. Barta:Takeda: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Seattle Genetics: Honoraria, Research Funding; Celgene: Research Funding; Mundipharma: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Mundipharma: Honoraria; Bayer: Consultancy, Research Funding. Noy:NIH: Research Funding; Pharamcyclics: Research Funding; Janssen: Consultancy; Medscape: Honoraria; Prime Oncology: Honoraria; Raphael Pharma: Research Funding. OffLabel Disclosure: Daratumumab is being used off-label on this clinical trial.

Ibrutinib in Combination with R-Gemox-D in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma: Phase II Clinical Trial of the Geltamo Group

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 16-17
Author(s):  
Beatriz Rey Búa ◽  
Ana Jiménez Ubieto ◽  
Jose Javier Sanchez Blanco ◽  
Pau Abrisqueta ◽  
Antonio Gutierrez ◽  
...  
Keyword(s):  
Clinical Trial ◽  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
New Combination ◽  
Advisory Committees ◽  
Large B Cell Lymphoma ◽  
Relapsed Disease

BACKGROUND Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), non-candidates for autologous stem-cell transplantation (ASCT), have few treatment options. Ibrutinib is an oral Bruton's tyrosine kinase inhibitor that has shown increased antitumor activity in patients with DLBCL of different subtype from germinal center B-cell like (non-GCB). In the present phase II clinical trial (NCT02692248), we investigated the efficacy and toxicity of the combination of Ibrutinib with the R-GEMOX-D regimen (rituximab, gemcitabine, oxaliplatin and dexamethasone), in patients with non- GCB DLBCL. METHODS We included patients with histological diagnosis of non-GCB DLBCL (according to Hans algorithm), with relapsed or refractory disease after at least 1 line of immunochemotherapy and non-candidates for ASCT. Patients received an induction treatment consisting of 6 (in case of complete remission [CR] after cycle 4) or 8 (in case of partial response [PR] or stable disease after cycle 4) cycles of R-GEMOX-D at standard doses every 2 weeks, in combination with ibrutinib (560 mg daily), followed by a maintenance treatment with ibrutinib for a maximum of 2 years. The primary objective was to evaluate the overall response rate (ORR) after 4 cycles, and the secondary objectives were: CR rate, progression-free survival (PFS), overall survival (OS) and toxicity. Analyses were performed in the intention to treat population (data cut-off 10th April 2020). RESULTS Sixty-four patients (59.4% male) were included between March 2016 and November 2018. Median age was 67 (25-84) years. Patients had received a median of 2 previous lines of treatment; 56.3% were refractory (&lt;PR) to the last regimen, whereas 43.7% had relapsed disease after a previous CR. Eleven (17.2%) patients had received a previous ASCT. IPI at study entry was 0-1, 2-3, and 4-5 in 9.4%, 67.2%, and 20.3% of patients, respectively (missing data in 2 patients). Of the 64 patients who started study treatment, 44 and 35 patients, respectively, were evaluated for response after 4th cycle and at the end of induction. Twenty-four (37%) patients started maintenance with ibrutinib, 7 of whom continue or have completed it. Causes of withdrawal from the trial (n=57) were progression (n=40), adverse event (n=6), transplantation (n=5), withdrawal of consent (n=3) and other causes (n=3). ORR and CR rate after 4th cycle were 53.2% and 35.9%, respectively. Patients with relapsed disease had significantly higher ORR (67.9% vs 41.7%, p=0.037) and CR rate (57.1% vs 19.4%, p=0.002) than patients with refractory disease. At the end of induction, ORR and CR rate were 35.9% and 29.7%, respectively. After a median follow-up of 22 months (range: 1 to 39 months), the estimated 2-year PFS and OS were 21% and 25%, respectively (Figure 1A and 1B), being significantly better in patients with relapsed disease (Figure 1C and 1D). In the multivariate analysis, status of lymphoma at study entry significantly influenced PFS (HR 0.45; 95% CI 0.25-0.82; p=0.009) and OS (HR 0.51; 95% CI 0.27-0.94; p=0.0031) independently from the IPI and the number of previous treatment lines. The most frequent adverse events (AE) (present in at least 20% of patients) were thrombocytopenia (67.2%), diarrhea (51.6%), neutropenia (46.9%), anemia (37.5%), fatigue (34.4%), nausea (29.7%) and paresthesia (20.3%). The most frequent grade 3-5 AE (present in at least 10% of patients) were thrombocytopenia (46.9%), neutropenia (35.9%), diarrhea (15.6%) and anemia (14.1%). Three patients presented a grade 5 AE, two of them related (aspergillosis and pneumonia, respectively) and one unrelated (heart failure). CONCLUSIONS The combination of ibrutinib with R-GEMOX-D as salvage therapy for patients with non-GCB DLBCL is associated with high response rates, especially in relapsed patients. The vast majority of refractory patients progress very early, so this regimen could be considered as a bridge to other consolidation therapies. Biological studies analyzing cell of origin by gene expression profiling, minimal residual disease and mutational spectrum are in progress. Disclosures Abrisqueta: Roche: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Speakers Bureau. Giné:Janssen: Research Funding; Gilead: Research Funding; Roche: Research Funding. Grande:Janssen: Research Funding. Caballero:Roche: Other: travel; Gilead: Other: travel; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: travel; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel; BMS: Other: travel; Takeda: Other: travel; Kite: Membership on an entity's Board of Directors or advisory committees. Martin Garcia-Sancho:Roche, Celgene, Janssen, Servier, Gilead: Honoraria; Celgene, Eusa Pharma, Gilead, iQuone, Kyowa Kirin, Roche, Morphosys: Consultancy. OffLabel Disclosure: Off-label use of a new combination in the context of a clinical trial. New combination (Ibrutinib + R-GEMOX)

scholarly journals Prevalence and the Impact of Hypogammaglobulinemia in Newly Diagnosed, Untreated Diffuse Large B Cell Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1604-1604
Author(s):  
Namrata Singh ◽  
Sarah L Mott ◽  
Ashley Noel McCarthy ◽  
Sergei Syrbu ◽  
Thomas M. Habermann ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Large B Cell Lymphoma ◽  
Treatment Naïve ◽  
Large B Cell

Background: While there is evidence in the literature of increased prevalence of hypogammaglobulinemia in chronic lymphocytic leukemia (CLL), there are no studies evaluating the prevalence of hypogammaglobulinemia in newly diagnosed diffuse large B cell lymphoma (DLBCL) or the relationship between hypogammaglobulinemia and presentation or outcomes. The objective of this study was to examine the prevalence of hypogammaglobulinemia in newly diagnosed DLBCL patients and to test the hypothesis that DLBCL patients with baseline hypogammaglobulinemia have a distinct clinical profile and outcome. Methods: We obtained banked frozen sera from 200 newly diagnosed, treatment-naïve, DLBCL patients from the Lymphoma SPORE Molecular Epidemiology Resource (MER), a prospective cohort study conducted at the Mayo Clinic and the University of Iowa. IgG/A/M levels were measured using immunoturbidimetric assay whereas IgE level was measured using electrochemiluminescence immunoassay; deficiency was defined using standard reference ranges. IgE levels were considered deficient if &lt;2 UI/ml. The associations between Ig deficiencies and clinical factors were evaluated with Wilcoxon rank sum and chi-squared (Fisher's exact, where appropriate) tests. Event-free survival (EFS) was defined as time from diagnosis to progression, relapse, retreatment, or death, and EFS24 was defined as EFS at 24 months after diagnosis (achieve or failure to achieve EFS24). The association of Ig levels with EFS24 was estimated using odds ratios (OR) and 95% confidence intervals (CI) from logistic regression, and with EFS, overall survival (OS), and lymphoma-specific survival (LSS) was estimated using Kaplan-Meier curves and hazard ratios (HR) and 95% CI from Cox regression. Results: The mean age (SD) of the cohort was 65.6 (13.4) years, 54% were males and 98% of the patients were white. Over a median follow-up of five years, there were 59 (29.5%) deaths. The prevalence of hypogammaglobulinemia, defined as any deficiency, in newly diagnosed, treatment-naïve DLBCL was 22.1% (44/199) in our cohort, and the most common Ig deficiency was for IgG (&lt;700 mg/dL, 13.5%), followed by IgM (&lt;40 mg/dL, 9.0%), IgE (&lt;2 UI/ml, 7.5%) and IgA (&lt;70 mg/dL, 4.0%) (Table1). There were no statistically significant differences between Ig deficient and non-deficient patients in terms of age at diagnosis, gender, stage, cell of origin, or MYC double hit status. However, median LDH levels were higher in Ig deficient patients (228 vs 194, p&lt;0.01). Any immunoglobulin deficiency was associated with inferior EFS (HR 1.94, 95% CI 1.16-3.24) (Figure 1) and OS (HR 2.02, 95% CI 1.17-3.49), and these associations were not attenuated after adjustment for the international prognostic index (IPI). Any Ig deficiency was also associated with failure to achieve EFS24 (OR=2.13, 95% CI 1.00-4.60) after adjusting for IPI. Conclusions: To the best of our knowledge, this is the first study to report the prevalence of hypogammaglobulinemia in treatment naïve DLBCL. We found that any Ig deficiency was not uncommon in our cohort and it was associated with an inferior EFS and OS in DLBCL patients. The prevalence of hypogammaglobulinemia in DLBCL patients seems to be lower than has been described in CLL patients. While the underlying relationship between these two immunologic disorders deserves further study, our findings highlight the interaction between global immune dysfunction and emergence of a clonal B cell process. Disclosures Nowakowski: Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding. Farooq:Celgene: Honoraria; Kite Pharma: Research Funding. Cerhan:NanoString: Research Funding; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Clonal Somatic Mutations Are a Biomarker for Inferior Prognosis in Diffuse Large B-Cell Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 26-27
Author(s):  
Nicholas J. Boddicker ◽  
Pinkal Desai ◽  
Mithun Vinod Shah ◽  
Vivekananda Sarangi ◽  
Matthew J. Maurer ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Peripheral Blood ◽  
Research Funding ◽  
Somatic Mutations ◽  
Cell Lymphoma ◽  
Univariate Analysis ◽  
B Cell Lymphoma ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Large B Cell Lymphoma

Background Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma subtype with a 5-year survival of ~64%. While DLBCL is treated using immunochemotherapy (IC) with curative intent, 20%-40% of patients do not reach remission or relapse post IC. Clonal somatic mutations have been associated with aging, hematologic malignancies (predominately myeloid), and reduced OS in the general population. The objective of this study was to evaluate the association of clonal somatic mutations with event-free survival (EFS) and overall survival (OS). Methods We studied newly diagnosed DLBCL cases treated with IC who were enrolled in the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence (SPORE). Clinical and treatment data were abstracted from medical records and all patients were systematically followed for disease outcomes. Pre-treatment DNA was extracted from matched peripheral blood and paraffin-embedded tumor tissue, and whole exome sequencing was conducted at 100x coverage. From the peripheral blood, allele counts from GVCF files produced by HaplotypeCaller in GATK were extracted for 42 genes commonly associated with clonal hematopoiesis (e.g. DNMT3A, TET2, and ASXL1). Mutations were deemed clonal somatic if the population minor allele frequency was &lt;0.5% in ExAC and had a variant allele fraction (VAF) that deviated from 0.5 using a binomial distribution test at p&lt;0.001. Furthermore, mutations had to have a minimum alternate read count of at least 5 reads, a VAF greater than or equal to 10%, and met at least one of the following criteria: CAVA impact of "HIGH"; pathogenic/likely pathogenic per ClinVar; or reported in COSMIC at least 10 times. EFS was defined as time from diagnosis to disease progression, relapse, retreatment, or death due to any cause. The association of clonal somatic mutations with prognosis was estimated using Kaplan-Meier curves, and hazard ratios (HR) and 95% confidence intervals (CI) from Cox regression. Associations were adjusted for age at diagnosis, sex, and the International Prognostic Index (IPI). Results The study consisted of 261 DLBCL patients treated with IC. The median age at diagnosis was 65 years (range 20-90) and 56% were male. With a median follow-up time of 5.1 years (range 0.1-15.0), there were 100 events and 80 deaths. A total of 17 (6.5%) patients had clonal somatic mutations, and16 patients were over the age of 60. A total of 8 (of 42) genes had clonal somatic mutations, with SF3B1, ASXL1, and TET2, being the most frequent (4 individuals per gene). VAFs ranged from 0.10 to 0.28 and none of the patients had multiple mutations. Additionally, the clonal somatic variants found in the peripheral blood were abscent in the tumor sample. Of the 17 patients with clonal somatic mutations, 12 had an event while 88 patients without a mutation had an event. In a univariate analysis, clonal somatic mutations were associated with inferior EFS (HR=2.55, 95% CI 1.39-4.68, p=0.002; Figure 1A). After adjusting for age, sex, and IPI, clonal somatic mutations remained associated with inferior EFS (HR=2.02, 95% CI 1.09-3.74, p=0.026). Clonal somatic mutations were also associated with inferior OS in the univariate analysis (HR=2.06, 95% CI 0.99-4.29, p=0.053), which attenuated after multivariate adjustment (HR=1.59, 95% CI: 0.76-3.34, p=0.22, Figure 1B). Although based on small numbers, mutations in SF3B1 were associated with inferior EFS (HR=3.25, 95% CI 1.16-9.12, p=0.025), but did not reach significance for OS (HR=2.56, 95% CI 0.78-8.38, p=0.120). Conclusions In this novel study of newly diagnosed DLBCL patients, clonal somatic mutations were identified in 6.5% of patients and were associated with inferior outcomes. Additional research is required at deeper sequencing to validate these findings and integration with tumor genomics is required to understand the prognosis of DLBCL patients with smaller clonal populations. Disclosures Shah: Dren Bio: Consultancy. Maurer:Celgene / BMS: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Nanostring: Research Funding. Martin:Celgene: Consultancy; Karyopharm: Consultancy, Research Funding; Morphosys: Consultancy; Regeneron: Consultancy; Incyte: Consultancy; Kite: Consultancy; Cellectar: Consultancy; Bayer: Consultancy; Beigene: Consultancy; Sandoz: Consultancy; I-MAB: Consultancy; Janssen: Consultancy; Teneobio: Consultancy. Witzig:AbbVie: Consultancy; Incyte: Consultancy; Acerta: Research Funding; Karyopharm Therapeutics: Research Funding; Immune Design: Research Funding; Spectrum: Consultancy; Celgene: Consultancy, Research Funding; MorphSys: Consultancy. Nowakowski:NanoString: Research Funding; Seattle Genetics: Consultancy; Curis: Consultancy; Kymera: Consultancy; Kite: Consultancy; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees; MorphoSys: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding. Novak:Celgene/BMS: Research Funding. Cerhan:NanoString: Research Funding; BMS/Celgene: Research Funding.

scholarly journals Impact of Interim FDG-PET (iPET) in the Outcomes of Patients with Aggressive B-Cell Lymphomas Receiving DA-EPOCH-R

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2898-2898
Author(s):  
Vania Phuoc ◽  
Leidy Isenalumhe ◽  
Hayder Saeed ◽  
Celeste Bello ◽  
Bijal Shah ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Fdg Pet ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Advisory Committees ◽  
End Of Treatment

Introduction: 2-[18F] fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) remains the standard of care for baseline and end of treatment scans for aggressive non-Hodgkin lymphomas (NHLs). However, the role of interim FDG-PET remains not as well defined across aggressive NHLs, especially in the era of high-intensity chemoimmunotherapy. Interim FDG-PET (iPET) can serve as an early prognostic tool, and prior studies evaluating the utility of iPET-guided treatment strategies primarily focused on diffuse large B-cell lymphomas (DLBCL) and frontline R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Classification criteria systems assessing response also differ between studies with no clear consensus between use of Deauville criteria (DC), International Harmonization Project (IHP), and the ΔSUVmax method. Methods: This study evaluates our institutional experience with iPET during treatment with DA-EPOCH ± R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin with or without Rituximab) in aggressive NHLs. We retrospectively evaluated 70 patients at Moffitt Cancer Center who started on DA-EPOCH ± R between 1/1/2014 to 12/31/2018 for aggressive NHLs. Response on interim and end-of-treatment (EOT) scans were graded per DC, IHP, and ΔSUVmax methods, and progression free survival (PFS) probability estimates were calculated with chi-square testing and Kaplan Meier method. PFS outcomes were compared between interim negative and positive scans based on each scoring method. Outcomes were also compared between groups based on interim versus EOT positive or negative scans. Results: We identified 70 patients with aggressive NHLs who received DA-EPOCH ± R at our institute. The most common diagnoses were DLBCL (61%) followed by Burkitt's lymphoma (10%), primary mediastinal B-cell lymphoma (9%), plasmablastic lymphoma (7%), gray zone lymphoma (6%), primary cutaneous large B-cell lymphoma (1%), primary effusion lymphoma (1%), and other high-grade NHL not otherwise specified (3%). Of the 43 patients with DLBCL, 21/43 (49%) had double hit lymphoma (DHL) while 7/43 (16%) had triple hit lymphoma (THL), and 3/43 (7%) had MYC-rearranged DLBCL while 2/43 (5%) had double expressor DLBCL. Thirty nine out of 70 (56%) were female, and median age at diagnosis was 58.39 years (range 22.99 - 86.86 years). Most patients had stage IV disease (49/70, 70%), and 43/70 (61%) had more than one extranodal site while 45/70 (64%) had IPI score ≥ 3. Forty-six out of 70 (66%) received central nervous system prophylaxis, most with intrathecal chemotherapy (44/70, 63%). Fifty-five out of 70 (79%) had iPET available while 6/70 (9%) had interim computerized tomography (CT) scans. Fifty-six out of 70 (80%) had EOT PET, and 4/70 (6%) had EOT CT scans. Sustained complete remission occurred in 46/70 (66%) after frontline DA-EPOCH ± R (CR1), and 12/70 (17%) were primary refractory while 5/70 (7%) had relapse after CR1. Four of 70 (6%) died before cycle 3, and 3/70 (4%) did not have long-term follow-up due to transition of care elsewhere. Median follow-up was 15.29 months (range 0.85 - 60.09 months). There was significantly better PFS observed if iPET showed DC 1-3 compared to DC 4-5 (Χ2=5.707, p=0.0169), and PFS was better if iPET was negative by IHP criteria (Χ2=4.254, p=0.0392) or ΔSUVmax method (Χ2=6.411, p=0.0113). Comparing iPET to EOT PET, there was significantly better PFS if iPET was negative with EOT PET negative (iPET-/EOT-) compared to iPET positive with EOT negative (iPET+/EOT-), and iPET+/EOT+ and iPET-/EOT+ had worse PFS after iPET-/EOT- and iPET+/EOT- respectively. This pattern in iPET/EOT PFS probability remained consistent when comparing DC (Χ2=30.041, p<0.0001), IHP (Χ2=49.078, p<0.0001), and ΔSUVmax method (Χ2=9.126, p=0.0104). These findings fit clinical expectations with positive EOT scans indicating primary refractory disease. There was no significant difference in PFS when comparing DLBCL versus non-DLBCL (Χ2=3.461, p=0.0628) or DHL/THL versus non-DHL/THL diagnoses (Χ2=2.850, p=0.0914). Conclusion: Our findings indicate a prognostic role of iPET during treatment with DA-EPOCH ± R for aggressive NHLs. Significant differences in PFS were seen when graded by DC, IHP, and ΔSUVmax methods used in prior studies and when comparing interim versus EOT response. Larger studies are needed to confirm these findings. Disclosures Bello: Celgene: Speakers Bureau. Shah:Novartis: Honoraria; AstraZeneca: Honoraria; Spectrum/Astrotech: Honoraria; Adaptive Biotechnologies: Honoraria; Pharmacyclics: Honoraria; Jazz Pharmaceuticals: Research Funding; Incyte: Research Funding; Kite/Gilead: Honoraria; Celgene/Juno: Honoraria. Sokol:EUSA: Consultancy. Chavez:Janssen Pharmaceuticals, Inc.: Speakers Bureau; Genentech: Speakers Bureau; Kite Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

Phase II Study Of Anti-CD19 Antibody Drug Conjugate (SAR3419) In Combination With Rituximab: Clinical Activity and Safety In Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma (NCT01470456)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4395-4395 ◽  
Author(s):  
Bertrand Coiffier ◽  
Catherine Thieblemont ◽  
Sophie de Guibert ◽  
Jehan Dupuis ◽  
Vincent Ribrag ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Clinical Activity ◽  
Advisory Committees ◽  
Large B Cell Lymphoma ◽  
Duration Of Response ◽  
Grade 3

Abstract Background SAR3419 is a humanized anti-CD19 antibody conjugated to maytansin DM4, a potent cytotoxic agent. SAR3419 targets CD19, an antigen expressed in the majority of B cell non-Hodgkin lymphomas (NHL). The recommended dose for single agent SAR3419 was previously determined to be 55 mg/m2 administered IV every week for 4 weeks, then bi-weekly. In phase I, clinical activity was shown mainly in patients with follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). (Trial funded by Sanofi). Methods Patients (pts) with a CD20+ and CD19+ DLBCL relapsing or refractory (R/R) after at least 1 standard treatment including rituximab and not candidate for or who already underwent transplantation, were eligible. Refractory disease was defined as unresponsive to or progressing within 6 months of regimen completion. Fresh (or recent formalin-fixed, paraffin-embedded) biopsy was required before SAR3419 start. Pts received 375 mg/m2 of rituximab (R) IV and 55 mg/m² of SAR3419 on day 1, 8, 15, 22 (35-day cycle 1), followed by bi-weekly R and SAR3419 at the same doses for 2 additional 28-day cycles, provided there was no disease progression or other study discontinuation criteria met. The primary objective was the overall response rate (ORR) following Cheson 2007 criteria, with the first tumor assessment being done 42 days after the last study treatment administration. Secondary objectives were: safety, pharmacokinetics (PK), duration of response (DOR), progression free survival (PFS), overall survival (OS) and correlation of the antitumor and biological activity of the combination with tumor biomarker status. Results Fifty-three pts were enrolled, 52 treated. Median age was 66.5 years (range 38-85), 50% were male; 23%, 33% and 40% of patients had received 1, 2 or ≥3 prior chemo/immunotherapy regimens for DLBCL, respectively. Of the enrolled patients, 3.8% had received no prior regimen for DLBCL and therefore were excluded from primary analysis for efficacy. Seventy-three percent had stage III/IV disease, 59% had elevated lactate dehydrogenase (LDH), and 63% had bulky disease. Sixty percent were refractory to first regimen (primary refractory), 16% were refractory to last regimen and 24% were relapsed pts. The ORR in the per-protocol population (n=45) was 31.1% (80% confidence interval (CI): 22.0% to 41.6%). Among the 14 responders, 5 had progressed at the time of analysis, with duration of response beyond 6 months for 3 of them. The ORR was 58.3% (80% CI: 36.2% to 78.1%) for patients with relapsed DLBCL (n=12), 42.9% (80% CI: 17.0% to 72.1%) for pts refractory to last regimen (n=7) and 15.4% (80% CI: 6.9% to 28.4%) for primary refractory pts (n=26). Overall survival and PFS data are not yet mature. Biomarkers and PK data will be presented at the meeting. The most common (≥10%) all grades non-hematologic treatment-emergent adverse events (TEAEs) were asthenia (25.0%), nausea (21.2%), cough (19.2%), diarrhea (17.3%), weight decrease (17.3%), vomiting (15.4%), dyspnea (15.4%), abdominal pain (13.5%), back pain (13.5%), pyrexia (13.5%) and constipation (11.5%). Related grade 3-4 TEAEs were: 1 syncope, 1 bronchospasm, 2 neutropenia and 1 anemia. No TEAEs led to treatment discontinuation, no grade 3-4 peripheral neuropathy or grade 3-4 ocular events were observed. Two pts experienced grade 2 keratitis, both rapidly recovered with local treatment. Hematological toxicity was moderate, with grade 3-4 neutropenia and thrombocytopenia in 15.7% and 9.8% pts, respectively. No complications related to neutropenia were reported. Grade 3 transaminase increase was observed in 1 patient. Conclusions The combination of SAR3419 plus R showed moderate ORR in R/R DLBCL; however the study population was of poor prognosis (60% refractory to first line therapy). In the relapsed DLBCL patients a higher ORR was observed. SAR3419 plus R presented with a favorable safety profile. Further investigations on biomarker expression are ongoing to identify a sub-group of pts who could have better benefited from this combination. Disclosures: Coiffier: Sanofi: Membership on an entity’s Board of Directors or advisory committees. Off Label Use: Phase II of SAR3419. Ribrag:Johnson & Johnson: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Takeda: Membership on an entity’s Board of Directors or advisory committees; Servier: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Cartron:LFB: Honoraria; GSK: Honoraria; Roche: Consultancy, Honoraria, Speakers Bureau. Casasnovas:Roche: Consultancy, Honoraria, Research Funding. Hatteville:Sanofi: Employment. Zilocchi:Sanofi: Employment. Oprea:Sanofi: Employment. Tilly:Amgen: Research Funding; Janssen: Honoraria; Pfizer: Honoraria; Takeda: Membership on an entity’s Board of Directors or advisory committees; Roche: Honoraria; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

Poor Outcomes Among Patients Failing Dose-Adjusted EPOCH in Aggressive Lymphoma: A Collaborative, Retrospective Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1518-1518 ◽  
Author(s):  
Jackie Vandermeer ◽  
Allison M Winter ◽  
Ajay K. Gopal ◽  
Ryan D. Cassaday ◽  
Brian T. Hill ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Salvage Therapy ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
First Line ◽  
Advisory Committees ◽  
First Line Therapy

Abstract Introduction Among patients with aggressive B-NHL who fail RCHOP, about half respond to standard salvage regimens and may proceed to curative-intent, transplant-based therapy. However, whether pts failing more intensive regimens such as dose-adjusted, infusional EPOCH benefit from standard salvage regimens is unclear. We hypothesized that such patients comprise a higher-risk cohort, facing inferior response rates and outcomes using standard salvage regimens. We undertook a collaborative study to assess response rates and survival among pts failing EPOCH for aggressive B-NHL, to inform patient management and design of clinical trials in this setting. Methods Pharmacy records and institutional databases were queried, identifying pts receiving EPOCH over the last 10 years at the University of Washington/SCCA and the Cleveland Clinic Foundation, for combined analysis. Under IRB approval, patient characteristics, histology, outcome with EPOCH, time to EPOCH failure, response to salvage, and overall survival were analyzed. Diffuse large B cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, B-cell-lymphoma unclassifiable, HIV-associated B cell lymphoma, and transformed B cell non-Hodgkin lymphoma were included. Pts receiving <2 cycles EPOCH, or who had inadequate follow-up (<3 months), were excluded. Failure of EPOCH was defined as failure to respond or progression during therapy, need for initiation of salvage therapy, or death during therapy of any cause. Adverse events or treatment change due to toxicity were not included in the definition of failure. JMP 11 was used to generate kaplan-meier survival estimates. Results 124 pts with aggressive B-NHL receiving EPOCH were identified. 54 had not relapsed, and among 70 remaining da-EPOCH failures, 37 met the above inclusion criteria. Median age was 55. 27% were female, and 23 received EPOCH as first-line therapy. All but 3 received rituximab with EPOCH. Histologies were primarily DLBCL in 22/37 (60%) and BCL-U in 12/37 (32%) carrying a MYC translocation; most of these harbored additional translocations in BCL2 and/or BCL6 (10/12). However, data regarding MYC rearrangement was not available for all pts. 2 had HIV-associated B-NHL and 3 had PMBCL. With 18 months follow up, the median time to EPOCH failure was 5 months. Only 3 EPOCH failures occurred late (>12 months). Median OS from the date of EPOCH failure was 10 months (Figure 1). Those receiving EPOCH as first-line therapy (23) had a median OS of 14 months from EPOCH failure, as opposed to 4 months for those receiving EPOCH as salvage therapy (log-rank p=.01). Salvage chemotherapy regimens after EPOCH were diverse, and generally ineffective; 6/28 (21%) regimens produced a response (Table 1). Among patients failing EPOCH within a year, platinum-containing salvage (RICE/RDHAP) was effective in only 2/13 patients (15%). 9 patients did not receive any salvage, most of whom died or proceeded to palliative measures and/or hospice care. Conclusions A relatively low overall response rate (21%) was observed in this retrospective analysis of patients failing EPOCH. Analogous to early RCHOP failure in the CORAL study, those failing EPOCH within a year may face inferior outcomes with platinum-based salvage therapy. While combined from two institutions, our data represent a modest sample size and require confirmation. If verified, examination of mechanisms of resistance to EPOCH, and selecting EPOCH failures for clinical trials of novel targeted therapies and transplant-based approaches, may prove critical. Table 1. Salvage Therapy for REPOCH failures Regimen: response/total number treated Notes Response to any salvage: 6/28 (21%) Some patients received more than 1 chemo salvage; responses were tabulated per regimen. RICE: 4/12 2/3 alive post transplant(1 auto 1 allo; 1 declined transplant and survived; 1 died) RDHAP: 1/6 Gemcitabine-based: 0/5 HyperCVAD (Part A and/or B): 1/5 Survivor had CNS only relapse, received regimen B and transplant 9- received no systemic treatmen; most died or proceeded to palliative measures and/or hospice Figure 1. Figure 1. Disclosures Gopal: Gilead: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Spectrum: Consultancy, Research Funding; Emergent/Abbott: Research Funding; Sanofi-Aventis: Honoraria; Seattle Genetics: Consultancy, Honoraria; BioMarin: Research Funding; Piramal: Research Funding; Janssen: Consultancy; Millenium: Honoraria, Research Funding; BMS: Research Funding; Merck: Research Funding. Hill:Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Till:Roche/Genentech: Research Funding; Pfizer: Research Funding.

scholarly journals Nanatinostat (Nstat) and Valganciclovir (VGCV) in Relapsed/Refractory (R/R) Epstein-Barr Virus-Positive (EBV +) Lymphomas: Final Results from the Phase 1b/2 VT3996-201 Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 623-623
Author(s):  
Bradley M. Haverkos ◽  
Onder Alpdogan ◽  
Robert Baiocchi ◽  
Jonathan E Brammer ◽  
Tatyana A. Feldman ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Phase 2 ◽  
Advisory Committees ◽  
Phase 1B

Abstract Introduction: EBV can be associated with several types of lymphomas, with reported frequencies of up to 8-10% in diffuse large B cell lymphoma (DLBCL), 30-100% in peripheral T cell lymphoma (PTCL) subtypes, 80% in post-transplant lymphoproliferative disease (PTLD), and 15-30% in classical Hodgkin lymphoma (HL), with adverse impact on outcomes. Nanatinostat (Nstat) is a Class-I selective oral HDAC inhibitor that induces the expression of the lytic BGLF4 EBV protein kinase in EBV + tumor cells, activating ganciclovir (GCV) via phosphorylation. This results in GCV-induced inhibition of viral and cellular DNA synthesis and apoptosis. Herein we report the final results from this exploratory study for patients with R/R EBV + lymphomas (NCT03397706). Methods: Patients aged ≥18 with histologically confirmed EBV + lymphomas (defined as any degree of EBER-ISH positivity), R/R to ≥1 prior systemic therapies with an absolute neutrophil count ≥1.0×10 9/L, platelet count ≥50×10 9/L, and no curative treatment options per investigator were enrolled into 5 dose escalation cohorts to determine the recommended phase 2 doses (RP2D) of Nstat + VGCV for phase 2 expansion. Phase 2 patients received the RP2D (Nstat 20 mg daily, 4 days per week + VGCV 900 mg orally daily) in 28-day cycles until disease progression or withdrawal. Primary endpoints were safety/RP2D (phase 1b) and overall response rate (ORR) (phase 2); secondary endpoints were pharmacokinetics, duration of response (DoR), time to response, progression free survival and overall survival. Responses were assessed using Lugano 2014 response criteria beginning at week 8. Results: As of 18 June 2021, 55 patients were enrolled (phase 1b: 25; phase 2: 30). Lymphoma subtypes were DLBCL (n=7), extranodal NK/T-cell (ENKTL) (n=9), PTCL, not otherwise specified (PTCL-NOS) (n=5), angioimmunoblastic T cell lymphoma (n=6), cutaneous T cell (n=1), HL (n=11), other B cell (n=3), and immunodeficiency-associated lymphoproliferative disorders (IA-LPD) (n=13), including PTLD (n=4), HIV-associated (n=5), and other [n=4: systemic lupus erythematosus (SLE) (n=2), common variable/primary immunodeficiency (n=2)]. Median age was 60 years (range 19-84), M/F 35/20, median number of prior therapies was 2 (range 1-11), 76% had ≥2 prior therapies, 78% were refractory to their most recent prior therapy, and 84% had exhausted standard therapies. EBER positivity ranged from &lt;1 to 90% in 42 tumor biopsies with central lab review. The most common treatment-emergent adverse events (TEAEs) of all grades were nausea (38%), neutropenia (34%), thrombocytopenia (34%), and constipation (31%). Grade 3/4 TEAEs in &gt;10% of patients included neutropenia (27%), thrombocytopenia (20%), anemia (20%), and lymphopenia (14%). Dose reductions and interruptions due to treatment-related AEs were reported in 14 (25%) and 16 (29%) patients, respectively. Only 1 patient had to discontinue therapy. There were no cases of CMV reactivation. For 43 evaluable patients (EBER-ISH + with ≥ 1 post-treatment response assessment) across all histologies, the investigator-assessed ORR and complete response (CR) rates were 40% (17/43) and 19% (8/43) respectively. Patients with T/NK-NHL (n=15; all refractory to their last therapy) had an ORR of 60% (n=9) with 27% (n=4) CRs. Two patients (ENKTL and PTCL-NOS) in PR and CR respectively were withdrawn at 6.7 and 6.6 months (m) respectively for autologous stem cell transplantation. For DLBCL (n=6), ORR/CR was 67%/33% (both CRs were in patients refractory to first-line R-CHOP). For IA-LPD (n=13), ORR/CR was 30%/20% (PTLD: 1 CR, other: 1 CR, 1 PR). For HL (n=10), there was 1 PR (4 SD). The median DoR for all responders was 10.4 m, with a median follow-up from response of 5.7 m (range 1.9-34.1 m). For the 17 responders, 8 lasted ≥ 6 months. Conclusions: The combination of Nstat and VGCV was well-tolerated with a manageable toxicity profile and shows promising efficacy in patients with R/R EBV + lymphomas, particularly in refractory T/NK-NHL, a heterogeneous group of aggressive lymphomas with dismal outcomes, with multiple durable responses. Further evaluation of this novel combination therapy for the treatment of recurrent EBV + lymphomas is ongoing in the phase 2 VT3996-202 trial. Disclosures Haverkos: Viracta Therapeutics, Inc.: Honoraria, Research Funding. Baiocchi: Prelude Therapeutics: Consultancy; viracta: Consultancy, Current holder of stock options in a privately-held company; Codiak Biosciences: Research Funding; Atara Biotherapeutics: Consultancy. Brammer: Seattle Genetics: Speakers Bureau; Celgene: Research Funding; Kymera Therapeutics: Consultancy. Feldman: Alexion, AstraZeneca Rare Disease: Honoraria, Other: Study investigator. Brem: Karyopharm: Membership on an entity's Board of Directors or advisory committees; SeaGen: Speakers Bureau; BeiGene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; KiTE Pharma: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Morphosys/Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Scheinberg: Roche: Consultancy; Abbvie: Consultancy; BioCryst Pharmaceuticals: Consultancy; Alexion pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Joffe: AstraZeneca: Consultancy; Epizyme: Consultancy. Katkov: Viracta Therapeutics, Inc.: Current Employment. McRae: Viracta Therapeutics, Inc.: Current Employment. Royston: Viracta Therapeutics, Inc.: Current Employment. Rojkjaer: Viracta Therapeutics, Inc.: Current Employment. Porcu: Viracta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Daiichi: Honoraria, Research Funding; Kiowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Spectrum: Consultancy; DrenBio: Consultancy.

scholarly journals Safety of Axicabtagene Ciloleucel CD19 CAR T-Cell Therapy in Elderly Patients with Relapsed or Refractory Large B-Cell Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 96-96 ◽  
Author(s):  
Dahlia Sano ◽  
Loretta J. Nastoupil ◽  
Nathan H. Fowler ◽  
Luis Fayad ◽  
F. B. Hagemeister ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Age Groups ◽  
B Cell Lymphoma ◽  
Advisory Committees ◽  
Large B Cell Lymphoma ◽  
Car T ◽  
Large B Cell

Abstract Background Axicabtagene ciloleucel (axi-cel) is an autologous CD19-specific CAR T-cell therapy product that was FDA approved for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after at least two lines of systemic therapy. In the pivotal ZUMA-1 study, the best overall response (ORR) and complete response (CR) rates observed in 108 patients treated with axi-cel were 82% and 58%, respectively. At a median follow-up of 15.4 months, 42% of the patients remain in ongoing response (Neelapu et al. N Eng J Med 2017). Analysis of efficacy outcomes in patients <65 years (N=81) and ³65 years (N=27) showed that the ORR and ongoing response at 12 months were comparable between the two subgroups (Neelapu et al. N Eng J Med 2017). Whether the safety is also comparable between the two subgroups is unknown. Here, we report safety outcomes in elderly patients (³65 years) with large B-cell lymphoma treated with axi-cel at our institution. Methods We retrospectively analyzed and reviewed the data from patients treated with axi-cel at our institution. Patients had a diagnosis of relapsed or refractory diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), high-grade B-cell lymphoma (HGBCL), and transformed follicular lymphoma (TFL). Patients were treated with conditioning chemotherapy with cyclophosphamide and fludarabine for 3 days followed by axi-cel infusion after 2 days of rest at a dose of 2 x 106 CAR+ T cells/kg body weight. Patients were monitored for toxicities for at least 7 days in the hospital after CAR T infusion and those who had at least 30 days of follow-up after axi-cel were considered to be evaluable for safety. Cytokine release syndrome (CRS) and neurological toxicity termed as CAR-related encephalopathy syndrome (CRES) were graded according to the CARTOX grading system (Neelapu et al. Nat Rev Clin Oncol 2018). Results A total of 61 patients with relapsed or refractory large B-cell lymphoma who received axi-cel at our institution were included. Of these, 44 (72%) patients were <65 years of age and 17 (28%) patients were ³65 years of age. The baseline characteristics of the patients are summarized in Table 1. ORR and CR rates at Day 30 were comparable between the two groups. CRS was common in both groups and was observed in 83% and 91% of the patients in the older and younger age groups, respectively. But most CRS events were grade 1-2. Grade 3 or higher CRS was observed in 18% vs. 11% in the older vs. younger age groups (P=0.67). One patient with a history of autoimmune disease in the elderly group died of hemophagocytic lymphohistiocytosis (HLH). CRES was observed in 58% and 71% of the patients in the older and younger age groups, respectively. Grade 3 or higher CRES was observed in 29% vs. 39% in the older vs. younger age groups (P=0.58). Median hospitalization period for axi-cel CAR T-cell therapy was comparable between the two groups. Conclusions Our results suggest that response rates are comparable between the elderly and younger age groups at day 30 after axi-cel therapy. Importantly, toxicities due to CRS and/or CRES after axi-cel CD19 CAR T cell therapy are comparable between the elderly (³65 years) and younger (<65 years) patients with relapsed or refractory large B-cell lymphoma. Table 1 Table 1. Disclosures Nastoupil: Merck: Honoraria, Research Funding; Janssen: Research Funding; Juno: Honoraria; Novartis: Honoraria; Genentech: Honoraria, Research Funding; TG Therappeutics: Research Funding; Karus: Research Funding; Celgene: Honoraria, Research Funding; Spectrum: Honoraria; Gilead: Honoraria. Fowler:Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Samaniego:ADC Therapeutics: Research Funding. Wang:Kite Pharma: Research Funding; Acerta Pharma: Honoraria, Research Funding; Novartis: Research Funding; Juno: Research Funding; Pharmacyclics: Honoraria, Research Funding; Dava Oncology: Honoraria; AstraZeneca: Consultancy, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MoreHealth: Consultancy; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Westin:Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Apotex: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees; Celgen: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Mutational Landscape of Grey Zone Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 21-21
Author(s):  
Clementine Sarkozy ◽  
Stacy Hung ◽  
Katsuyoshi Takata ◽  
Elizabeth Chavez ◽  
Tomohiro Aoki ◽  
...  
Keyword(s):  
B Cell ◽  
Exome Sequencing ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Grey Zone ◽  
Advisory Committees ◽  
Mutational Landscape ◽  
Intermediate Morphology

Introduction: Grey zone lymphoma (GZL), a B-cell lymphoma with features intermediate between large B-cell lymphoma (LBCL) and classical Hodgkin lymphoma (cHL), is a rare and poorly defined entity. To decipher its mutational landscape and discover new therapeutic targets, we performed exome sequencing of 31 GZL cases. Methods: GZL cases from the LYSA group (N=139) and BC Cancer (N=30) were centrally reviewed and classified as previously published (Sarkozy et al, Am J Surg Pathol 2019). Whole-exome sequencing was performed on 31 cases with available fresh frozen tissue, using laser micro-dissection (LMD, MMI technology) to enrich for tumor cells and obtain matching normal DNA from microenvironment cells. DNA was extracted (Agencourt® DNAdvance kit) and genomic libraries were constructed with the Ovation ultra-low kit (Nugen®). Exome capture was performed using Agilent SureSelectXT V6+UTR followed by paired-end sequencing (NextSeq®). Somatic nucleotide variants (SNVs) and indels were identified using VarScan, Strelka and Mutect. Parameters affecting the sensitivity and specificity of variant calling were optimized using 7 "gold standard" cases for which DNA from peripheral blood cells was additionally available. Possible oncogenic drivers were identified based on rate of recurrence, MutSigCV and literature review. Results: Among the 31 GZL cases, the median age was 41 y (14-83) with a sex ratio of 15M:16F; 21 cases had mediastinal involvement, including 15 within the thymic area; EBER in-situ hybridization (ISH) was positive in 8 cases. Seven (23%) cases were classified as group-0 (cHL morphology with 100% CD20 expression), 22 (71%) with an intermediate morphology as group-1 (N=9, cHL-like morphology) or group-2 (N=13, LBCL-like morphology) and 2 (6%) as group-3 (LBCL with 100% of CD30 expression). The mean coverage was 96X (42-203) for tumor samples. One case was excluded due to failure in the LMD process. Among the 30 cases, 6628 variants across 4826 genes were found, including 2903 coding mutations (325 indels and 2808 SNVs, mean of 104/sample, range: 15-678), 721 affecting the 5' UTR and 2774 the 3' UTR. A total of 152 genes were identified as being potential oncogenic drivers, with a mean of 11 mutated genes per case (range 2-36). The most recurrently mutated genes were SOCS1 (33%), B2M (23%), GNA13 (20%), LRRN3 (17%), and ZNF217, NCOR1, ITPKB, IRF2BP2, CSF2RB, and CSMD3 (13% each). The epigenetic SWI/SNF and transcription regulation pathway (including NCOR1/2, ARID1A, KMT2D, KMT2A) was affected in 73% of the cases, JAK/STAT in 70% and NF-kB in 19%. As assessed by CNVkit and GISTIC, the most recurrent gains/amplifications identified were in 9p24.1 (JAK2, CD274, PDCD2LG2; 69%) and 2p16.1 (REL, BCL11A; 62%), and losses in 11q14.3 (ATM; 48%) and 12q24.33 (NCOR2; 48%). Based on mutational signature analysis, individual base substitutions were linked to mutagenic processes, with the highest contributions associated with aging (29%) and defective DNA mismatch repair (27%); moreover, mutations attributable to AID/APOBEC activity (5%), were found to be significantly enriched in EBV- vs. EBV+ cases (p = 0.013). EBV+ cases had fewer total variants (mean 98 vs 258, p=0.08) and potential oncogenic variants (mean 7 vs 15, p=0.03) compared to EBV- cases. EBV+ cases also lacked mutations in the NF-kB pathway and MHC-class I components (B2M and HLA-B: 0% vs 43% in EBV-, p=0.06) but had mutations in STAT3, DHX58, ACTB and ATP13A4 (6/7 cases) not present in the 23 EBV- cases. LRRN3 and GNA13 mutations were significantly associated with thymic area involvement (40% vs 0%, p=0.01). Furthermore, fluorescence-ISH indicated that 20% (1/5) of EBV+ cases had a rearrangement in the CIITA locus (16p13.13) vs 53% (9/17) in EBV- cases. Patients with an intermediate morphology had more oncogenic variants than those in group 0 and 3 (mean of 15 vs 6 variants/case, p=0.01 affecting 12 vs 5 genes, p=0.004). Finally, NCOR1 (N=4) and NCOR2 (N=2) mutations were exclusively found in cases with intermediate morphology (23% vs 0% for those with group 0 or 3 morphology). Conclusion: These data suggest that GZL is a highly heterogenous disease harboring somatic driver events shared with PMBCL and HL. We also discovered novel gene mutations pointing to the importance of previously unrecognized pathways in the pathogenesis of GZL. The distinct mutational pattern in EBV+ GZL suggests divergent evolutionary trajectories. Disclosures Sarkozy: Takeda: Research Funding. Salles:Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Epizyme: Consultancy, Honoraria; BMS: Honoraria; Amgen: Honoraria, Other: Educational events; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events. Savage:BMS, Merck, Novartis, Verastem, Abbvie, Servier, and Seattle Genetics: Consultancy, Honoraria; Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding. Scott:Celgene: Consultancy; Roche/Genentech: Research Funding; Janssen: Consultancy, Research Funding; NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoSting [Institution], Research Funding. Steidl:Juno Therapeutics: Consultancy; Tioma: Research Funding; Roche: Consultancy; Bristol-Myers Squibb: Research Funding; Nanostring: Patents & Royalties: Filed patent on behalf of BC Cancer; Seattle Genetics: Consultancy; Bayer: Consultancy.

scholarly journals Predictors of Relapse and Survival Following Autologous Stem Cell Transplant in Patients with Diffuse Large B-Cell Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1832-1832
Author(s):  
Marie Hu ◽  
Marcus P Watkins ◽  
Qing Cao ◽  
Saba Raya ◽  
David A. Russler-Germain ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Standard Of Care ◽  
Disease Status ◽  
Advisory Committees ◽  
Factors Associated ◽  
Molecular Features

Abstract Background: Although the majority of patients with diffuse large B-cell lymphoma (DLBCL) can be cured with intensive chemotherapy and rituximab, 30-40% of patients will be refractory to or relapse after first line treatment. For these patients, the current standard of care is salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT). Prior studies have largely examined clinical risk factors associated with higher risk of relapse after ASCT; however, there is limited data integrating both pathologic and molecular features. Thus, we aimed to identify high-risk features associated with relapse and survival after ASCT using a combination of clinical, molecular, pathologic, and transplant characteristics. Methods: We retrospectively analyzed the medical records of all adult patients with DLBCL who underwent ASCT at our two institutions from 2010 to 2020. Patients with primary CNS lymphoma, primary mediastinal B-cell lymphoma, or Burkitt lymphoma were excluded. We analyzed demographics, clinical characteristics, cell of origin (COO) by immunohistochemistry (IHC), fluorescence in-situ hybridization (FISH) testing, and treatment/transplant characteristics. The primary endpoints were 3-year progression-free survival (PFS) and overall survival (OS) from ASCT. The Kaplan-Meier method was used to estimate survival with univariate and multivariate Cox proportional hazards regression performed to identify factors associating with PFS and OS, summarized using hazard ratios (HR) with 95% confidence intervals (CI). Results: A total of 235 DLBCL patients underwent ASCT from 2010 to 2020. Median age at ASCT was 61 years (range: 25-75) and 63% were male. At DLBCL diagnosis, 80% had advanced stage disease, 74% had extranodal involvement, 13% had poor performance status, and 65% had elevated lactate dehydrogenase (LDH). 71 patients (30%) had a prior or concurrent indolent lymphoma diagnosis indicating transformed disease. Of the patients with available COO and molecular data, 115 (60%) had germinal center B-cell (GCB) phenotype by IHC, 10 (6%) had a single MYC rearrangement by FISH, and 35 (22%) had MYC plus BCL2 and/or BCL6 rearrangements (DHL/THL). After first-line treatment, 12% remained refractory and 62% later relapsed at a median of 13 months (range: 1-240). Patients received a median of 2 (range: 1-5) lines of treatment pre-ASCT. At time of ASCT, 66% were in complete response (CR) and 32% were in partial response (PR) by standard of care imaging and response criteria. With median follow-up of 5.2 years from time of ASCT, 98 patients (42%) relapsed and 78 (33%) died. 3-year PFS and OS were 58% (95% CI 51-64%) and 74% (95% CI 67-79%), respectively. In univariate analysis, factors associated with worse PFS and worse OS included 3 or more lines of treatment pre-ASCT (p&lt;0.01 for both) and non-CR at ASCT (p&lt;0.01 for both) (Figure 1A and B). Transformed disease was also associated with worse PFS (p=0.03). In multivariate analysis, non-CR at ASCT remained significant (HR 2.22, 95% 1.26-3.90, p&lt;0.01) for worse OS, along with non-GCB COO (HR 1.81, 95% CI 1.03-3.18, p=0.04) and age &gt;60 at ASCT (HR 1.92, 95% CI 1.06-3.47, p=0.03) (Figure 1C). Stratifying by COO and disease status at transplant, 3-year OS was best in the GCB/CR group (84%, 95% CI 73-90%), while worse but similar in the GCB/non-CR and non-GCB/CR groups (68%, 95% CI 51-80% and 71%, 95% CI 56-83%, respectively) (Figure 1D). The non-GCB/non-CR group had the worst 3-year OS (48%, 95% CI 27-67%). No individual factors beyond CR/non-CR at ASCT were associated with worse 3-year PFS. Notably, DHL/THL patients (77% of whom were in CR at time of ASCT) had similar PFS (p=0.08) and OS (p=0.30) to non-DHL/THL patients, suggesting that response to therapy may be more prognostic than high-risk molecular features alone. Conclusions: This analysis indicated that factors associated with OS after ASCT were disease status at time of transplant and COO, with non-GCB patients not in CR having the poorest outcomes. GCB patients not in CR were still able to be cured by ASCT at a high rate. Molecular rearrangements including DHL/THL were not prognostic, although interpretation may be limited by the modest number of DHL/THL patients. These findings may inform which patients should undergo ASCT, while the highest risk group may be better treated with alternatives including novel targeted agents or chimeric antigen receptor cell therapy. Figure 1 Figure 1. Disclosures Bachanova: FATE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; KaryoPharma: Membership on an entity's Board of Directors or advisory committees; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Fehniger: Compass Therapeutics: Research Funding; Affimed: Research Funding; ImmunityBio: Research Funding; Wugen: Consultancy, Current equity holder in publicly-traded company, Patents & Royalties: related to memory like NK cells, Research Funding; OrcaBio: Other; Kiadis: Other; HCW Biologics: Research Funding; Indapta: Other. Weisdorf: Fate Therapeutics: Research Funding; Incyte: Research Funding.

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