scholarly journals Safety and Clinical Activity of Temsirolimus in Combination with Rituximab and DHAP in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma - Report of the Prospective, Multicenter Phase II STORM Trial

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3028-3028
Author(s):  
Mathias Witzens-Harig ◽  
Andreas Viardot ◽  
Ulrich Keller ◽  
Christian Buske ◽  
Anne Crombé ◽  
...  
Keyword(s):  
Overall Survival ◽  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Advisory Committees ◽  
Free Survival ◽  
Multicenter Phase

Abstract Purpose. To evaluate the safety, tolerability and efficacy of the combination of the mTOR inhibitor Temsirolimus and a standard salvage regimen (R-DHAP) in patients with relapsed or refractory diffuse large cell B-Cell lymphoma (DLBCL). Methods. This is a prospective, multicenter, phase II, open-label study. Patients with relapsed or refractory DLBCL with a maximum of two prior treatment lines were eligible. The STORM regimen consisted of Rituximab 375 mg/m² (day 2) and DHAP (Dexamethasone 40mg day 3-6, Cisplatine 100 mg/m² day 3, Cytarabine 2x2 g/m² day 4) with Temsirolimus added on day 1 and 8 of a 21 d cycle, with 2-4 cycles planned. In part I, dose levels of 25, 50, 75 and 100 mg for Temsirolimus were predefined. Based on the observed toxicity profile, the independent data safety committee recommended a Temsirolimus dose of 25 mg given on day 1 and 8 for the part II extension cohort of the trial. Results. We here report on 46 patients (pts), 15 from part I and 31 from part II. Seven pts were not evaluable for response. Of the evaluable 39 patients, median age was 63 and median number of prior regimen was 1. Temsirolimus dose was 50 mg on day 1 and 8 in 7 pts from the part I of the trial and 25 mg in the remaining 39 pts. The overall response rate was 82% (32/39pts) with 22 partial and 10 complete responses. After a median follow up of 10 months for the total study population, median PFS and OS have not been reached (Figure 1A and 1B). Early safety analysis includes preliminary data of 22 pts. The most frequent non-hematologic side effects were nausea (14 pts, 64%), epistaxis (11 pts, 50%), fatigue (12 pts, 55%), fever (11 pts, 50%) and diarrhea (11 pts, 50%). Frequent grade 3/4 events (n>2) included leukopenia (21 pts, 95%), thrombocytopenia (20 pts, 91%), lymphopenia (11pts, 50%), anemia (8 pts, 36%), neutropenia (10 pts, 45%), renal failure (3 pts, 20%) and infections (7 pts, 32%, bladder infection, esophagus infection, central venous access infection, soft tissue infection, mucositis). Two therapy-related deaths occurred (one patient died from sepsis during neutropenia, another from cerebral bleeding, both events occurring after cycle 3). Conclusion. Temsirolimus can be safely added to DHAP and Rituximab with promising activity. Figure 1 Progression free survival Figure 1. Progression free survival Figure 2 Overall survival Figure 2. Overall survival Disclosures Witzens-Harig: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Viardot:Pfizer: Honoraria; Takeda: Other: travel support; Roche: Honoraria; BMS: Consultancy; Janssen: Consultancy; Amgen: Consultancy. Keller:Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Spectrum Pharmaceutical: Consultancy, Membership on an entity's Board of Directors or advisory committees. Buske:Celltrion, Inc.: Consultancy, Honoraria. Meissner:Amgen: Other: Travel Support; Takeda: Other: Travel Support; Teva: Other: Travel Support; Celgene: Other: Travel Support. LaRosee:Pfizer: Honoraria. Marks:Pfizer: Honoraria. Hess:Celgene: Honoraria; Roche, CTI, Pfizer, Celgene: Research Funding; Janssen: Honoraria; Roche: Honoraria; Pfizer: Honoraria; Novartis: Honoraria.

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.

scholarly journals Real-world practice patterns and outcomes in Veterans with relapsed/refractory diffuse large B-cell lymphoma

2020 ◽  
Author(s):  
Hsu-Chih Chien ◽  
Deborah Morreall ◽  
Vikas Patil ◽  
Kelli M Rasmussen ◽  
Chunyang Li ◽  
...  
Keyword(s):  
Overall Survival ◽  
B Cell ◽  
Cell Lymphoma ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Line Treatment ◽  
Electronic Health Record Data ◽  
Free Survival ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Aim: To describe practices and outcomes in veterans with relapsed/refractory diffuse large B-cell lymphoma. Patients & methods: Using Veteran Affairs Cancer Registry System and electronic health record data, we identified relapsed/refractory diffuse large B-cell lymphoma patients completing second-line treatment (2L) in 2000–2016. Treatments were classified as aggressive/nonaggressive. Analyses included descriptive statistics and the Kaplan–Meier estimation of progression-free survival and overall survival. Results: Two hundred and seventy patients received 2L. During median 9.7-month follow-up starting from 2L, 470 regimens were observed, averaging 2.7 regimens/patient: 219 aggressive, 251 nonaggressive. One hundred and twenty-one patients proceeded to third-line, 50 to fourth-line and 18 to fifth-line treatment. Median progression-free survival in 2L was 5.2 months. Median overall survival was 9.5 months. Forty-four patients (16.3%) proceeded to bone marrow transplant. Conclusion: More effective, less toxic treatments are needed and should be initiated earlier in treatment trajectory.

Survival of Limited Stage Peripheral T-Cell Lymphoma Is Similar To Diffuse Large B-Cell Lymphoma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2817-2817 ◽  
Author(s):  
Kerry J. Savage ◽  
Mukesh Chhanabhai ◽  
Nicholas Voss ◽  
Shenkier Tamara ◽  
Randy D. Gascoyne ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cell ◽  
B Cell ◽  
Cell Lymphoma ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Free Survival ◽  
Limited Stage ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Background: Peripheral T-cell lymphomas (PTCL) represent a heterogeneous group of diseases with an overall poor prognosis. Little information is available regarding the outcome of PTCL patients who present with limited stage disease. We sought to determine the outcome of PTCL patients presenting with limited disease in comparison with a cohort of patients with limited stage diffuse large B-cell lymphoma (DLBCL). Methods: In a retrospective analysis we identified all patients with limited stage (non-bulky (<10cm) stage I/II disease no symptoms) PTCL diagnosed at the British Columbia Cancer Agency (BCCA) between 1983 and 2004. Patients were excluded if they had cutaneous anaplastic large cell lymphoma (CutALCL) (n=13), NK/T-cell lymphoma nasal type (n=9) or primary CNS/ocular involvement (n=6). Results: Thirty-seven patients with PTCL were identified according to the World Health Organization Classification: ALK-neg ALCL 8 (22%); PTCL-unspecified (PTCLUS) 28 (78%); enteropathy associated TCL (EATL) 1 (3 %). The majority received CHOP-type chemotherapy (n=31, 86%), most with brief chemotherapy followed by involved-field radiation (n=19, 61%). The 5 y OS and PFS was similar between PTCLUS and ALK-neg ALCL. There was no difference in survival between extranodal and nodal cases. The outcome of PTCL patients (including ALK-neg ALCL and PTCLUS) was compared to a cohort of limited stage DLBCL patients (excluding CNS/ocular lymphoma) (n=305) diagnosed over the same time period and treated similarly. There was no difference in 5 y OS or PFS (Figure 1,2). Interestingly, there were no late relapses observed in PTCLUS, in marked contrast to DLBCL. Conclusions: Limited stage PTCL is rare, however outcomes appear to be comparable to early stage DLBCL, supporting that they should be treated in a similar manner. Unlike limited stage DLBCL where late relapses occur, a plateau in the progression-free survival curve is observed, highlighting a distinct natural history for limited stage PTCL. Overall Survival Limited Stage PTCL vs DLBCL p=.18 Overall Survival Limited Stage PTCL vs DLBCL p=.18 Progression-Free Survival Limited Stage PTCL vs DLBCL p=.07 Progression-Free Survival Limited Stage PTCL vs DLBCL p=.07

Significance of c-myc Rearrangements in Diffuse Large B-Cell Lymphoma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2030-2030
Author(s):  
Philip Bierman ◽  
Fausto Loberiza ◽  
Bhavana Dave ◽  
Warren Sanger ◽  
R. Gregory Bociek ◽  
...  
Keyword(s):  
Overall Survival ◽  
B Cell ◽  
Cell Lymphoma ◽  
Survival Rates ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Free Survival ◽  
Large B Cell Lymphoma ◽  
Large B Cell ◽  
Overall Survival Rates

Abstract Rearrangements of the c-myc oncogene can be seen in 5–10% of patients with diffuse large B-cell lymphoma. However, studies examining the significance of this finding have yielded conflicting results. Therefore, we performed a retrospective analysis to determine the clinical significance of c-myc rearrangements in diffuse large B-cell lymphoma. The results of classical cytogenetic studies and FISH analyses were used to identify diffuse large B-cell lymphoma cases in the database of the Nebraska Lymphoma Study Group with or without c-myc rearrangements. Patients who were HIV positive and those with post-transplant lymphoproliferative disease were excluded. We identified 16 patients with diffuse large B-cell lymphoma and c-myc rearrangements. All patients were initially treated with doxorubicin- or mitoxantrone-containing chemotherapy regimens. The median age of these 16 patients was 61 years (range 40 to 80), and 5 (31%) were males. The International Prognostic Index (IPI) was 0–2 at diagnosis in 9 patients (56%), and 3–5 in 7 patients (44%). Eleven patients (69%) had bulky disease (≥ 5 cm) at diagnosis. No significant differences in outcome were identified when the 16 c-myc positive patients were compared with 97 c-myc negative diffuse large B-cell lymphoma patients in the same age range. The actuarial 5-year progression-free survival for the c-myc positive patients was 23% (95% CI 6% to 46%), as compared with 38% (95% CI 29% to 48%) for c-myc negative patients (p=0.17). The actuarial 5-year overall survival rates were 36% (95% CI 14% to 59%) and 47% (95% CI 36% to 56%), respectively (p=0.19). Classical cytogenetics and FISH analyses were also used to examine the 16 c-myc positive cases for bcl-2 rearrangements. Eight (50%) cases had rearrangements of bcl-2 in addition to c-myc rearrangements. These patients were similar to the c-myc positive/bcl-2 negative patients except for a higher likelihood of an elevated LDH level at diagnosis (88% vs. 25%; p=0.03). The actuarial 5-year progression-free survival for c-myc positive/bcl-2 positive patients was 0%, as compared to 33% (95% CI 6% to 66%) for patients with rearrangements of c-myc alone, and 37% (95% CI 28% to 47%) for c-myc negative patients. The actuarial 5-year overall survival rates were 12% (95% CI 1% to 42%), 47% (95% CI 12% to 76%), and 41% (95% CI 31% to 51%), respectively. A multivariate analysis, adjusting for IPI score, demonstrated that the relative risk (RR) of treatment failure was significantly worse for the c-myc positive/bcl-2 positive patients, as compared to the c-myc negative patients (RR 2.86, 95% CI 1.32–6.23; p=0.008). Similarly, mortality was also significantly worse for the c-myc positive/bcl-2 positive patients, as compared to the c-myc negative patients (RR 2.69, 95% CI 1.18–6.11; p=0.02). In contrast, no significant differences in treatment failure or overall survival were demonstrated when c-myc positive/bcl-2 negative patients were compared with c-myc negative patients. Our results demonstrate that the c-myc rearrangement is not associated with poorer survival in patients with diffuse large B-cell lymphoma. However, patients with rearrangements of bcl-2 in addition to c-myc had significantly worse progression-free survival and overall survival.

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

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2676-2676
Author(s):  
Jung Yong Hong ◽  
Moon Ki Choi ◽  
Young Saing Kim ◽  
Chi Hoon Maeng ◽  
Su Jin Lee ◽  
...  
Keyword(s):  
Overall Survival ◽  
B Cell ◽  
Cell Lymphoma ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Clinical Impact ◽  
Free Survival ◽  
Large B Cell Lymphoma ◽  
The Impact ◽  
Large B Cell

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

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.

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