A Phase I/II Trial of Lenalidomide and RCHOP (R2CHOP) in Patients with Newly Diagnosed Diffuse Large B -Cell (DLBCL) and Follicular Grade 3 Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1669-1669 ◽  
Author(s):  
Grzegorz S. Nowakowski ◽  
Betsy LaPlant ◽  
Thomas Habermann ◽  
David J Inwards ◽  
Patrick L Johnston ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Dose Escalation ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Hematological Toxicity ◽  
Newly Diagnosed ◽  
Chop Chemotherapy ◽  
Grade 3

Abstract Abstract 1669 Poster Board I-695 Background The addition of rituximab to chemotherapy significantly improved the results of therapy in aggressive non-Hodgkin's B cell lymphoma (NHL). However, significant number of the patients relapse following initial therapy. Lenalidomide was shown to have significant single agent activity in relapsed aggressive B cell lymphoma (J Clin Oncol 26:4952-7, 2008) however the safety in combination with standard first line immunochemotherapy is unknown. We initiated a phase I/II trial of R2-CHOP (cyclophosphamide, vincristine, doxorubicin, prednisone rituximab and lenalidomide) to establish the safety and efficacy of this therapy in the treatment of patients with newly diagnosed aggressive B cell NHL. Herein, we report the results of phase I portion of this study. Methods A phase I study was designed to define the maximum tolerated dose (MTD) of lenalidomide administered on days 1-10 with R-CHOP chemotherapy (rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50mg/m2, vincristine 1.4 mg/m2, all on day 1, prednisone 100 mg/m2 days 1-5 of 21 day cycle) utilizing 3+3 dose escalation design. Lenalidomide dose escalation levels were 15 mg, 20 mg and 25 mg. All patients received 6 mg pegfilgrastim injection on day 2. Dose limiting toxicity (DLT) was defined as any grade 3 or more non-hematological toxicity or a hematological toxicity requiring a delay of the next cycle of chemotherapy due to cytopenia. The latter criterion was to ensure maintenance of the dose intensity and schedule of RCHOP; a potentially curative therapy in this setting. Eligible patients were adults newly diagnosed with CD20 positive diffuse large cell or follicular grade III B cell lymphoma, ECOG PS 0-2 and good organ function. There was no upper age restriction to participate in this study. Results Twelve patients were enrolled in phase I of this study. The median age was 69 years (range, 49-82) and 58% (7/12) of patients were males. Ten patients (83%) had DLBCL and two (17%) patients had follicular grade 3B lymphoma. International prognostic index was intermediate, high- intermediate and high in 6, 4 and 2 patients respectively. Patients distribution by lenalidomide dose was: 3 patients received 15 mg/day, 3 received 20 mg/day and 6 received 25 mg/day on days 1-10. Non-hematological toxicities included: grade 3 toxicity - neuropathy in one patient (8.3%), grade 2 toxicities were: infection in 17% (2/12) patients (skin in one patient, otitis media, and urinary tract infection in one patient); nausea 8% (1/12), rash 8% (1/12) and alopecia 41% (5/12). The most common toxicity to R2-CHOP was myelosuppresion. Grade 3 and 4 neutropenia occurred in 17% (2/12) and 41% (5/12) of patients, respectively. The neutropenia was of short duration, and no patients developed neutropenic complications. Grade 3 thrombocytopenia was seen in 8% (1/12). Most importantly, there were no delays in chemotherapy due to cytopenias. No DLT was seen. The 25 mg/day days 1-10 dose of lenalidomide was taken forward to an ongoing phase 2 trial. Conclusion Lenalidomide at a dose of 25 mg/day for days 1- 10 combined with R-CHOP chemotherapy is well tolerated. The addition of lenalidomide did not affect hematological recovery and did not result in treatment delays. This dose and schedule is now being evaluated in the phase II part of the trial. Disclosures Zent: Genentech, Bayer, Genzyme, Novartis: Research Funding. Witzig:Novartis: Research Funding.

scholarly journals A Phase I Study of Romidepsin, Gemcitabine, Dexamethasone and Cisplatin Combination Therapy in the Treatment of Peripheral T-Cell and Diffuse Large B-Cell Lymphoma: Canadian Cancer Trials Group Study LY.15

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4162-4162 ◽  
Author(s):  
Tony Reiman ◽  
Kerry J. Savage ◽  
Michael Crump ◽  
Matthew Cheung ◽  
David A. MacDonald ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Phase I ◽  
B Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Hematological Toxicity ◽  
Large B Cell Lymphoma ◽  
Grade 3 ◽  
Large B Cell

Abstract Background: The outcome of peripheral T-cell lymphomas (PTCLs) remains poor and improved therapies are needed. Retrospective data suggest that integration of anthracyclines in the primary therapy may not impact outcome, providing the rationale to explore alternative regimens. Histone deacetylase inhibitors appear to have a class effect in PTCLs andromidepsin monotherapy demonstrates activity in a proportion of patients with relapsed/refractory PTCLs and can induce durable remissions. Gemcitabine is reported to be a highly active agent in PTCL, and the GDP (gemcitabine, dexamethasone, cisplatin) regimen has become a standard chemotherapy backbone for relapsed aggressive lymphomas (Crump, JCO 2014). We investigated the feasibility, safety and efficacy of GDP combined with romidepsin in a phase I dose escalation trial. Patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) were also included. Methods: Patients with relapsed/refractory PTCL or DLBCL, PS 0-2, with measurable disease and who had received one or two prior lines of systemic therapy, were treated with standard doses of GDP (gemcitabine, 1000 mg/m2 d1, d8; dexamethasone, 40 mg po d1-4; cisplatin, 75 mg/m2 d1) every 21 days, plus escalating doses of romidepsin (6, 8, 10 and 12 mg/m2) on days 1 and 8 to a maximum of 6 cycles in a standard 3+3 design. After the first 4 patients were enrolled, based on the observed pattern of thrombocytopenia, the treatment schedule was modified so that gemcitabine and romidepsin were given on days 1 and 15 and cycles extended to every 28 days. Dose-limiting toxicities (DLTs) were assessed during the first 2 cycles and defined as requiring platelet transfusion for bleeding, grade 3 hematological toxicity lasting >10 days, grade 4 hematological toxicity lasting >7 days, febrile neutropenia, or grade 3-4 non-hematological toxicity attributable to romidepsin. Responses were as per Cheson, JCO 2007 excluding PET scans. Results: 20 eligible patients (PTCL n=10; DLBCL n=10) were enrolled between 10/2013 and 01/2016 and treated with GDP plus romidepsin. The main PTCL subtype was PTCL, not otherwise specified (50%). Median age was 65 years (24-74); 9 were female; ECOG performance status was 0 (n=2), 1 (n=13), or 2 (n=5). Number of prior therapies was 1 (n=17) or 2 (n=3). 17 (85%) patients received >90% of the planned dose each cycle. The median number of cycles was 2 (range, 1-6); one patient is still on therapy. The reasons for treatment discontinuation were lymphoma progression (n=10), toxicity (n=2), proceeding to autologous stem cell transplant (ASCT, n=3), intercurrent illness (n=1), or completion of 6 cycles (n=3). On the 21-day schedule at 6 mg/m2 romidepsin, there were 3 DLTs among four patients (2 with grade 3-4 thrombocytopenia, 1 venous thromboembolic event). On the 28-day schedule, there were no DLTs observed in the three patients treated at each of the 6, 8 or 10 mg/m2 dose levels. At 12 mg/m2 there were 4 observed grade 3 DLTs among six evaluable patients (hypotension, acute kidney injury, anorexia, thrombocytopenia >10 days). Notable toxicities during any cycle were: febrile neutropenia (n=2); grade 3-4 thrombocytopenia (n=9); grade 3-4 neutropenia (n=4); and grade 3-4 anemia (n=4); grade 2 atrial fibrillation (n=2); grade 2 QTc prolongation (n=1); grade 1 sinus tachycardia (n=1); grade 2-3 infections (n=16); grade 1-3 cutaneous toxicity (n=9); grade 1-3 thromboembolic events (n=2); TIA (n=2) or stroke (n=1). One patient died after cycle 1 due to sepsis. 7 other patients have died of progressive lymphoma. The overall response rate was 9/20 (45%), all were partial remissions (PR), 3 had stable disease (SD), 4 had progressive disease (PD), and 4 were not objectively evaluable. Of the responders, 5 had PTCL and 4 had DLBCL. Four patients went on to ASCT. With a median follow-up of 5.8 months, the median duration of response was 2.8 months and median PFS is 2.2 months. For all patients, the 1 year PFS was 6% and 1 year OS was 43% Discussion: Full doses of GDP can be combined with a recommended phase II romidepsin dose of 10 mg/m2 given on a day 1, 15 every 28 days schedule. Thrombocytopenia prohibits this combination on a 21-day schedule. Toxicity is otherwise acceptable and as expected. Further study at the recommended dose and schedule would be required to properly define the activity of this regimen in PTCLs and DLBCL. Disclosures Reiman: Celgene: Honoraria, Research Funding. Buckstein:Novartis: Honoraria; Celgene: Honoraria, Research Funding. Kuruvilla:Merck & Co., Inc.: Consultancy, Honoraria. Villa:Lundbeck: Honoraria; Roche: Honoraria, Research Funding; Celgene: Honoraria. Hay:Amgen: Research Funding; Novartis: Research Funding; Janssen: Research Funding; Kite Pharmaceuticals: Research Funding.

A Phase I Open-Label, Multi-Dose Escalation Study of the Dual Syk/Jak Inhibitor PRT062070 (Cerdulatinib) in Patients with Relapsed/Refractory B Cell Malignancies

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3103-3103
Author(s):  
Manish Patel ◽  
Paul Hamlin ◽  
Donald K Strickland ◽  
Anjali Pandey ◽  
Greg Coffey ◽  
...  
Keyword(s):  
Steady State ◽  
B Cell ◽  
Dose Escalation ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
B Cell Lymphoma ◽  
Markers Of Inflammation ◽  
Equity Ownership ◽  
Grade 3

Abstract Introduction: Preclinical studies of the Syk-mediated B-cell receptor pathway and Jak-mediated cytokine pathways have demonstrated a potential therapeutic advantage for the dual inhibition of both Syk and Jak kinases in the treatment of B-cell malignancies. Cerdulatinib (PRT062070) was identified from a chemistry screen as a potent and selective inhibitor of Syk, Jak1, Jak3, and Tyk2, with minimal activity against Jak2. Cerdulatinib is efficacious in rodent models of B-cell lymphoma and autoimmune disease (Coffey et al., ASH 2012) and has demonstrated anti-tumor activity in genetically diverse B-cell lymphoma cell lines that is greater than that of Syk- or Jak- selective inhibitors alone (Ma et al., ASH 2013). Methods: This Phase 1 3+3 dose escalation study is evaluating cerdulatinib, given continuously on either a once daily (QD) or twice daily (BID) schedule, for relapsed/refractory chronic lymphocytic leukemia (CLL) or B-cell non-Hodgkin lymphoma (NHL). The primary objective is to determine the maximum tolerated dose (MTD) of cerdulatinib in patients with CLL or NHL. Secondary objectives are to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of cerdulatinib and to make a preliminary assessment of antitumor activity. Toxicity is graded according to the National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4. Clinical response is evaluated according to published criteria (Hallek et al., Blood 2008:111:5446-5456; Cheson et al., J. Clin. Oncol. 2012: 25:579-586). The level of inhibition of Syk and Jak is determined using a variety of whole blood assays measuring signaling via receptors for the B-cell antigen, IL2, IL4, IL6, and GM-CSF. Serum markers of tumor burden, including CCL3, CCL4, and other markers of inflammation, are also being measured. Results: As of 4 August 2014, twelve patients have been enrolled in once daily dose cohorts of 15 mg QD, 30 mg QD, and 45 mg QD. No dose-limiting toxicities have been reported. Grade ≥3 adverse events (AEs), regardless of causality, were: Grade 3 anemia (n=1), Grade 3 neutropenia (n=1), Grade 3 fatigue (n=1), Grade 3 hypotension (n=1), Grade 3 AST increased (n=1), Grade 3 hematochezia (n=1), and Grade 5 Pneumocystis pneumonia (PCP; n=1). The patient who experienced PCP pneumonia was a 76 year old male with CLL who had received prior therapy with bendamustine and rituximab. Cerdulatinib is well-absorbed with an average terminal elimination half-life at steady state of 14 hours. Selective inhibition of Syk and Jak in whole blood assays was observed post-treatment, with IC25-IC50 (Cmin to Cmax at steady-state) against these targets achieved at the 15 mg dose level, and IC50-IC80 (Cmin to Cmax at steady-state) achieved at the 30 mg and 45 mg doses. Reductions of >50% in serum markers of inflammation, as well as in CCL3 and CCL4, were noted at all dose levels post-treatment. Two patients treated at the 15 mg dose (1 CLL, 1 follicular lymphoma [FL]) remained on study for >230 and >200 days, respectively, with stable disease (SD) prior to disease progression. One patient treated at the 30 mg dose (diffuse large B-cell lymphoma [DLBCL], who did not respond to prior R-CHOP therapy), remained on study with SD for 140 days. One patient treated at the 30 mg dose (CLL) experienced a >60% decrease in peripheral lymphocyte count prior to coming off study for PCP pneumonia. Another patient treated at the 30 mg dose (CLL) experienced early lymphocytosis and a 33% reduction in lymph node size at the end of Cycle 2 and remains on study in Cycle 3. One patient treated at the 45 mg dose (FL) experienced a 40% decrease in lymph node size at the end of Cycle 4 and remains on study in Cycle 5. Conclusions: Cerdulatinib has been well tolerated in the initial cohorts of this Phase 1 study, with no dose-limiting toxicities and preliminary evidence of anti-tumor activity. Dose escalation continues and Phase 2 expansion cohorts are planned in CLL, DLBCL and FL. Disclosures Hamlin: Gilead, Spectrum, Seattle Genetics, Genentech: Consultancy; Spectrum, GSK, Jansen and Jansen/Pharmacyclics, Portola, Seattle Genetics: Research Funding. Strickland:SCRI Development Innovations: Employment. Pandey:Portola Pharmaceuticals, Inc.: Employment; Portola Pharmaceuticals, Inc.: Equity Ownership. Coffey:Portola Pharmaceuticals: Employment, Equity Ownership. Leeds:Portola Pharmaceuticals, Inc.: Employment. Levy:Portola Pharmaceuticals: Employment; University of Michigan: Patents & Royalties. Curnutte:Portola Pharmaceuticals, Inc.: Employment, Equity Ownership; Sea Lane Biotechnologies: Consultancy; 3-V Biosciences: Equity Ownership. Wagner-Johnston:Gilead: Consultancy; Gilead: Speakers Bureau; Celgene: Research Funding. Flinn:Portola Pharmaceuticals, Inc.: Research Funding.

Pegylated Recombinant Human Granulocyte Colony Stimulating Factor (pegfilgrastim) Reduces Hematological Toxicity in Dose-Adjusted (DA) R-EPOCH in the treatment of Diffuse Large B Cell Lymphoma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4631-4631
Author(s):  
Susanna Hong ◽  
Nouneh J. Gostanian ◽  
Douglas E. Gladstone ◽  
Kenneth W. Zamkoff
Keyword(s):  
B Cell ◽  
Dose Escalation ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Hematological Toxicity ◽  
Sale Price ◽  
Large B Cell Lymphoma ◽  
Grade 3 ◽  
Large B Cell

Abstract Hematological toxicity is a significant dose limiting side effect in the aggressive treatment of Diffuse Large B Cell Lymphoma (DLBCL). In the current study, pegfilgrastim was given to patients following each cycle of DA R-EPOCH. ANC and platelet nadirs were then compared to a previous report utilizing filgrastim. Pegfilgrastim is a covalent conjugate form of filgrastim, whereby a molecule is covalently bonded to the N terminal of filgastrim, allowing the molecule to be cleared slower than filgastrim. The prolonged effect on the promotion of granulocyte proliferation allows for pegfilgrastim to be given once every 2 weeks in comparison to filgrastim which is injected daily. In this study, records of 5 patients treated with DA R-EPOCH for DLBCL were examined. There were a total of 20 cycles with 15 cycles qualifying for analysis in regards to hematological toxicity. To qualify each cycle met the following criteria: i) treatment with R-EPOCH at starting dose or dose-escalation; ii) pegfilgrastim was administered 24 to 48 hours after completion of chemotherapy at the standard dose of 6mg sc; iii) follow-up of at least two weeks following each cycle; iv) CBC monitored at least once weekly. Of the cycles excluded, 3 cycle did not have at least 2 weeks of follow-up, 1 cycle was followed by filgrastim and 1 cycle was treated with R-CHO. Nadir was defined as lowest value obtained from initiation of one cycle to initiation of next cycle or to two weeks from last day of all chemotherapy. Hematological toxicities were graded according to WHO criteria. Grade 4 neutropenia (ANC less than 0.5 x 109/L) occurred in 13% (2/15) of cycles. There was no Grade 3 neutropenia (ANC 0.5 – 1.0 x 109/L). Range of ANC nadir was 0.02 – 4.4 x 109/L with mean of 2.4 x 109/L. There was no Grade 3 thrombocytopenia (Platelet 25 – 50 25 x 109/L) nor Grade 4 thrombocytopenia (Platelet < 25 x 109/L). Range of platelet nadir was 53 – 230 x 109/L with mean of 130. Examining treatment records, 13 cycles of 20 were candidates for dose escalation. Each cycle was included if it followed a cycle of R-EPOCH and the patient had received pegfilgrastim for neutropenic support. Excluded cycles included 5 cycles at starting doses, 1 cycle in which filgrastim was administered prior, and 1 cycle in which the R-CHO was given prior. Following the criteria for allowable DA EPOCH according to the paradigm published in Blood Apr 15, 2002, Vo 99, No 8 pp 2685– 2693, dose escalation was allowed for ANC of at least 0.5 x 109/L and platelets of at least 25 x 109/L. 11 of 13 (85%) cycles in this study were eligible for dose escalation based on the above mentioned paradigm. In the previous mentioned publication filgrastim was given after completion of each cycle of EPOCH with 49% of cycles complicated by Grade 4 neutropenia and 7% complicated by Grade 4 thrombocytopenia. 58% of the cycles were dose escalated in the previous study. In conclusion this study indicates that pegfilgrastim results in less hematological toxcity in DA R-EPOCH. This allows for DA in a higher percentage of treatment cycles. In addition, examination of the cost reveals the average whole sale price of a single 6 mg dose of pegfilgrastim is $3127, while the average whole sale price of a daily dose of 480 mcg of filgrastim for 10 days is $3500.

Everolimus Plus RCHOP-21 Is Safe and Highly Effective for New Untreated Diffuse Large B-Cell Lymphoma (DLBCL): Results of the Phase I Trial NCCTG1085 (Alliance)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 813-813 ◽  
Author(s):  
Patrick B. Johnston ◽  
Betsy R. Laplant ◽  
Ellen D. McPhail ◽  
Thomas M. Habermann ◽  
David J. Inwards ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Research Funding ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Response Assessment ◽  
Newly Diagnosed ◽  
Pet Ct ◽  
Grade 3

Abstract Background: The PI3K/mTORC pathway is upregulated in DLBCL and can be targeted with mTORC1 inhibitors such as everolimus. Everolimus has demonstrated single agent activity in relapsed DLBCL (Leukemia. 2011; 25(2):341-7). These data provide the rationale to combine everolimus with standard RCHOP-21 to improve the effectiveness of upfront therapy for DLBCL. Methods: A phase I study was designed to determine the maximum tolerated dose of everolimus on days 1-10 or 1-14 in combination with RCHOP-21 along with a feasibility cohort to examine response in patients with newly diagnosed CD20+ DLBCL. Response assessment was evaluated using PET/CT and standard criteria. Results: We previously reported (J Clin Oncol 33, 2015 suppl; 8518) that in the phase I portion of trial N1085 that the dose of everolimus recommended for further study was everolimus 10 mg daily days 1-14; RCHOP day 1 and pegfilgrastim 6 mg day two for each of six 21-day cycles. The trial has now completed enrollment with a total of 26 patients. Two phase I patients were replaced during cycle 1 for personal, non-medical issues leaving 24 eligible patients for response assessment. The median age was 59.5 years (23 - 78); 42% were female; 18 (75%) stages III/IV; 12 (50%) had an elevated LDH; 29% had a high IPI score; and 4 (17%) had B-symptoms. Genotype was performed by immunohistochemistry using the Hans algorithm and 54% (13/24) were non-GCB; 13 (5 GCB, 8 non-GCB) had FISH for double hit and all were negative. Twenty-one (88%) patients received everolimus at 10 mg d1-14; the other three patients received 10 mg d1-10. Twenty-two (92%) patients received all 6 cycles. All patients have now completed therapy and the overall response rate was 96% (23/24) with 23 patients attaining functional CR by PET/CT. The remaining patient went off study for refusal in cycle 1, received further RCHOP-21 off study, and attained a CR off study. The median follow-up for the 24 patients is now 16.8 months (7.3 - 35.7) with 20 patients having ≥12 months of follow-up and 8 patients having ≥24 months of follow-up. To date, none of the 24 patients have died and none have experienced relapse with DLBCL. One patient relapsed 16 months from DLBCL diagnosis with a biopsy-proven follicular grade 1 NHL and received off-study Zevalin and achieved a second CR. The most common grade 3/4 toxicity was hematologic with 71% of patients having grade 4. Five (21%) patients had febrile neutropenia. Only 1 patient had grade 3 hyperglycemia and 3 patients had grade 3 hypertriglyceridemia. Reversible rash and pneumonitis were observed in 1 case each. Conclusions: The mTORC1 inhibitoreverolimus at 10 mg daily d1-14 of a standard RCHOP-21 cycle is tolerable with a 96% CR rate in both GCB and non-GCB DLBCL. With a median follow-up of 16.8 months and 8 patients out ≥24 months, the lack of DLBCL relapse is encouraging. Longer follow-up and a larger trial will be necessary to confirm the benefits of this novel combination. Clinical trial information: NCT01334502 Disclosures Off Label Use: Everolimus is an mTOR inhibitor which has activity in B cell lymphomas. It is being investigated in combination with SOC therapy for newly diagnosed DLBCL to examine potential toxicity as well as potential for enhanced disease response.. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding.

scholarly journals Combination of Nivolumab, Lenalidomide and Rituximab in Relapsed/Refractory Non-Germinal Center Diffuse Large B Cell Lymphoma: Results from a Dose-Escalation Cohort

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4100-4100
Author(s):  
Tarsheen Sethi ◽  
Alexandra E. Kovach ◽  
Emily F Mason ◽  
Heidi Chen ◽  
Tamara Moyo ◽  
...  
Keyword(s):  
B Cell ◽  
Dose Escalation ◽  
Germinal Center ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Equity Ownership ◽  
Grade 3 ◽  
Large B Cell

Background: Ten to 15% of diffuse large B cell lymphoma (DLBCL) patients exhibit primary refractory disease (nonresponse or relapse within 3 months of therapy) and an additional 20-25% relapse following initial response. There is an unmet need for effective therapeutic regimens in relapsed/refractory (R/R) DLBCL. Lenalidomide is an immune modulator that reverses T cell dysfunction and also inhibits the NFκB pathway, which is constitutively active in non-germinal center (non-GCB) DLBCL. Lenalidomide and nivolumab, an anti-PD-1 antibody, each have single agent activity in R/R DLBCL. Here, we report the results of the dose-escalation cohort of this investigator-initiated, single-arm open-label study of the combination of nivolumab, lenalidomide and rituximab (NiLeRi) in R/R non-GCB DLBCL. Methods: Adult patients with R/R non-GCB DLBCL, as determined by the Hans algorithm, with adequate organ function and an ECOG performance status of ≤2 were eligible for the study. The primary objective was to evaluate the safety of NiLeRi, and determine the maximum tolerated dose (MTD) of lenalidomide in combination with fixed doses of rituximab and nivolumab, using a 3+3 dose escalation design. The secondary objectives were to determine efficacy in terms of overall response rate (ORR), progression free survival (PFS), and overall survival (OS) of patients treated with NiLeRi. All patients received nivolumab IV 3 mg/kg on days 1 and 15 and rituximab IV 375mg/m2 on day 1 of each 28-day cycle. Lenalidomide was initiated at 5 mg po once daily on days 1-21. Additional planned dose levels were 10 mg, 15 mg and 20 mg. Patients were evaluable for toxicity if they received all doses of nivolumab and rituximab and at least 16 doses of lenalidomide during cycle 1 or if they experienced a dose limiting toxicity (DLT), regardless of the number of doses. NiLeRi was given for 8 cycles and patients with partial response could receive lenalidomide and nivolumab for an additional 4 cycles. Response was assessed by PET-CT after 2, 5 and 8 cycles and defined by Lugano criteria. Results: Six patients with non-GCB subtype of DLBCL were enrolled in this study. The median age was 60.5 years (range 28-79), and 5 patients were male. The median number of prior lines of therapy was 4 (range 2-5), and the median IPI score was 3. None of the patients had bone marrow involvement. One patient each had been treated with autologous stem cell transplant (Auto-SCT) and CAR-T cell therapy. One patient withdrew consent before completing cycle 1 and was not evaluable for safety or efficacy. Safety: Five out of the six enrolled patients were evaluable for safety. All patients received lenalidomide 5 mg dose. Two patients experienced DLTs (grade 3 rash) resulting in lenalidomide discontinuation during cycle 2. The most common grade 3/4 toxicities were fatigue (20%), neutropenia (60%), thrombocytopenia (40%), and rash (40%). A total of 3 patients experienced grade 1/2 diarrhea and elevated liver enzymes. One patient experienced a grade 1 infusion reaction with rituximab. Efficacy: Patients who completed at least 1 cycle of therapy were evaluable for response, and this included 5 out of the 6 enrolled patients. The ORR and complete response (CR) rate were both 40%. Patients who responded did so early, with one patient achieving CR after 2 cycles and another patient achieving CR after 5 cycles. The best response seen in patients with primary refractory disease was PR. At a median follow up of 9.5 months, median PFS was 8.4 months (95% CI; 4.3 to not reached), and median OS was not reached. Discussion: This is the first study reporting the safety results of the combination of lenalidomide, nivolumab and rituximab in non-Hodgkin lymphoma. Rash was the most common DLT, limiting dose escalation of lenalidomide above 5mg in this cohort of patients. Two patients experienced durable CR early in the study after 2 and 5 cycles, respectively. This ORR and CR rate of 40% each in this small cohort of patients who had relapsed after multiple prior lines of therapy is encouraging. Correlative studies, including whole exome sequencing of patient samples, are underway, in an attempt to explore predictive markers for response and toxicity. Figure. Disclosures Mason: Sysmex: Honoraria. Oluwole:Pfizer: Consultancy; Spectrum: Consultancy; Gilead Sciences: Consultancy; Bayer: Consultancy. Morgan:Biogen: Equity Ownership; Eli Lilly: Equity Ownership; Vertex: Equity Ownership; Zoetis: Equity Ownership; Pfizer: Equity Ownership; Novo Nordisk: Equity Ownership; Gilead: Equity Ownership; Johnson and Johnson: Equity Ownership; Merck: Equity Ownership. Reddy:Abbvie: Consultancy; Genentech: Research Funding; Celgene: Consultancy; BMS: Consultancy, Research Funding; KITE Pharma: Consultancy. OffLabel Disclosure: Nivolumab and lenalidomide are not FDA approved for use in diffuse large B cell lymphoma

The BCL-2-Specific BH3-Mimetic ABT-199 (GDC-0199) Is Active and Well-Tolerated in Patients with Relapsed Non-Hodgkin Lymphoma: Interim Results of a Phase I Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 304-304 ◽  
Author(s):  
Matthew S. Davids ◽  
Andrew W. Roberts ◽  
Mary Ann Anderson ◽  
John M. Pagel ◽  
Brad S. Kahl ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Dose Escalation ◽  
Research Funding ◽  
Board Member ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Advisory Board ◽  
Tumor Lysis ◽  
Bh3 Mimetic

Abstract Abstract 304 Background: BCL-2 is highly expressed in indolent non-Hodgkin lymphomas (NHL), mantle cell lymphoma (MCL) and other selected aggressive lymphomas, and is a promising target for therapeutic intervention. The first-generation BCL-2 inhibitor navitoclax showed some activity in indolent lymphoma, but its co-inhibition of BCL-xL resulted in dose-limiting thrombocytopenia, precluding the full exploration of the potential of BCL-2 inhibition with this drug in NHL. ABT-199 is an orally bioavailable, second-generation BH3-mimetic that inhibits BCL-2 (Ki<0.10 nM), but has 500-fold less activity for BCL-xL (Ki=48 nM). ABT-199 demonstrated antitumor activity against a variety of human cell lines and xenograft models that include B cell NHL, follicular lymphomas (FL), diffuse large B-cell Lymphoma (DLBCL) and MCL. Methods: This is a phase-I dose-escalation trial using a modified Fibonacci design in patients with relapsed/refractory NHL. The primary objectives of this study are to determine the safety, pharmacokinetics (PK) and maximum tolerated dose (MTD) of ABT-199; to recommend a phase-2 dose; and to assess efficacy and biomarkers in patients with relapsed/refractory NHL. Adult patients requiring therapy, with ECOG performance status £1, and adequate marrow function received ABT-199 on Week 1 Day −7 (W1D-7), followed by continuous once-daily dosing from W1D1, until progressive disease (PD) or unacceptable toxicity. Due to concerns of potential tumor lysis, a strategy of commencing with a 2 to 3 week lead-in period with step-wise increases to the target cohort dose is being evaluated. In the first four cohorts, the starting dose increased from 50 to 200 mg (50, 100, 200, and 200 mg, respectively), with target cohort doses of 200 mg [n=3], 300 mg [n=3], 400 mg [n=4], and 600 mg [n=7]. Evaluations include: adverse events (AE; NCI-CTCAE-V4) and tumor response (IWG 2007 criteria). Results: To date, 17 patients (median age, 71 [35–85]) have been treated with ABT-199. Median prior therapies were 3 (range, 1–7) and 6 patients had bulky adenopathy (>5cm). Most common AEs (experienced by >2 patients) were nausea (41%), diarrhea (24%), dyspepsia (24%), fatigue (24%), extremity pain (24%); and anemia, constipation, upper respiratory tract infection and cough (18% each). Grade 3 or 4 AEs occurring in >1 patient were anemia (18%) and neutropenia (12%). Treatment-related thrombocytopenia has not been reported and no dose-limiting toxicities (DLTs) have been identified to date. After a single dose administration with a high-fat meal, ABT-199 reached Cmax at approximately 7 hrs with a terminal half-life of about 15 hrs. Food increased ABT-199 exposure by approximately 3-fold. With a median follow-up of 2.8 months (range, 1.2 to 10.8), 14 patients remain on study and 3 have discontinued due to PD. In patients who have completed at least a W6 assessment, reductions of >50% in target lesions have been observed in 8/15 patients (53%); 6/6 patients with MCL, 1/2 patients with WM and 1/2 patients with DLBCL. Additionally, 5 FL patients have been evaluated (3 with rituxan-refractory disease) with a median time on study of 6.4 months (range, 3.5 to 10.8). 4/5 FL patients had nodal disease reductions ranging from 18% to 40%. Conclusions: ABT-199 shows single agent anti-tumor activity in patients with NHL; particularly in MCL. Activity is also observed in DLBCL and WM. To date, no DLTs have been identified and tumor lysis syndrome related to ABT-199 has not been reported. Dose escalation is continuing to identify the optimal dosing regimen and MTD of ABT-199 in NHL. Updated results will be presented. Disclosures: Roberts: Abbott: Research Funding; Genentech: Research Funding. Anderson:Genentech: Research Funding; Abbott: Research Funding; Walter and Eliza Hall Institute of Medical Research: Employment, receives commercial income related to ABT-199, receives commercial income related to ABT-199 Other. Kahl:Genentech: Consultancy, Research Funding; Abbott: Research Funding. Darden:Abbott: Employment, owner of Abbott stock Other. Nolan:Abbott: Employment, own Abbott stock Other. Gressick:Abbott: Employment, stock owner Other. Yang:Abbott: Employment, own Abbott stock Other. Chyla:Abbott: Employment, Stock owner Other. Busman:Abbott: Employment, Stock owner Other. Graham:Abbott: Employment, Stock owner Other. Cerri:Abbott: Employment, Stock owner Other. Enschede:Abbott: Employment, own Abbott stocks Other. Humerickhouse:Abbott: Employment, own Abbott stocks Other. Seymour:Roche: Advisory board member, Advisory board member Other, Consultancy; Genentech: Advisory board member, Advisory board member Other, Consultancy.

Brentuximab Vedotin in Combination with Multi-Agent Chemotherapy Is Well Tolerated and Shows Promising Activity As Frontline Treatment for Primary Mediastinal B-Cell Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2694-2694 ◽  
Author(s):  
Jakub Svoboda ◽  
Lauren E. Strelec ◽  
Sunita Dwivedy Nasta ◽  
Daniel J. Landsburg ◽  
Anthony R. Mato ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Systemic Therapy ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Brentuximab Vedotin ◽  
Genetics Research ◽  
Frontline Treatment ◽  
Grade 3

Abstract Background: Primary mediastinal B-cell lymphoma (PMBL) is a rare subtype of diffuse large B-cell lymphoma (DLBCL) with distinctive clinical and immunophenotypic features. Most PMBL patients (pts) present at young age and with bulky mediastinal mass. Over 80% of PMBL cases are CD30 positive by immunohistochemistry (IHC). Standard frontline systemic therapy for PMBL remains controversial and the use of intensive regimens may be associated with increased toxicity. Brentuximab vedotin (BV) is a CD30-directed immunoconjugate with established efficacy in relapsed Hodgkin lymphoma and several other CD30 positive lymphoid malignancies, but this targeted agent has not been utilized in frontline combinations for PMBL. Methods: We designed an open label phase I/II trial using BV administered concurrently with rituximab, cyclophosphamide, doxorubicin, and prednisone (standard R-CHOP with the omission of vincristine to minimize risk of neuropathy) as frontline treatment for PMBL, grey zone lymphoma (GZL), and other CD30-positive DLBCLs. Pts with any Ann Arbor stage and at least equivocal CD30 expression on IHC were eligible. Consolidative radiation was allowed after completion of therapy at discretion of the treating physician. Phase I utilized a 3+3 de-escalation design with starting dose of BV 1.8 mg/kg on Day 1 in combination with rituximab 375 mg/m2 on Day 1, cyclophosphamide 750 mg/m2 on Day 1, doxorubicin 50 mg/m2 on Day 1, and prednisone 100 mg daily on Days 1-5 every 3 weeks for 6 cycles. The primary objective of phase I was assessment of safety and dose limiting toxicity (DLT) defined as any grade 3/4 non-hematologic toxicity observed in Cycle 1 requiring dose delay >14 days from the planned Day 1 of Cycle 2. Secondary end points included overall response rate (ORR), progression free survival (PFS), and overall survival (OS). The primary phase II objective was ORR with secondary endpoints of PFS, OS, safety, and correlation with CD30 expression. Revised Response Criteria for Malignant Lymphoma was used for response assessment (Cheson, 2007). Enrollment began in January 2014 and is reported through July 27, 2015. Results: Twelve pts including 9 PMBL (75%), 1 GZL (8%), and 2 DLBCL (17%) have been enrolled and treated; 11 patients are evaluable after completing protocol defined therapy. Median age was 37 years (range 25 - 58), 5 (45%) were female, 9 (82%) had elevated LDH, and 6 (55%) had stage III-IV disease. No DLT was observed during phase I and no BV dose de-escalation was required. There were no grade 3/4 non-hematologic adverse events (AEs). Hematologic grade 3/4 AEs included febrile neutropenia in 2 pts and afebrile neutropenia in 1 pt. Five pts had grade 2 non-hematologic AEs at least possibly related to BV including mucositis, nausea/vomiting, diarrhea, abdominal pain, anorexia, hypotension, and neuropathy. No study related deaths were observed. The ORR among evaluable pts was 100% (10 pts with CR, 1 pt with GZL with PR). The PFS and OS with median follow-up of 8 months (range: 4 -18 months) is 100%. Eight pts completed consolidative radiation therapy after systemic therapy. Conclusions: We established safety of administrating BV 1.8 mg/kg in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone as frontline therapy for PMBL, GZL and CD30-positive DLBCL. This outpatient regimen was well tolerated. Clinical outcomes observed in this initial cohort are very encouraging and will be validated in the ongoing phase II part of the trial. Disclosures Svoboda: Celgene: Research Funding; Immunomedics: Research Funding; Seattle Genetics: Research Funding; Celldex: Research Funding. Off Label Use: Brentuximab is not FDA approved for front-line therapy in PMBL and CD30+ DLBCL. Nasta:Seattle Genetics: Research Funding; BMS: Research Funding. Mato:Celgene Corporation: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; TG Therapeutics: Research Funding; Pharmacyclics: Consultancy, Research Funding; Pronai Pharmaceuticals: Research Funding; AbbVie: Consultancy, Research Funding; Genentech: Consultancy. Pro:Seattle Genetics: Consultancy, Other: Travel expenses, Research Funding; Takeda: Honoraria, Other: Travel expenses. Barta:Seattle Genetics: Research Funding. Schuster:Janssen: Research Funding; Celgene: Consultancy, Research Funding; Nordic Nanovector: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Phamacyclics: Consultancy, Research Funding; Hoffman-LaRoche: Research Funding; Novartis: Research Funding; Gilead: Research Funding.

scholarly journals Relapses after Achieving EFS24 in Patients with Diffuse Large B-Cell Lymphoma in the Rituximab Era

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 454-454 ◽  
Author(s):  
Yucai Wang ◽  
Umar Farooq ◽  
Brian K. Link ◽  
Mehrdad Hefazi ◽  
Cristine Allmer ◽  
...  
Keyword(s):  
B Cell ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Salvage Chemotherapy ◽  
Newly Diagnosed ◽  
Indolent Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Introduction: The addition of Rituximab to chemotherapy has significantly improved the outcome of patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). Patients treated with immunochemotherapy for DLBCL who achieve EFS24 (event-free for 2 years after diagnosis) have an overall survival equivalent to that of the age- and sex-matched general population. Relapses after achieving EFS24 have been considered to be unusual but have been understudied. We sought to define the rate, clinical characteristics, treatment pattern, and outcomes of such relapses. Methods: 1448 patients with newly diagnosed DLBCL from March 2002 to June 2015 were included. Patients were enrolled in the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma SPORE, treated per physician choice (predominantly R-CHOP immunochemotherapy) and followed prospectively. An event was defined as progression or relapse, unplanned re-treatment after initial therapy, or death from any cause. Cumulative incidence of relapse and non-relapse mortality after achieving EFS24 were analyzed as competing events using Gray's test in the EZR software. Post-relapse survival was defined as time from relapse to death from any cause and analyzed using Kaplan-Meier method in SPSS (V22). Results: Among the 1448 patients, 1260 (87%) had DLBCL alone at diagnosis, and 188 (13%) had concurrent indolent lymphoma (follicular lymphoma 115, marginal zone lymphoma 18, chronic lymphocytic leukemia 14, lymphoplasmacytic lymphoma 4, unspecified 37) at diagnosis. After a median follow-up of 83.9 months, 896 patients achieved EFS24. For all 896 patients who achieved EFS24, the cumulative incidence of relapse (CIR) was 5.7%, 9.3% and 13.2%, respectively, at 2, 5 and 10 years after achieving EFS24. Patients with concurrent indolent lymphoma at diagnosis had a higher CIR compared to those with DLBCL alone at diagnosis (10.2 vs 4.8% at 2 years, 15.7 vs 8.0% at 5 years, 28.8 vs 9.7% at 10 years, P<0.001; Figure 1). There were a total of 84 patients who relapsed after achieving EFS24. The median age at initial diagnosis was 66 years (range 35-92), and 48 (57%) were male. At diagnosis, 11 (13%) had ECOG PS >1, 37 (50%) had LDH elevation, 62 (74%) were stage III-IV, 14 (17%) had more than 1 extranodal site, and 26 (31%) were poor risk by R-IPI score. There were 58 patients with DLBCL alone at diagnosis who relapsed after achieving EFS24, and 38 (75%) relapsed with DLBCL, 13 (25%) relapsed with indolent lymphoma (predominantly follicular lymphoma), and pathology was unknown in 7 patients. In contrast, there were 26 patients with concurrent indolent lymphoma at diagnosis who relapsed after achieving EFS24, and 9 (41%) relapsed with DLBCL, 13 (59%) relapsed with indolent lymphoma, and pathology was unknown in 4 patients. In the 47 patients who relapsed with DLBCL after achieving EFS24, 45% received intensive salvage chemotherapy, 19% received regular intensity chemotherapy, 9% received CNS directed chemotherapy, and 36% went on to receive autologous stem cell transplant (ASCT). In the 26 patients who relapsed with indolent lymphoma after achieving EFS24, 27% were initially observed, 54% received regular intensity chemotherapy, 4% received intensive salvage chemotherapy, and 19% received ASCT after subsequent progression. The median post-relapse survival (PRS) for all patients with a relapse after achieving EFS24 was 38.0 months (95% CI 27.5-48.5). The median PRS for patients who relapsed with DLBCL and indolent lymphoma after achieving EFS24 were 29.9 (19.9-39.9) and 89.9 (NR-NR) months, respectively (P=0.002; Figure 2). Conclusions: Relapses after achieving EFS24 in patients with DLBCL were uncommon in the rituximab era. Patient with DLBCL alone at diagnosis can relapse with either DLBCL or indolent lymphoma (3:1 ratio). Patients with concurrent DLBCL and indolent lymphoma at diagnosis had a significantly higher CIR, and relapses with DLBCL and indolent lymphoma were similar (2:3 ratio). Even with high intensity salvage chemotherapy and consolidative ASCT, patients who relapsed with DLBCL had a significantly worse survival compared to those who relapsed with indolent lymphoma. Late relapses with DLBCL remain clinically challenging, with a median survival of 2.5 years after relapse. Figure 1. Figure 1. Disclosures Maurer: Celgene: Research Funding; Nanostring: Research Funding; Morphosys: Research Funding. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ansell:Takeda: Research Funding; Pfizer: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Celldex: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Merck & Co: Research Funding; Bristol-Myers Squibb: Research Funding. Cerhan:Celgene: Research Funding; Jannsen: Other: Scientific Advisory Board; Nanostring: Research Funding.

scholarly journals Third-generation anti-CD19 chimeric antigen receptor T-cells incorporating a TLR2 domain for relapsed or refractory B-cell lymphoma: a phase I clinical trial protocol (ENABLE)

BMJ Open ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. e034629 ◽  
Author(s):  
Philip George ◽  
Nathaniel Dasyam ◽  
Giulia Giunti ◽  
Brigitta Mester ◽  
Evelyn Bauer ◽  
...  
Keyword(s):  
T Cells ◽  
Phase I ◽  
B Cell ◽  
Chimeric Antigen Receptor ◽  
Dose Escalation ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Third Generation ◽  
Car T Cells ◽  
Car T

IntroductionAutologous T-cells transduced to express a chimeric antigen receptor (CAR) directed against CD19 elicit high response rates in relapsed or refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL). However, r/r B-NHL remissions are durable in fewer than half of recipients of second-generation CAR T-cells. Third-generation (3G) CARs employ two costimulatory domains, resulting in improved CAR T-cell efficacy in vitro and in animal models in vivo. This investigator-initiated, phase I dose escalation trial, termed ENABLE, will investigate the safety and preliminary efficacy of WZTL-002, comprising autologous T-cells expressing a 3G anti-CD19 CAR incorporating the intracellular signalling domains of CD28 and Toll-like receptor 2 (TLR2) for the treatment of r/r B-NHL.Methods and analysisEligible participants will be adults with r/r B-NHL including diffuse large B-cell lymphoma and its variants, follicular lymphoma, transformed follicular lymphoma and mantle cell lymphoma. Participants must have satisfactory organ function, and lack other curative options. Autologous T-cells will be obtained by leukapheresis. Following WZTL-002 manufacture and product release, participants will receive lymphodepleting chemotherapy comprising intravenous fludarabine and cyclophosphamide. A single dose of WZTL-002 will be administered intravenously 2 days later. Targeted assessments for cytokine release syndrome and immune cell effector-associated neurotoxicity syndrome, graded by the American Society Transplantation and Cellular Therapy criteria, will be made. A modified 3+3 dose escalation scheme is planned starting at 5×104 CAR T-cells/kg with a maximum dose of 1×106 CAR T-cells/kg. The primary outcome of this trial is safety of WZTL-002. Secondary outcomes include feasibility of WZTL-002 manufacture and preliminary measures of efficacy.Ethics and disseminationEthical approval for the study was granted by the New Zealand Health and Disability Ethics Committee (reference 19/STH/69) on 23 June 2019 for Protocol V.1.2. Trial results will be reported in a peer-reviewed journal, and results presented at scientific conferences or meetings.Trial registration numberNCT04049513

scholarly journals Clinical efficacy and molecular biomarkers in a phase II study of tucidinostat plus R-CHOP in elderly patients with newly diagnosed diffuse large B-cell lymphoma

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Mu-Chen Zhang ◽  
Ying Fang ◽  
Li Wang ◽  
Shu Cheng ◽  
Di Fu ◽  
...  
Keyword(s):  
Elderly Patients ◽  
B Cell ◽  
Response Rate ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Molecular Biomarkers ◽  
Newly Diagnosed ◽  
Large B Cell Lymphoma ◽  
Grade 3 ◽  
Large B Cell

Abstract Background Elderly patients with diffuse large B-cell lymphoma (DLBCL) present with poor clinical outcome and intolerance to intensive chemotherapy. Histone deacetylase inhibitors (HDACIs) show anti-lymphoma activities and can be applied to treat DLBCL. This study aimed to evaluate efficacy and safety of oral HDACI tucidinostat (formerly known as chidamide) plus R-CHOP (CR-CHOP) in elderly patients with newly diagnosed DLBCL (International Prognostic Index ≥ 2). Results Among 49 patients, the complete response rate was 86%, with overall response rate achieving 94%. The 2-year progression survival (PFS) and overall survival (OS) rates were 68% (95% CI 52–79) and 83% (95% CI 68–91). Comparing with historical control (NCT01852435), the 2-year PFS and OS rates of double-expressor lymphoma phenotype (DEL) were improved, and negative prognostic effect of histone acetyltransferases CREBBP/EP300 mutations was also mitigated by CR-CHOP. Grade 3–4 neutropenia was reported in 171, grade 3–4 thrombocytopenia in 27, and grade 3 anemia in 11 of 283 cycles. No grade 4 non-hematological adverse event was reported. Conclusion CR-CHOP is effective and safe in elderly patients with newly diagnosed DLBCL. Relevance of DEL phenotype and molecular biomarkers on CR-CHOP response warrants further investigation in DLBCL. Trial registration ClinicalTrial.gov, NCT02753647. Registered on April 28, 2016.

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