Pembrolizumab in Combination with Standard RCHOP Therapy for Previously Untreated Diffuse Large B-Cell Lymphoma

Abstract Background: Rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP) remains standard therapy for previously untreated diffuse large B-cell lymphoma (DLBCL). However, a substantial proportion of patients (pts) will relapse. The anti-PD-1 monoclonal antibody pembrolizumab has shown modest efficacy in previously treated DLBCL. We postulated that the first-line setting, with relatively intact host immunity and coexistence of malignant cells with T-cells in the microenvironment, may represent an opportunity for effective immune checkpoint inhibition. We carried out the first known prospective trial of anti-PD1 therapy with anthracycline chemotherapy in lymphoma, to evaluate the safety of this combination. Methods: Pts age 18 years or older with previously untreated DLBCL, transformed lymphoma and grade 3B follicular lymphoma with a plan for 6-cycle, curative-intent RCHOP were eligible. Steroids within 7 days of treatment, active autoimmune disease, or history of pneumonitis were excluded. This phase I study combined pembrolizumab (200 mg IV q 3 weeks x 6) to RCHOP x 6, with supportive care per standard practice. A 30-pt sample size permitted estimation of the rate of clinically relevant grade 3-5 toxicity, assumed to occur in 40% of pts with RCHOP alone. A stopping rule for more than 3 instances of non-relapse death or inability to complete 6 cycles of RCHOP for any reason was applied. Secondary endpoints included response rates, overall (OS) and progression-free survival (PFS). Baseline PDL1 expression was analyzed centrally (Merck/Qualtek). Peripheral blood flow cytometry for changes in PD1, PDL-1, and PDL-2 subsets were performed. After PET-based response assessment, pts were followed for relapse and survival. Results: Since March 2016, 29 pts were treated on study; 28 have finished all therapy. One is currently on therapy, and 1 remains to be enrolled. Pt characteristics are in Table 1. In 29 pts to date, 18 grade 3-5 clinically significant AE's occurred in 13 unique pts (13/29, 45%). 16 SAE's occurred in 11 pts (11/29, 38%); none qualified as unanticipated events. Two deaths occurred: One in the first accured patient, who had extensive gastric involvement by DLBCL, and died during cycle 1 of bleeding from the responding tumor bed despite maximal inpatient intervention. The other death occurred due to steroid-refractory GVHD after haploidenticial allogeneic transplant for relapsed disease. Four immune-related adverse events (IRAE) occurred: grade 3 rash, resolving with oral steroids and not recurring with further pembrolizumab, grade 1 hyperthyroidism, grade 2 colitis, and 1 episode of grade 3 pneumonitis. This case of pneumonitis was the only immune-related SAE, occurring in a 78 yo with a history of tobacco use and COPD, and resulted in stopping therapy after cycle 3. Among 27 completing treatment (excluding the pt who died during cycle 1), average anthracycline dose was 95% of expected; anthracycline relative dose intensity (RDI: delivered dose intensity/standard dose intensity) was 94%. PET response assessment among 26 evaluable pts showed 18 CR (69%), 7 PR, and 1 primary refractory disease. Among 7 PR, 1 relapsed, 3 had negative biopsies, and 3 remain in remission. Median follow-up of survivors is 13 months and 2 relapses (1 primary progressive disease, 1 after PET PR) occurred. One-year PFS is 87% (Figure 1). Baseline PDL-1 staining available for 19 pts showed a median % tumor cell staining of 30% (moderate 2+ plus strong 3+ staining; range, 0-100%). Tumor PDL1 was ≤5% in 4, 10-29% in 5, 30-49% in 4, and ≥50% in 6 pts. Both EBV+ DLBCL had 60% tumor PDL1 expression. 1 relapsing pt had no detectable tumor PDL1, and the THRLBL failed for technical reasons. Conclusions: RCHOP with pembrolizumab 200 mg q 3 weeks x 6 cycles is safe, with toxicity similar to RCHOP alone and only 4 IRAE's. Anthracycline dose intensity, CR rate, and PFS are favorable. PDL1 tumor cell expression of 10% or more was observed in 15/19 pts. These data support further study of pembrolizumab with chemotherapy in untreated lymphoid malignancies. Final response/progression, correlative studies, and survival data will be presented in December after final accrual. Disclosures Smith: Merck Sharp and Dohme Corp.: Consultancy, Research Funding; Pharmacyclics: Research Funding; Portola Pharmaceuticals: Research Funding; Acerta Pharma BV: Research Funding; Genentech: Research Funding; Seattle Genetics: Research Funding; Incyte Corporation: Research Funding. Lynch:Johnson Graffe Keay Moniz & Wick LLP: Consultancy; Incyte Corporation: Research Funding; Takeda Pharmaceuticals: Research Funding; T.G. Therapeutics: Research Funding; Rhizen Pharmaceuticals S.A.: Research Funding. Till:Mustang Bio: Patents & Royalties, Research Funding. Cowan:Sanofi: Research Funding; Juno Therapeutics: Research Funding; Abbvie: Research Funding; Janssen: Research Funding. Shadman:Acerta Pharma: Research Funding; Genentech: Research Funding; Verastem: Consultancy; Gilead Sciences: Research Funding; Qilu Puget Sound Biotherapeutics: Consultancy; Celgene: Research Funding; Genentech: Consultancy; Beigene: Research Funding; Pharmacyclics: Research Funding; AbbVie: Consultancy; Mustang Biopharma: Research Funding; TG Therapeutics: Research Funding; AstraZeneca: Consultancy. Shustov:Seattle Genetics: Research Funding. Cassaday:Amgen: Consultancy, Research Funding; Incyte: Research Funding; Seattle Genetics: Other: Spouse Employment, Research Funding; Merck: Research Funding; Jazz Pharmaceuticals: Consultancy; Adaptive Biotechnologies: Consultancy; Pfizer: Consultancy, Research Funding; Kite Pharma: Research Funding. Gopal:Pfizer: Research Funding; Janssen: Consultancy, Research Funding; BMS: Research Funding; Takeda: Research Funding; Incyte: Consultancy; Spectrum: Research Funding; Gilead: Consultancy, Research Funding; Merck: Research Funding; Aptevo: Consultancy; Asana: Consultancy; Seattle Genetics: Consultancy, Research Funding; Brim: Consultancy; Teva: Research Funding.

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R-CHOEP-14 × 6 Followed by Systemic CNS Prophylaxis for Diffuse Large B-Cell Lymphoma/Follicular Lymphoma Grade 3 with Age Adjusted IPI Score 2–3: Final Results of a Nordic Lymphoma Group Phase 2 Study Including 156 Patients Aged 18–65 Years.

Blood ◽

10.1182/blood.v116.21.2805.2805 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2805-2805 ◽

Cited By ~ 2

Author(s):

Harald Holte ◽

Sirpa LeppÃ¤ ◽

Magnus Bjorkholm ◽

Øystein Fluge ◽

Sirkku Jyrkkiö ◽

...

Keyword(s):

Treatment Failure ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

High Dose ◽

Cns Prophylaxis ◽

Large B Cell Lymphoma ◽

Residual Masses ◽

Grade 3 ◽

Large B Cell

Abstract Abstract 2805 CHOP – based chemotherapy for aggressive lymphomas in patients with age-adjusted International Prognostic Index (IPI) score of 2–3 resulted in a historical 3-year progression free survival of approximately 30% in a previous Nordic phase III study. The aim of the present study is to determine whether an intensified regimen with chemoimmunotherapy and CNS prophylaxis improves outcome. Methods: From October 2004 to June 2008 patients were included in a phase II study. Inclusion criteria: 1) Age 18–65 years. 2) Newly diagnosed de novo diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL) grade III. 3) No clinical sign of CNS disease and negative CSF cytology/flow cytometry by lumbar puncture. 4) No HIV infection. 5) WHO performance score 0–3. 6) Adequate organ functions. Schedule: Six courses of R-CHOEP14. Pegfilgrastim 6 mg sc. day four of each cycle. One course of high dose cytarabine 12 g/m2 (6 g/m2 for patients 60–65 years). One course of high dose methtrexate 3 g/m2 (1 g/m2 for patients 60–65 years). Biopsy and/or 18FDG PET/CT imaging of residual masses after fulfilled therapy was recommended, but not mandatory. Radiotherapy was given to residual masses of uncertain significance. Results. Demographic data:.156 eligible patients were included (97 males). Median age: 54 years (range 20–64). Histology: DLBCL: 145, FL grade 3: 12 (three patients no data). Age adjusted IPI score: 2: 117; 3: 39. Stage III-IV: 150 patients. LDH elevated: 151 patients. Performance status 2–3: 51 patients. B-symptoms were registered in 97 patients, more than one extranodal site in 42 and bulky lesions (≥ 10 cm) in 68. Median observation time for patients alive at last follow up was 36 months. Toxicity: Three toxic deaths are registered, one large bowel perforation, one fulminant hepatic necrosis and one septic shock. Hematological toxicity grade 4 was seen in 78% of the patients, infection grade 4 in 8%. Radiotherapy was given to 16% of the patients. Response: Response rates at end of therapy: CR/CRu: 69%, PR: 22%, SD: 1%, PD: 4.5%. Seventeen patients (7%) were not treated according to protocol, either due to lack of response (6 patients) or due to toxicity (eleven patients). The majority of the PR patients were considered to have residual masses and not viable tumour tissue. Survival: Three year overall survival was 80% (95% CI +/− 6.5%) and three year treatment failure free time 67% (95% CI +/−8.0%). CNS events: Seven patients had a CNS relapse, all but one were isolated (4 intracerebral, 3 meningeal). All CNS relapses occurred within 6 months after inclusion. Conclusions: The results are promising with a low three year treatment failure rate, a low toxic death rate and fewer CNS events than expected. The CNS events might be further reduced by earlier CNS prophylaxis. The study was supported by an unrestricted grant from Amgen Disclosures: Holte: Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. LeppÃ: Roche: Honoraria. Bjorkholm:Roche: Research Funding. Jyrkkiö:Roche: Honoraria. Kolstad:Roche: Honoraria; Amgen: Honoraria. Fosså:Roche: Honoraria. φstenstad:Roche: Honoraria; Amgen: Honoraria. Eriksson:Amgen: Research Funding.

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Rituximab and CODOX-M / IVAC Without Stem Cell Transplantation For Poor Risk Diffuse Large B Cell Lymphoma (IPI3-5) and Burkitts Lymphoma Is Feasible and Gives a High Response Rate: Preliminary Results Of a Phase 2 UK National Cancer Research Institute Trial

Blood ◽

10.1182/blood.v122.21.4348.4348 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4348-4348 ◽

Cited By ~ 1

Author(s):

Andrew McMillan ◽

Kirit M Ardeshna ◽

Jo Gambell ◽

Andrew Jack ◽

Amy Kirkwood ◽

...

Keyword(s):

Research Funding ◽

Response Rate ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Poor Risk ◽

Large B Cell Lymphoma ◽

Pet Scanning ◽

Burkitts Lymphoma ◽

Grade 3 ◽

Large B Cell

Abstract Introduction R-CHOP is the standard of care for patients with diffuse large B cell lymphoma (DLBCL) however poor risk patients (IPI 3-5) still have an inadequate outcome. Neither first remission high dose chemotherapy and peripheral blood stem cell transplantation (HDC+PBSCT) nor selection of cases for intensification by interim PET scanning have demonstrated a proven benefit. In the case of Burkitts lymphoma (BL) there is a paucity of data on the addition of Rituximab to the CODOX-M and IVAC regimen. Patients and Methods 113 patients with DLBCL and 37 with BL were recruited from 53 UK sites between May 2008 and April 2013. Median age was 49 years (18-65). For DLBCL patients IPI scores were 3 – 72 ( 64%), 4 -40 (35%) and 5 – 1 (1%). All patients received the modified CODOX-M and IVAC regimen including all CNS directed therapy( Mead et al Ann Oncol. 2002 Aug;13(8):1264-74) and 8 doses of rituximab. The primary end point of the study was Progression Free survival (PFS) and secondary endpoints included toxicity and CR rate. Results The main toxicities reported were neutropenia ( 89% grade 3 or 4), thrombocytopenia (84.2% grade 3 or 4), infection 61.6% grade 3 or 4 and mucositis (30.1% grade 3 or 4). 4 patients were excluded from toxicity assessment as they did not start therapy after registration. There were 8 treatment related deaths observed (infection with neutropenia (5), GI haemorrhage (1), acute cerebral haemorrhage (1) and bowel perforation (1) ). 78 patients with DLBCL and 31 with BL have completed all therapy ( 78.5 % of patients with available data) with an overall response rate of 92 % for DLBCl and 94% for BL. In patients who completed all therapy CR was achieved in 34 (44%), CR (u) in 8 (10%) and PR in 30 (38%) for DLBCL patients and CR was achieved in 21 (68%), CR (u) in 6 (19%) and PR in 2 (6%) in BL patients. 3 patients ( 2 DLBCL and 1 BL) who progressed during therapy have been included in the response analysis. End of treatment PET scanning was not obligatory. 80 patients with DLBCL and 30 patients with BL remain alive and without progression at a median follow up of 18.6 and 19.3 months respectively. Conclusion The R-CODOX-M -R-IVAC regimen can be delivered to patients with poor risk DLBCL in a multicentre setting. High rates of haematological toxicity and consequent infection are inevitable with treatment of this intensity but appear acceptable when compared with other treatments such as HDC+PBSCT. Response rates are encouraging in view of the very poor risk IPI profile of the patients included in this study. Burkitts lymphoma patients also achieved an excellent response rate with no apparent additional toxicity attributable to the addition of rituximab to the regimen. We currently plan the first analysis for the primary endpoint of PFS in 2015. The Trial was supported by Leukaemia and Lymphoma Research (LLR). Disclosures: McMillan: Roche: Consultancy, Honoraria; Amgen: Research Funding. Off Label Use: Rituximab usage in Burkitts Lymphoma. Ardeshna:Roche: Honoraria, Research Funding. Jack:Roche/Genentech: Research Funding. Patmore:Roche: Consultancy, Honoraria. Pettengell:Roche: Honoraria; Amgen: Honoraria. Linch:Roche: Honoraria, Research Funding.

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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 ◽

10.1182/blood.v122.21.4395.4395 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4395-4395 ◽

Cited By ~ 8

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.

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R-CHOP14 Compared to R-CHOP21 in Elderly Patients with Diffuse Large B-Cell Lymphoma: Results of the Interim Analysis of the LNH03-6B GELA Study.

Blood ◽

10.1182/blood.v114.22.406.406 ◽

2009 ◽

Vol 114 (22) ◽

pp. 406-406 ◽

Cited By ~ 8

Author(s):

Richard Delarue ◽

Herve Tilly ◽

Gilles Salles ◽

Christian Gisselbrecht ◽

Nicolas Mounier ◽

...

Keyword(s):

Elderly Patients ◽

B Cell ◽

Interim Analysis ◽

Response Rate ◽

Cell Lymphoma ◽

Dose Intensity ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Grade 3 ◽

Large B Cell

Abstract Abstract 406 Introduction: In 2000, the Gela demonstrated the survival advantage of adding Rituximab to CHOP21 over CHOP21 in the treatment of diffuse large B-cell lymphoma (DLBCL) in elderly patients. Two consecutive studies from the German group have shown an improvement of survival with CHOP14 compared to CHOP21, and then after with R-CHOP14 compared to CHOP14. Here, we report the results of the planned interim analysis of the LNH03-6B, a multicentric, phase III open-label, randomized trial evaluating the efficacy of R-CHOP given every 14 days compared to R-CHOP given every 21 days, held after the inclusion of the first 202 patients, with a median follow-up of 24 months. Patients and methods: Patients between 60 and 80 years old with DLBCL and aaIPI ≥ 1 were eligible. They were randomized between two immunochemotherapy regimens combining Rituximab and CHOP given every 2 (R-CHOP14, arm A) or 3 weeks (R-CHOP21, arm B) for 8 cycles. They were subsequently randomized between a prophylactic treatment with Darbepoetin alfa and a conventional treatment of chemotherapy-induced anemia. G-CSF was given according to physician decision. The primary objective was to evaluate the efficacy of R-CHOP14 compared to R-CHOP 21 as measured by the EFS, events being defined as death from any cause, relapse for complete responders and unconfirmed complete responders, progression during or after treatment and changes of therapy during allocated treatment. Secondary objectives were OS, PFS, DFS, response rate and analysis of dose-intensity and toxicity. According to previous LNH98-5 protocol, sample size was calculated to demonstrate an improvement of 2-year EFS from 55% to 65% with R-CHOP14. Six-hundred patients, randomized 1:1 between the two treatment groups recruited over 4 years and followed for a minimum of one year, will provide 80% power at the overall 5% (2-sided) significance level to detect the expected difference. Results: In this planned interim analysis, 202 patients were randomized and 201 received study treatment, 103 with R-CHOP14 and 98 with R-CHOP21. Median age was 72 years. Patients' characteristics were similar in both groups with a slightly higher proportion of patients with aaIPI 2-3 in R-CHOP14 arm (67% vs 59%) whereas a higher proportion of patients in R-CHOP21 arm presented with B symptoms (43% vs 37%). The median interval between cycles was 15 days in R-CHOP14 group and 21 days in R-CHOP21 group; 73 patients (71%) in R-CHOP14 group and 74 patients (76%) in R-CHOP21 group completed 8 cycles without progression. In the R-CHOP14 group, the increase of dose-intensity at the end of treatment, calculated according to 3-week interval as a reference, was 125% for cyclophosphamide and doxorubicin. Ninety percent of patients treated with R-CHOP14 received G-CSF, whereas only 66% in R-CHOP21 group. Response rate (CR+CRu) was 67% in R-CHOP14 arm and 75% in R-CHOP21 arm (p=NS). The 2-year EFS was 48% in R-CHOP14 arm compared with 61% in R-CHOP21 (p=NS). A similar trend was observed for 2-year PFS (49% vs 63%), 2-year DFS (57% vs 70%) and 2-year OS (67% vs 70%) (p=NS for all). Grade 3-4 hematological toxicity was more frequent in R-CHOP14 group, with a higher proportion of patients receiving red cell or platelet transfusions and/or experiencing febrile neutropenia, resulting in higher proportion of patients hospitalized for adverse events. In contrast, there was no difference for extra-hematological grade 3-4 toxicities. Conclusions: The results of this interim analysis of the LNH03-6B trial favor treatment with R-CHOP21 in elderly patients with DLBCL, with trends toward higher efficacy and lower toxicity compared to R-CHOP14. These results should be confirmed by the final analysis, concerning the 602 patients included, planned in 2010. Disclosures: No relevant conflicts of interest to declare.

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Prognostic Factors of Elderly Diffuse Large B-Cell Lymphoma Treated with R-CHOP: Performance Status and Age Over Eighty, but Neither Lactate Dehydrogenase Level, Stage, Nor Relative Dose Intensity Delivered, Associated with Clinical Outcome

Blood ◽

10.1182/blood.v118.21.1610.1610 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1610-1610

Author(s):

Kazunari Aoki ◽

June Takeda ◽

Yuki Hunayama ◽

Nobuhiko Yamauchi ◽

Aiko Kato ◽

...

Keyword(s):

Multivariate Analysis ◽

Prognostic Factors ◽

Cox Regression ◽

Cell Lymphoma ◽

Performance Status ◽

Dose Intensity ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Grade 3 ◽

Large B Cell

Abstract Abstract 1610 Introduction: As for the prognostic factors of elderly patients with diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP, limited reports have been available. Although the maintenance of relative dose intensity (RDI) has been considered to improve the outcome, recent reports show that dose-reduced R-CHOP also has successful results on elderly DLBCL (Lancet Oncology. 2011; 12: 460). As rigid adherence to R-CHOP protocol is difficult in the treatment of elderly DLBCL, we investigated the relationship between RDI delivered and clinical outcomes in elderly patients with DLBCL. Method: We retrospectively analyzed a total of 109 consecutive DLBCL patients over 70 years who were diagnosed and received R-CHOP in our institution between January 2004 and January 2011. Among them, 56 % were male, and 38 % were over 80 years. 49 % of patients had an Ann Arbor stage III or IV, and ECOG performance status (PS) were >= 2 in 37 %. Lactate dehydrogenase (LDH) levels were higher than normal in 60 %. Age-adjusted IPI was 2–3 in 45 %. Charlson comorbidity index (CCI) was >= 2 in 23 %. Most patients with localized disease received 3 cycles of R-CHOP (delivered with 21-day interval) followed by radiation, and patients with advanced disease received 6 or 8 cycles of R-CHOP. In the first cycles of R-CHOP therapy, patients aged 70–79 years received 70 % dose of cyclophosphamide, adriamycin and vincristine. Patients over 80 years received 50 % dose of them. Predonisolone was also reduced to 40–60 mg on day 1–5 according to patients' condition. Thereafter, the doses were individually adjusted according to attending physicians' judgment. 78 % of the patients experienced grade 3–4 neutropenia and 21 % grade 3 febrile neutropenia. Two patients died of neutropenia and infection. 65 % of patients received prophylactic G-SCF. By using clinical records of these patients, we estimated the prognostic factors using the Cox regression model. Estimates of prognostic factors were expressed as hazard ratios (HR) and 95 % confidence interval (CI) based on the Cox regression. We did two-sided statistical tests, with a 5 % level of significance. This study was approved by our institutional review board. Result: After median follow up for living patients of 25.5 months, 41 deaths has occurred (including 22 due to lymphoma), and 2-year overall survival (OS) and progression-free survival (PFS) were 71.3 % [95 % CI 60.8 %–79.5 %] and 53.5 % [95 % CI 42.7 –63.1 %], respectively. Univariate and multivariate analysis revealed that LDH and staging at diagnosis were not associated with prognosis. PS >= 2 (HR 2.94, 95 % CI 1.48–5.84, P=0.002) and age >= 80 years (HR 2.05, 95 % CI 1.04–4.04, P=0.039) retained independent adverse prognostic values for 2-year OS in multivariate analysis. Dividing entire population into 3 groups using these 2 prognostic factors, 2-year OS were 82.7 % (70 <= age < 80 and PS < 2), 67.3 % (70 <= age < 80 and PS>=2 or age>=80 and PS < 2), and 52.5 % (age >= 80 and PS >= 2), respectively (log-rank, P=0.0004). Among the all 109 patients, 91 patients received >=3 cycles of R-CHOP and RDI could be calculated. RDI was strongly associated with age (R-squared 0.42, RDI (%) = 201-1.90x age (years)). When high age-adjusted RDI group (H-aaRDI) was defined as the group of patients who satisfied □eRDI > 201 - 1.90x age', and low age-adjusted RDI group (L-aaRDI) as □eRDI< 201 - 1.90x age', 2-year OS were equivalent between H-aaRDI and L-aaRDI groups (79.8 % vs 78.7 %, log-rank, P=0.36). When multivariate analysis was performed against those 91 patients, 2-year OS was also independently associated with PS >=2 (HR 3.12, 95 % CI 1.35–7.20, P=0.008) and age >=80 (HR 2.41, 95 % CI 1.04–5.59, P=0.041). Lower age-adjusted RDI did not have prognostic value (HR 1.28, 95 % CI 0.55 – 2.94, P=0.57). Conclusion: Our retrospective analysis confirmed the efficacy of reduced-dose R-CHOP against elderly DLBCL, as was reported previously. Their prognosis was not associated with LDH level, staging, nor RDI delivered, but with ECOG PS and age over 80. Our findings indicated that strict adherence to keep RDI may not be necessary in the treatment of elderly DLBCL. The simple method to define optimal dose of R-CHOP for elderly should be explored. Disclosures: No relevant conflicts of interest to declare.

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Single Agent Ofatumumab In Patients With Relapsed and/Or Refractory Diffuse Large B-Cell Lymphoma (DLBCL): Results From a Phase II Open Label Study

Blood ◽

10.1182/blood.v122.21.5131.5131 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5131-5131

Author(s):

Jagoda Jasielec ◽

David Peace ◽

Sarah Edwards ◽

Kathy Tolzien ◽

Sonali M. Smith ◽

...

Keyword(s):

Phase Ii ◽

Clinical Benefit ◽

Research Funding ◽

Cell Lymphoma ◽

Single Agent ◽

B Cell Lymphoma ◽

Open Label ◽

Open Label Study ◽

Large B Cell Lymphoma ◽

Grade 3

Abstract Background Relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) remains a clinical challenge, with no standard options for elderly or transplant-ineligible patients. Ofatumumab is a fully humanized monoclonal antibody with specificity for CD20 that is currently approved for R/R chronic lymphocytic leukemia. Ofatumumab given for 4 weekly doses elicited an overall response rate (ORR) of 11% in a prior French study of R/R DLBCL. However, a maintenance strategy for stable or responding DLBCL has not been tested and could improve the overall clinical benefit. This phase II open label study of single agent ofatumumab tested the efficacy of a combined induction and maintenance schedule. Methods Patients with R/R DLBCL who were transplant-ineligible or who had relapsed after transplantation were included. The treatment schedule was ofatumumab 1000 mg weekly for 8 weeks (induction phase). Patients achieving stable disease (SD) or better continued on a maintenance phase receiving ofatumumab at 1000 mg every other week until objective evidence of disease progression or patient/physician decision to withdraw. The primary end-points were overall response (OR) defined as the sum of partial response (PR) and complete response (CR) (Cheson Criteria), and toxicity using NCI criteria (CTCAE v.4). Secondary end-points included time to disease progression (TTP), overall survival (OS), and the overall clinical benefit defined as the sum of SD, CR, and PR. Results Eleven patients were enrolled in this trial before it was stopped due to slow accrual. Median age was 67 years (range: 41-89) and 4/11 patients were male. All patients had advanced stage III/IV disease and 10/11 had an Eastern Cooperative Oncology Group performance status of 0 or 1. Median LDH was 246 U/l (range: 160-966), one patient had bulky disease, and one patient had B symptoms. Patients were heavily pre-treated with a median of 4 prior therapies (range: 1-7). One patient had relapsed disease, while the other 10 had disease that was rituximab-refractory. Four patients (36%) had prior transplants (2 autologous, 1 allogeneic, and 1 both). All patients were evaluable for response and toxicity. One patient was taken off study without progression due to hemolytic anemia (possibly related) after 6 months of therapy. Best responses achieved were 2 PR and 2 SD, while 7 patients progressed for an OR of 18% and a clinical benefit rate of 36%. Five patients (1 PD patient received maintenance ofatumumab inadvertently) went on to receive ofatumumab maintenance for a median duration of 4 cycles (range: 1-18). Response lasted for 6 and 9 months respectively in the 2 patients with PR. Subsequent therapies for progressing patients were offered (2 received bendamustine and rituximab, 1 received single agent bendamustine, and 3 had investigational therapies). At a median follow-up of 23 months (range: 5-38), 3 patients remain (27%) alive, median event free survival (EFS) was 2 months (range: 1-11), and median overall survival was 7 months (range: 1-31). Ofatumumab was generally well tolerated with 3 patients developing grade 1/2 infusion reactions. Other toxicities included grade 1/2 diarrhea (63%), anorexia (45%), hyponatremia (36%), and fatigue (36%). No grade 3/4 non-hematologic toxicities were observed. Grade 3/4 neutropenia occurred in 3/11 (27%) patients, one of whom was hospitalized for neutropenic fever. In addition, grade 4 thrombocytopenia occurred in 1 pt. Conclusion In this phase II study, we demonstrate modest single agent activity for ofatumumab in heavily pretreated rituximab-refractory DLBCL patients who have failed multiple standard therapies. Ofatumumab was well-tolerated with an acceptable safety profile. Maintenance therapy did not appear to add additional benefit in this small cohort. However, the favorable toxicity profile and modest clinical benefit justify further studies of this antibody in combination with chemotherapy or with other targeted agents. Disclosures: Nabhan: Genentech: Research Funding, Speakers Bureau; GSK: Research Funding.

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A Pilot Study of Brentuximab Vedotin, Rituximab and Dose Attenuated CHP in Patients 75 Years and Older with Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood-2020-140384 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 5-6

Author(s):

Patrick M. Reagan ◽

Craig A. Portell ◽

Carla Casulo ◽

Andrea M. Baran ◽

Allison Magnuson ◽

...

Keyword(s):

Older Patients ◽

Research Funding ◽

Sensory Neuropathy ◽

B Cell Lymphoma ◽

Brentuximab Vedotin ◽

Genetics Research ◽

Large B Cell Lymphoma ◽

Grade 3 ◽

Peripheral Sensory

Older patients with hematologic malignancies are underrepresented on prospective clinical trials relative to the incidence of disease in this group (Kanapuru et al, 2020). There are few studies in diffuse large B-cell lymphoma (DLBCL) focused specifically on older patients. Rituximab and dose attenuated cyclophosphamide, doxorubicin, vincristine, and prednisone (R-miniCHOP) has been studied on a prospective trial in fit patients aged 80 years and older. Seventy-two percent of patients on this study completed 6 cycles of R-miniCHOP. The overall response rate (ORR) was 73%, and the 2-year progression free survival (PFS) was 47% (Peyrade et al, 2011). Novel regimens are needed to improve upon the efficacy of therapy while preserving tolerability. Brentuximab vedotin (BV) has demonstrated activity in relapsed and refractory DLBCL (Jacobsen et al, 2015) as well as in combination with chemoimmunotherapy (Svoboda, 2020). This study evaluates the feasibility of BV with dose attenuated chemoimmunotherapy. Methods: Patients with both CD30 positive (cut off 1%) and CD30 negative DLBCL aged 75 years and older were enrolled on the study. Patients received six, 3-week cycles of BV 1.8 mg/kg, cyclophosphamide 400 mg/m2, doxorubicin 25 mg/m2, vincristine 1 mg and prednisone 40 mg/m2 days 1-5 (BV R-miniCHP). For the first cycle patients received BV and prednisone as a prephase starting one week prior to cycle 1. All patients received pegfilgrastim. All patients underwent geriatric assessments at screening, following prephase and at the end of treatment. The primary endpoint was feasibility of this regimen in older patients. The regimen was considered feasible if 71% of patients completed 6 cycles of treatment with a 90% confidence interval (CI)=(58.0, 90.6%). Secondary endpoints included toxicity, ORR and complete response (CR) evaluated by positron emission tomography, PFS and overall survival (OS). Response assessments used the Lugano Criteria (Cheson et al, 2014). PFS and OS were estimated using the Kaplan-Meier method. Results: Twenty-two patients were enrolled and started prephase with BV and prednisone. Their baseline characteristics are summarized in the table. Seventy-seven percent (17/22) of patients completed 6 cycles of BV R-miniCHP. Reasons for not completing treatment included progressive disease in 2 patients, myocardial infarction, fatigue, and an unrelated injury in 1 patient each. Twenty-one patients were evaluable for response. ORR was 86% (18/21) in all patients, with 67% (14/21) achieving CR. In CD30 positive patients the ORR was 80% (8/10) and the CR rate was 70% (7/10). In CD30 negative patients the ORR was 91% (10/11) and the CR rate was 64% (7/11). With a median follow up of 23 months, median OS and PFS (figure) were not reached. The 2-year PFS was 60.6%, 90% CI=(40.0%, 76.1%), and the 2-year OS was 73.9%, 90% CI=(52.4%, 86.8%). The most common adverse events (AEs) were fatigue (82%), anemia (50%), diarrhea (50%), dysgeusia (45%) and peripheral sensory neuropathy (45%). Grade ≥3 AEs seen in more than 2 patients included neutropenia (23%), fatigue (18%), pneumonia (18%), hypoxia (14%), thrombocytopenia (9%) and thromboembolism (9%). Grade ≥3 peripheral sensory neuropathy was seen in 9% of patients. There were two deaths in patients receiving study treatment. These included a myocardial infarction related to treatment, and a bowel obstruction secondary to disease progression. Three other patients have died in follow up with 2 secondary to disease progression and 1 due to an unrelated event. Conclusions: The study met its primary feasibility endpoint with 77% of patients completing 6 cycles of therapy. This regimen was delivered safely in this population and toxicities were consistent with those reported in larger prospective studies with R-miniCHOP or ofatumumab and miniCHOP (Peyrade et al, 2011; Peyrade et al 2017). Peripheral neuropathy is a key AE of interest given the inclusion of BV and while nearly half of patients experienced some peripheral neuropathy, it was severe in only 9% of pts. The ORR and CR rate, as well as the 2-year PFS compare favorably to other prospective studies in a population that included patients with high clinical risk, histologic transformation, and double hit lymphoma. BV and R-miniCHP may be a feasible regimen in older patients, and warrants further study based on these preliminary data demonstrating clinical activity and tolerability. Figure 1 Disclosures Reagan: Seattle Genetics: Research Funding; Curis: Consultancy; Kite, a Gilead Company: Consultancy. Portell:Xencor: Research Funding; Roche/Genentech: Consultancy, Research Funding; Infinity: Research Funding; TG Therapeutics: Research Funding; AbbVie: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Bayer: Consultancy; BeiGene: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding. Barr:Gilead: Consultancy; Verastem: Consultancy; Abbvie/Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy; AstraZeneca: Consultancy, Research Funding; Janssen: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy; Morphosys: Consultancy; TG therapeutics: Consultancy, Research Funding; Merck: Consultancy. Friedberg:Acerta Pharma - A member of the AstraZeneca Group, Bayer HealthCare Pharmaceuticals.: Other; Roche: Other: Travel expenses; Kite Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding; Portola Pharmaceuticals: Consultancy; Astellas: Consultancy; Bayer: Consultancy.

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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 ◽

10.1182/blood.v128.22.4162.4162 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4162-4162 ◽

Cited By ~ 2

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.

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Phase I Study of Oral Azacitidine (CC-486) Plus Salvage Chemotherapy in Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood-2021-145493 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3567-3567

Author(s):

Brian T. Hess ◽

Leandro Cerchietti ◽

Lindsey Hendrickson ◽

Elizabeth Hill ◽

Anshu Giri ◽

...

Keyword(s):

Stem Cell ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Salvage Chemotherapy ◽

Global Methylation ◽

Large B Cell Lymphoma ◽

Grade 3 ◽

Methylation Patterns ◽

Large B Cell

Abstract Background A significant portion of diffuse large B-cell lymphoma (DLBCL) patients (35-40%) relapse or are refractory to frontline chemotherapy. The standard of care for relapsed/refractory (R/R) DLBCL patients has been salvage chemotherapy followed by consolidation with autologous stem cell transplant (ASCT) in eligible patients. Epigenetic alterations, such as aberrant DNA methylation patterns, have been linked to chemotherapy resistance in DLBCL. CC-486 is an oral hypomethylating inhibitor that inhibits DNA methyltransferase, and has provided evidence for chemotherapy sensitization in DLBCL (Clozel T, et al. Cancer Discovery, 2013). This provides rationale for addition of CC-486 to standard cytotoxic chemotherapy rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) in R/R DLBCL patients who are candidates for ASCT. Here we report the results of the phase 1 trial investigating this combination. Methods Eligibility included age ≥ 18, a diagnosis of R/R DLBCL, follicular lymphoma grade 3B, or DLBCL transformed from indolent lymphoma who were candidates for salvage chemotherapy and ASCT consolidation. The study was conducted via standard 3+3 dose escalation of CC-486 at 200 mg (dose level (DL) 1), 300 mg (DL 2), and 150 mg (DL -1). A Dose limiting toxicity (DLT) was defined as grade ≥ 3 adverse event (AE) as defined by CTCAE v5 leading to ≥ 7 day delay in cycle (C) 1 or 2 of R-ICE chemotherapy as well as grade ≥ 2 vomiting/diarrhea, persisting 48 hours despite best supportive care. Patients received up to three 21-day cycles. CC-486 was given as a 7 day lead in prior to C1 and then on days 8-21 of C1 and C2 with doses held based on cytopenias/AE's per protocol. G-CSF was mandated with each cycle. The primary objective was to determine the recommended phase 2 dose (RP2D) of CC-486 in combination with R-ICE chemotherapy. Secondary objectives included overall response rate (ORR)/complete remission (CR) per 2014 IWG criteria, peripheral blood stem cell (PBSC) collection feasibility, and proportion of patients receiving ASCT consolidation. Biomarker objectives included assessment of locus specific and global methylation patterns in ctDNA at set time points. Results The study has completed accrual with enrollment of nine patients from two institutions, all of which completed planned therapy. Eight (89%) of the patients had relapsed < 1 year from completion of frontline chemotherapy. Six patients were treated at the DL1 (200 mg), three patients were treated at DL2 (300 mg), and zero patients were treated at DL-1 (150 mg) with baseline characteristics described in table 1. The most common AE's (figure 1) included nausea (78%), thrombocytopenia (78%), anemia (56%), neutropenia (55.6%), fatigue (44%), and constipation (44%). Compared with DL1, DL2 was associated with greater incidence of grade ≥ 3 hematologic AE's/cycle including neutropenia (42% v 6%), anemia (29% v 11%), and thrombocytopenia (42% v 6%); higher incidence of neutropenic fever/cycle (28.5% vs 0%); more frequent delays in day 1 of C2 or C3 of R-ICE chemotherapy (80% vs 0%); and higher rate of CC-486 doses missed in C2 and C3 due to cytopenias (40% and 4%) respectively. One DLT occurred at DL2 in a patient with grade 5 neutropenic sepsis. A planned safety review of the three patients at DL2 established that no further patients would be enrolled at this dose. No DLTs were noted in the six patients enrolled at DL1. The ORR(CR) of the 8 evaluable patients was 50%(50%) and 4/9 patients proceeded to ASCT. With a median follow up of 9.5 months (range 1.2-25.1) the median PFS and OS were 4.0 months (95% CI 2.1-NR) and 10.7 months (95% CI 9.5-NR) respectively. All 4 patients successfully collected PBSCs (defined as ≥ 3.0 x 10^6 CD34 cells/kg) with median of 4.08 x 10^6 cells/kg. Biomarker studies are pending. Discussion Patients enrolled at DL1 (200 mg) tolerated this combination well with expected hematologic AE's, no episodes of neutropenic fever, few missed doses of CC-486, no delays in R-ICE chemotherapy, and no DLTs. The CR rate was 50% and a high proportion of patients (89%) enrolled after relapsing < 1 year from completion of frontline therapy. Biomarker studies may provide information regarding DLBCL populations likely to benefit from combinations of chemotherapy and epigenetic priming. Biomarker studies related to locus specific and global methylation patterns in ctDNA will be presented at the ASH conference. Figure 1 Figure 1. Disclosures Hess: BMS: Speakers Bureau; ADC Therapeutics: Consultancy. Cerchietti: Celgene: Research Funding; Bristol Myers Squibb: Research Funding. Hill: Eli Lilly and Company: Ended employment in the past 24 months.

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CD30 Expression in Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood.v120.21.1558.1558 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1558-1558 ◽

Cited By ~ 2

Author(s):

Graham W. Slack ◽

Christian Steidl ◽

Laurie H. Sehn ◽

Randy D. Gascoyne

Keyword(s):

B Cell ◽

Mrna Expression ◽

Research Funding ◽

Cell Lymphoma ◽

Independent Predictor ◽

B Cell Lymphoma ◽

Brentuximab Vedotin ◽

Genetics Research ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract Abstract 1558 Background: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with a variable clinical course. The addition of rituximab (R) to CHOP combination chemotherapy has improved overall (OS) and progression free survival (PFS) but some patients progress despite treatment and alternative therapies are needed. Brentuximab vedotin is an antibody-drug conjugate that targets CD30. It is efficacious in the treatment of relapsed Hodgkin lymphoma and relapsed systemic anaplastic large cell lymphoma, two lymphomas associated with CD30 expression. The association between DLBCL and CD30 expression has not been well described. The aim of this study was to examine CD30 expression in DLBCL. Design: 395 cases of formalin-fixed paraffin-embedded DLBCL (excluding PMBCL) in a tissue microarray were independently evaluated by two pathologists for expression of CD30, CD10, BCL6, and MUM1 by immunohistochemistry (IHC) and EBV RNA (EBER) by in situ hybridization. CD30 expression was correlated with cell of origin (COO) phenotype, OS and PFS, EBV infection, International Prognostic Index (IPI) score and CD30 mRNA expression. The COO phenotype, germinal center B-cell like (GCB) or non-GCB, was determined by IHC using the Hans algorithm. CD30 mRNA expression and COO genotype by gene expression profiling (GEP) were determined using Affymetrix U133 2.0 Plus arrays (n=170). Outcome analysis only included patients treated with R-CHOP chemotherapy. CD30 was considered positive by IHC if any malignant cells exhibited membranous staining. The threshold for calling higher CD30 expression by GEP was determined using X-Tile software. Results: 25% (95/385) of DLBCL cases expressed CD30 by IHC with excellent concordance between two observers (r = 0.94). CD30 expression trended towards a non-GCB phenotype but was not significantly different (p=0.067). CD30 expression was not associated with PFS or OS in all R-CHOP treated cases (n=313); however, it was associated with a prolonged PFS in GCB-DLBCL (n=147) (p=0.019). In GCB-DLBCL CD30 expression remained an independent predictor of PFS in a multivariate analysis with IPI (p=0.038). CD30 expression by IHC was significantly associated with higher levels of CD30 mRNA (p=0.002). ABC-DLBCL exhibited significantly higher expression levels of CD30 mRNA (p=0.037). Higher CD30 mRNA expression was associated with a prolonged PFS in all R-CHOP treated DLBCL (p=0.012) as well as in DLBCL with a GCB-genotype (p=0.008), but not ABC or U-genotypes. Higher CD30 mRNA expression was also associated with a prolonged OS in the GCB-genotype (p=0.022). In the GCB-genotype higher CD30 mRNA expression remained an independent predictor of PFS, but not OS, in a multivariate analysis with IPI (p=0.037). EBV was identified in 3% of DLBCL (11/391), all of which exhibited a non-GCB phenotype (p=0.001) and were almost exclusively positive for CD30 expression (10/11)(p=<0.001). Conclusions: CD30 is expressed in approximately 25% of DLBCL and brentuximab vedotin could be considered for study in combination with traditional front-line therapies or as an alternative therapy in the relapsed or refractory disease. CD30 immunohistochemistry may be useful as a prognostic marker in R-CHOP treated GCB-DLBCL and the significant association of CD30 with EBV-positive non-GCB DLBCL suggests a distinct pathobiology for these cases. Disclosures: Slack: Seattle Genetics: Research Funding. Steidl:Seattle Genetics: Research Funding. Gascoyne:Seattle Genetics: Research Funding.

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