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

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.

Download Full-text

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

Blood ◽

10.1182/blood-2018-99-113213 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 454-454 ◽

Cited By ~ 1

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.

Download Full-text

The Efficacy of R-ICE Therapy as a Salvage Treatment for Relapse and Refractory Diffuse Large B-Cell Lymphoma.

Blood ◽

10.1182/blood.v110.11.4441.4441 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4441-4441

Author(s):

Makoto Kodaira ◽

Masahiro Yokoyama ◽

Hiroaki Asai ◽

Shuhei Yamada ◽

Kyoko Ueda ◽

...

Keyword(s):

B Cell ◽

De Novo ◽

Cell Lymphoma ◽

Progression Free Survival ◽

B Cell Lymphoma ◽

Salvage Chemotherapy ◽

Salvage Treatment ◽

Large B Cell Lymphoma ◽

Grade 3 ◽

Large B Cell

Abstract <Background> Patients with relapsed and refractory diffuse large B-cell lymphoma are usually treated with platinum-based salvage chemotherapy. We retrospectively analyzed the efficacy of adding rituximab with ICE as a salvage treatment for relapsed and refractory diffuse large B-cell lymphoma. <Method>From November 2003 to December 2006, patients with relapsed or refractory de novo diffuse large B-cell lymphoma represented CD20 positivty who received R-ICE (rituximab375mg/m2, Ifosfamide 1200mg/m2, calboplatin 400mg/m2 and etopside100mg/m2 ), were analyzed retrospectively. <Result>23 patients (19 relapse and 4 reflactory) (M:F=14:9) (median age 69, 28–77) were included. At starting treatment, twelve patients received rituximab and 11 patients were rituximab naive. In all 23 patients, responses were 11 Complete remission (CR), and 6 partial response (PR), resulting in overall response (ORR) was 74.9%. With median follow up of 10.5 months, estimated 1yr-progression free survival (PFS) was 49% and 1yr-overall survival (OS) was 70%.In patients received rituximab, ORR was 66.7% and 5 patiets achieved CR (41.7%).In the without rituximab, ORR was 90.9% and 7 patiets achieved CR (63.6%). No statistical differences were observed in response even with retuximab pretreatment. Estimated 1yr-PFS was 23% and 70% (p=0.0752) and 1yr-OS was 59% and83% (P=0.0049),respectively. NCI-CTC grade 3/4 neutropenia and thrombocytopenia were reported 100% and 91%, For non-hematological adverse event, there were grade 3 liver dysfunction (2/23) and grade 3 arrythmia (1/23). No toxic death was reported in this study. <Conclusion> R-ICE showed promising efficacy with tolelable toxicity. Available date suggested adding rituximab to ICE is more effective for patients not received rituximab in the pretreament.

Download Full-text

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.

Download Full-text

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.

Download Full-text

Rituximab Maintenance Therapy After Autologous Stem-Cell Transplantation in Patients With Relapsed CD20+ Diffuse Large B-Cell Lymphoma: Final Analysis of the Collaborative Trial in Relapsed Aggressive Lymphoma

Journal of Clinical Oncology ◽

10.1200/jco.2012.41.9416 ◽

2012 ◽

Vol 30 (36) ◽

pp. 4462-4469 ◽

Cited By ~ 158

Author(s):

Christian Gisselbrecht ◽

Norbert Schmitz ◽

Nicolas Mounier ◽

Devinder Singh Gill ◽

David C. Linch ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Salvage Chemotherapy ◽

High Dose ◽

Large B Cell Lymphoma ◽

Relapsed Disease ◽

Large B Cell

Purpose The standard treatment for relapsed diffuse large B-cell lymphoma (DLBCL) is salvage chemotherapy followed by high-dose therapy and autologous stem-cell transplantation (ASCT). The impact of maintenance rituximab after ASCT is not known. Patients and Methods In total, 477 patients with CD20+ DLBCL who were in their first relapse or refractory to initial therapy were randomly assigned to one of two salvage regimens. After three cycles of salvage chemotherapy, the responding patients received high-dose chemotherapy followed by ASCT. Then, 242 patients were randomly assigned to either rituximab every 2 months for 1 year or observation. Results After ASCT, 122 patients received rituximab, and 120 patients were observed only. The median follow-up time was 44 months. The 4-year event-free survival (EFS) rates after ASCT were 52% and 53% for the rituximab and observation groups, respectively (P = .7). Treatment with rituximab was associated with a 15% attributable risk of serious adverse events after day 100, with more deaths (six deaths v three deaths in the observation arm). Several factors affected EFS after ASCT (P < .05), including relapsed disease within 12 months (EFS: 46% v 56% for relapsed disease after 12 months), secondary age-adjusted International Prognostic Index (saaIPI) more than 1 (EFS: 37% v 61% for saaIPI < 1), and prior treatment with rituximab (EFS: 47% v 59% for no prior rituximab). A significant difference in EFS between women (63%) and men (46%) was also observed in the rituximab group. In the Cox model for maintenance, the saaIPI was a significant prognostic factor (P < .001), as was male sex (P = .01). Conclusion In relapsed DLBCL, we observed no difference between the control group and the rituximab maintenance group and do not recommend rituximab after ASCT.

Download Full-text

R-ICE Versus R-DHAP in Relapsed Patients with CD20 Diffuse Large B-Cell Lymphoma (DLBCL) Followed by Stem Cell Transplantation and Maintenance Treatment with Rituximab or Not: First Interim Analysis on 200 Patients. CORAL Study.

Blood ◽

10.1182/blood.v110.11.517.517 ◽

2007 ◽

Vol 110 (11) ◽

pp. 517-517 ◽

Cited By ~ 7

Author(s):

Christian Gisselbrecht ◽

Norbert Schmitz ◽

Nicolas Mounier ◽

David Ma ◽

Marek Trneny ◽

...

Keyword(s):

Stem Cell ◽

Interim Analysis ◽

Response Rate ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Salvage Chemotherapy ◽

Early Relapse ◽

Large B Cell Lymphoma ◽

Intent To Treat ◽

Large B Cell

Abstract Salvage chemotherapy followed by high dose therapy (HDT) and autologous stem cell transplantation (ASCT) is the standard of treatment for chemosensitive relapses in diffuse large B cell lymphoma. Improvement of salvage chemotherapy was suggested with the association rituximab, Ifosfamide, etoposide, carboplatinum, R-ICE. What is the optimal chemotherapy regimen and can we reduce the post ASCT relapses rate? The ongoing CORAL trial was designed to answer these questions. DLBCL CD 20+ in first relapse or pts refractory after first line therapy were randomized between rituximab plus DHAP and R-ICE. Stratification was made on centers, prior rituximab exposure and refractory/<12months relapses. Responding patients received HDT (BEAM) and ASCT and were randomized between observation and maintenance with rituximab one injection every 2 months for 1 yr. Over 400 pts have been randomized in 11 countries since 2003. The planned interim analysis was performed on the 200 first pts with a minimum follow up of 1 yr. Six pts did not receive any treatment. Intent to treat analysis was made on 194 pts (100 R ICE arm, 94 R DHAP arm): median age 55 yrs.; 86 relapses >12months, 108 refractory/early relapses; 97 pts with prior exposure to rituximab; Stage 3-4 107 pts; elevated LDH 88 pts; secondary IPI 0–1 112 pts; sIPI 2-3 63pts. The two arms were well balanced. In the prior rituximab cohort exposure more pts had refractory disease and adverse prognostic factors. However, at inclusion patients characteristics were not significantly different in the stratified subgroups. The overall response rate was 68%, with 41% complete remission rate. Toxicity was similar to what is expected with intensive therapy, 72 SAE were reported with 12 deaths during the initial salvage regimens. In univariate analysis factors significantly affecting response rate (p<.0001) were: refractory/relapse < 12 months 52% vs 88%, secondary IPI >1 54% vs 77% and prior exposure to rituximab 54% vs 82%. In a logistic regression model only refractory/early relapse and secondary IPI remain significant for response rate. Intent to treat 2 yrs EFS and OS were 50% (CI 42–57%) and 69% (CI 61–75%) respectively. Only 107 pts in this prospective study received, per protocol ASCT. For patients transplanted, 2 yrs EFS was 75% (CI 63–84%) with OS 89%. Two yrs EFS was affected by: prior treatment with rituximab, 34% vs 66% (p=.0001); refractory/early relapse 36% vs 68% (p <.0001); secondary IPI 2–3: 39% vs 0–1: 56% (p=.03). After ASCT 104 pts were randomized between observation and rituximab. Only 17% events occurred so far without unexpected toxicity, preventing to give results between the different arms according to Data Safety Monitoring Board. Conclusion: Salvage chemotherapy incorporating rituximab provide a high 82% response rate in pts not previously treated with rituximab. Patients who refractory to upfront rituximab-based chemotherapy have a poor response rate and prognosis. The study is on going to include 240 pts in the second randomisation for the EFS primary endpoint.

Download Full-text

PD-1 Blockade for Diffuse Large B-Cell Lymphoma after Autologous Stem Cell Transplantation

Blood ◽

10.1182/blood-2018-99-114914 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 706-706 ◽

Cited By ~ 1

Author(s):

Yi-Bin Chen ◽

Philippe Armand ◽

Robert A. Redd ◽

Jad Bsat ◽

Reid W Merryman ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Disease Relapse ◽

Advisory Committees ◽

Prior Therapy ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract Background: The leading cause of death after high-dose chemotherapy and autologous stem cell transplantation (ASCT) for relapsed / refractory (R/R) diffuse large B-cell lymphoma (DLBCL) remains disease relapse. Except for specific subsets, DLBCL appears to have relatively low susceptibility to single-agent PD-1 blockade. However, administering PD-1 blockade early after ASCT could leverage the remodeling immune landscape and minimal residual disease state to increase the therapeutic effect of PD-1 blockade and decrease the relapse rate after ASCT. A prior study with pidilizumab showed encouraging results in this setting (Armand et al. JCO 2013;31:4199-206), but the specificity of that antibody is still under investigation. We therefore conducted a phase 2 multi-center single-arm study of the anti-PD-1 monoclonal antibody pembrolizumab (pembro) in patients with chemosensitive DLBCL after ASCT. Another arm of this study enrolled pts with R/R classical Hodgkin lymphoma and will be presented separately. Methods: Patients ≥ 18y with R/R DLBCL who had received no more than 3 lines of prior therapy and had undergone ASCT with chemosensitive disease were enrolled on this study. In addition to meeting standard eligibility criteria for pembro treatment, pts had to have recovered from ASCT toxicities and had to begin study treatment within 60 days of stem cell infusion, with a goal of starting treatment within 21 days of hospital discharge. All patients received pembro 200mg IV every 3 weeks for 8 cycles. PET-CT scans were obtained at post-ASCT baseline, after 3 and 7 cycles, then at 12 and 18 months post-ASCT. The primary endpoint was the progression-free survival rate (PFS) at 18 months after ASCT, assessed using the International Harmonization Project 2007 criteria, with the approach considered promising if 22 patients were alive and in remission at 18 months. Results: 31 pts were enrolled and 2 withdrew consent before starting treatment. Among the 29 eligible pts, median age was 57 (22-76). Prior to ASCT, 18 (62%) were in CR and 11 (38%) were in PR. At study baseline (post-ASCT), 25 (86%) were in CR. 18 pts (62%) completed all 8 cycles of pembro per protocol. 11 pts (38%) stopped pembro early for pt choice (n=1, after febrile neutropenia), toxicity (n=6, including 3 pts with gr3 pneumonitis, 1 with g3 hepatitis, 1 with gr4 aplastic anemia) or progressive disease (n=4). 23 pts (79%) experienced a total of 57 gr3 or higher adverse events (AEs). The most common gr4 AE was neutropenia (n=6, 21%). Concerning related AEs, 9 pts (31%) experienced 14 gr3-4 AEs at least probably related to pembro including neutropenia (4 gr3, 1 gr 4) and pneumonitis (2 gr3). 10 pts (34%) experienced at least one immune-related AE of gr2 or higher severity including pneumonitis (n=1 gr2, n=2 gr3), transaminitis (n=1 gr2, n=1 gr3) and rash (n=1 gr2, n=1 gr3). There were no treatment-related deaths. Among the 29 eligible pts, 1 patient withdrew consent after cycle 1 and 1 pt was lost to follow-up after the 12m assessment (in CR). 27 pts (93%) were evaluable for the primary endpoint. 10 patients (34%, 95% CI: 18-54%) experienced disease relapse at a median of 5 months (3-18) after ASCT, and all other evaluable patients (n=17, 59%, 95% CI: 39-76%) were in CR at the 18m timepoint. 2 pts have died, both of whom had relapse at 3m after ASCT. Correlative studies including immune reconstitution and MRD analyses are ongoing. Conclusions: Pembrolizumab administered after ASCT in patients with R/R DLBCL is feasible with toxicity similar to its use in the R/R setting for other hematological malignancies. The high rate of neutropenia on this study, which is not a common AE of pembro in other settings, may be related to the burden of prior therapy or possibly to an accentuated toxicity of pembro in this specific patient population. The 18-month progression-free rate did not meet the protocol-specified primary objective, and therefore does not support a larger confirmatory study. Future studies in this setting should likely focus on specific subsets of DLBCL, e.g. primary mediastinal BCL, EBV+ DLBCL, T cell histiocyte rich LCL, which may be especially sensitive to PD1 blockade. Disclosures Chen: REGiMMUNE: Consultancy; Magenta Therapeutics: Consultancy; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceuticals: Consultancy. Armand:Pfizer: Consultancy; Adaptive: Research Funding; Merck: Consultancy, Research Funding; Infinity: Consultancy; Affimed: Consultancy, Research Funding; Otsuka: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Roche: Research Funding; Tensha: Research Funding. Herrera:Seattle Genetics: Research Funding; KiTE Pharma: Consultancy, Research Funding; Gilead Sciences: Research Funding; Merck, Inc.: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Research Funding; Genentech: Consultancy, Research Funding; Immune Design: Research Funding. LaCasce:Humanigen: Consultancy, Honoraria; Bristol-Myers Squibb: Other: Data safety and monitoring board; Research to Practice: Speakers Bureau; Seattle Genetics: Consultancy, Honoraria. Jacobson:Pfizer: Consultancy; Precision Bioscience: Consultancy; Kite: Consultancy; Novartis: Consultancy; Bayer: Consultancy; Humanigen: Consultancy. Jacobsen:Merck: Consultancy; Seattle Genetics: Consultancy. Rodig:Merck & Co., Inc.: Research Funding; Affimed Inc.: Research Funding; KITE Pharma: Research Funding; Bristol-Meyers-Squibb: Research Funding. Shipp:AstraZeneca: Honoraria; Merck: Research Funding; Bayer: Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Download Full-text

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.

Download Full-text

Sequencing-Based Detection of Circulating Tumor DNA in the Autologous Stem Cell Grafts of Patients with Diffuse Large B-Cell Lymphoma Undergoing Hematopoietic Stem Cell Transplantation

Blood ◽

10.1182/blood.v126.23.3156.3156 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3156-3156 ◽

Cited By ~ 2

Author(s):

Alex F. Herrera ◽

Reid W. Merryman ◽

Katherine A. Kong ◽

Heather Sun ◽

Jennifer R. Brown ◽

...

Keyword(s):

Stem Cell ◽

Peripheral Blood ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Circulating Tumor Dna ◽

Large B Cell Lymphoma ◽

Consensus Primers ◽

Tumor Dna ◽

Large B Cell

Abstract Introduction: High dose chemotherapy followed by autologous stem cell transplantation (ASCT) cures a subset of patients with chemosensitive relapsed or refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL). Several factors associated with post-ASCT outcome have been identified, including pre-ASCT PET status, but better biomarkers are needed in order to optimally select candidates for the procedure. In other lymphoma subtypes with defining chromosomal translocations, PCR detection of pre- and post-ASCT minimal residual disease (MRD) in peripheral blood and of tumor contamination in the stem cell product is associated with inferior outcome. Until recently, MRD detection in DLBCL was limited by the rarity of detectable circulating disease using conventional techniques. The immunosequencing platform (Adaptive Biotechnologies, Corp.) is a next-generation-sequencing (NGS)-based MRD assay that detects small amounts of circulating tumor DNA (CTD) in patients with lymphoid malignancies. The assay detects CTD at diagnosis in most DLBCL patients and CTD levels track with response to induction therapy (Armand, 2013). Persistence of CTD or recurrence of CTD after completion of therapy is highly associated with DLBCL relapse (Kurtz, 2015; Roschewski, 2015). We evaluated whether CTD in autologous stem cell grafts was predictive of outcome in patients with rel/ref DLBCL undergoing ASCT. Methods: We retrospectively studied patients with rel/ref DLBCL, including transformed indolent lymphoma (TIL), who had paired archival tumor and autologous stem cell specimens and underwent ASCT at Brigham and Women's Hospital/Dana-Farber Cancer Institute from 2003-2013. Genomic tumor DNA was extracted from archival formalin-fixed paraffin-embedded (FFPE) tissue and analyzed using the NGS-based MRD assay. PCR amplification of IGH-VDJ, IGH-DJ,and IGK regions using universal consensus primers was performed followed by NGS to determine the tumor clonotype(s), defined as having a frequency > 5% in the tumor specimen. DNA from all available autologous peripheral blood or bone marrow stem cell specimens from each patient was amplified using universal consensus primers and sequenced to determine the level of CTD, defined as the number of lymphoma molecules per diploid genome. Results: We identified 98 eligible patients with rel/ref DLBCL/TIL. The median age was 60 (range 22-77) years; 63% were male; 65% had DLBCL, 29% had TIL, and 5% had primary mediastinal DLBCL; the median number of prior lines of therapy was 2 (range 2-5); all had received prior rituximab; 38% had primary refractory disease; 60% were in complete remission at ASCT; 96% received CBV conditioning. Median follow-up was 56 (range 19-123) months. The 4y progression-free survival (PFS) and overall survival (OS) in the entire cohort were 46% and 64%, respectively. Among 83 patients (85%) with sufficient DNA for clonotype determination, a clonotype was identified in 59 (71%). CTD data was complete in 53 patients (52 received peripheral blood stem cells (PBSC) and 1 received bone marrow). Eight patients (15%) had detectable CTD (CTD+) in the stem cell autografts (all PBSC) and 6/8 relapsed after ASCT. One CTD+ patient had early non-relapse mortality less than 1 month after ASCT and was never restaged. Seven of 8 CTD+ patients had TIL histology, 5 of whom relapsed (4 with aggressive lymphoma). The 4y PFS and OS in CTD+ v CTD- patients were 13% v 48% (p=0.01), and 38% v 67% (p=0.013), respectively [Figure 1]. In multivariable models including CTD status and pre-ASCT characteristics, CTD+ was the only factor associated with OS (HR 3.1, p=0.018), but was not significantly associated with PFS. Discussion: In patients with rel/ref DLBCL undergoing ASCT, the presence of CTD in the autologous stem cell graft is associated with inferior survival. CTD detection in the autograft may be more common in patients with TIL. In studies evaluating CTD detection in DLBCL, the plasma compartment has been more sensitive for detecting CTD than mononuclear cells. The use of concentrated cell specimens in this study may have decreased the sensitivity of the assay. Nevertheless, if the present findings are confirmed in a larger population, CTD detection may permit the identification of a subgroup of patients with a particularly poor outcome after ASCT, for whom alternative approaches could be considered. Figure 1. Overall (A) and Progression-Free (B) Survival in CTD+ vs CTD- Patients Figure 1. Overall (A) and Progression-Free (B) Survival in CTD+ vs CTD- Patients Figure 2. Figure 2. Disclosures Herrera: Sequenta, Inc.: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding. Kong:Adaptive Biotechnologies, Corp.: Employment, Other: Stockholder. Davids:Genentech: Other: ad board; Pharmacyclics: Consultancy; Janssen: Consultancy. Rodig:Perkin Elmer: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Research Funding. Faham:Adaptive Biotechnologies Corp.: Employment, Other: Stockholder. Armand:BMS: Research Funding; Infinity: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Sequenta, Inc.: Research Funding.

Download Full-text

Impact of the Addition of Rituximab to Initial CHOP Chemotherapy Compared with CHOP Alone in Patients with Relapsed Diffuse Large B-Cell Lymphoma Who Underwent Autologous Stem Cell Transplantation.

Blood ◽

10.1182/blood.v110.11.5124.5124 ◽

2007 ◽

Vol 110 (11) ◽

pp. 5124-5124

Author(s):

Yi-Bin Chen ◽

Ephraim P. Hochberg ◽

Yang Feng ◽

Gabriela Motyckova ◽

Donna Neuberg ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Salvage Chemotherapy ◽

Large B Cell Lymphoma ◽

Ann Arbor ◽

Localized Disease ◽

Large B Cell

Abstract Standard therapy for chemosensitive relapsed diffuse large B-cell lymphoma (DLBCL) is high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) based on the results of the Parma study (NEJM1995;333:1540–5). However, the addition of rituximab to initial chemotherapy has improved progression-free and overall survival compared with CHOP alone. Patients who relapse after R-CHOP may have disease which is less sensitive to second line therapy or, alternatively, the benefit of ASCT may be independent of the impact of rituxuimab, and, therefore, the true benefit of ASCT in current patients with relapsed DLBCL is unclear. We performed a retrospective cohort analysis of patients who received ASCT for DLBCL during the period of 1997–2006. Our goal was to evaluate the benefit of ASCT for patients with relapsed DLBCL who received R-CHOP as initial chemotherapy compared to those who were treated with CHOP alone. A total of 145 patients at first relapse with chemotherapy sensitive disease who underwent ASCT were identified. 111 received a CHOP-like regimen, and 34 received R-CHOP as their initial chemotherapy regimen. All patients received salvage chemotherapy prior to ASCT. 86.5% of CHOP patients and 88.2% of R-CHOP patients achieved a CR/CRu with their initial chemotherapy (p=0.99). At initial diagnosis, Ann Arbor stage and ECOG performance status (PS) between the two groups were also similar. The two groups of patients had significant differences in the following characteristics: median age at ASCT (51 for CHOP vs 57 for R-CHOP, p=0.002), Ann Arbor stage of disease at relapse (22.5% localized disease for CHOP vs 55.9% localized disease for R-CHOP, p=0.001), and percentage of patients who underwent nuclear imaging to evaluate response to salvage chemotherapy (37.8% in CHOP vs 79.4% in R-CHOP, p<0.0001). The majority of patients in both groups received either CBV or Bu/Cy conditioning chemotherapy at ASCT. 2-year relapse-free survival (RFS) was 57% in the CHOP group versus 35% in the R-CHOP/ASCT group (p=0.10). 2-year OS was 75% (CHOP) and 67% (R-CHOP/ASCT), respectively (p=0.09). Longer follow-up is essential and further analysis examining the potential impact of rituximab containing salvage therapy in rituximab naïve patients is needed. In conclusion, although this is a retrospective comparison, the trend toward inferior RFS and OS in the patients who initially received R-CHOP suggests that the benefit of ASCT in patients who subsequently relapse after R-CHOP may be inferior compared to patients who received CHOP alone. Figure Figure

Download Full-text