scholarly journals Karonudib Has Potent Anti-Tumor Effects in Preclinical Models of B-Cell Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 18-19
Author(s):  
Morten P Oksvold ◽  
Ulrika Warpman Berglund ◽  
Helge Gad ◽  
Baoyan Bai ◽  
Trond Stokke ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Medical Research ◽  
B Cell ◽  
Board Of Directors ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Advisory Committees ◽  
Knock Out ◽  
Non Profit

Although chemo-immunotherapy has improved survival in B-cell lymphoma patients, refractory and relapsed disease still represents a major challenge, urging for development of new therapeutics. A new approach is to target nucleotide metabolism. Karonudib (TH1579), was developed to inhibit MutT-homologue-1/Nudix hydrolase 1 (MTH1/NUDT1), an enzyme that prevents oxidized nucleotides to be incorporated into DNA. Under normal conditions with low reactive oxygen species (ROS) burden, MTH1 is not essential for cell survival. This contrasts cancer cells which frequently upregulate MTH1 to compensate for increased ROS with corresponding higher oxidized nucleotide levels, and therefore become more susceptible for MTH1 inhibition. Here, our aim was to perform preclinical testing of karonudib in B-cell lymphoma. Using two different gene expression datasets, we demonstrate that NUDT1, the gene encoding MTH1, was highly upregulated in tumor biopsies from patients with diffuse large B-cell lymphoma (DLBCL) and Burkitt's lymphoma as compared to follicular lymphoma and peripheral blood B cells from healthy donors, hence demonstrating a rationale for targeting MTH1 in aggressive B-cell lymphoma. We tested the efficacy of karonudib (0.06-1 µM) in vitro in a range of B-cell lymphoma cell lines using CellTiterGlo and by flow cytometry detection of active caspase-3 and TUNEL to identify apoptotic cells. Karonudib strongly reduced viability in all B-cell lymphoma cell lines tested (n = 12) and induced apoptosis at concentrations well tolerated by peripheral blood B cells from healthy donors. Cell cycle analysis and microscopy revealed that most cells arrested in prometaphase in the presence of karonudib. Failed spindle assembly led to mitotic arrest and subsequent apoptosis. Prometaphase arrest was seen in TP53 mutant as well as in TP53 wild type cell lines, confirming that karonudib induced apoptosis independent of TP53 mutational status. To test the efficacy of karonudib in vivo, we utilized two different lymphoma xenograft models, including an ABC DLBCL patient-derived model. Mice were treated with karonudib (90 mg/kg) or vehicle b.i.d, three times a week and tumor growth was monitored by in vivo imaging system or MR. In both models, karonudib as single agent completely controlled tumor growth, and significantly prolonged survival (p<0.0001, as compared to control mice). The specificity of MTH1 inhibitors has been debated and TH588, the first generation MTH1 inhibitor, was recently shown to bind b-tubulin and induce mitotic arrest in MTH1 knock out cell lines (Patterson et al, Cell Syst 2019). To elucidate the mechanism of karonudib in B-cell lymphoma, we generated MTH1 knock out cells using CRISPR/Cas9, and compared the functional effects of karonudib in these clones with the original lymphoma cells. We demonstrated on-target effect of the inhibitor as the MTH1 knock out clones were less sensitive towards karonudib. However, MTH1 knock out clones exhibited a similar cell cycle arrest as the wild type cells after karonudib treatment. This clearly indicates that karonudib can induce cell cycle arrest independent of MTH1, and hence has a dual mechanism of action. Our preclinical data suggest that karonudib is a promising drug with potential therapeutic use in B-cell lymphoma, and may be particular effective in aggressive lymphoma types. Disclosures Warpman Berglund: Oxcia AB: Other: shareholders; non profit Thomas Helleday Foundation for Medical Research: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Gad:Oxcia: Other: shareholder; non profit Thomas Helleday Foundation for Medical Research: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Pham:Oxcia AB: Other: Shareholder. Sanjiv:Oxcia AB: Other: Shareholder; non profit Thomas Helleday Foundation for Medical Research: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Helleday:Oxcia AB: Other: Shareholder; non profit Thomas Helleday Foundation for Medical Research: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

scholarly journals Targeting MYC-Driven B-Cell Lymphoma By Inhibition of the Histone Methyltransferase DOT1L

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2839-2839 ◽  
Author(s):  
Anagha Deshpande ◽  
Benson Chen ◽  
Parham Ramezani-Rad ◽  
Alessandro Pastore ◽  
Luyi Zhao ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Cell Lines ◽  
Target Genes ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Lymphoma Cell ◽  
Advisory Committees ◽  
Genome Wide

Abstract Aberrant activation of the MYC proto-oncogene is a recurrent feature in human B-cell lymphomas of diverse sub-types, correlating with adverse prognosis and therapy resistance. Direct pharmacological MYC-targeting has proved difficult, but recent studies have shown that targeting chromatin regulators critical for MYC-driven oncogenesis may provide alternative avenues for therapeutic intervention. Recently, it has been demonstrated that MYC-driven oncogenesis in certain solid tumors is dependent on the histone 3 lysine 79 (H3K79) methyltransferase DOT1L. We hypothesized that B-cell lymphomas with hyperactive MYC-signaling might be responsive to DOT1L inhibition. In order to test this hypothesis, we tested the effect of the DOT1L inhibitor Pinometostat (EPZ-5676) on a panel of human B-cell lymphoma cell lines featuring elevated MYC. Pinometostat treatment reduced global H3K79 methylation levels, accompanied by a time and dose-dependent decrease in proliferation of several Burkitt's lymphoma cell lines including P493-6, Daudi and Raji. We observed that key MYC-target genes including CDK4, PPAT and NPM1 were significantly downregulated upon Pinometostat treatment, suggesting that DOT1L is required for the transcriptional activation of MYC-target genes in these cells. Pinometostat-treated B-lymphoma cells showed a significant decrease of cells in S-phase compared to controls as assessed by BrdU-labeling assays. Similar results were also obtained in a panel of B-cell lymphoma cell lines with MYC-rearrangements including mantle cell lymphoma (MCL) cell lines Jeko-1, JVM2, Mino-1 and Maver-1 and the diffused large B-cell lymphoma (DLBCL) cell line Karpas 422. Next, we sought to investigate whether the DOT1L-dependence of MYC-driven B-cell lymphoma could be reproduced in a well-defined model of MYC-driven B-cell lymphoma. Towards this end, we utilized a mouse model in which expression of the Cre recombinase from a B cell specific promoter leads to ectopic expression of a transgenic human MYC allele and concomitant deletion of the tumor suppressor Pten in B cells. Similar to our in vitro studies, Pinometostat treatment led to a significant reduction in proliferation of B-cell lymphoma cells from these mice with an IC50 of 0.5 µM. Furthermore, we sought to ascertain whether these findings reflected on-target effects related to DOT1L inhibition. Therefore, we deleted DOT1L using CRISPR/Cas9 in B-cell lymphoma cell lines and assessed the effect on proliferation using competitive-proliferation assays. We observed that DOT1L-deletion progressively diminished the relative growth of anti-DOT1L sgRNA-expressing P493-6 and Jeko1 cells compared to non-targeted cells invitro. In order to test the requirement for DOT1L in lymphoma propagation in vivo, we performed intravenous injections of equal number of Jeko-1 cells with either anti-DOT1L or anti-Renilla control sgRNAs into sub-lethally irradiated non-obese diabetic/severe combined immunodeficiency mice (NOD/SCID) mice. Mice injected with control anti-Renilla sgRNAs succumbed to disease with a median latency of 34 days while the latency of disease in the anti-DOT1L sgRNA cohort was 45 days. In summary, DOT1L depletion significantly delayed disease latency in this invivo disseminated model of B-cell lymphoma (P=0.02). We then performed transcriptomic analyses of Pinometostat-treated B-cell lymphoma cell lines compared to DMSO-treated counterparts using RNA-seq. Gene-set enrichment analysis (GSEA) of RNA-seq data from three different B-cell lymphoma cell lines demonstrated that Pinometostat treatment significantly decreased the expression of MYC-target genes. In order to investigate the intriguing role of DOT1L in regulating MYC-target gene expression, we used ChIP-seq to assess the genome-wide occupancy of MYC following DOT1L inhibitor treatment. Strikingly, our studies demonstrated that DOT1L inhibition significantly reduced the chromatin occupancy of MYC. Taken together, our experiments demonstrate the role of DOT1L in MYC-driven B-cell lymphoma pathogenesis invitro and invivo. Furthermore, our genome-wide studies demonstrate the importance of DOT1L for genomic MYC occupancy. Based on these findings, we propose that therapeutic DOT1L targeting may be a viable strategy in MYC-driven B-cell lymphoma. Disclosures Weigert: Roche: Research Funding; Novartis: Research Funding. Rickert:Pfizer: Employment. Ren:Elli Lilly: Consultancy, Membership on an entity's Board of Directors or advisory committees; Arima Genomics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Deshpande:Salgomed Therapeutics: Membership on an entity's Board of Directors or advisory committees; A2A Pharma: Membership on an entity's Board of Directors or advisory committees.

Analysis of Adct-602 Pre-Clinical Activity in B-Cell Lymphoma Models and Identification of Potential Biomarkers for Its Activity

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 10-11
Author(s):  
Eugenio Gaudio ◽  
Chiara Tarantelli ◽  
Luciano Cascione ◽  
Filippo Spriano ◽  
Gaetanina Golino ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Cell Lines ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Lymphoma Cell ◽  
Advisory Committees ◽  
Travel Grant

Introduction. CD22 is a cell surface marker expressed by the vast majority of normal and neoplastic B-cells. ADCT-602 is an antibody drug conjugate (ADC) composed of Emab-C220, an engineered version of the anti-CD22 humanized IgG1 antibody epratuzumab, site-specifically conjugated to SG3249, which includes the DNA minor groove crosslinking pyrrolobenzodiazepine (PBD) dimer SG3199 linked to the antibody via a protease-cleavable linker (Zammarchi et al, ASH 2016). ADCT-602 is currently being tested in a phase I/II clinical trial (NCT03698552) in recurrent or refractory B-cell acute lymphoblastic leukemia (B-ALL) patients. Here, we assessed its in vitro anti-lymphoma activity, also exploring for potential biomarkers and mechanisms of resistance. Methods. Fifty-seven human lymphoma cell lines were exposed to ADCT-602, an isotype-control ADC and the PBD dimer SG3199 as single agents for 96h, followed by MTT proliferation assay and IC50 calculation. Quantum Simply Cellular (QSC) microspheres were used for the quantitative determination of cellular CD22 antigen expression (Bangs Laboratories. Inc). Differences in IC50 values among lymphoma subtypes were calculated using the Wilcoxon rank-sum test. Statistical significance was defined by P values of 0.05 or less. Sensitivity analysis to ADCT-602 was performed by integrating different omics data, such as Illumina HT-12 microarray data (GSE94669), HTG EdgeSeq Oncology Biomarker Panel data (GSE103934) and DNA copy number variations. Results. The median IC50 for ADCT-602 was 200 pM (95%C.I, 90-400 pM) in 48 B-cell lymphoma lines (including three Hodgkin lymphoma cell lines), and 1850 pM in nine T-cell lymphoma lines (95%C.I, 700-15000 pM). ADCT-602 was more active in B- than in T-cell lymphomas, as expected based on the pattern of CD22 expression (P < 0.005). Focusing on B-cell lymphomas, ADCT-602 in vitro activity was not correlated with its target expression measured both at the cell surface protein level (absolute quantitation, n=48, r=0.06 P=ns) and at the RNA level (Illumina HT-12 arrays, n=42, r=0.28, P=ns; HTG EdgeSeq Oncology Biomarker Panel, n=36, r=0.24, P=ns). In vitro activity was stronger in marginal zone lymphoma (MZL) cell lines than other B-cell lymphoma models (median IC50s 62.5 vs 312.5 pM; P = 0.03) as well as in diffuse large B-cell lymphoma (DLBCL) cell lines with BCL2 and MYC translocations (DHT DLBCL) versus DLBCL with none or a single translocation (median IC50s 25 vs 400 pM, P = 0.03). No associations were seen with TP53 status or other histology (mantle cell lymphoma, DLBCL, DLBCL cell of origin). We then exploited the gene expression profiling data using the Illumina HT-12 microarray gene expression technology. Within all the B-cell lymphoma cell lines (sensitive, n= 25; resistant, n= 23) we identified 1.207 genes down-regulated (FC-) and 1,104 genes up-regulated (FC+) in resistant cell lines. To delineate the pathways associated with the different degrees of sensitivity to ADCT-602, we performed a gene set enrichment analysis (GSEA; GSEA hallmarks and c2.common pathways) on the pre-ranked limma data. Transcripts up-regulated in resistant cell lines were enriched of genes coding for proteins involved in respiratory electron transport, oxidative phosphorylation and proteasome. Conversely, transcripts up-regulated in the sensitive cell lines were enriched of genes coding for proteins involved in inflammation, chemokine signaling, p53 response, IL2/STAT5 signaling, hypoxia, TGF-beta and interferon response. Similar gene signatures were picked up using the HTG platform, which can be applied to formalin-fixed paraffin-embedded clinical specimens, despite the smaller number of investigated genes. Conclusion. ADCT-602 showed in vitro anti-tumor activity across a large panel of B-cell lymphoma models of various histology. Expression signatures and other features (MZL or DHT DLBCL histology), but not the expression levels of its target, were associated with different sensitivity to the ADC. Our data supports the clinical evaluation of ADCT-602 in patients with B-cell lymphoma in addition to B-ALL. Disclosures Zucca: Kite: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Membership on an entity's Board of Directors or advisory committees; Abbvie: Other: Travel Grants; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Research Funding; Celltrion Healthcare: Membership on an entity's Board of Directors or advisory committees. Stathis:PharmaMar: Other: Travel Grant; Member of the steering committee of the trial of this abstract: Other; Loxo: Honoraria, Other, Research Funding; Cellestia: Research Funding; Roche: Other, Research Funding; Novartis: Other, Research Funding; Bayer: Other, Research Funding; Merck: Other, Research Funding; Pfizer: Other, Research Funding; MEI Pharma: Other, Research Funding; ADC Therapeutcis: Other, Research Funding; Abbvie: Other: Travel Grant. Van Berkel:ADC-Therapeutics: Current Employment, Current equity holder in publicly-traded company. Zammarchi:ADC-Therapeutics: Current Employment, Current equity holder in publicly-traded company. Bertoni:ADC-Therapeutics: Research Funding; Bayer AG: Research Funding; Helsinn: Research Funding; Menarini Ricerche: Consultancy, Research Funding; NEOMED Therapeutics 1: Research Funding; Nordic Nanovector ASA: Research Funding; Astra Zeneca: Other: travel grant; Amgen: Other: travel grant.

Sirtuin Inhibition in Combination with Histone Deacetylase (HDAC) Inhibition Is Effective Therapy for Aggressive B-Cell Lymphomas in Both Pre-Clinical and Clinical Studies of Disease.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2725-2725
Author(s):  
Jennifer E Amengual ◽  
Sean Clark-Garvey ◽  
Matko Kalac ◽  
Luigi Scotto ◽  
Enrica Marchi ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
Hdac Inhibitors ◽  
B Cell Lymphoma ◽  
Advisory Committees ◽  
Heavily Pretreated ◽  
Pretreated Patients ◽  
Grade 3

Abstract Abstract 2725 There is a critical inverse relationship between Bcl6 and p53, the functional status of which is linked to each transcription factor's degree of acetylation. Deacetylation of Bcl6 is required for its transcriptional repressor effects allowing for the oncogene to drive lymphomagenesis. Conversely, acetylation of p53 is activating when class III HDACs, or sirtuins, are inhibited by agents such as niacinamide. One therapeutic strategy for lymphomas addicted to Bcl6 overexpression is the pharmacologic modification of Bcl6 and p53 using HDAC inhibitors. Here we report on the combination of sirtuin inhibitor, niacinamide (NIA), plus HDAC inhibitors in preclinical models, and a phase Iclinical trial in patients with relapsed or refractory lymphoma. Cytotoxicity was measured in 8 diffuse large B-cell lymphoma (DLBCL) cell lines (4 ABC and 4 GC) with 4 HDAC inhibitors (romidepsin, vorinostat, panobinostat and belinostat) in combination with NIA. Synergy was achieved predominantly in GC vs ABC cell lines, with romidepsin plus NIA having the greatest synergy. Acetylation of Bcl6 was observed in cells treated with HDAC inhibitors, or the combination, compared with control as measured by immunoprecipitation. Cells treated with the combination had increased acetylated-p53, p21 and BLIMP-1 content. In vivo effects of the drug combination were studied in a double transgenic mouse model of aggressive spontaneous B-cell lymphoma (l-myc overexpressing crossed with CD19-tagged mCherry luciferase). These mice express equal basal levels of Bcl6 and p53 as GC cell lines. Mice treated with NIA and romidepsin for 5 hrsachieved increased acetylation of Bcl6 and p53, and accumulation of p21 and BLIMP1. Mice treated with the combination exhibited decreased tumor burden achieving complete responses (CR=30%) compared to single agents and control (CR=0) after 3 weeks of treatment. The combination was well tolerated. Based on this rationale, a phase I clinical trial of vorinostat plus NIA was conducted in patients with relapsed or refractory lymphoid malignancies. Twenty-five patients enrolled between 3/2009 and 3/2011. Median age was 43 (range:25–75), 44% female, and 84% white. This was a group of heavily pretreated patients, median number of therapies was 4; with 16 auto- and 4 allo-transplants. Patients were treated on a 14/21 day cycle. Vorinostatwas given orally as a fixed dose of 400 mg daily. NIA was given orally, daily, in escalating doses from 20–100 mg/kg. A range of 1–18 cycles were given. The most common toxicities included fatigue (84%), nausea (80%), diarrhea (72%), and anorexia (56%). There was a DLT in cohort 4 (vorinostat 400 mg/NIA 80 mg/kg) of grade 3 infection. Two DLTs occurred at dose level 5 (vorinostat 400mg/NIA 100 mg/kg), a grade 4 transaminitis, not otherwise explained; and grade 4 hypotension. These events led to the determination of dose cohort 4 as the MTD. In total, there were 12 different grade 3–4 toxicities including neutropenia, infection, and transaminitis that occurred in 11 patients. There were two deaths that occurred within safety follow-up period in patients who had fulminant disease progression (POD); none of these events were related to the study drugs. Overall this was a very well tolerated treatment regimen and the responses seen were with the weakest HDAC and sirtuininhibitors available given to extremely heavily pretreated patients. The overall response rate was 24%, with 2 CRs and 3 partial responses (PR). CRs were maintained for 13 to 18 weeks. All PRs were in HL patients with 6–10 prior regimens including auto- and allo-transplants, and maintained for 4–13 weeks. Twelve patients achieved stable disease (SD) (57%), 2 of whom achieved near-PR. Of the 7 patients with germinal center derived lymphomas (4 DLBCL + 3 FL), there was 1 CR, 3 SD, and 3 POD. The preclinical and clinical data establish proof-of-principle that the Bcl6: p53 axis may be therapeutic targets, and that acetylation of these transcription factors could potentially serve as biomarkers for activity. Currently we are exploring new, more potent sirtuin inhibitors with second generation HDAC inhibitors, and working to further define mechanism of action. By targeting discrete molecular subtypes of DLBCL it may be possible to increase complete response rates in this challenging disease. Disclosures: Amengual: Acetylon Pharmaceuticals, Inc: Research Funding. Off Label Use: Vorinostat is not FDA approved for the treatment of B-cell and Hodgkins lymphoma. Niacinamide is not FDA approved for the treatment of lymphoma. Neylon:Seattle Genetics, Inc: Consultancy, Speakers Bureau; Allos Therapeutics, Inc: Speakers Bureau. Zain:Allos Therapeutics, Inc: Speakers Bureau; Seattle Genetics, Inc: Speakers Bureau. O'Connor:Allos Therapeutics, Inc: Consultancy; Seattle Genetics, Inc: Membership on an entity's Board of Directors or advisory committees; Millenium Pharaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics, Inc: Consultancy.

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

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

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

scholarly journals Intrathecal (IT) Chemotherapy for Central Nervous System (CNS) Prophylaxis in Diffuse Large B-Cell Lymphoma (DLBCL): A Single Centre Retrospective Observational Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 18-19
Author(s):  
Luke Attwell ◽  
Benjamin Gray ◽  
Rachel Hall ◽  
Sally Killick ◽  
Helen McCarthy ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Advisory Committees ◽  
Cns Prophylaxis ◽  
Large B Cell Lymphoma ◽  
Cns Relapse ◽  
Educational Meetings ◽  
Large B Cell

Introduction: CNS relapse of DLBCL is associated with poor prognosis. Estimated incidence varies between 1.9 and 8.4%1. The CNS-International prognostic index (IPI)2 help risk stratify and estimate the 2-year risk of CNS relapse in DLBCL patients treated with R-CHOP chemotherapy. CNS prophylaxis is indicated in patients with a high risk of CNS relapse (a score of ≥4 equated to a 10.2% risk). High-risk DLBCL patients outside the CNS-IPI system include double/triple-hit (MYC/BCL-2/BCL-6 translocations) lymphoma, HIV lymphoma, testicular lymphoma, primary cutaneous lymphoma-leg type, stage IE breast lymphoma3. IT methotrexate or cytarabine administered during the course of systemic chemotherapy has been the most widely employed method of CNS prophylaxis but there is paucity of data validating its efficacy. Aim: The primary aim of the study was to evaluate the CNS relapse rates in DLBCL patients who received CNS prophylaxis. Patients and Methods: This was a single-centre retrospective observational study conducted in a district general hospital. Data was extracted from the regional (Dorset Cancer Network) DLBCL database and laboratory reports for CSF analysis at the time of the first intrathecal chemotherapy. Medical records of patients with DLBCL who received CNS prophylaxis were evaluated for the following patient-related and disease-related demographics: age at diagnosis, gender, stage, systemic treatment, CNS prophylaxis, treatment response, remission duration, systemic relapse rates, CNS relapse rates and survival. CNS-IPI scores were retrospectively calculated and additional indications evaluated for patients who received CNS prophylaxis. Results: Between 2013 and 2018, 178 patients were diagnosed with DLBCL. All patients were treated with RCHOP chemo-immunotherapy. CNS prophylaxis was administered in 47 (26%) patients. Median age was 69 years (range 20-86 years) and 62% were males. All 47 patients (100%) received IT methotrexate as CNS prophylaxis, with 43 (91%) receiving all of the planned 4 doses of IT methotrexate 12.5 mg each. A CNS-IPI score of ³4 was present in 31 (66%) patients, and a score of 2-3 in 9 (19%) patients. Additional risk factors identified included testicular lymphoma in 3 patients, breast lymphoma in 2 patients and oropharyngeal lymphoma in 2 patients. Ten (21%) patients received their treatment at the outset with courses 1-4 of R-CHOP. Of the 47 patients who received CNS prophylaxis, 5 (10%) relapsed; all had isolated CNS lymphoma at relapse. Median time to CNS relapse was 25 months (range 12-36 months) from initial diagnosis of DLBCL. Median survival after CNS relapse was 5 months (range 2-9 months). Of the remaining 141 patients, 2 patients relapsed with isolated CNS lymphoma. Conclusion: Although the overall incidence was low (4%), CNS relapse was observed in 10% of high-risk patients all of whom received CNS prophylaxis with IT methotrexate. The efficacy of CNS prophylaxis with IT chemotherapy remains unproven. There is no randomised study to show that IT prophylaxis alone is effective. Current British guidelines recommend high-dose intravenous methotrexate over IT methotrexate if patient's physiological fitness and renal function are acceptable4. The median age in our cohort was 69 years which makes it challenging to deliver dose-intensive systemic therapy concurrently with intravenous high-dose methotrexate. The role of CNS prophylaxis in high-risk patients including its efficacy and safety in older patients need further evaluation in prospective randomised studies. References Eyre T et al.Efficacy of central nervous system prophylaxis with stand-alone intrathecal chemotherapy in diffuse large B-cell lymphoma patients treated with anthracycline-based chemotherapy in the rituximab era: a systematic review. Hematologica. 2019;105(7):1914-1924.Norbert Schmitz et al.CNS International prognostic Index: A risk model for CNS relapse in patients with diffuse large B-cell lymphoma treated with R-CHOPJ Clin Oncol 2016; 34:3150-3156.Andrew D Zelenetz et al.National Comprehensive Cancer Network (NCCN) Guidelines: B-Cell Lymphomas.Version 2.2020.Pamela McKay et al.The prevention of central nervous system relapse in diffuse large B-cell lymphoma: a British Society for Haematology good practice paper. Onlinelibrary.wiley.com. 2020. Available from: https://onlinelibrary.wiley.com/doi/epdf/10.1111/bjh.16866 Disclosures Hall: Janssen:Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored for educational meetings;Karyopharm:Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored for educational meetings;Takeda:Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored for educational meetings;Celgene:Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored for educational meetings.Killick:Celgene:Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending educational meetings;Jazz Pharmaceuticals:Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending educational meetings;Novartis:Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending educational meetings;Gilead:Honoraria, Other: Support for attending education meetings.McCarthy:Janssen:Honoraria;Abbvie:Membership on an entity's Board of Directors or advisory committees.Walewska:AbbVie:Other: sponsored for educational meetings, Speakers Bureau;Janssen:Other: sponsored for educational meetings, Speakers Bureau;Gilead:Speakers Bureau;Astra Zeneca:Membership on an entity's Board of Directors or advisory committees.Chacko:Astellas:Honoraria;Daiichi-Sankyo:Honoraria;Novartis:Honoraria, Other: Travel Grants;Gilead:Other: Travel grants;Jazz Pharmaceuticals:Other: Travel grants;Celgene:Other: Travel grants.

IVAC +/- R for Relapsed or Refractory B-Cell Non-Hodgkin Lymphomas: Real-World Experience in the Modern Era

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 10-10
Author(s):  
Michael J Buege ◽  
Phuong H Dao ◽  
Esther Drill ◽  
Andréa C LeVoir ◽  
Terry Pak ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Board Of Directors ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Hematologic Toxicity ◽  
Low Grade ◽  
Advisory Committees ◽  
Prophylactic Measures ◽  
Grade 3

Introduction Part B of the modified Magrath regimen (ifosfamide, etoposide, and cytarabine; IVAC) with or without rituximab (R) is utilized as a standalone regimen in the management of relapsed/refractory Burkitt lymphoma and other non-Hodgkin lymphomas (NHL). There are no comparative or prospective data and a paucity of retrospective, non-comparative data to support use of this regimen. A small retrospective study described second-line IVAC use without R in a mixed cohort of patients with diffuse large B-cell lymphoma (DLBCL) or peripheral T-cell lymphoma, suggesting utility as a bridge to hematopoietic cell transplantation (HCT) (Pereira J, et al. Leuk Res. 2006 Jun;30(6):681-5). The activity of this regimen in B-cell NHL, particularly in conjunction with R, and its toxicity remain incompletely described. In this study, we describe our institutional experience with IVAC +/- R in relapsed/refractory B-cell NHL. Methods We reviewed all patients with relapsed/refractory B-cell NHL treated with IVAC +/- R between 1 January 2004 and 30 September 2019 at Memorial Sloan Kettering Cancer Center to assess efficacy and toxicity. Patients who received IVAC as part of sequential or alternating chemotherapy were excluded. Standard dosing consisted of ifosfamide 1500mg/m2 IV over 60min days 1-5, etoposide 60mg/m2 IV over 60min days 1-5, cytarabine 2000mg/m2 IV over 3 hours every 12 hours days 1-2, with or without rituximab 375mg/m2 IV day 0 or 1 in 21- to 28-day cycles (Lacasce A, et al. Leuk Lymphoma. 2004 Apr;45(4):761-7). Results Cohort and treatment characteristics are described in Table 1. Among 54 eligible patients (median age 51 years), 76% had DLBCL; 30% had lymphomatous central nervous system involvement at the time of initiating IVAC. Patients had received median 2 prior lines of therapy, with the last dose of the most recent line of therapy administered a median of 3 weeks prior to initiating IVAC. Patients received median 2 cycles of IVAC +/- R; 48% received IVAC-R. Prophylactic antimicrobials with cycle 1 were utilized in 94%. Most patients received herpesvirus- (81%) and Pneumocystis- (80%) directed prophylaxis; broad-spectrum prophylaxis with a fluoroquinolone was less common (24%). Primary granulocyte colony stimulating factor (GCSF) was utilized in 93% of patients with cycle 1; primary or secondary GCSF was utilized in 94% of cycles. Efficacy outcomes are described in Table 1. Objective response rate (ORR) among 46 evaluated patients was 48%; 17% achieved CR. ORR did not vary significantly between patients who did or did not receive R (58% vs 42%; p = 0.5) but was associated with number of IVAC cycles administered (among responders, 69% received 3-4 cycles while 31% received 1-2 cycles; p &lt; 0.001). At median follow-up of 22 months, median progression-free survival (PFS) and overall survival (OS) were 3.1 months and 4.9 months, respectively (Figure). In Cox proportional hazard regression analysis of survival, patients who received R with every cycle (p = 0.025) and received 3 or more cycles (p &lt; 0.001) experienced significantly longer PFS. Patients who achieved CR (p &lt; 0.001) or PR (p = 0.003), received R with every cycle (p &lt; 0.001), received 3 or more cycles (p &lt; 0.001), or underwent subsequent HCT or CAR-T cell therapy (p = 0.001) experienced significantly longer OS. Toxicity outcomes are described in Table 2. Grade ≥ 3 anemia (93%), neutropenia (94%), and thrombocytopenia (100%; all grade 4) were common, regardless of number of cycles received. Febrile neutropenia (FN) occurred in 65% of patients and complicated 47% of cycles; documented infection occurred in 44%. Risk of FN and infection did not appear to be influenced by use of antimicrobial or GCSF prophylaxis. Grade ≥ 3 elevations in AST/ALT or total bilirubin were uncommon (5.6% and 9.3%, respectively). Neurotoxicity attributed to cytarabine or ifosfamide occurred in 17% of patients and was usually low-grade; hemorrhagic cystitis occurred in one patient. In patients for whom cause of death was documented (n = 37), mortality was attributed to a treatment-related complication in 19%. Conclusion IVAC-R may be a useful bridging therapy for patients with relapsed/refractory B-cell NHL who are planned for HCT. However, its potential for profound hematologic toxicity and life-threatening complications despite prophylactic measures requires careful consideration of less toxic alternatives. Disclosures Straus: Elsevier: Membership on an entity's Board of Directors or advisory committees, Other: CME writer; Targeted Oncology: Consultancy, Speakers Bureau; Imedex, Inc.: Speakers Bureau; NY Lymphoma Rounds: Consultancy; Takeda Pharmaceuticals: Research Funding, Speakers Bureau; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees; OncLive: Speakers Bureau; ASH: Other: Conference in December 2019 on HL to other physicians during ASH; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees.

B Cell Lymphoma In Association with Multiple Myeloma: Analysis of the Biologic Relationship

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1590-1590 ◽  
Author(s):  
Anuj K. Mahindra ◽  
Aliyah R. Sohani ◽  
Christiana E. Toomey ◽  
James S. Michaelson ◽  
Jeffrey A. Barnes ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
B Cell ◽  
Board Of Directors ◽  
Light Chain ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Prior History ◽  
Advisory Committees ◽  
Age Of Diagnosis ◽  
History Of

Abstract Abstract 1590 Background: The occurrence of a secondary lymphoma in patients with a prior history of B-cell lymphomas has been reported.1, 2 There are few reported occurrences of Multiple Myeloma (MM) in patients (pts) with a prior history of lymphoma and the biologic relationship between the two neoplasms in such cases is unknown. Methods: We queried our IRB approved clinicopathologic database of hematologic malignancies for patients with lymphoma and MM. Of the 4165 pts with B-cell lymphoma and 804 pts with MM, 6 pts with a history of B-cell lymphoma developed MM and 1 patient with a prior history of MM developed a B-cell lymphoma. We describe the morphology, immunophenotype, and clinical features of the 7 pts. The clonal relationship of the 2 components was analyzed using sequencing analysis of immunoglobulin heavy chain variable region (IgVH) genes and by light chain restriction. Results: There were 5 men and 2 women (median age of diagnosis of lymphoma, 65 years; median age of diagnosis of MM, 71 years). The pts with lymphoma included 2 pts with diffuse large B cell lymphoma, 2 pts with small lymphocytic lymphoma, 2 pts with follicular lymphoma and 1 patient with lymphoplasmacytic lymphoma. The development of MM was metachronous in 5 cases, following B-cell lymphoma by 3 years to 23 years and synchronous in 1 case. In 1 patient, the B-cell lymphoma developed 6 years after the diagnosis of MM. 6 pts achieved complete remission after treatment for lymphoma and 1 patient is ongoing treatment. 6 of the 7 pts required treatment for MM soon after diagnosis. 1 patient has smoldering MM and continues to be observed 57 months after diagnosis. FISH analysis indicated IgH rearrangement in 3 pts with MM; 1 patient with 17p deletion and monosomy 13; 3 pts had normal FISH and metaphase cytogenetics. In 3 pts, both neoplasms were kappa light chain restricted; in 1 patient both were lambda restricted; in 1 patient, the lymphoma was lambda light chain restricted while the MM was kappa light chain restricted and the reverse in another pt; in 1 patient the B-cell lymphoma was light chain negative and the MM was kappa restricted. IgVH rearrangement studies in 4 patients in whom tissue samples were available indicated that the two were clonally unrelated in 3 patients and related in only 1 patient. Conclusion: Clonality analysis of rearranged immunoglobulin genes from patients with both B-cell lymphoma and MM provide evidence of separate clonal origins of the two tumors in the majority of cases, thus excluding secondary transformation of the original B-cell clone. The presence or absence of a genetic predisposition to the development of multiple B cell malignancies requires further study.3 Disclosures: Off Label Use: The combination of lenalidomide and everolimue is an off label use in multiple myeloma. Abramson:Genentech: Consultancy; Novartis: Consultancy. Raje:Amgen: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Millenium: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Acetylon: Research Funding.

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

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

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

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

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

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

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