The Germinal Center/Activated B-Cell Subclassification Has a Prognostic Impact for Response to Salvage Therapy in Relapsed/Refractory Diffuse Large B-Cell Lymphoma: A Bio-CORAL Study

Thiéblemont, Catherine; Brière, Josette; Mounier, Nicolas; Voelker, Hans-Ullrich; Cuccuini, Wendy; Hirchaud, Edouard; Rosenwald, Andreas; Jack, Andrew; Sundström, Christer; Cogliatti, Sergio; Trougouboff, Philippe; Boudová, Ludmila; Ysebaert, Loïc; Soulier, Jean; Chevalier, Catherine; Bron, Dominique; Schmitz, Norbert; Gaulard, Philippe; Houlgatte, Rémi; Gisselbrecht, Christian

doi:10.1200/jco.2011.35.4423

Cited by 247 publications

(174 citation statements)

References 40 publications

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Section: Discussionmentioning

confidence: 66%

“…ABC-DLBCL lymphomas treated with R-CHOP typically have an inferior EFS and OS compared with GCB-type tumors. 6,32,33 In this study, pSTAT3, although more frequent in non-GCB tumors, did not correlate with EFS possibly because of the small numbers of patients in this study or the fact that ER-CHOP has potentially improved the EFS of the non-GCB type DLBCL.A number of studies have evaluated translocations of MYC with immunoglobulin genes in Burkitt lymphoma and DLBCL. 16 Although the incidence of MYC translocation in DLBCL is only 5%-10%, these cases have an unfavorable prognosis.…”

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confidence: 87%

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Expression of Myc, but not pSTAT3, is an adverse prognostic factor for diffuse large B-cell lymphoma treated with epratuzumab/R-CHOP

Gupta¹,

Maurer²,

Wellik³

et al. 2012

Blood

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35% of cases were pSTAT3-positive, and pSTAT3 positivity was more frequent in the non-GCB (P ‫؍‬ .06) type but did not correlate with event-free survival (EFS). Myc expression was observed in 50% of cases and was more frequent in non-GCB type (P ‫؍‬ .07). Myc-positive cases had inferior EFS in all patients, including the GCB and pSTAT3-positive cases, were more likely to express Myc (P ‫؍‬ .06). Myc translocations involving the major breakpoint regions were found in 10% (3 of 29) of cases, and all 3 cases were GCB and had an inferior EFS (P ‫؍‬ .09). pSTAT3, but not Myc expression, was correlated with elevated pretreatment serum cytokines, such as IL-10 (P ‫؍‬ .05), G-CSF (P ‫؍‬ .03), and TNF-␣ (P ‫؍‬ .04). pSTAT3 IHC in DLBCL tumors has the potential to identify patients for STAT3 pathway-directed therapy; Myc IHC is a potential marker for inferior EFS in GCB patients. (Blood. 2012; 120(22):4400-4406) IntroductionThe most significant advance in the treatment of diffuse large B-cell lymphoma (DLBCL) over the past 15 years has been the addition of rituximab to standard CHOP chemotherapy (R-CHOP). [1][2][3] We recently demonstrated in a phase 2 study (N0489; www.clinicaltrials.gov, #NCT00301821) that the anti-CD22 monoclonal antibody epratuzumab can be successfully added to R-CHOP (ER-CHOP) without additional toxicity and with potentially improved survival parameters. 4 Despite these advances, 30%-40% of patients still relapse and die of disease. Current pathology practice classifies DLBCL into at least 3 distinct subtypes: germinal center B cell-like (GCB), activated B cell-like (ABC), and primary mediastinal B-cell lymphoma by gene expression profiling or immunohistochemistry (IHC). 5,6 These classifications are being evaluated in new DLBCL trials, and there have been some reports suggesting that agents, such as bortezomib and lenalidomide, are more effective in non-GCB type DLBCL. 7,8 To improve outcomes for DLBCL patients, it is necessary to identify additional novel targets within GCB and non-GCB classifications to further stratify patients for prognosis and assist in choosing therapy for the individual patient.Signal transducer and activator of transcription 3 (STAT3) is a latent cytoplasmic transcription factor that resides in the cytoplasm. 9 Phosphorylation of STAT3 (pSTAT3) at its Tyr-705 residue (pSTAT3 Tyr705 ) leads to activation and translocation to the nucleus where pSTAT3 regulates several target genes, such as MYC. 10,11 Constitutively active STATs (particularly STAT3 and STAT5) contribute to the malignant phenotype in both human cancer cell lines and primary tumors. 12,13 Recently, it has been reported that STAT3 is overexpressed in ABC-type DLBCL human cell lines. 14,15 The role of pSTAT3 as a prognostic factor in DLBCL patients treated with R-CHOP-based therapies is unknown.Translocations involving the MYC gene at 8q24 are associated with Burkitt lymphoma. 16 Moreover, MYC translocations have been reported to occur in DLBCL with a frequency of 5%-10%. [17][18][19] Myc protein can be expressed ...

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Section: Discussionmentioning

confidence: 66%

mentioning

confidence: 87%

Expression of Myc, but not pSTAT3, is an adverse prognostic factor for diffuse large B-cell lymphoma treated with epratuzumab/R-CHOP

Gupta¹,

Maurer²,

Wellik³

et al. 2012

Blood

View full text Add to dashboard Cite

show abstract

“…With R-ICE, there was no difference in PFS according to the cell of origin. 11 In a non-randomized trial of patients with relapsed and refractory DLBCL, bortezomib plus dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin) showed a significantly improved response rate (83% vs 13%, Po0.001) and median OS (10.8 vs 3.2 months, P ¼ 0.003) in non-germinal center B cell relative to germinal center B cell DLBCL. 12 These results suggest that specific salvage regimens may be more effective, depending on the molecular subtype.…”

Section: Modification Of Salvage Therapymentioning

confidence: 99%

Allogeneic hematopoietic cell transplantation for diffuse large B cell lymphoma: who, when and how?

Klyuchnikov

Bacher

Kroll

et al. 2013

Bone Marrow Transplant

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Despite overall improvements in outcomes of patients with diffuse large B cell lymphoma (DLBCL), B30-40% of patients develop relapsed or refractory disease. For patients with chemo refractory disease, or recurrent disease following autologous hematopoietic SCT (auto-HCT), the prognosis is poor, with no consensus on the optimal therapy. Currently, owing to the graft vs lymphoma effect, hematopoietic allogeneic hematopoietic cell transplantation (allo-HCT) is the only potentially curative option for such patients. In addition, many patients who are considered today for auto-HCT actually have a low likelihood of benefit. For example, a patient with prior rituximab exposure who relapses within 1 year of diagnosis and has a second-line age-adjusted International Prognosis Index of 2 or 3 at relapse has a o25% chance of being cured by auto-HCT. It is possible that such patients may be better served with an allo-HCT. Unfortunately, in many cases, allo-HCT applicability is limited by patient age, comorbidities, performance status and treatment-related toxicities. Recent attempts to improve the efficacy of auto-HCT, such as incorporating radio-immunotherapy into the conditioning regimen, have not resulted in improved outcomes. However, incorporation of novel agents such as antiprogrammed death-1 antibodies as maintenance therapy after auto-HCT show promise. Allo-HCT in relapsed/refractory DLBCL patients can result in a 30-40% PFS rate at 3 years, in part due to a graft vs DLBCL effect. While reduced-intensity/nonmyeloablative conditioning is increasingly being used, certain patients may benefit from myeloablative conditioning. We present an algorithm intended to discriminate which relapsed and refractory DLBCL patients are most likely to benefit from auto-HCT vs allo-HCT. New approaches, using novel agents that target the molecular heterogeneity in DLBCL, will be an essential component of moving the field forward. Lastly, we propose a prospective registry-based study as the only feasible mechanism to define the optimal position of allo-HCT in the overall treatment strategy for DLBCL. It is hoped that this review will promote the development of prospective multicenter efforts to determine whether such patients do, in fact, benefit from earlier and/or more effective implementation of allo-HCT.

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“…29 Thus, MYC rearrangements indicate poor response to salvage therapy with BEAM and autologous transplantation in the salvage therapy setting. 30,31 Recently, a biologic prognostic model was established based on immunohistochemical staining in combination with IPI, providing a practical method for stratifying patients for riskadapted therapies. 32 Expanding on the data of our risk-adapted approach, we propose the following hypothetical treatment algorithm to be confirmed in prospective studies:…”

Section: Discussionmentioning

confidence: 99%

Risk-adapted, treosulfan-based therapy with auto- and allo-SCT for relapsed/refractory aggressive NHL: a prospective phase-II trial

Koenigsmann

Casper

Kahl

et al. 2013

Bone Marrow Transplant

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Since the outcome of relapsed/refractory aggressive non-Hodgkin's lymphoma (NHL) is highly variable, a risk-adapted treatment approach was evaluated. After two cycles of DHAP, patients received high-dose treosulfan/etoposide/carboplatinum (TEC) and autologous stem cell rescue. After TEC, low-risk patients with late relapse (41 year after first CR who achieved CR after DHAP received no further treatment. Patients with late relapse who achieved CR or PR only after TEC underwent a second cycle of TEC. High-risk patients with early relapse/refractory disease received treosulfan/fludarabine followed by allogeneic transplantation. Rituximab was added in patients with B-cell lymphoma (86%). At entry, 36% of all 57 patients had refractory disease, 32% early and 32% late relapse. During DHAP treatment, progression occurred in 32% of patients. Of 33 patients who received TEC, 5 received second TEC and 15 allogeneic transplantation. Main toxicity after TEC was oral mucositis (CTC grades 3 and 4 in 50% and 13%, respectively). In total, 42% patients achieved CR. Median OS was 21.4 months for all patients and 32.6 for those who underwent allogeneic transplantation. International prognostic index (IPI) at study entry was highly discriminative at predicting OS (Po0.0001). Risk-adapted, treosulfan-based therapy with auto-and allo-SCT is feasible. Long-term survival is possible with allogeneic transplantation. Keywords: relapsed non-Hogkin's lymphoma; treosulfan; autologous transplantation; allogeneic transplantation; risk-adapted therapy INTRODUCTION High-dose chemotherapy with auto-SCT has been the standard approach for relapsed aggressive non-Hodgkin's lymphoma (NHL) since the PARMA trial, 1 which reported a higher 5-year OS rate (53%) compared with that of conventional chemotherapy only (32%). Disease-free survival after a high-dose therapy is higher in cases of chemosensitive relapse than in cases of chemoresistant relapse, 2 and cytoreductive salvage therapy is more efficient after late relapse than after early relapse. 3 The application of allogeneic transplantation for these patients has evolved at a slower pace, 4-8 and a treatment-related mortality greater than 40% has led to the questioning of its role. 9 Treosulfan is an alkylating agent with a steep dose-response curve. High-dose treosulfan and fludarabine before allogeneic transplantation has shown efficacy with little toxicity in AML and myelodysplastic syndromes. 10,11 Treosulfan has also been investigated as a high-dose therapy before auto-SCT in ovarian cancer and other solid tumors. 12,13 A previous study demonstrated its activity in a high-dose combination regimen for relapsed Bone Marrow Transplantation

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The Germinal Center/Activated B-Cell Subclassification Has a Prognostic Impact for Response to Salvage Therapy in Relapsed/Refractory Diffuse Large B-Cell Lymphoma: A Bio-CORAL Study

Abstract: COO remains a major and independent factor in relapsed/refractory DLBCL, with a better response to R-DHAP in GCB-like DLBCL. This needs confirmation by a prospective study.

Cited by 247 publications

References 40 publications

Expression of Myc, but not pSTAT3, is an adverse prognostic factor for diffuse large B-cell lymphoma treated with epratuzumab/R-CHOP

Expression of Myc, but not pSTAT3, is an adverse prognostic factor for diffuse large B-cell lymphoma treated with epratuzumab/R-CHOP

Allogeneic hematopoietic cell transplantation for diffuse large B cell lymphoma: who, when and how?

Risk-adapted, treosulfan-based therapy with auto- and allo-SCT for relapsed/refractory aggressive NHL: a prospective phase-II trial

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