Front‐line, dose‐escalated immunochemotherapy is associated with a significant progression‐free survival advantage in patients with double‐hit lymphomas: a systematic review and meta‐analysis

Howlett, Christina; Snedecor, Sonya J.; Landsburg, Daniel J.; Svoboda, Jakub; Chong, Elise A.; Schuster, Stephen J.; Nasta, Sunita Dwivedy; Feldman, Tatyana; Rago, Allison; Walsh, Kristy M.; Weber, Scott; Goy, André; Mato, Anthony R.

doi:10.1111/bjh.13463

Cited by 150 publications

(112 citation statements)

References 34 publications

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“…Doseadjusted rituximab plus etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (R-EPOCH) had a superior complete response rate compared with R-CHOP and was less toxic than other high-dose regimens; thus, it has been adopted as one of the preferred induction regimens for HGBL-DH in many centers. 16,82 In this study, 72% of patients had a good performance status, indicative of patients being selected to exclude those who were frail. 16 Furthermore, over half of the patients included in the study were treated after 2009, which reflects that increased cytogenetic testing in the modern era resulted in an increased detection of HGBL-DH with low-risk features.…”

Section: Treatmentmentioning

confidence: 86%

Approach to the diagnosis and treatment of high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements

Sesques

Johnson

2017

Blood

137

121

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High-grade B-cell lymphomas (HGBLs) with MYC and BCL2 and/or BCL6 rearrangements, so-called “double-hit” lymphomas (HGBL-DH), are aggressive lymphomas that form a separate provisional entity in the 2016 revised World Health Organization Classification of Lymphoid Tumors. Fluorescence in situ hybridization (FISH) will be required to identify HGBL-DH and will reclassify a subset of diffuse large B-cell lymphomas (DLBCLs) and HGBLs with features intermediate between DLBCL and Burkitt lymphoma into this new category. Identifying patients with HGBL-DH is important because it may change clinical management. This poses a challenge for centers that may not be ready to handle the additional workload and financial burden associated with the increase in requests for FISH testing. Herein, we review the mechanisms of deregulation of these oncogenes. We identify the factors associated with a poor prognosis and those that can guide diagnostic testing. Restricting FISH analysis to the 10% of DLBCL patients who have a germinal center B-cell phenotype and coexpress MYC and BCL2 proteins would be cost-effective and would identify the subset of patients who are at highest risk of experiencing a relapse following conventional therapy. These patients may benefit from intensified chemotherapy regimens or, ideally, should enroll in clinical trials investigating novel regimens.

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Section: Treatmentmentioning

confidence: 86%

Approach to the diagnosis and treatment of high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements

Sesques

Johnson

2017

Blood

137

121

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“…17 The efficacy of these intensified or doseescalated regimens was corroborated in another study. 18 The results of that study are waiting to be confirmed in a randomized, currently ongoing study (R-CHOP vs DA-R-EPOCH; NCT00118209). The studies assessing the benefit of high-dose therapy plus autologous transplant in first CR, however, showed no improvement over chemotherapy alone.…”

Section: Strategies For Refractory Patientsmentioning

confidence: 99%

“…20 Another study confirmed that first-line dose-escalated immunochemotherapy resulted in a significant PFS advantage in DHL patients. 18 Associations with new agents at diagnosis. Given that intensified regimens may not be appropriate for all patients and may be associated with higher toxicity, a better strategy for treating high-risk patients would be to use a regimen other than R-CHOP.…”

Section: Strategies For Refractory Patientsmentioning

confidence: 99%

Diffuse large B-cell lymphoma: R-CHOP failure—what to do?

2016

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Although rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the standard treatment for patients with diffuse large B-cell lymphoma (DLBCL),~30% to 50% of patients are not cured by this treatment, depending on disease stage or prognostic index. Among patients for whom R-CHOP therapy fails, 20% suffer from primary refractory disease (progress during or right after treatment) whereas 30% relapse after achieving complete remission (CR). Currently, there is no good definition enabling us to identify these 2 groups upon diagnosis. Most of the refractory patients exhibit double-hit lymphoma (MYC-BCL2 rearrangement) or double-protein-expression lymphoma (MYC-BCL2 hyperexpression) which have a more aggressive clinical picture. New strategies are currently being explored to obtain better CR rates and fewer relapses. Although young relapsing patients are treated with high-dose therapy followed by autologous transplant, there is an unmet need for better salvage regimens in this setting. To prevent relapse, maintenance therapy with immunomodulatory agents such as lenalidomide is currently undergoing investigation. New drugs will most likely be introduced over the next few years and will probably be different for relapsing and refractory patients. Learning Objectives• To be able to determine at diagnosis which DLBCL patients will likely experience treatment failure with R-CHOP • To understand the mechanisms that underlie resistance to standard treatments • To be able to assess the new proposed drugs, along with their efficacy for specific lymphoma populations such as those with double-hit lymphoma or double-protein-expression lymphoma • To learn more about potential solutions for refractory or relapsing patients

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“…A retrospective study of 129 cases of DHL demonstrated that R-EPOCH regimen resulted in better EFS compared to standard R-CHOP or rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, alternating with cytarabine plus methotrexate (R-HyperCVAD/MA), with 2-year EFS rates of 67%, 25%, and 32%, respectively [93]. A recent meta-analysis synthesized data from 11 studies examining 394 DHL patients in first-line setting [94]. HRs of dose-escalated treatments versus R-CHOP were estimated using a Weibull proportional hazards model within a Bayesian meta-analysis framework.…”

Section: High Risk Dlbclmentioning

confidence: 99%

Rituximab-Based Therapy in Newly Diagnosed Diffuse Large B-Cell Lymphoma Patients: Individualized Risk-Adapted Therapy Approach Using Molecular Subtypes

Fan

Zhou

et al. 2017

J Hematol

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Rituximab (R) with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) is the current standard of care as first-line treatment for diffuse large B-cell lymphoma (DLBCL), the most common lymphoma subtype. Patients who fail R-CHOP have a poor outcome with relapse or refractory disease resulting in fatality in majority of patients. This review focuses on novel therapies which are currently being assessed as first-line treatment in combination with R-CHOP in patients with DLBCL. Targeted drug development is a possibility with recent developments like gene expression profiling, RNA interference screening, DNA sequencing, identification of new biomarkers and signaling pathways. Newer drugs such as bortezomib, lenalidomide, and ibrutinib are being investigated as first-line therapy in combination with R-CHOP (XR-CHOP) in the activated B-cell (ABC) subtype of DLBCL. Additionally, inhibitors of BCL6, EZH2, and PI3K/Akt/mTOR are being considered for treatment of germinal center B-cell (GCB) subtype of DLBCL in patients with probable survival of less than 5 years. Double-or triple-hit lymphomas and double-expressor lymphomas also have poor prognosis and research to identify effective first-line therapy in these patients remains an unmet need. Presently, individualized approach that includes effective therapeutic combinations with acceptable safety profiles for use in routine practice, especially in patients likely to have poor outcomes such as relapsed/refractory DLBCL remains a distant possibility. Current evidence shows that untreated high risk patients do not have the greater benefit with use of newer drugs compared with R-CHOP. Therefore, R-CHOP remains the first-line treatment for newly diagnosed DLBCL patients.

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Front‐line, dose‐escalated immunochemotherapy is associated with a significant progression‐free survival advantage in patients with double‐hit lymphomas: a systematic review and meta‐analysis

Cited by 150 publications

References 34 publications

Approach to the diagnosis and treatment of high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements

Approach to the diagnosis and treatment of high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements

Diffuse large B-cell lymphoma: R-CHOP failure—what to do?

Rituximab-Based Therapy in Newly Diagnosed Diffuse Large B-Cell Lymphoma Patients: Individualized Risk-Adapted Therapy Approach Using Molecular Subtypes

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