Long-term follow up of the FL2000 study comparing CHVP-interferon to CHVP-interferon plus rituximab in follicular lymphoma

Bachy, Emmanuel; Houot, Roch; Morschhauser, F.; Sonet, Anne; Brice, Pauline; Belhadj, Karim; Cartron, Guillaume; Audhuy, B.; Fermé, Christophe; Feugier, Pierre; Sebban, Catherine; Delwail, Vincent; Maisonneuve, Hervé; Gouill, Steven Le; Lefort, Sophie; Brousse, Nicole; Foussard, Charles; Salles, Gilles

doi:10.3324/haematol.2012.082412

Cited by 75 publications

(43 citation statements)

References 27 publications

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“…Patient outcomes are favorable, with median overall survival extending well beyond 10 y [3–5]. However, FL remains an incurable malignancy as most patients eventually experience progressive disease.…”

Section: Introductionmentioning

confidence: 99%

Histological Transformation and Progression in Follicular Lymphoma: A Clonal Evolution Study

et al. 2016

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BackgroundFollicular lymphoma (FL) is an indolent, yet incurable B cell malignancy. A subset of patients experience an increased mortality rate driven by two distinct clinical end points: histological transformation and early progression after immunochemotherapy. The nature of tumor clonal dynamics leading to these clinical end points is poorly understood, and previously determined genetic alterations do not explain the majority of transformed cases or accurately predict early progressive disease. We contend that detailed knowledge of the expansion patterns of specific cell populations plus their associated mutations would provide insight into therapeutic strategies and disease biology over the time course of FL clinical histories.Methods and FindingsUsing a combination of whole genome sequencing, targeted deep sequencing, and digital droplet PCR on matched diagnostic and relapse specimens, we deciphered the constituent clonal populations in 15 transformation cases and 6 progression cases, and measured the change in clonal population abundance over time. We observed widely divergent patterns of clonal dynamics in transformed cases relative to progressed cases. Transformation specimens were generally composed of clones that were rare or absent in diagnostic specimens, consistent with dramatic clonal expansions that came to dominate the transformation specimens. This pattern was independent of time to transformation and treatment modality. By contrast, early progression specimens were composed of clones that were already present in the diagnostic specimens and exhibited only moderate clonal dynamics, even in the presence of immunochemotherapy. Analysis of somatic mutations impacting 94 genes was undertaken in an extension cohort consisting of 395 samples from 277 patients in order to decipher disrupted biology in the two clinical end points. We found 12 genes that were more commonly mutated in transformed samples than in the preceding FL tumors, including TP53, B2M, CCND3, GNA13, S1PR2, and P2RY8. Moreover, ten genes were more commonly mutated in diagnostic specimens of patients with early progression, including TP53, BTG1, MKI67, and XBP1.ConclusionsOur results illuminate contrasting modes of evolution shaping the clinical histories of transformation and progression. They have implications for interpretation of evolutionary dynamics in the context of treatment-induced selective pressures, and indicate that transformation and progression will require different clinical management strategies.

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Section: Introductionmentioning

confidence: 99%

Histological Transformation and Progression in Follicular Lymphoma: A Clonal Evolution Study

et al. 2016

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“…Tumor specimens of patients with FL, histologic grades 1, 2 and 3A were retrieved from the randomized Lymphoma Study Association (LYSA) FL2000 study, 4,6 the German Low-Grade Lymphoma Study Group (GLSG) GLSG2000 study, 3 and the St Bartholomew's Hospital Registry, London, UK. The patients required treatment and the inclusion criteria in the trials were comparable.…”

Section: Patient Selection For An End Of Spectrum Designmentioning

confidence: 99%

“…[1][2][3][4][5][6][7] Approximately 15% of patients die within the first few years, largely due to histological transformation or refractory disease. In contrast, the majority of patients show prolonged survival without relapse and a substantial number of patients never require treatment.…”

Section: Introductionmentioning

confidence: 99%

Prognostic relevance of CD163 and CD8 combined with EZH2 and gain of chromosome 18 in follicular lymphoma: a study by the Lunenburg Lymphoma Biomarker Consortium

et al. 2017

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In follicular lymphoma, studies addressing the prognostic value of microenvironment-related immunohistochemical markers and tumor cell-related genetic markers have yielded conflicting results, precluding implementation in practice. Therefore, the Lunenburg Lymphoma Biomarker Consortium performed a validation study evaluating published markers. To maximize sensitivity, an end of spectrum design was applied for 122 uniformly immunochemotherapy-treated follicular lymphoma patients retrieved from international trials and registries. The criteria were: early failure, progression or lymphoma-related death <2 years versus long remission, response duration of >5 years. Immunohistochemical staining for T cells and macrophages was performed on tissue microarrays from initial biopsies and scored with a validated computer-assisted protocol. Shallow whole-genome and deep targeted sequencing was performed on the same samples. The 96/122 cases with complete molecular and immunohistochemical data were included in the analysis. EZH2 wild-type ( P =0.006), gain of chromosome 18 ( P =0.002), low percentages of CD8+ cells ( P =0.011) and CD163+ areas ( P =0.038) were associated with early failure. No significant differences in other markers were observed, thereby refuting previous claims of their prognostic significance. Using an optimized study design, this Lunenburg Lymphoma Biomarker Consortium study substantiates wild-type EZH2 status, gain of chromosome 18, low percentages of CD8+ cells and CD163+ area as predictors of early failure to immunochemotherapy in follicular lymphoma treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP [-like]), while refuting the prognostic impact of various other markers.

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“…Four randomized studies were identified comparing rituximab plus chemotherapy with chemotherapy alone (Table 7). [49][50][51][52][53][54] The use of chemoimmunotherapy produced ORRs of 81% to 96% and median remission duration of about 27 to 66 months. Although not supported in head-to-head studies, the response to chemoimmunotherapy appears to be superior to that of rituximab monotherapy.…”

Section: Methodsmentioning

confidence: 99%

A Canadian Evidence-Based Guideline for the First-Line Treatment of Follicular Lymphoma: Joint Consensus of the Lymphoma Canada Scientific Advisory Board

Kuruvilla

Assouline

Hodgson

et al. 2015

Clinical Lymphoma Myeloma and Leukemia

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Long-term follow up of the FL2000 study comparing CHVP-interferon to CHVP-interferon plus rituximab in follicular lymphoma

Cited by 75 publications

References 27 publications

Histological Transformation and Progression in Follicular Lymphoma: A Clonal Evolution Study

Histological Transformation and Progression in Follicular Lymphoma: A Clonal Evolution Study

Prognostic relevance of CD163 and CD8 combined with EZH2 and gain of chromosome 18 in follicular lymphoma: a study by the Lunenburg Lymphoma Biomarker Consortium

A Canadian Evidence-Based Guideline for the First-Line Treatment of Follicular Lymphoma: Joint Consensus of the Lymphoma Canada Scientific Advisory Board

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