Risk Factors and Outcomes for Patients With Follicular Lymphoma Who Had Histologic Transformation After Response to First-Line Immunochemotherapy in the PRIMA Trial

Sarkozy, Clémentine; Trněný, Marek; Xerri, Luc; Wickham, Nick; Feugier, Pierre; Leppä, Sirpa; Brice, Pauline; Soubeyran, Pierre; Silva, Maria Gomes da; Mounier, Christiane; Offner, Fritz; Dupuis, Jehan; Caballero, Dolores; Canioni, Danielle; Marlton, Paula; Delarue, Richard; Zachée, Pierre; Seymour, John; Salles, Gilles; Tilly, Hervé

doi:10.1200/jco.2015.65.7163

Cited by 147 publications

(141 citation statements)

References 32 publications

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“…30 In several studies of transformed lymphoma, ASCT consolidation appears to provide benefit even in the rituximab era. [56][57][58] The benefit of ASCT on patients with double-hit transformation has not been established in these studies, but no doubt a subset of patients included in these retrospective analyses of transformed lymphomas had double-hit lymphoma at the time of transformation.…”

Section: Org Frommentioning

confidence: 99%

How I treat double-hit lymphoma

Friedberg

2017

Blood

115

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The 2016 revision of the World Health Organization (WHO) classification for lymphoma has included a new category of lymphoma, separate from diffuse large B-cell lymphoma, termed high-grade B-cell lymphoma with translocations involving myc and bcl-2 or bcl-6. These lymphomas, which occur in <10% of cases of diffuse large B-cell lymphoma, have been referred to as double-hit lymphomas (or triple-hit lymphomas if all 3 rearrangements are present). It is important to differentiate these lymphomas from the larger group of double-expressor lymphomas, which have increased expression of MYC and BCL-2 and/or BCL-6 by immunohistochemistry, by using variable cutoff percentages to define positivity. Patients with double-hit lymphomas have a poor prognosis when treated with standard chemoimmunotherapy and have increased risk of central nervous system involvement and progression. Double-hit lymphomas may arise as a consequence of the transformation of the underlying indolent lymphoma. There are no published prospective trials in double-hit lymphoma, however retrospective studies strongly suggest that aggressive induction regimens may confer a superior outcome. In this article, I review my approach to the evaluation and treatment of double-hit lymphoma, with an eye toward future clinical trials incorporating rational targeted agents into the therapeutic armamentarium. (Blood. 2017; 130(5):590-596) Case presentation 1A 53-year-old man presents with a 2-month history of left hip pain. He did not respond to initial conservative management, including rest and physical therapy. Magnetic resonance imaging (MRI) of the left hip was eventually performed and showed a destructive, enhancing lesion involving the left iliac wing, acetabulum, and pubic ramus, measuring 8 3 7 3 7 cm. Computed tomographic (CT) scan of the chest, abdomen and pelvis was then performed, demonstrating enlarged left supraclavicular and right hilar lymph nodes. The soft tissue component of the dominant mass contacted the prostate gland and displaced the urinary bladder. A lucency was also seen in the left T11 pedicle. A biopsy of the bone lesion was performed, revealing a poorly differentiated and pleomorphic infiltrate of large malignant cells, with extensive areas of necrosis. Immunohistochemical stains demonstrated that the infiltrate was CD20 and CD79a positive. This finding was consistent with diffuse large B-cell lymphoma (DLBCL), stage IVA. Clinical risk factors included high-stage, high-LDH, and extranodal disease; performance status was normal, making this high intermediate-risk disease based on the international prognostic index and the age-adjusted international prognostic index.1 Subsequent immunohistochemical stains revealed the lymphoma to be positive for BCL-6, BCL-2, and MYC and negative for CD10, CD30, MUM1, and EBER; the Ki-67 fraction was 50%. This suggests the tumor is of germinal-center origin (using the Hans algorithm 2 ) and a double-expressor phenotype (MYC and BCL-2). The patient was started urgently on standard rituximab, cyclophospham...

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Section: Org Frommentioning

confidence: 99%

How I treat double-hit lymphoma

Friedberg

2017

Blood

115

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“…The median of the overall survival (OS) is lengthy (about 10 years) and OS rate up to five years over 75% [7]. Additionally, transformation to more aggressive histological forms, usually diffuse large B-cell lymphoma (DLBCL), may also occur, which implies, in general, very poor prognosis [8]. The risk of transformation appears to be independent of the type of treatment used (or lack thereof) [9].…”

Section: Introductionmentioning

confidence: 99%

Impact of treatment in long-term survival patients with follicular lymphoma: A Spanish Lymphoma Oncology Group registry

et al. 2017

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BackgroundFollicular lymphoma is the second most common non-Hodgkin lymphoma in the United States and Europe. However, most of the prospective randomized studies have very little follow-up compared to the long natural history of the disease. The primary aim of this study was to investigate the long-term survival of our series of patients with follicular lymphoma.Patients and methodsA total of 1074 patients with newly diagnosed FL were enrolled. Patients diagnosed were prospectively enrolled from 1980 to 2013.ResultsMedian follow-up was 54.9 months and median overall survival is over 20 years in our series. We analyzed the patients who are still alive beyond 10 years from diagnosis in order to fully assess the prognostic factors that condition this group. Out of 166 patients who are still alive after more than 10 years of follow-up, 118 of them (73%) are free of evident clinical disease. Variables significantly associated with survival at 10 years were stage < II (p <0.03), age < 60 years (p <0.0001), low FLIPI (p <0.002), normal β2 microglobulin (p <0.005), no B symptoms upon diagnosis (p <0.02), Performance Status 0–1 (p <0.03) and treatment with anthracyclines and rituximab (p <0.001), or rituximab (p <0.0001).ConclusionsA longer follow-up and a large series demonstrated a substantial population of patients with follicular lymphoma free of disease for more than 10 years.

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“…[6][7][8][9] Similarly, transformation to aggressive lymphoma, occurring in 2% to 3% of patients per year, has repeatedly been linked to adverse prognosis when compared with patients not experiencing transformation. [10][11][12][13][14][15] There is an association between early progression and transformation. Indeed, in the experience from 2 regional cancer centers in Ontario, 27% of early progressors had either documented transformation or were suspected to harbor transformed disease based on clinical grounds.…”

Section: Medscape Continuing Medical Education Onlinementioning

confidence: 99%

“…One of the most rigorous assessments of features associated with transformation comes from the PRIMA trial in which Sarkozy et al report progression in 463 patients of 1018 after a median follow-up of 6 years. 15 Of these 463 cases, 194 patients had histologic confirmation of progression, with TFL and FL found in 40 and 154 instances, respectively. The authors compared the 40 cases with documented transformation to 708 cases with either no progression, or progression but without evidence of transformation.…”

Section: Clinical Risk Factorsmentioning

confidence: 99%

“…However, the number of patients in at least some of these groups was small. 15 In summary, it appears that transformation is largely independent of treatment received, and that with currently available therapies, it might not be preventable. Such a statement, however, will need to continue to be challenged in the future as newer treatment modalities emerge.…”

Section: Can Histologic Transformation Be Prevented?mentioning

confidence: 99%

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Can histologic transformation of follicular lymphoma be predicted and prevented?

Kridel

Sehn

Gascoyne

2017

Blood

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Transformation to aggressive lymphoma is a critical event in the clinical course of follicular lymphoma (FL) patients. Yet, it is a challenge to reliably predict transformation at the time of diagnosis. Understanding the risk of transformation would be useful for guiding and monitoring patients, as well as for evaluating novel treatment strategies that could potentially prevent transformation. Herein, we review the contribution of clinical, pathological, and genetic risk factors to transformation. Patients with multiple clinical high-risk factors are at elevated risk of transformation but we are currently lacking a prognostic index that would specifically address transformation rather than disease progression or overall survival. From the biological standpoint, multiple studies have correlated individual biomarkers with transformation. However, accurate prediction of this event is currently hampered by our limited knowledge of the evolutionary pathways leading to transformation, as well as the scarcity of comprehensive, large-scale studies that assess both the genomic landscape of alterations within tumor cells and the composition of the microenvironment. Liquid biopsies hold great promise for achieving precision medicine. Indeed, mutations detected within circulating tumor DNA may be a better reflection of the inherent intratumoral heterogeneity than the biopsy of a single site. Last, we will assess whether evidence exists in the literature that transformation might be prevented altogether, based on the choice of therapy for FL.

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Risk Factors and Outcomes for Patients With Follicular Lymphoma Who Had Histologic Transformation After Response to First-Line Immunochemotherapy in the PRIMA Trial

Abstract: HT in patients with FL who previously responded to immunochemotherapy is an early event associated with a poor outcome that may deserve intensive salvage with autologous stem cell transplantation. These data emphasize the necessity for biopsy at the first recurrence of FL.

Cited by 147 publications

References 32 publications

How I treat double-hit lymphoma

How I treat double-hit lymphoma

Impact of treatment in long-term survival patients with follicular lymphoma: A Spanish Lymphoma Oncology Group registry

Can histologic transformation of follicular lymphoma be predicted and prevented?

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