Impact of dual expression of MYC and BCL2 by immunohistochemistry on the risk of CNS relapse in DLBCL

Savage, Kerry J.; Slack, Graham W.; Mottok, Anja; Sehn, Laurie H.; Villa, Diego; Kansara, Roopesh; Kridel, Robert; Steidl, Christian; Ennishi, Daisuke; Tan, King; Ben-Neriah, Susana; Johnson, Nathalie A.; Connors, Joseph M.; Farinha, Pedro; Scott, David W.; Gascoyne, Randy D.

doi:10.1182/blood-2015-10-676700

Cited by 161 publications

(126 citation statements)

References 35 publications

Supporting

Mentioning

116

Contrasting

Unclassified

Order By: Relevance

“…Based on these results Fletcher and Kahl 2 recommended that patients with DLBCL and MYC rearrangements be considered at high risk of CNS relapse. In another recent study, Savage et al 29 reported that DLBCL patients and dual expression of MYC (≥40% positivity) and BCL2 (≥50% positivity) determined by immunohistochemistry, had higher risk of CNS relapse (2-year risk of 9.7% vs. 2.2%, P=0.001). This study also showed increased risk for those patients with activated B-cell or non-germinal center B-cell origin, but significance was not retained in the multivariate analysis.…”

Section: Guidelines For Diagnosis Prevention and Management Of Centrmentioning

confidence: 99%

Guidelines for diagnosis, prevention and management of central nervous system involvement in diffuse large B-cell lymphoma patients by the Spanish Lymphoma Group (GELTAMO)

et al. 2016

View full text Add to dashboard Cite

Several factors hinder the identification of risk factors for central nervous system (CNS) involvement in diffuse large B-cell lymphoma (DLBCL), including the retrospective nature of most studies, the relatively low frequency of CNS relapse in DLBCL, and the heterogeneity of CNS prophylaxis methods used in these studies. Moreover, the impact of newly developed diagnostic tools (such as multiparameter flow cytometry [FCM]) and new treatments introduced in the last decade, in particular rituximab, has still not been fully clarified.Several studies 4,5,[7][8][9][10] and a recent meta-analysis 1 have described a decrease in rates D iffuse large B-cell lymphoma patients have a 5% overall risk of central nervous system events (relapse or progression), which account for high morbidity and frequently fatal outcomes, 1 and shortened overall survival of <6 months.2 Early diagnosis of central nervous system events is critical for successful treatment and improved prognosis. Identification of patients at risk of central nervous system disease is critical to accurately identify candidates for central nervous system prophylaxis vs. therapy. [3][4][5] This report by the Spanish Lymphoma Group (GELTAMO) aims to provide useful guidelines and recommendations for the prevention, diagnosis, and treatment of central nervous system diffuse large B-cell lymphoma patients with, or at risk of, leptomeningeal and/or brain parenchyma lymphoma relapse. A panel of lymphoma experts working on behalf of GELTAMO reviewed all data published on these topics available in PubMed up to May 2016. Recommendations were classified according to the Grading of Recommendations Assessment Development and Evaluation (GRADE) approach. 6 A practical algorithm based on the proposed recommendations was then developed (Figure 1 have concluded that the incidence of CNS relapse decreased after the introduction of rituximab (Table 1). The identification of risk factors has been the major goal of many studies of CNS involvement. Several large retrospective studies conducted in the pre-rituximab era [12][13][14][15] reported higher rates of CNS relapse in patients with increased serum lactate dehydrogenase (LDH) levels and/or involvement of >1 extranodal site, although these factors failed to predict CNS relapse in more than half of all cases.12 In addition to the involvement of >1 extranodal site and increased LDH, International Prognostic Index (IPI) score was also identified as an independent predictor for CNS relapse in other studies.13,16 A post-rituximab era study of 399 DLBCL patients, randomized to R-CHOP or CHOP chemotherapy, 3 identified an age-adjusted IPI (aaIPI) >1 as the only risk factor for CNS involvement, although a high aaIPI score was recorded for more than 60% of the patients. When aaIPI was excluded from the analysis, elevated LDH and a poor performance status (PS >1) were identified as independent predictive factors for CNS relapse. Similarly, in the randomized RICOVER-60 trial, 4 the combination of increased LDH levels, the involvement of >1 ex...

show abstract

Section: Guidelines For Diagnosis Prevention and Management Of Centrmentioning

confidence: 99%

Guidelines for diagnosis, prevention and management of central nervous system involvement in diffuse large B-cell lymphoma patients by the Spanish Lymphoma Group (GELTAMO)

et al. 2016

View full text Add to dashboard Cite

show abstract

“…15 In an analysis from the British Columbia database, ;10% of patients with double-expressor lymphoma (including a subset with double-hit lymphoma) subsequently relapsed in the CNS. 33 For these reasons, unlike the situation with routine DLBCL, I recommend baseline lumbar puncture and CSF sampling in most patients with double-hit lymphoma. Exceptions include patients who present with early-stage disease, where CSF involvement is much less common, or frail elderly patients, where treatment with curative intent is contraindicated.…”

Section: How Do I Evaluate Patients With Double-hit Lymphoma?mentioning

confidence: 99%

How I treat double-hit lymphoma

Friedberg

2017

Blood

120

View full text Add to dashboard Cite

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...

show abstract

“…In addition, these patients frequently present with a central nervous system relapse, which is always associated with poor outcome. 10 There is typically a clonal evolution among lymphoma cells, with some heterogeneity of genes involved in lymphoma growth that might explain the chemorefractoriness and difficulties of salvage. 11 Furthermore, it has also been shown that DLBCL pathogenesis is strongly related to epigenetic perturbations and that high epigenomic heterogeneity correlated with a higher relapse rate and poor outcome.…”

Section: Patients With Early Relapsementioning

confidence: 99%

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

2016

View full text Add to dashboard Cite

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

show abstract

Impact of dual expression of MYC and BCL2 by immunohistochemistry on the risk of CNS relapse in DLBCL

Cited by 161 publications

References 35 publications

Guidelines for diagnosis, prevention and management of central nervous system involvement in diffuse large B-cell lymphoma patients by the Spanish Lymphoma Group (GELTAMO)

Guidelines for diagnosis, prevention and management of central nervous system involvement in diffuse large B-cell lymphoma patients by the Spanish Lymphoma Group (GELTAMO)

How I treat double-hit lymphoma

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

Contact Info

Product

Resources

About