Impact of induction regimen and stem cell transplantation on outcomes in double-hit lymphoma: a multicenter retrospective analysis

Petrich, Adam M.; Gandhi, Mitul; Jovanovic, Borko; Castillo, Jorge J.; Rajguru, Saurabh; Yang, David T.; Shah, Khushboo A; Whyman, Jeremy D.; Lansigan, Frederick; Hernandez‐Ilizaliturri, Francisco J.; Lee, Lisa X; Barta, Stefan K.; Melinamani, Shruthi; Karmali, Reem; Adeimy, Camille; Smith, Scott E.; Dalal, Neil; Nabhan, Chadi; Peace, David; Vose, Julie M.; Evens, Andrew M.; Shah, Namrata; Fenske, Timothy S.; Zelenetz, Andrew D.; Landsburg, Daniel J.; Howlett, Christina; Mato, Anthony R.; Jaglal, Michael; Chávez, Julio C.; Tsai, Judy; Reddy, Nishitha; Li, Shaoying; Handler, Caitlin; Flowers, Christopher R.; Cohen, Jonathon B.; Blum, Kristie A.; Song, Kevin; Sun, Hao; Press, Oliver W.; Cassaday, Ryan D.; Jaso, Jesse Manuel; Medeiros, L. Jeffrey; Sohani, Aliyah R.; Abramson, Jeremy S.

doi:10.1182/blood-2014-05-578963

Cited by 411 publications

(419 citation statements)

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“…Although early studies of patients with DLBCL bearing MYC and/or BCL2 rearrangements indicated markedly increased risk of CNS involvement at diagnosis of up to 44%, 50,51 2 larger retrospective studies indicated that 4% to 7% of patients had CNS involvement at diagnosis with a 3-year cumulative CNS risk of 13%. 26,52 Both studies also suggested use of CNS prophylaxis may improve outcomes: in the first, IT MTX prophylaxis was associated with a reduction in CNS progression (3-year incidence, 5% v 15%; P 5 .017) 26 ; in the second, use of CNS prophylaxis was associated with improvement in overall survival. 52 We therefore consider HGBL-DH at high risk of CNS involvement and consider these patients for CNS-directed prophylaxis.…”

Section: Casementioning

confidence: 99%

“…26,52 Both studies also suggested use of CNS prophylaxis may improve outcomes: in the first, IT MTX prophylaxis was associated with a reduction in CNS progression (3-year incidence, 5% v 15%; P 5 .017) 26 ; in the second, use of CNS prophylaxis was associated with improvement in overall survival. 52 We therefore consider HGBL-DH at high risk of CNS involvement and consider these patients for CNS-directed prophylaxis. The 2017 WHO categories of HGBL-DH and HGBL not otherwise specified (HGBL-NOS) have created difficulty in applying evidence from older datasets (based on the superseded BCL-U).…”

Section: Casementioning

confidence: 99%

“…We favor dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) for fit patients with HGBL-DH based on retrospective 26,52,55 and prospective data. 56 However, given substantial comorbidities including cardiac dysfunction, we used 6 cycles of cyclophosphamide, etoposide, prednisone, vincristine, and rituximab (R-CEOP; anthracycline substituted for etoposide).…”

Section: Casementioning

confidence: 99%

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How I treat patients with aggressive lymphoma at high risk of CNS relapse

Chin

Cheah

2017

Blood

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Central nervous system (CNS) relapses are an uncommon yet devastating complication of non-Hodgkin lymphomas. The identification of patients at high risk of secondary CNS relapse is therefore paramount. Retrospective data indicate prophylactic CNS-directed therapies may reduce the risk of CNS involvement; however, no consensus exists about dose, timing, or route of therapy. In addition, prophylaxis is not without risk of treatment-related complications and morbidity. Here, we present a series of case vignettes highlighting our approach to common dilemmas encountered in routine clinical practice. We review the method of assessing CNS relapse risk, factors that increase the likelihood of relapse including histologic subtype, MYC rearrangement, protein expression, and extranodal involvement, and review our clinical practice based on available evidence in administering CNS-directed prophylaxis. (Blood. 2017;130(7):867-874) IntroductionNon-Hodgkin lymphomas are biologically and clinically diverse hematological malignancies. Treatment is influenced by patient fitness, disease biology, and tumor burden. Identifying patients at high risk of central nervous system (CNS) relapse is important as the outcome of secondary CNS lymphoma is poor. [1][2][3][4] Risk of CNS progression is influenced by histologic subtype and subtype-specific clinicopathologic features (eg, site of involvement, protein expression, or gene rearrangements). Patients with highly aggressive lymphomas (eg, lymphoblastic, Burkitt lymphoma) are at high risk and frontline protocols include CNS-directed prophylaxis. In contrast, indolent lymphomas rarely involve the CNS and CNS prophylaxis is not required. Between these extremes fall diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma (HGBL) with MYC and BCL2 or BCL6 rearrangements, so-called "double-hit" lymphomas (HGBL-DH), and (nodal) peripheral T-cell lymphomas (PTCLs). The addition of rituximab has slightly reduced CNS relapse in DLBCL, probably through superior systemic control as there is negligible CNS penetration of the drug across the intact blood-brain barrier. 1,5 However, ;4% of unselected patients with DLBCL treated with prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (R-CHOP) experience CNS relapse, 6,7 and considerable efforts have been made to identify those at greatest risk. In this review, we will summarize our approach to this problem with case vignettes drawn from our practice. How I identify patients at increased risk for CNS relapseMany investigators have examined risk factors for CNS relapse, but studies have yielded inconsistent results, due to heterogeneity in patient populations, treatment, and/or limited sample size. [8][9][10][11][12][13][14][15][16] To address some of these limitations, Schmitz et al developed a 6-point score from 2164 patients treated on prospective German studies and validated in 1597 patients with DLBCL treated with R-CHOP in the British Columbia Cancer Agency (BCCA) Lymphoid Malignancies Database. 6 The components of the s...

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Section: Casementioning

confidence: 99%

Section: Casementioning

confidence: 99%

Section: Casementioning

confidence: 99%

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How I treat patients with aggressive lymphoma at high risk of CNS relapse

Chin

Cheah

2017

Blood

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“…5 In a recent multi-center trial involving patients with double-hit lymphomas treated with high-intensity chemotherapy regimens, the progressionfree survival and overall survival rates at 2 years were 40% and 49%, respectively. 5 An alternate regimen that has been recently shown to be effective for penetration into the cerebrospinal fluid consists of rituximab, cyclophosphamide, vincristine, doxorubicin, and dexamethasone (R-hyperCVAD). 6 This regimen, however, is more cumbersome and has the potential to cause severe toxicity.…”

Section: To the Editormentioning

confidence: 99%

Double-Hit Lymphoma:

Goyal

Caponetti

Silberstein

2015

J Clin Exp Hematopathol

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Diffuse large B-cell lymphomas (DLBCL) are a heterogeneous group of aggressive lymphomas. Approximately 40% of all B-cell lymphomas have a recurrent reciprocal chromosomal translocation, commonly involving an oncogene and an immunoglobulin loci enhancer. Lymphomas with recurrent chromosomal breakpoints that activate multiple oncogenes, one of which is MYC, are known as "double hit" lymphomas. These chromosomal breakpoints, when present, portend a worse prognosis. Most common double-hit lymphomas involve MYC and BCL2 gene translocations. We describe a very rare case of a patient with DLBCL involving the gene loci MYC and BCL6.A 34-year-old male presents to the emergency department with bilateral lower extremity weakness and shooting pain. He was unable to ambulate without using a walker and had suffered multiple falls. He had no significant past medical or surgical history. Computed tomography scan of lumbar spine was normal so an magnetic resonance imaging (MRI) was performed that showed homogeneous hyperintense lesion extending posteriorly from L3-S1 vertebral bodies with obstruction of spinal canal (Fig. 1). The patient underwent L4-L5 laminectomy with resolution of symptoms. He was discharged subsequently with rest of the work-up and treatment planned on an outpatient basis.Histopathologic evaluation of the biopsy of the lumbar mass revealed the presence of adipose tissue infiltrated by sheets of predominantly medium-sized to large lymphoid cells with round to ovoid nuclei, one to a few conspicuous nucleoli, and variably clumped to fine chromatin ( Fig. 2A & 2B). In addition, frequent mitoses, karyorrhectic debris and apoptotic cells were observed, and these findings raised the possibility of shrinkage artifact on the lymphoma cells. By immunohistochemistry, the cells of the infiltrate were show to be positive for CD20 (Fig. 2C), PAX5 (Fig. 2D), MUM1 (Fig. 2E), FOXP1, and weakly positive for BCL2 (Fig. 2F). An immunostain for Ki-67 showed expression in approximately 95% of the lymphoma cells (Fig. 2G), whereas immunostains for CD3, CD5, CD10, BCL6, GCET1, MYC, CD23, cyclin D1, TdT and CD34 were negative. The immunophenotype was indicative of an activated B-cell (ABC) subtype, according to the Choi algorithm. Limited flow-cytometric evaluation identified a mature B-cell population expressing CD19, CD20 and high-density monotypic k surface immunoglobulin light chains present at 60% of the lymphocytes (less than 0.1% of all CD45-positive events). Cytogenetic (fluorescence in situ hybridization: FISH) testing of the tumor were positive for IGH/MYC fusion (93%) and BCL6/3q27 alternate breakpoint locus rearrangement (93%), without a BCL2/18q21 rearrange-

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“…Patients with DHL can frequently present with adverse prognostic findings such as advanced clinical stage, elevated lactate dehydrogenase level and increased Ki67 expression on immunohistochemical staining [1,2]; however, baseline clinicopathologic characteristics may not be predictive of the presence of double hit lymphoma in patients diagnosed with aggressive B cell NHL [3].…”

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confidence: 99%

Untitled

2017

Oncotarget

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Impact of induction regimen and stem cell transplantation on outcomes in double-hit lymphoma: a multicenter retrospective analysis

Abstract: Key Points A subset of DHL patients may be cured, and some patients may benefit from intensive induction. Further investigations into the roles of SCT and novel agents are needed.

Cited by 411 publications

References 33 publications

How I treat patients with aggressive lymphoma at high risk of CNS relapse

How I treat patients with aggressive lymphoma at high risk of CNS relapse

Double-Hit Lymphoma:

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