Relapsed or Refractory Double-Expressor and Double-Hit Lymphomas Have Inferior Progression-Free Survival After Autologous Stem-Cell Transplantation

Herrera, Alex F.; Mei, Matthew; Low, Lawrence K.; Kim, Haesook T.; Griffin, Gabriel K.; Song, Joo Y.; Merryman, Reid W.; Bedell, Victoria; Pak, Christine J.; Sun, Heather H.; Paris, Tanya; Stiller, Tracey; Brown, Jennifer R.; Budde, Lihua E.; Chan, Wing C.; Chen, Robert; Davids, Matthew S.; Freedman, Arnold S.; Fisher, David C.; Jacobsen, Eric; Jacobson, Caron A.; LaCasce, Ann S.; Murata-Collins, Joyce; Nademanee, Auayporn; Palmer, Joycelynne; Pihán, Germán; Pillai, Raju; Popplewell, Leslie; Siddiqi, Tanya; Sohani, Aliyah R.; Zain, Jasmine; Rosen, Steven T.; Kwak, Larry W.; Weinstock, David M.; Forman, Stephen J.; Weisenburger, Dennis D.; Kim, Young; Rodig, Scott J.; Krishnan, Amrita; Armand, Philippe

doi:10.1200/jco.2016.68.2740

Cited by 157 publications

(137 citation statements)

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“…60 In a recently published larger series of 117 patients examining the role of ASCT in double-expressor and double-hit lymphomas, the outcome of patients with doubleexpressor and double-hit lymphoma was dismal (4-year progressionfree survival, 0%). 61 These results emphasize the importance of dedicated trials, including double-hit patients in the relapsed setting. 62 Based on these results, if a patient with double-hit lymphoma were treated with intensive induction and still experienced progressive disease, I would refer them to a clinical trial involving novel agents rather than try conventional salvage therapy.…”

Section: Relapsed Double-hit Lymphoma and Novel Agentsmentioning

confidence: 98%

How I treat double-hit lymphoma

Friedberg

2017

Blood

119

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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: Relapsed Double-hit Lymphoma and Novel Agentsmentioning

confidence: 98%

How I treat double-hit lymphoma

Friedberg

2017

Blood

119

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“…Although DE-DLBCL and HGBL-DH were each associated with an inferior outcome, patients with concurrent HGBL-DH and DE-DLBCL all experienced an early lymphoma relapse within months of the transplant. 63 Approximately 20% to 30% of patients with HGBL-DH have primary refractory disease, despite receiving intensive induction regimens, which indicates an unmet clinical need to improve the initial treatment strategy in this disease. 16 Enrollment in a clinical trial testing regimens that include novel therapies would be the preferred choice for eligible patients.…”

Section: 89mentioning

confidence: 99%

“…Beyond R-CHOP, it predicts for a poor response to intensified induction regimens, salvage chemotherapy, autologous stem cell transplant (ASCT), and the novel histone deacetylase inhibitor panobinostat. 63,68,70,71 BCL2 and MYC protein expression in DE-DLBCL may be considered a functional readout of the cumulative genomic alterations that ultimately lead to their overexpression, mainly BCR and NF-kB signaling in the ABC patients and translocations in the GCB patients. These mechanisms may be clinically relevant, given that targeting BCR signaling and BCL2 may be an effective strategy in ABC-DE-DLBCL but not in GCB-DE-DLBCL or in patients with IG translocations.…”

Section: Biology Of Hgbl-dh and De-dlbclmentioning

confidence: 99%

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

116

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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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“…However, it has been recently reported that the adverse prognosis may be mitigated by other factors such as that lack of BCL-2 protein, and absence/low MYC protein expression 5 . The clinical significance of MYC-IHC and BCL-2-IHC expression has been extensively studied but the results have not been consistent; hence, a clinical utility of protein expression evaluation is still unclear [13][14] .…”

mentioning

confidence: 99%