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Year : 2020  |  Volume : 16  |  Issue : 1  |  Page : 183-185

Brentuximab vedotin demonstrates an objective response in a patient with refractory CD30+ primary mediastinal B-cell lymphoma

1 Department of Internal Medicine, Texas Tech University of Health Sciences Center, Texas, USA
2 Department of Pathology, Texas Tech University of Health Sciences Center, Texas, USA
3 Division of Hematology/Oncology, Department of Internal Medicine, Texas Tech University of Health Sciences Center, El Paso, Texas, USA

Date of Submission28-Jun-2016
Date of Decision08-Oct-2017
Date of Acceptance25-Feb-2018
Date of Web Publication26-Oct-2018

Correspondence Address:
Nabeel Badri
Department of Internal Medicine, Texas Tech University of Health Sciences Center, 4800 Alberta Avenue, El Paso, Texas 79905
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_696_16

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 > Abstract 

Diffuse large B-cell lymphomas (DLBCL) with MYC translocations combined with translocations involving BCL-2 or BCL-6 are referred to as double-hit lymphomas. These lymphomas are generally refractory to currently available therapies and have a poor prognosis. Primary mediastinal B-cell lymphoma (PMBL) is a rare subtype of DLBCL, which shares clinical, pathologic, and genetic similarities with classical Hodgkin's lymphoma. Unlike DLBCL, rearrangements involving MYC, BCL-2, and BCL-6 are typically absent in PMBL. We present a patient with PMBL who had increased gene copy numbers of MYC and BCL-2 along with increased protein expression of BCL-2 (c-Myc expression was about 15%–20% by immunostain). The disease was refractory to standard and salvage chemotherapies. The lymphoma, however, responded to brentuximab vedotin, a CD30-directed chemoimmunoconjugate.

Keywords: B-cell lymphomas 2, B-cell lymphomas 6, brentuximab, diffuse large B-cell lymphomas, MYC, primary mediastinal B-cell lymphoma

How to cite this article:
Badri N, Ngamdu KS, Torabi A, Guar S. Brentuximab vedotin demonstrates an objective response in a patient with refractory CD30+ primary mediastinal B-cell lymphoma. J Can Res Ther 2020;16:183-5

How to cite this URL:
Badri N, Ngamdu KS, Torabi A, Guar S. Brentuximab vedotin demonstrates an objective response in a patient with refractory CD30+ primary mediastinal B-cell lymphoma. J Can Res Ther [serial online] 2020 [cited 2020 May 30];16:183-5. Available from: http://www.cancerjournal.net/text.asp?2020/16/1/183/244231

 > Introduction Top

Diffuse large B-cell lymphomas (DLBCL) with MYC translocations combined with translocations involving BCL-2 or BCL-6 are referred to as double-hit lymphomas (DHL), while increased protein expression of MYC and BCL-2 is also called immunohistochemical double-hit or double protein expression (DPL) lymphomas. These lymphomas are correlated with refractoriness to treatment and poor prognosis.[1],[2] Primary mediastinal B-cell lymphoma (PMBL) is a subtype of DLBCL, which shares similarities with classical Hodgkin's lymphoma. Unlike DLBCL, MYC, BCL-2, and BCL-6 rearrangements are typically absent in PMBL.[3],[4] We are presenting a patient with PMBL with increased gene copy numbers of MYC and BCL-2 along with increased protein expression of BCL-2.

 > Case Report Top

A 38-year-old Hispanic woman presented with a 4 month history of shortness of breath, cough, intermittent fever, and night sweats. Her past medical history was unremarkable. On examination, blood pressure was 116/72 mmHg, respiratory rate 19 BPM, heart rate 120/min, and temperature 38.2°C. Oxygen saturation was 88% on room air. Facial plethora and fullness of the neck veins were apparent. Right supraclavicular adenopathy was apparent. She had dullness to percussion in the left lower lung fields along with decreased breath sounds. The computed tomography (CT) scan of the thorax showed a large anterior mediastinal mass measuring 15.6 cm × 10 cm in diameter. The tumor was abutting the superior vena cava, narrowing its lumen. A left-sided pleural effusion was present. Paratracheal and right supraclavicular lymph nodes, measuring 2 cm in size, were present. CT scans showed no lesions in the liver or the spleen, and no intra-abdominal lymph nodes were noted. An excision biopsy of the right supraclavicular node was performed that showed diffuse infiltration of malignant CD20-positive large B-cells [Figure 1]a, coexpressing CD79a, PAX-5, and CD30 (heterogeneous and patchy) [Figure 1]b while immunostain for CD15 was negative. Proliferation index was 80% by Ki67 immunostain. Immunohistochemistry also showed expression of BCL-2 in 60% of tumor cells [Figure 1]e and MYC in 15%–20% [Figure 1]f. Bone marrow was not involved. Fluorescent in situ hybridization showed gain of c-Myc and BCL-2 genes without any evidence of rearrangement of these two genes [Figure 1]c and d].
Figure 1: (a) Excision biopsy of the right supraclavicular node showed diffuse infiltration with malignant large B-cells. (b) The malignant cells expression of CD30. (c) Fluorescent in situ hybridization studies demonstrate tumor cells carried extra copies of MYC. (d) Fluorescent in situ hybridization studies demonstrate tumor cells carried extra copies of B-cell lymphomas-2. (e) Immunohistochemistry showed expression of B-cell lymphomas-2 in 60% of tumor cells. (f) Immunohistochemistry showed expression of MYC in 15%–20% of tumor cells

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On the basis of clinical, pathological, and radiological findings, the patient was diagnosed as having superior vena cava syndrome due to Stage IIB PMBL.

The patient was treated with six cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Her symptoms of superior vena cava syndrome resolved during the first cycle. During the sixth cycle, she felt a new lump developed in her left breast. CT scans showed regression of the anterior mediastinal mass which now measured 4.3 cm × 4.1 cm. However, there were new lesions noted in her breasts measuring 1.6 cm on the right side and 1 cm on the left side. She then underwent ultrasound-guided biopsies of both breast lesions and CT-guided biopsy of the residual mediastinal mass. All three showed residual large B-cell lymphoma. The patient then received salvage therapy with two cycles of rituximab, ifosfamide, carboplatin, and etoposide (R-ICE). Follow-up CT scans showed progressive disease. The disease did not respond to dexamethasone, high-dose cytarabine, and cisplatin (DHAP) as well. The patient was offered brentuximab vedotin on a compassionate use protocol. She received two doses of 1.8 mg/kg on a 3-week interval. Follow-up CT scans showed >50% reduction in the size of the lymphoma [Figure 2]. She then received high-dose chemotherapy followed by autologous stem cell transplant. Unfortunately, the disease relapsed rapidly and then did not respond to brentuximab, high-dose cytarabine, or lenalidomide. The patient subsequently succumbed to the disease, 18 months after her initial diagnosis.
Figure 2: Computed tomography scan of thorax before treatment with brentuximab vedotin and follow-up computed tomography scan showed >50% reduction in the size of the lymphoma

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 > Discussion Top

PMBL is a rare disease and accounts for 10% of all diffuse large B-cell lymphoma. Gene expression profiling has helped to stratify DLBCL into prognostically relevant subgroups and more closely resembles classical Hodgkin's lymphoma.[1],[2]

In addition, recurrent chromosomal translocations which target MYC, BCL-2, and BCL-6 have been detected in up to 40% of all B-cell lymphomas. Aggressive lymphomas that harbor rearrangements involving MYC/8q24 locus along with t (14; 18) (q32; q31) involving the BCL-2 oncogene are referred to as DHL. These DHLs are generally refractory to chemotherapy, and addition of rituximab has not improved on their prognosis.[2],[3]

More recently, many groups have identified increased protein expression of MYC and BCL-2 in subsets of DLBCL. These immunohistochemical double-hit or DPL lymphomas have a worse outcome compared to DLBCL-NOS and slightly better than DHLs. Cutoff values of 40% for MYC expression and 50% for BCL-2 expression have been defined as identifying increased expression of these proteins.[4]

In addition to translocations, the MYC oncogene can also be activated and overexpressed by other mechanisms including copy number aberrations, mutations, or by microRNA-dependent mechanisms. Clinical significance of such copy number aberrations, in the absence of MYC translocation or increased protein expression, is not clear. A recent study suggests that it may also be a marker of poor prognosis.[2],[5]

Due to the relative rareness of the disease and lack of studies, prevalence and prognostic relevance of MYC aberrations in PMBL are uncertain. A recent report suggests, unlike DLBCL, that protein expression of MYC does not have prognostic relevance in PMBL and MYC translocation is distinctly uncommon.[6]

In the lack of randomized trials, optimal first-line treatment for patients with PMBL is controversial. An acceptable approach is using R-CHOP regimen with/without radiation therapy or R-CHOP followed by ICE with/without radiation therapy or dose-adjusted etoposide + prednisone + vincristine + cyclophosphamide + doxorubicin + rituximab. However, refractory PMBL is common, and relapses tend to occur relatively early after the completion of treatment. In such cases, the optimal treatment is uncertain and the prognosis is dismal.[7],[8]

Our patient had PMBL, which was refractory to R-CHOP, and did not respond to two different salvage regimens. Although increased copy numbers of MYC and BCL-2 were noted, only overexpression of BCL-2 was observed by immunostain. Hence, copy number aberrations might have contributed to refractoriness to standard therapy. Given the genetic similarities between PMBL and classical Hodgkin's lymphoma, we treated the patient with brentuximab vedotin after confirming the expression of CD30 on the tumor cells. Despite being refractory to CHOP, ICE, and DHAP, our patient had a 50% regression in the size of her lymphoma to this antibody drug conjugate.

The antibody drug conjugate directed against CD30, brentuximab vedotin in the settings of DLBCL, and PMBL has been an area of interest in recent studies. Jacobsen et al . have reported that brentuximab vedotin has a 44% response rate in refractory DLBCL, which expresses CD30. In their cohort of 48 patients, six had PMBL. Of these six, one is reported to have had a complete response.[8],[9]

Subsequently, a phase II clinical trial conducted by the Italian Lymphoma Foundation assessed the efficacy of brentuximab vedotin in 15 patients with relapsed/refractory CD30-positive PMBL. Out of the 15 patients, only two responded, with an objective response rate of 13%. Similarly, both were partial responses, of short duration, like our patient in this study. Thus, there are three patients in the literature with partial remission to brentuximab in this disease state, all with similar outcomes. Nonetheless, the study was halted beforehand with the surprising conclusion of drug inefficacy in the PMBL setting. Adversely, brentuximab vedotin produced ORR 30%–80% among the CD30 lymphomas. Such results raised questions regarding biologic resistance despite target availability.[8],[10]

Altogether, these reports suggest brentuximab vedotin has activity in refractory PMBL, including ones which have MYC alterations. However, further studies regarding novel therapies and their ability to overcome chromosomally unstable tumors that are refractory to standard therapy are warranted.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

 > References Top

Johnson PW, Davies AJ. Primary mediastinal B-cell lymphoma. Hematology Am Soc Hematol Educ Program 2008;1:349-58.  Back to cited text no. 1
Horn H, Ziepert M, Becher C, Barth TF, Bernd HW, Feller AC, et al. MYC status in concert with BCL2 and BCL6 expression predicts outcome in diffuse large B-cell lymphoma. Blood 2013;121:2253-63.  Back to cited text no. 2
Aukema SM, Siebert R, Schuuring E, van Imhoff GW, Kluin-Nelemans HC, Boerma EJ, et al. Double-hit B-cell lymphomas. Blood 2011;117:2319-31.  Back to cited text no. 3
Sarkozy C, Traverse-Glehen A, Coiffier B. Double-hit and double-protein-expression lymphomas: Aggressive and refractory lymphomas. Lancet Oncol 2015;16:e555-e567.  Back to cited text no. 4
Lu TX, Fan L, Wang L, Wu JZ, Miao KR, Liang JH, et al. MYC or BCL2 copy number aberration is a strong predictor of outcome in patients with diffuse large B-cell lymphoma. Oncotarget 2015;6:18374-88.  Back to cited text no. 5
Li KD, Miles R, Tripp SR, Glenn MJ, Perkins SL, Salama M, et al. Clinicopathologic evaluation of MYC expression in primary mediastinal (thymic) large B-cell lymphoma. Am J Clin Pathol 2015;143:598-604.  Back to cited text no. 6
Dunleavy K, Wilson WH. Primary mediastinal B-cell lymphoma and mediastinal gray zone lymphoma: Do they require a unique therapeutic approach? Blood 2015;125:33-9.  Back to cited text no. 7
Zinzani PL, Pellegrini C, Chiappella A, Di Rocco A, Salvi F, Cabras MG, et al. Brentuximab vedotin in relapsed primary mediastinal large B-cell lymphoma: Results from a phase 2 clinical trial. Blood 2017;129:2328-30.  Back to cited text no. 8
Jacobsen ED, Sharman JP, Oki Y, Advani RH, Winter JN, Bello CM, et al. Brentuximab vedotin demonstrates objective responses in a phase 2 study of relapsed/refractory DLBCL with variable CD30 expression. Blood 2015;125:1394-402.  Back to cited text no. 9
Berger GK, McBride A, Lawson S, Royball K, Yun S, Gee K, et al. Brentuximab vedotin for treatment of non-hodgkin lymphomas: A systematic review. Crit Rev Oncol Hematol 2017;109:42-50.  Back to cited text no. 10


  [Figure 1], [Figure 2]


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