Dear Editor,
Primary mediastinal B-cell lymphoma (PMBCL) is an aggressive neoplasm arising in the thymus and constitutes 2–3% of all non-Hodgkin’s lymphoma. It has been recognized as a separate entity by the World Health Organization (WHO) based on its overlapping immuno-morphological and genetic characteristics with classical Hodgkin’s lymphoma [1].
Traditionally, as it was considered a subtype of Diffuse large B-cell lymphoma (DLBCL), chemo-immunotherapy with or without consolidation radiotherapy (RT) is the standard first-line treatment of PMBCL. The improved understanding of disease biology, especially the role of drug efflux pumps in mediating resistance to chemotherapeutic drugs in tumor cells, has led to the development of newer treatment protocols that rely on continuous administration of cytotoxic drugs [2]. Dose adjusted EPOCH-R(DAEPOCH-R) is one such regimen that seems to improve long term cure rates of PMBCL while obviating the need for mediastinal radiation in this young patient population [3, 4]. Indeed, there is no randomized controlled study of R-DAEPOCH in PMBCL, and its real-world experience in developing countries like India is sparse [5].
We retrospectively analyzed 12 consecutive patients of PMBCL treated at our center from 1st May 2013 to 30th April 2019 based on information from the case record files of the patients. The stage and responses were assessed according to the Lugano criteria [6].
The median age of the patients was 28 (16–52) years, and 50% were male. The stage distribution was: stage I, 3 (25%); stage II, 6 (50%); stage III, 1 (8.33%); and stage IV, 2 (16.66%). At presentation, 7 (58.3%) patients had superior vena cava syndrome (SVCS), 8 (66%) had bulky disease, and 9 (75%) patients had elevated lactate dehydrogenase (LDH). Apart from mediastinal mass, 4 (33%) patients had supraclavicular lymphadenopathy. The extranodal presentation was seen in 2 patients; one with renal and pulmonary parenchymal involvement while other patients showed pulmonary parenchymal involvement. Upfront pleural or pericardial effusion was present in 7 (58.3%) patients. None of the patients had a bone marrow or central nervous system (CNS) involvement at presentation. Of the patients receiving the R-DAEPOCH regimen, the maximum dose intensity achieved was level 3 in 4 patients and level 2 in the rest of them. After the median 6 cycles (range 5–6) of chemotherapy, the overall response rate was 91.6%, with 9 (75%) patients achieving complete remission (CR), two partial remissions (CR after RT), and 1 progressed on chemotherapy. Among 9 patients who achieved a CR after 6 cycles, 3 relapsed within 1 year [median time of relapse: 6 months (range 3–12)]. The sites at relapse were in CNS/mediastinum (one patient), loco-regional (2 patients).All three patients (baseline stage I in 2 and stage IV in one patient) in who relapsed and died had bulky disease upfront with mediastinal mass > 10 cm, high LDH, pleuropericardial effusion, and SVCS in 2 patients), none received RT as end of treatment (PET-CT) scan confirmed CR and had the uncontrolled disease after second-line chemotherapy. Rituximab, Ifosfamide, Carboplatin, Etoposide (RICE) protocol was given as salvage after confirming the relapse. All three patients progressed after salvage chemotherapy (two patients after 2nd cycle, one after the 3rd cycle).
Upfront thrombotic manifestations (TM) were observed in 3 patients. Four patients developed TM during chemotherapy. Therefore, a total of 7 patients had TM in our patient cohort. The common sites of TM were upper limb in 6 patients (right-3, left-2, bilateral-1) and lower limb in one patient. The most common toxicities (grade 3–4) were neutropenia in 3 patients, thrombocytopenia in 1, and anemia in one patient. Febrile neutropenia was observed in 4 patients. Grade 3 peripheral neuropathy was observed in 2 patients and required dose modification of vincristine. In our study, the 2-year event-free survival and (EFS) and overall (OS) were 75% and 83%, respectively, with a median follow-up period of 29 months
Real-world experience at our center showed a similar age but different sex ratio, compared to the western literature [3, 4]. Recent evidence suggests that DA-EPOCH-R has superior outcomes to R-CHOP. Table 1 shows selected studies of PMBCL patients treated with DAEPOCH-R and other protocols [7]. In the prospective phase, 2 study of PMBCL, where 51 patients received DA-EPOCH-R, EFS of 93%, and OS of 97%, was observed at a median follow-up of 63 months [3]. These results were supported by a retrospective study in the larger cohort (n = 156) of PMBCL patients by Giuliano-Roth et al. [4]. While the prognostic markers for PMBCL are still not clear, there is evidence that baseline pleural/pericardial effusions and substantial burden of disease (SVCS and elevated LDH), are associated with poor outcomes [10]. In our study, the 2 year EFS and OS were 75% and 83%, respectively. A high incidence (75% of our patients) of poor prognostic factors may have been possible for increased relapses in our setting. The maximum dose intensity of R-DAEPOCH was level two in 2/3rd of our patient cohort, which may also be one of the reasons for more relapses. As suggested by previous studies [4], TM is associated with poor outcomes in PMBCL, and the upfront antithrombotic measure at the time of diagnosis might help prevent TM during the further course of treatment since 4 of our patients developed TM during the treatment. This analysis questions whether our patients of PMBCL who are unable to achieve higher dose intensity with R-DAEPOCH should receive further consolidation with mediastinal radiation, as the patients who received mediastinal RT did well. However, a small sample size precludes any definitive answer from this study. We eagerly await results of an ongoing randomized controlled trial-IELSG37 (NCT01599559) that may answer whether mediastinal RT is essential for patients where PET scan has shown that tumor is no longer active.
Table 1.
Studies of Adults with PMBCL treated in the Rituximab Era (published onwards 2013)
| References | Type of the study | Regimen | Number of patients | Median age (years) | PFS, % |
|---|---|---|---|---|---|
| Zinzani et al. [8] | Retrospective | R-MACOP-B | 74 | 34 | 88 (10 years) |
| Gleeson et al. [9] | Prospective |
RCHOP 14 RCHOP 21 |
50 | 38.5 |
84 (5 years) 80 (5 years) |
| Dunleavy et al. [3] | Prospective | DA‐EPOCH‐R | 51 | 30 | 93 (3 years) |
| Giulino-Roth et al. [4] | Retrospective | DA‐EPOCH‐R | 118 | 31 | 87 (3 years EFS) |
| Present study | Retrospective | DA‐EPOCH‐R | 12 | 28 | 75 (2 years EFS) |
EFS event-free survival, PFS progression-free survival
Funding
No funding received for the study.
Compliance with Ethical Standards
Conflict of Interest
No potential conflict of interest.
Ethical Approval
Institute ethical clearance was obtained for the retrospective study.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Contributor Information
Ajay Gogia, Email: ajaygogia@gmail.com.
Sudhir Kumar, Email: sudhirkirar@gmail.com.
Santosh Kumar Chellapurum, Email: santosh.chellapuram@gmail.com.
Ahitagni Biswas, Email: dr_ahitagni@yahoo.co.in.
Soumya Mallick, Email: drsmallick.aiims@gmail.com.
References
- 1.Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, Advani R, Ghielmini M, Salles GA, Zelenetz AD, Jaffe ES. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375–2390. doi: 10.1182/blood-2016-01-643569. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Lai GM, Chen YN, Mickley LA, Fojo AT, Bates SE. P-glycoprotein expression and schedule dependence of adriamycin cytotoxicity in human colon carcinoma cell lines. Int J Cancer. 1991;49(5):696–703. doi: 10.1002/ijc.2910490512. [DOI] [PubMed] [Google Scholar]
- 3.Dunleavy K, Pittaluga S, Maeda LS, et al. Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma. N Engl J Med. 2013;368(15):1408–1416. doi: 10.1056/NEJMoa1214561. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Giulino-Roth L, O’Donohue T, Chen Z, et al. Outcomes of adults and children with primary mediastinal B-cell lymphoma treated with dose-adjusted EPOCH-R. Br J Haematol. 2017;179(5):739–747. doi: 10.1111/bjh.14951. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Ganesan P, Ganesan TS, Atreya H, et al. DA-EPOCH-R in aggressive CD 20 positive B cell lymphomas: real-world experience. Indian J Hematol Blood Transf. 2018;34(3):454–459. doi: 10.1007/s12288-017-0901-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059–3068. doi: 10.1200/JCO.2013.54.8800. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Giulino-Roth L. How I treat primary mediastinal B-cell lymphoma. Blood. 2018;132(8):782–790. doi: 10.1182/blood-2018-04-791566. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Zinzani PL, Broccoli A, Casadei B, et al. The role of rituximab and positron emission tomography in the treatment of primary mediastinal large B-cell lymphoma: experience on 74 patients. Hematol Oncol. 2015;33(4):145–150. doi: 10.1002/hon.2172. [DOI] [PubMed] [Google Scholar]
- 9.Gleeson M, Hawkes EA, Cunningham D, et al. Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) in the management of primary mediastinal B-cell lymphoma: a subgroup analysis of the UK NCRI R-CHOP 14 versus 21 trial. Br J Haematol. 2016;175(4):668–672. doi: 10.1111/bjh.14287. [DOI] [PubMed] [Google Scholar]
- 10.Aoki T, Izutsu K, Suzuki R, et al. Novel prognostic model of primary mediastinal large B-cell lymphoma (PMBL): a multicenter cooperative retrospective study in Japan. ASH Annu Meet Abstr. 2013;122(21):638. [Google Scholar]