00:03

Primary Mediastinal B-Cell Lymphoma

beau hilton, 2023-12-15

current

Presentation

35M, athlete, no known medical problems.

(all dates modified for HIPAA, relative time spans preserved for instruction)

2023-04-15: Working in the crawl space under his house, developed progressive and eventually severe L arm pain and swelling.

Went to local ED: LUE DVT, put on rivaroxaban. CTPE: +supraclav LN, o/p f/u recommended.

2023-04-20: Called 911 for dyspnea.

2023-04-21: OSH obtained cervical LN core bx: paracortical hyperplasia w focal necrosis

2023-05-05: OSH ER for f/ns and arthralgia, given amox x5d

2023-05-10: Our ER for f/c/ns/n/v, weight loss, chest pain, HA, pruritus.

CT chest: +mediastinal mass, SVC compression w/o critical stenosis, R pleural effusion

No notes.

Primary Mediastinal B-Cell Lymphoma

beau hilton, 2023-12-15

Presentation

35M, athlete, no known medical problems.

(all dates modified for HIPAA, relative time spans preserved for instruction)

2023-04-15: Working in the crawl space under his house, developed progressive and eventually severe L arm pain and swelling.

Went to local ED: LUE DVT, put on rivaroxaban. CTPE: +supraclav LN, o/p f/u recommended.

2023-04-20: Called 911 for dyspnea.

2023-04-21: OSH obtained cervical LN core bx: paracortical hyperplasia w focal necrosis

2023-05-05: OSH ER for f/ns and arthralgia, given amox x5d

2023-05-10: Our ER for f/c/ns/n/v, weight loss, chest pain, HA, pruritus.

CT chest: +mediastinal mass, SVC compression w/o critical stenosis, R pleural effusion

CT

https://radiopaedia.org/cases/8655

Presentation continued

2023-05-15: core bx of mediastinal LN done

2023-05-16: feeling much better (fluids and other supportive care), d/c home

2023-05-17: bx resulted as large B-cell neoplasm. Primary team notified him, he was doing ok and o/p f/u scheduled already for next week, so deferred readmission.

Office visit and admission

2023-05-24: HR 130s, dyspneic, plethoric, but able to get around w/o assistance and speak in complete sentences.

Discussed DLBCL vs PMBCL, possibility of cure in either case, recommended admission for expedited w/u and tx start.

Contacted thoracic team for mediastinoscopy, which they accommodated same-day (+chest tube).

Mostly fibrotic tissue, "like chopping through wood".

Wrote for R-EPOCH to start next day.

Admission continued

FDG-PET CT: 9.4x6.3cm mediastinal mass, LAD, diffuse axial skeleton uptake (hyperplasia vs infiltration)
BMBx: NED
Mediastinal bx: results came back a few days later, mostly fibrosis, crush artifact, necrosis
- mature B-cell markers: CD20+, CD45+, PAX5+.
- PMBCL: CD23 patchy ( -ve in DLBCL, cHL, MGZL), CD30 patchy (30% DLBCL, but weak+ in most PMBCL), CD10- (nonGC), equivocal [BCL2/6, c-MYC, MUM1], EBER-
SVC syndrome: much back and forth re SVC stent, RT.
- Ultimately pursued neither, sx slowly improved.

Subsequent cycles

C2: dose level +0
- (late onset severe neutropenia - ?GCSF)
C3: dose level +1
Interval FDG-PET CT: "near complete resolution" (tiny remnant FDG+, ?malignant vs reactive)
C4: dose level +0 (late onset severe neutropenia)
C5: dose level +1
C6: dose level +2
EOT FDG-PET: next week!

Questions

How common is it and who gets it?
What is the typical presentation?
What are the key parts of the workup?
How common are nondiagnostic biopsies?
What are the key parts of treatment?
What is the role of radiotherapy?
How should we approach post-treatment surveillance?
What are the long-term adverse effects of surviving therapy?

Epidemiology

2-4% of all NHL (SEER 2023 estimate 80,550 NHL * 2% = ~1600-3200/yr)¹
~60% female²
median age 30-35^2,3

S/sx prevalence at presentation (~%)

Tumor size ≥10cm¹	60
Clinical SVC syndrome¹	55
Radiographic SVC compromise¹	80
Pleural effusion²	50
VTE³	35
B symptoms⁴	30-50

Selected clinicopathological features (~%)

Bone marrow involvement¹	2
CNS involvement²	5-10
Marked fibrosis¹	25

Management

Cancer 1988: CHOP21 + 40Gy RT.

NEJM 2013: DA-R-EPOCH.

Management

NEJM 2013: DA-R-EPOCH.

BJH 2018: R-CHOP vs DA-R-EPOCH.

Monitoring

NEJM 2013: DA-R-EPOCH.

NEJM 2013: No increased cardiotoxicity.

Future directions

PD-L1++
- KEYNOTE-170
  - pembro monotherapy for R/R PMBCL
  - N=53, median LoT 3 (26.4% ASCT)
  - ORR 41.5%, CR 20.8%, mOS 22.3mo, 4y OS 45.3%
- –> frontline chemo + pembro
  - NCT04759586 (investigator’s choice + pembro)
Cellular therapy
- e.g. ZUMA-1
  - axi-cel CAR-T
  - N=101, R/R LCL, 8% PMBCL
  - ORR 83%, CR 58%, mOS 25.8mo, 5y OS 42.6%

Bibliography

Ahmed, Z., Afridi, S. S., Shahid, Z., Zamani, Z., Rehman, S., Aiman, W., Khan, M., Mir, M. A., Awan, F. T., Anwer, F., & Iftikhar, R. (2021). Primary Mediastinal B-Cell Lymphoma: A 2021 Update on Genetics, Diagnosis, and Novel Therapeutics. Clinical Lymphoma Myeloma and Leukemia, 21(11), e865–e875. https://doi.org/10.1016/j.clml.2021.06.012

Al Shemmari, S., Sankaranarayanan, S. P., & Krishnan, Y. (2014). Primary mediastinal large B-cell lymphoma: Clinical features, prognostic factors and survival with RCHOP in Arab patients in the PET scan era. Lung India : Official Organ of Indian Chest Society, 31(3), 228–231. https://doi.org/10.4103/0970-2113.135760

Aoki, T., Izutsu, K., Suzuki, R., Nakaseko, C., Arima, H., Shimada, K., Tomita, A., Sasaki, M., Takizawa, J., Mitani, K., Igarashi, T., Maeda, Y., Fukuhara, N., Ishida, F., Niitsu, N., Ohmachi, K., Takasaki, H., Nakamura, N., Kinoshita, T., … Ogura, M. (2014). Prognostic significance of pleural or pericardial effusion and the implication of optimal treatment in primary mediastinal large B-cell lymphoma: A multicenter retrospective study in Japan. Haematologica, 99(12), 1817–1825. https://doi.org/10.3324/haematol.2014.111203

Bea, S., Zettl, A., Wright, G., Salaverria, I., Jehn, P., Moreno, V., Burek, C., Ott, G., Puig, X., Yang, L., Lopez-Guillermo, A., Chan, W. C., Greiner, T. C., Weisenburger, D. D., Armitage, J. O., Gascoyne, R. D., Connors, J. M., Grogan, T. M., Braziel, R., … Lymphoma/Leukemia Molecular Profiling Project. (2005). Diffuse large B-cell lymphoma subgroups have distinct genetic profiles that influence tumor biology and improve gene-expression-based survival prediction. Blood, 106(9), 3183–3190. https://doi.org/10.1182/blood-2005-04-1399

Belay, Y., Yirdaw, K., & Enawgaw, B. (2017). Tumor Lysis Syndrome in Patients with Hematological Malignancies. Journal of Oncology, 2017, 9684909. https://doi.org/10.1155/2017/9684909

Bhatt, V. R., Mourya, R., Shrestha, R., & Armitage, J. O. (2015). Primary mediastinal large B-cell lymphoma. Cancer Treatment Reviews, 41(6), 476–485. https://doi.org/10.1016/j.ctrv.2015.04.006

Bishop, P. C., Wilson, W. H., Pearson, D., Janik, J., Jaffe, E. S., & Elwood, P. C. (1999). CNS involvement in primary mediastinal large B-cell lymphoma. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 17(8), 2479–2485. https://doi.org/10.1200/JCO.1999.17.8.2479

Bibliography

Camus, V., Drieux, F., & Jardin, F. (2022). State of the art in the diagnosis, biology and treatment of primary mediastinal B-cell lymphoma: A review. Annals of Lymphoma, 6(0), Article 0. https://doi.org/10.21037/aol-22-13

Cazals-Hatem, D., Lepage, E., Brice, P., Ferrant, A., d’Agay, M. F., Baumelou, E., Brière, J., Blanc, M., Gaulard, P., Biron, P., Schlaifer, D., Diebold, J., & Audouin, J. (1996). Primary mediastinal large B-cell lymphoma. A clinicopathologic study of 141 cases compared with 916 nonmediastinal large B-cell lymphomas, a GELA (“Groupe d’Etude des Lymphomes de l’Adulte”) study. The American Journal of Surgical Pathology, 20(7), 877–888. https://doi.org/10.1097/00000478-199607000-00012

Chen, H., Pan, T., He, Y., Zeng, R., Li, Y., Yi, L., Zang, H., Chen, S., Duan, Q., Xiao, L., & Zhou, H. (2021). Primary Mediastinal B-Cell Lymphoma: Novel Precision Therapies and Future Directions. Frontiers in Oncology, 11. https://www.frontiersin.org/articles/10.3389/fonc.2021.654854

Cwynarski, K., Marzolini, M. A. V., Barrington, S. F., Follows, G., Illidge, T., Stern, S., Davies, A., & Guidelines, the B. S. for H. (2019). The management of primary mediastinal B-cell lymphoma: A British Society for Haematology Good Practice Paper. British Journal of Haematology, 185(3), 402–409. https://doi.org/10.1111/bjh.15731

Dunleavy, K., Pittaluga, S., Maeda, L. S., Advani, R., Chen, C. C., Hessler, J., Steinberg, S. M., Grant, C., Wright, G., Varma, G., Staudt, L. M., Jaffe, E. S., & Wilson, W. H. (2013). Dose-Adjusted EPOCH-Rituximab Therapy in Primary Mediastinal B-Cell Lymphoma. New England Journal of Medicine, 368(15), 1408–1416. https://doi.org/10.1056/NEJMoa1214561

Hayden, A. R., Tonseth, P., Lee, D. G., Villa, D., Gerrie, A. S., Scott, D. W., Freeman, C. L., Slack, G. W., Farinha, P., Skinnider, B., Yenson, P. R., Benard, F., Lo, A., Pickles, T., Wilson, D., Connors, J. M., Sehn, L. H., & Savage, K. J. (2020). Outcome of primary mediastinal large B-cell lymphoma using R-CHOP: Impact of a PET-adapted approach. Blood, 136(24), 2803–2811. https://doi.org/10.1182/blood.2019004296

Jacobson, J. O., Aisenberg, A. C., Lamarre, L., Willett, C. G., Linggood, R. M., Miketic, L. M., & Harris, N. L. (1988). Mediastinal large cell lymphoma. An uncommon subset of adult lymphoma curable with combined modality therapy. Cancer, 62(9), 1893–1898. https://doi.org/10.1002/1097-0142(19881101)62:9<1893::aid-cncr2820620904>3.0.co;2-x

Bibliography

Lees, C., Keane, C., Gandhi, M. K., & Gunawardana, J. (2019). Biology and therapy of primary mediastinal B-cell lymphoma: Current status and future directions. British Journal of Haematology, 185(1), 25–41. https://doi.org/10.1111/bjh.15778

Lekovic, D., Miljic, P., & Mihaljevic, B. (2010). Increased risk of venous thromboembolism in patients with primary mediastinal large B-cell lymphoma. Thrombosis Research, 126(6), 477–480. https://doi.org/10.1016/j.thromres.2010.08.017

Martelli, M., Ferreri, A., Di Rocco, A., Ansuinelli, M., & Johnson, P. W. M. (2017). Primary mediastinal large B-cell lymphoma. Critical Reviews in Oncology/Hematology, 113, 318–327. https://doi.org/10.1016/j.critrevonc.2017.01.009

National Cancer Institute (NCI). (2023). A Randomized Phase 3 Trial of Nivolumab (NSC# 748726) in Combination With Chemo-Immunotherapy for the Treatment of Newly Diagnosed Primary Mediastinal B-Cell Lymphoma (Clinical Trial Registration NCT04759586). clinicaltrials.gov. https://clinicaltrials.gov/study/NCT04759586

Neelapu, S. S., Jacobson, C. A., Ghobadi, A., Miklos, D. B., Lekakis, L. J., Oluwole, O. O., Lin, Y., Braunschweig, I., Hill, B. T., Timmerman, J. M., Deol, A., Reagan, P. M., Stiff, P., Flinn, I. W., Farooq, U., Goy, A. H., McSweeney, P. A., Munoz, J., Siddiqi, T., … Locke, F. L. (2023). Five-year follow-up of ZUMA-1 supports the curative potential of axicabtagene ciloleucel in refractory large B-cell lymphoma. Blood, 141(19), 2307–2315. https://doi.org/10.1182/blood.2022018893

Papageorgiou, S. G., Diamantopoulos, P., Levidou, G., Angelopoulou, M. K., Economopoulou, P., Efthimiou, A., Constantinou, N., Katsigiannis, A., Korkolopoulou, P., Pappa, V., Economopoulou, C., Georgiou, G., Dimou, M., Tsirigotis, P., Kyrtsonis, M.-C., Kotsianidis, I., Kalpadakis, C., Dimopoulos, M.-A., Beris, P., … Vassilakopoulos, T. P. (2013). Isolated central nervous system relapses in primary mediastinal large B-cell lymphoma after CHOP-like chemotherapy with or without Rituximab. Hematological Oncology, 31(1), 10–17. https://doi.org/10.1002/hon.2012

Purroy, N., Bergua, J., Gallur, L., Prieto, J., Lopez, L. A., Sancho, J. M., García-Marco, J. A., Castellví, J., Montes-Moreno, S., Batlle, A., de Villambrosia, S. G., Carnicero, F., Ferrando-Lamana, L., Piris, M. A., & Lopez, A. (2015). Long-term follow-up of dose-adjusted EPOCH plus rituximab (DA-EPOCH-R) in untreated patients with poor prognosis large B-cell lymphoma. A phase II study conducted by the Spanish PETHEMA Group. British Journal of Haematology, 169(2), 188–198. https://doi.org/10.1111/bjh.13273

Bibliography

Savage, K. J., Al-Rajhi, N., Voss, N., Paltiel, C., Klasa, R., Gascoyne, R. D., & Connors, J. M. (2006). Favorable outcome of primary mediastinal large B-cell lymphoma in a single institution: The British Columbia experience. Annals of Oncology: Official Journal of the European Society for Medical Oncology, 17(1), 123–130. https://doi.org/10.1093/annonc/mdj030

Shah, N. N., Szabo, A., Huntington, S. F., Epperla, N., Reddy, N., Ganguly, S., Vose, J., Obiozor, C., Faruqi, F., Kovach, A. E., Costa, L. J., Xavier, A. C., Okal, R., Kanate, A. S., Ghosh, N., Kharfan-Dabaja, M. A., Strelec, L., Hamadani, M., Fenske, T. S., … Svoboda, J. (2018). R-CHOP versus dose-adjusted R-EPOCH in frontline management of primary mediastinal B-cell lymphoma: A multi-centre analysis. British Journal of Haematology, 180(4), 534–544. https://doi.org/10.1111/bjh.15051

Sheikh, Y., & Gaillard, F. (2010). Mediastinal lymphoma—Large B-cell. In Radiopaedia.org. Radiopaedia.org. https://doi.org/10.53347/rID-8655

Velasques, R. D., da Silva, W. F., Bellesso, M., Rocha, V., & Pereira, J. (2022). Less Intensive Regimens May Still Be Suitable for the Initial Treatment of Primary Mediastinal B-Cell Lymphoma in Resource-Limited Settings. Journal of Oncology, 2022, 2099456. https://doi.org/10.1155/2022/2099456

Yu, Y., Dong, X., Tu, M., & Wang, H. (2021). Primary mediastinal large B cell lymphoma. Thoracic Cancer, 12(21), 2831–2837. https://doi.org/10.1111/1759-7714.14155

Yuan, J., Wright, G., Rosenwald, A., Steidl, C., Gascoyne, R. D., Connors, J. M., Mottok, A., Weisenburger, D. D., Greiner, T. C., Fu, K., Smith, L., Rimsza, L. M., Jaffe, E. S., Campo, E., Martinez, A., Delabie, J., Braziel, R. M., Cook, J. R., Ott, G., … Project (LLMPP), F. the L. L. M. P. (2015). Identification of Primary Mediastinal Large B-cell Lymphoma at Nonmediastinal Sites by Gene Expression Profiling. The American Journal of Surgical Pathology, 39(10), 1322. https://doi.org/10.1097/PAS.0000000000000473

Bibliography

Zinzani, P. L., Thieblemont, C., Melnichenko, V., Bouabdallah, K., Walewski, J., Majlis, A., Fogliatto, L., Garcia-Sancho, A. M., Christian, B., Gulbas, Z., Özcan, M., Perini, G. F., Ghesquieres, H., Shipp, M. A., Thompson, S., Chakraborty, S., Marinello, P., & Armand, P. (2023). Pembrolizumab in relapsed or refractory primary mediastinal large B-cell lymphoma: Final analysis of KEYNOTE-170. Blood, 142(2), 141–145. https://doi.org/10.1182/blood.2022019340

Zucca, E., Davies, A., Kryachok, I., Ciccone, G., Ceriani, L., Botto, B., Mikhaeel, N. G., Dabrowska-Iwanicka, A., Zhao, W., Inescu, C., Janikova, A., Fossa, A., Hodgson, D., Jerkeman, M., Balzarotti, M., Tucci, A., Ricardi, U., Barrington, S., Johnson, P. W. M., & Martelli, M. (2023). Observation vs. radiotherapy in primary mediastinal B-cell lymphoma patients with complete response to standard immunochemotherapy: The IELSG37 randomized trial. Journal of Clinical Oncology, 41(17_suppl), LBA7505–LBA7505. https://doi.org/10.1200/JCO.2023.41.17_suppl.LBA7505