A new target/therapy in the treatment of Hodgkin Lymphoma
Myron Yaster MD and Micah Maxwell MD PhD
Never heard of brentuximab vedotin in the medical management of Hodgkin Lymphoma (or is Hodgkin’s lymphoma)? Neither had I and when I read about it while scanning the New England J of Medicine for the PAAD,1, 2 I realized as physicians who take care of these patients we need to! We see patients with Hodgkin Lymphoma frequently during the course of their disease whether it be for diagnosis, central line placement, surveillance bone marrow aspirations, radiation, ICU and pain management, etc. Indeed, there are few patient encounters more terrifying than anesthetizing a patient with a new anterior mediastinal mass, which is where we often first meet these patients when they come to the OR or interventional radiology suite for tissue diagnosis. We also treat the survivors years later when they return with secondary tumors/cancers or with cardiac dysfunction secondary to chemo and radiation therapy.
This is hardly an area of my expertise, so I asked my “nephew”, Dr. Micah Maxwell (son of Dr. Lynne Maxwell), a pediatric oncologist, to assist in writing today’s PAAD. Myron Yaster MD
Original article
Sharon M Castellino, Qinglin Pei, Susan K Parsons, David Hodgson, Kathleen McCarten, Terzah Horton, et al. Brentuximab Vedotin with Chemotherapy in Pediatric High-Risk Hodgkin's Lymphoma. N Engl J Med. 2022 Nov 3;387(18):1649-1660. PMID: 36322844
Editorial
Mark Roschewski, Catherine M Bollard. Are We Too Reliant on Radiation Therapy for Children with Hodgkin's Lymphoma? N Engl J Med. 2022 Nov 3;387(18):1710-1712. PMID: 36322850
Hodgkin Lymphoma accounts for 10% of all lymphomas and 0.6% of all cancers in the developed world. In the United States, it is estimated that 9,000 new cases, primarily in adolescents and young adults, are diagnosed annually, and approximately 1,150 will die of their disease. Hodgkin Lymphoma is histologically defined by rare mononuclear Hodgkin cells and multinucleated Reed-Sternberg (HRS) cells residing in a sea of inflammatory cells.3
Despite an excellent cure rate with modern frontline Hodgkin Lymphoma therapy, approximately 15 to 20% of patients are not cured with first line or second line therapy, and will require additional treatments. For those who are cured, treatment-related late toxicities continue to impact patients’ quality of life and survival. Therefore, there is need to develop new therapeutic agents to further improve the current cure rate and to reduce treatment toxicity. HRS cells are characterized by the expression of CD30 receptors. CD30 is a transmembrane glycoprotein that belongs to the tumor necrosis factor (TNF) receptor superfamily.4 CD30 expression is very restricted making it an ideal therapeutic target for monoclonal antibodies.
Brentuximab vedotin is an antibody-drug conjugate (ADC) that was developed by conjugating the tubulin toxin monomethyl auristatin E (MMAE) to the chimeric monoclonal anti-CD30 antibody cAC10. On average, four molecules of MMAE are conjugated to one cAC10. After binding to CD30, brentuximab vedotin in internalized and processed into lysosomal vesicles leading to the release of MMAE from the antibody by reduction or acid hydrolysis within the lysosomes. Subsequently, MMAE is released into cytoplasm and inhibits microtubule polymerization leading to cell cycle arrest followed by cell death. As HRS cells die, a small amount of MMAE is released into the tumor microenvironment which can kill neighboring cells by a CD30-independent manner.
How Hodgkin Lymphoma is initially treated by pediatric and adult oncologists is different. “The standard treatment regimen for adults is doxorubicin, bleomycin, vinblastine, and dacarbazine for six to eight cycles. In contrast, pediatric oncologists use regimens such as ABVE-PC (doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide for five cycles), with lower cumulative doses of anthracyclines and alkylating agents, which are designed to decrease long-term risks.”1, 2 The goal of this dose-dense therapy using six drugs is to maximize intensity without exceeding thresholds of toxicity. “Response-adapted approaches further reduce toxicity by eliminating either chemotherapy or radiation therapy on the basis of positron-emission tomographic (PET) scans obtained during or after therapy” that demonstrate rapid early response.1, 2 Children with large bulky tumors are generally treated with radiation, while adults treated with brentuximab vedotin are not.
“The anti-CD30 antibody–drug conjugate brentuximab vedotin has been evaluated in both children and adults with Hodgkin’s lymphoma with the goal of improving short-term disease control while avoiding the use of bleomycin [and its associated risk of pulmonary fibrosis] and reducing the reliance on radiation therapy.”1, 2, 5, 6 In today’s PAAD, Castellino et al. randomized children with Hodgkin’s Lymphoma to brentuximab vedotin plus AVE-PC or to the standard bleomycin-containing therapy (ABVE-PC) and found similar initial response rates but better 3-year event free survival. Improvement in overall survival and reduction in radiation therapy was not achieved as it has been in adult patients. Of note, there was less high grade neuropathy in this pediatric cohort treated with brentuximab vedotin than has been seen in adults. More research is planned and we urge you to keep your eyes open to not only this new therapy but to the use of monoclonal antibody-drug conjugates in other cancer trials in the future.
References
1. Roschewski M, Bollard CM. Are We Too Reliant on Radiation Therapy for Children with Hodgkin’s Lymphoma? New England Journal of Medicine. 2022;387(18):1710-1712. doi:10.1056/NEJMe2211587
2. Castellino SM, Pei Q, Parsons SK, et al. Brentuximab Vedotin with Chemotherapy in Pediatric High-Risk Hodgkin’s Lymphoma. New England Journal of Medicine. 2022;387(18):1649-1660. doi:10.1056/NEJMoa2206660
3. Alperovich A, Younes A. Targeting CD30 Using Brentuximab Vedotin in the Treatment of Hodgkin Lymphoma. Cancer J. Jan-Feb 2016;22(1):23-6. doi:10.1097/ppo.0000000000000168
4. Falini B, Pileri S, Pizzolo G, et al. CD30 (Ki-1) molecule: a new cytokine receptor of the tumor necrosis factor receptor superfamily as a tool for diagnosis and immunotherapy. Blood. Jan 1 1995;85(1):1-14.
5. Ansell SM, Radford J, Connors JM, et al. Overall Survival with Brentuximab Vedotin in Stage III or IV Hodgkin's Lymphoma. The New England journal of medicine. Jul 28 2022;387(4):310-320. doi:10.1056/NEJMoa2206125
6. Metzger ML, Link MP, Billett AL, et al. Excellent Outcome for Pediatric Patients With High-Risk Hodgkin Lymphoma Treated With Brentuximab Vedotin and Risk-Adapted Residual Node Radiation. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. Jul 10 2021;39(20):2276-2283. doi:10.1200/jco.20.03286