Liposomal Vincristine as a Bridge Therapy Prior to CAR-T Therapy in Relapsed and Refractory Diffuse Large B-Cell Lymphoma?
We report a case of a 76-year-old male with a history of relapsed and refractory diffuse large B-cell lymphoma (DLBCL).Our patient was initially treated with front line chemotherapy along with central nervous system (CNS) prophylaxis with complete response. He subsequently relapsed, was sensitive to second-line chemotherapy, and underwent autologous stem cell transplantation achieving a complete remission. Only a few months after transplant, the patient suffered his second relapse and was deemed a candidate for Chimeric Antigen Receptor T-Cell Therapy (CAR-T). Given his aggressive disease, combined with the time needed to generate CAR-T cells, a multidisciplinary team recommended to treat our patient with liposomal vincristine in combination with rituximab as a bridge therapy. Durable responses have been seen using liposomal vincristine based on results from a recent phase II trial in heavily pretreated patients with DLBCL1. This therapy was effective in stabilizing and reducing active disease in our patient. This case looks to illustrate the use of liposomal vincristine in combination with immunotherapy in a novel setting bridging highly selected patients with active and refractory lymphoma prior to CAR-T. Moreover, we expanded an additional therapeutic point, highlighting the importance of optimal disease control prior to CAR-T cell harvesting, as recent literature has shown that residual malignant cells in the pheresis product may be inadvertently be transfected with the CAR gene, resulting in resistance and further relapse2.
2. Ruella M, Xu J, Barrett DM, et al. Induction of resistance to chimeric antigen receptor T cell therapy by transduction of a single leukemic B cell. Nat Med; 2018. 24(10): 1499-1503.
3. Douer D. Efficacy and Safety of Vincristine Sulfate Liposome Injection in the Treatment of Adult Acute Lymphocytic Leukemia. Oncologist. 2016; 21(7): 840–847.
4. Pulte D, Jansen L, Gondos A, et al. Survival of adults with acute lymphoblastic leukemia in Germany and the United States. PLoS One. 2014; 9(1):e85554.
5. Thomas DA, Kantarjian H, Smith TL, et al. Primary refractory and relapsed adult acute lymphoblastic leukemia: Characteristics, treatment results, and prognosis with salvage therapy. Cancer. 1999; 86(7):1216-30.
6. Henderson, NV: Spectrum Pharmaceuticals launches Marqibo (vincristine sulfate LIPOSOME injection) 2013 September. Available from: https://www.marketwatch.com/press-release/spectrum-pharmaceuticals-launches-marqibo. Accessed March 10, 2019.
7. O'Brien S, Thomas D, Ravandi F, et al. Outcome of adults with acute lymphocytic leukemia after second salvage therapy. Cancer. 2008; 113(11):3186-91.
8. Food and Drug Administration approves Marqibo to treat rare type of leukemia. August 9, 2012. Available from: http://medimoon.com/2012/08/fda-approves-marqibo-to-treat-rare-type-of-leukemia. Accessed March 10, 2019.
9. Pathak P, Hess R, Weiss MA. Liposomal vincristine for relapsed or refractory Ph-negative acute lymphoblastic leukemia; A review of literature. Ther Adv Hematol. 2014; 5(1):18-24.
10. Markman JL, Rekechenetskiy A, Holler E, et al. Nanomedicine therapeutic approaches to overcome cancer drug resistance. Adv Drug Deliv Rev. 2013; 65(13-14):1866-79.
11. Silverman JA, Deitcher SR. Marqibo (vincristine sulfate liposome injection) improves the pharmacokinetics and pharmacodynamics of vincristine. Cancer Chemother Pharmacol. 2013. 71(3); 555-64.
12. Mufamadi MS, Pillay V, Choonara YE, et al. A review on composite liposomal technologies for specialized drug delivery. J Drug Deliv. 2011; 2011: 939851.
13. Thomas DA, Kantarjian H, Smith TL, et al. Primary refractory and relapsed adult acute lymphoblastic leukemia: Characteristics, treatment results, and prognosis with salvage therapy. Cancer. 1999; 86(7): 1216-30.
14. Krishna R, Webb MS, St Onge G, et al. Liposomal and nonliposomal drug pharmacokinetics after administration of liposome-encapsulated vincristine and their contribution to drug tissue distribution properties. J Pharmacol Exp Ther. 2001; 298(3):1206-12.
15. Marqibo [package insert]. Henderson, NV: Spectrum Pharmaceuticals, Inc 2013. www.investor.sppirx.com/static-files/bd37ee75-aac0-437e-9188-57d12f75255a
16. Kanter PM, Klaich GM, Bullard GA, et al. Liposome encapsulated vincristine: Preclinical toxicologic and pharmacologic comparison with free vincristine and empty liposomes in mice, rats, and dogs. Anticancer Drugs; 1994. 5(5): 579-90.
17. Webb MS, Logan P, Kanter PM, et al. Preclinical pharmacology, toxicology, and efficacy of sphingomyelin/cholesterol liposomal vincristine for therapeutic treatment of cancer. Cancer Chemother Pharmacol; 1998. 42(6): 461-70.
18. Ait-Oudhia S, Mager DE, Straubinger RM. Application of pharmacokinetic and pharmacodynamic analysis to the development of liposomal formulations for oncology. Pharmaceutics. 2014. 6(1): 137-74.
19. Balis FM, Holcenberg JS, Bleyer WA. Clinical pharmacokinetics of commonly used anticancer drugs. Clin Pharmacokinet. 1983; 8(3):202-32.
20. Gidding CE, Kellie SJ, Kamps WA, et al. Vincristine revisited. Crit Rev Oncol Hematol. 1999. 29(3): 267-87.
21. Webb MS, Harasym TO, Masin D, et al. Sphingomyelin-cholesterol liposomes significantly enhance the pharmacokinetic and therapeutic properties of vincristine in murine and human tumour models. Br J Cancer.1995; 72(4): 896-904.
22. O'Brien S, Schiller G, Lister J, et al. High-dose vincristine sulfate liposome injection for advanced, relapsed, and refractory adult Philadelphia chromosome-negative acute lymphoblastic leukemia. J Clin Oncol. 2013; 31(6): 676-83.
23. Rodriguez MA, Pytlik R, Kozak T, Chhanabhai M, Gascoyne R, Lu B. et al. Vincristine sulfate liposomes injection (Marqibo) in heavily pretreated patients with refractory aggressive non-Hodgkin lymphoma: report of the pivotal phase 2 study. Cancer. 2009; 115: 3475-82.
24. CAR T Cells: Engineering Patients’ Immune Cells to Treat Their Cancers. December 2017. Available from. https://www.cancer.gov/about-cancer/treatment/research/car-t-cells. Accessed March 10, 2019
25. Schuster SJ, Svoboda J, Chong EA, et al. Chimeric Antigen Receptor T Cells in Refractory B-Cell Lymphomas. N Engl J Med. 2017; 377(26): 2545-2554.
26. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. N Engl J Med. 2017; 377: 2531-44.