Tuberous sclerosis (TS) is a rare autosomal dominant genetic multisystem disease caused by mutations in either the TSC1 or TSC2 gene and results in the growth of non-cancerous masses in several organs. Diffuse large B-cell lymphoma (DLBCL) is the predominant non-Hodgkin lymphoma in adolescents and young adults. Metronomic chemotherapy (mCHEMO) can be defined as the frequent, regular administration of drug doses able to maintain a low, but active, range of concentrations of chemotherapeutic drugs during prolonged periods of time. We present the case of a young woman with severe TS who developed DLBCL. She was treated consecutively with the mCHEMO schedule R-DEVEC (prednisone, vinorelbine, etoposide, cyclophosphamide, plus rituximab) and then ibrutinib, achieving an impressive long-lasting complete remission. In conclusion, alternative treatments could be necessary when comorbidities are present in patients, and mCHEMO can be a potential successful therapeutic approach in frail subjects.

1.
Osborne JP, Fryer A, Webb D. Epidemiology of tuberous sclerosis. Ann N Y Acad Sci. 1991;615:125–7.
2.
Curatolo P, Bombardieri R, Jozwiak S. Tuberous sclerosis. Lancet. 2008 Aug;372(9639):657–68.
3.
Hochberg J, El-Mallawany NK, Abla O. Adolescent and young adult non-Hodgkin lymphoma. Br J Haematol. 2016 May;173(4):637–50.
4.
Kahn JM, Ozuah NW, Dunleavy K, Henderson TO, Kelly K, LaCasce A. Adolescent and young adult lymphoma: collaborative efforts toward optimizing care and improving outcomes. Blood Adv. 2017 Oct;1(22):1945–58.
5.
de Groen RAL, Schrader AMR, Kersten MJ, Pals ST, Vermaat JSP. MYD88 in the driver’s seat of B-cell lymphomagenesis: from molecular mechanisms to clinical implications. Haematologica. 2019 Dec;104(12):2337–48.
6.
Hartleben G, Müller C, Krämer A, Schimmel H, Zidek LM, Dornblut C, et al. Tuberous sclerosis complex is required for tumor maintenance in MYC-driven Burkitt’s lymphoma. EMBO J. 2018 Nov;37(21):e98589.
7.
Campo E. MYC in DLBCL: partners matter. Blood. 2015 Nov;126(22):2439–40.
8.
Perini GF, Campregher PV, Ross JS, Ali S, Hamerschlak N, Santos FPS. Clinical response to everolimus in a patient with Hodgkin’s lymphoma harboring a TSC2 mutation. Blood Cancer J. 2016 May;6(5):e420.
9.
Bocci G, Kerbel RS. Pharmacokinetics of metronomic chemotherapy: a neglected but crucial aspect. Nat Rev Clin Oncol. 2016 Nov;13(11):659–73.
10.
Natale G, Bocci G. Does metronomic chemotherapy induce tumor angiogenic dormancy? A review of available preclinical and clinical data. Cancer Lett. 2018 Sep;432:28–37.
11.
Cox MC, Bocci G. Metronomic chemotherapy regimens and targeted therapies in non-Hodgkin lymphoma: the best of two worlds. Cancer Lett. 2022 Jan;524:144–50.
12.
Banchi M, Fini E, Crucitta S, Bocci G. Metronomic chemotherapy in pediatric oncology: from preclinical evidence to clinical studies. J Clin Med. 2022 Oct;11(21):6254.
13.
Cox MC, Musuraca G, Battistini R, Casaroli I, Zoli V, Anticoli-Borza P, et al. Aggressive lymphomas of the elderly: the DEVEC metronomic chemotherapy schedule fits the unfit. Br J Haematol. 2018;183(5):819–22.
14.
Cox MC, Pelliccia S, Marcheselli L, Battistini R, Arcari A, Borza PA, et al. The metronomic all-oral DEVEC is an effective schedule in elderly patients with diffuse large b-cell lymphoma. Invest New Drugs. 2019 Jun;37(3):548–58.
15.
Cox MC, Banchi M, Pelliccia S, Di Napoli A, Marcheselli L, Patti C, et al. All-oral metronomic DEVEC schedule in elderly patients with peripheral T cell lymphoma. Cancer Chemother Pharmacol. 2020;86(6):841–6.
16.
Bocci G, Pelliccia S, Orlandi P, Caridi M, Banchi M, Musuraca G, et al. Remarkable remission rate and long-term efficacy of upfront metronomic chemotherapy in elderly and frail patients, with diffuse large B-cell lymphoma. J Clin Med. 2022 Dec;11(23):7162.
17.
Vermaat JS, Somers SF, de Wreede LC, Kraan W, de Groen RAL, Schrader AMR, et al. MYD88 mutations identify a molecular subgroup of diffuse large B-cell lymphoma with an unfavorable prognosis. Haematologica. 2020;105(2):424–34.
18.
Wilson WH, Young RM, Schmitz R, Yang Y, Pittaluga S, Wright G, et al. Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma. Nat Med. 2015 Aug;21(8):922–6.
19.
Hohloch K, Zeynalova S, Held G, Ziepert M, Loeffler M, Wulf G, et al. Excellent outcome of young adults with aggressive non-Hodgkin lymphomas treated with CHOP-like regimens. Leukemia. 2014 Nov;28(11):2260–3.
20.
Younes A, Sehn LH, Johnson P, Zinzani PL, Hong X, Zhu J, et al. Randomized phase III trial of ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in non–germinal center B-cell diffuse large B-cell lymphoma. J Clin Oncol. 2019;37(15):1285–95.
21.
Inoki K, Li Y, Zhu T, Wu J, Guan K-L. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol. 2002 Sep;4(9):648–57.
22.
Kim E, Hurtz C, Koehrer S, Wang Z, Balasubramanian S, Chang BY, et al. Ibrutinib inhibits pre-BCR(+) B-cell acute lymphoblastic leukemia progression by targeting BTK and BLK. Blood. 2017 Mar;129(9):1155–65.
You do not currently have access to this content.