Chapter 27
Innovative Chemotherapy-free Approaches for the Treatment of Peripheral T-Cell Lymphoma
Enrica Marchi,
Ahmed Sawas,
Helen Ma,
Luigi Scotto,
Francesca Montanari,
Enrica Marchi
University of Virginia Cancer Center, Charlottesville, VA, USA
Search for more papers by this authorAhmed Sawas
Center for Lymphoid Malignancies, Columbia University Medical Center, New York, NY, USA
Search for more papers by this authorHelen Ma
Center for Lymphoid Malignancies, Columbia University Medical Center, New York, NY, USA
Search for more papers by this authorLuigi Scotto
Center for Lymphoid Malignancies, Columbia University Medical Center, New York, NY, USA
Search for more papers by this authorFrancesca Montanari
Center for Lymphoid Malignancies, Columbia University Medical Center, New York, NY, USA
Search for more papers by this authorEnrica Marchi,
Ahmed Sawas,
Helen Ma,
Luigi Scotto,
Francesca Montanari,
Enrica Marchi
University of Virginia Cancer Center, Charlottesville, VA, USA
Search for more papers by this authorAhmed Sawas
Center for Lymphoid Malignancies, Columbia University Medical Center, New York, NY, USA
Search for more papers by this authorHelen Ma
Center for Lymphoid Malignancies, Columbia University Medical Center, New York, NY, USA
Search for more papers by this authorLuigi Scotto
Center for Lymphoid Malignancies, Columbia University Medical Center, New York, NY, USA
Search for more papers by this authorFrancesca Montanari
Center for Lymphoid Malignancies, Columbia University Medical Center, New York, NY, USA
Search for more papers by this authorBook Editor(s):Owen A. O'Connor M.D., Ph.D.,
Won Seog Kim,
Pier Luigi Zinzani M.D., Ph.D.,
Owen A. O'Connor M.D., Ph.D.
American Cancer Society Research Professor Professor of Medicine
Department of Medicine, Division of Hematology and Oncology, Program for T-Cell Lymphoma Research, Department of Microbiology, Immunology, and Cancer Research, University of Virginia Cancer Center, Charlottesville, VA, USA
Search for more papers by this authorWon Seog Kim
Sungkyunkwan University School of Medicine, Seoul, Korea
Search for more papers by this authorPier Luigi Zinzani M.D., Ph.D.
Professor of Hematology
Department of Medicine, Program for Lymphomas and Chronic Lymphocytic Leukemia, University of Bologna, Bologna, Italy
Search for more papers by this authorFirst published: 19 February 2021
Summary
The discovery of new therapeutic agents followed by the subsequent development of novel drug–drug combinations has been one of the most exciting areas in cancer medicine. This has been especially true over the past decade for the primary cutaneous T-cell lymphoma (PTCL). Modifications to conventional cytotoxic chemotherapy has been generally unsuccessful in advancing the care of patients with PTCL. Alongside the approved drugs, many lines of evidence have identified other drugs that have demonstrated compelling activity in PTCL. These agents include, but are not necessarily limited to, the hypomethylating agent (HMA) 5-azacytidine, the phosphatidylinositol 3-kinase (P13K) inhibitors, Aurora A kinase inhibitor (alisertib), proteasome inhibitors (bortezomib and carfilzomib), and a host of biologics targeting CD37, CD70, CD47 and bispecific natural killer (NK) engagers. The biologic and preclinical observations provided the rationale for a phase I–II study of oral 5-azacytidine plus romidepsin.
References
- Horwitz, S., O'Connor, O.A., Pro, B. et al. (2019). Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial. Lancet 393: 229–240.
- O'Connor, O.A., Marchi, E., Volinn, W., and Kim, W.S. (2016). Case match control analysis of propel reveals survival advantage for patients with relapsed/refractory (R/R) peripheral T-cell lymphoma (PTCL) treated with pralatrexate. Blood 128: 4149–4149.
- Chihara, D., Fanale, M.A., Miranda, R.N. et al. (2017). The survival outcome of patients with relapsed/refractory peripheral T-cell lymphoma-not otherwise specified and angioimmunoblastic T-cell lymphoma. Br J Haematol 176: 750–758.
- Kim, S.J., Yoon, D.H., Kang, H.J. et al. (2012). Bortezomib in combination with CHOP as first-line treatment for patients with stage III/IV peripheral T-cell lymphomas: a multicentre, single-arm, phase 2 trial. Eur J Cancer 48: 3223–3231.
- Shustov, A., Johnston, P.B., Barta, S.K. et al. (2017). Pralatrexate in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in previously untreated patients with peripheral T-cell lymphoma (PTCL): a phase 1 dose-escalation study. Blood 130: 818.
- Dupuis, J., Morschhauser, F., Ghesquières, H. et al. (2015). Combination of romidepsin with cyclophosphamide, doxorubicin, vincristine, and prednisone in previously untreated patients with peripheral T-cell lymphoma: a non-randomised, phase 1b/2 study. Lancet Haematol 2: e160–e165.
- Marchi, E., Paoluzzi, L., Scotto, L. et al. (2010). Pralatrexate is synergistic with the proteasome inhibitor bortezomib in in vitro and in vivo models of T-cell lymphoid malignancies. Clin Cancer Res 16: 3648–3658.
- Toner, L.E., Vrhovac, R., Smith, E.A. et al. (2006). The schedule-dependent effects of the novel antifolate pralatrexate and gemcitabine are superior to methotrexate and cytarabine in models of human non-Hodgkin's lymphoma. Clin Cancer Res 12: 924–932.
- Jain, S., Jirau-Serrano, X., Zullo, K.M. et al. (2015). Preclinical pharmacologic evaluation of pralatrexate and romidepsin confirms potent synergy of the combination in a murine model of human T-cell lymphoma. Clin Cancer Res 21: 2096–2106.
- Amengual, J.E., Lichtenstein, R., Lue, J. et al. (2017). A phase I study of romidepsin and pralatrexate reveals marked activity in relapsed and refractory T-cell lymphoma. Blood 131 (4): 397–407.
- Delarue, R., Dupuis, J., Sujobert, P. et al. (2016). Treatment with hypomethylating agent 5-azacytidine induces sustained response in angioimmunoblastic T cell lymphomas. Blood 128: 4164.
- Coiffier, B., Pro, B., Prince, H.M. et al. (2012). Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy. J Clin Oncol 30: 631–636.
- O'Connor, O.A., Horwitz, S., Masszi, T. et al. (2015). Belinostat in patients with relapsed or refractory peripheral T-cell lymphoma: results of the pivotal phase II BELIEF (CLN-19) study. J Clin Oncol 33: 2492–2499.
- Marchi, E., Zullo, K.M., Amengual, J.E. et al. (2015). The combination of hypomethylating agents and histone deacetylase inhibitors produce marked synergy in preclinical models of T-cell lymphoma. Br J Haematol 171 (2): 215–226.
- Palomero, T., Couronné, L., Khiabanian, H. et al. (2014). Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas. Nat Genet 46: 166–170.
- Cortes, J.R., Ambesi-Impiombato, A., Couronné, L. et al. (2018). RHOA G17V induces T follicular helper cell specification and promotes lymphomagenesis. Cancer Cell 33: 259–273e7.
-
Scotto, L., Kinahan, C., Casadei, B., and O'Connor, O.A. (2017). Azacytidine and decitabine exhibit differential effects on cytotoxicity and methylation and exhibit class synergy with HDACI in models of PTCL. Hematol Oncol
35 (Suppl 2): 404.
10.1002/hon.2439_180 Google Scholar
- O'Connor, O.A., Falchi, L., Lue, J.K. et al. (2019). Oral 5-azacytidine and romidepsin exhibit marked activity in patients with PTCL: a multicenter phase I study. Blood 134 (7): 1395–1405.
- Furman, R.R., Sharman, J.P., Coutre, S.E. et al. (2014). Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 370: 997–1007.
- Flinn, I.W., O'Brien, S., Kahl, B. et al. (2018). Duvelisib, a novel oral dual inhibitor of PI3K-delta,gamma, is clinically active in advanced hematologic malignancies. Blood 131: 877–887.
- Dreyling, M., Santoro, A., Mollica, L. et al. (2017). Phosphatidylinositol 3-kinase inhibition by copanlisib in relapsed or refractory indolent lymphoma. J Clin Oncol 35: 3898–3905.
- Burris, H.A. 3rd, Flinn, I.W., Patel, M.R. et al. (2018). Umbralisib, a novel PI3Kdelta and casein kinase-1epsilon inhibitor, in relapsed or refractory chronic lymphocytic leukaemia and lymphoma: an open-label, phase 1, dose-escalation, first-in-human study. Lancet Oncol 19: 486–496.
- Dreyling, M., Morschhauser, F., Bouabdallah, K. et al. (2017). Phase II study of copanlisib, a PI3K inhibitor, in relapsed or refractory, indolent or aggressive lymphoma. Ann Oncol 28: 2169–2178.
- Horwitz, S.M., Koch, R., Porcu, P. et al. (2018). Activity of the PI3K-delta,gamma inhibitor duvelisib in a phase 1 trial and preclinical models of T-cell lymphoma. Blood 131: 888–898.
- Horwitz, S.M., Soto, J., Youssoufian, H. et al. (2018). The PRIMO study: a phase 2 study of duvelisib efficacy and safety in patients with relapsed or refractory peripheral t-cell lymphoma (PTCL). J Clin Oncol 36 (15 Suppl): TPS7590.
- Moskowitz, A., Koch, R., Mehta-Shah, N. et al. (2017). In vitro, in vivo, and parallel phase I evidence support the safety and activity of duvelisib, a PI3K δ,γ inhibitor, in combination with romidepsin or bortezomib in relapsed/refractory T-cell lymphoma. Blood 130 (Suppl 1): 819.
- Morschhauser, F., Fitoussi, O., Haioun, C. et al. (2013). A phase 2, multicentre, single-arm, open-label study to evaluate the safety and efficacy of single-agent lenalidomide (Revlimid) in subjects with relapsed or refractory peripheral T-cell non-Hodgkin lymphoma: the EXPECT trial. Eur J Cancer 49: 2869–2876.
- Toumishey, E., Prasad, A., Dueck, G. et al. (2015). Final report of a phase 2 clinical trial of lenalidomide monotherapy for patients with T-cell lymphoma. Cancer 121: 716–723.
- Zinzani, P.L., Pellegrini, C., Broccoli, A. et al. (2011). Lenalidomide monotherapy for relapsed/refractory peripheral T-cell lymphoma not otherwise specified. Leuk Lymphoma 52: 1585–1588.
- Cosenza, M., Civallero, M., Fiorcari, S. et al. (2016). The histone deacetylase inhibitor romidepsin synergizes with lenalidomide and enhances tumor cell death in T-cell lymphoma cell lines. Cancer Biol Ther 17: 1094–1106.
- Mehta-Shah, N., Lunning, M.A., Boruchov, A.M. et al. (2015). A phase I/II trial of the combination of romidepsin and lenalidomide in patients with relapsed/refractory lymphoma and myeloma: activity in T-cell lymphoma. J Clin Oncol 33: 8521–8521.
-
Mehta-Shah, N., Moskowitz, A.J., Lunning, M.A. et al. (2017). A phase Ib/IIa trial of the combination of romidepsin, lenalidomide and carfilzomib in patients with relapsed/refractory lymphoma shows complete responses in relapsed and refractory B- and T-cell lymphomas. Blood
130 (Suppl 1): 821.
10.1182/blood.V130.Suppl_1.821.821 Google Scholar
- Fujisawa, M., Chiba, S., and Sakata-Yanagimoto, M. (2017). Recent progress in the understanding of angioimmunoblastic T-cell lymphoma. J Clin Exp Hematop 57: 109–119.
- Fujisawa, M., Sakata-Yanagimoto, M., Nishizawa, S. et al. (2018). Activation of RHOA-VAV1 signaling in angioimmunoblastic T-cell lymphoma. Leukemia 32: 694–702.
- Vallois, D., Dobay, M.P.D., Morin, R.D. et al. (2016). Activating mutations in genes related to TCR signaling in angioimmunoblastic and other follicular helper T-cell-derived lymphomas. Blood 128: 1490–1502.
- Lee, S.H., Kim, J.S., Kim, J. et al. (2015). A highly recurrent novel missense mutation in CD28 among angioimmunoblastic T-cell lymphoma patients. Haematologica 100: e505–e507.
- Manso, R., Rodríguez-Pinilla, S.M., González-Rincón, J. et al. (2015). Recurrent presence of the PLCG1 S345F mutation in nodal peripheral T-cell lymphomas. Haematologica 100: e25–e27.
- Rohr, J., Guo, S., Huo, J. et al. (2016). Recurrent activating mutations of CD28 in peripheral T-cell lymphomas. Leukemia 30: 1062–1070.
- Paoluzzi, L., Scotto, L., Marchi, E. et al. (2010). Romidepsin and belinostat synergize the antineoplastic effect of bortezomib in mantle cell lymphoma. Clin Cancer Res 16: 554–565.
- Gao, M., Chen, G., Wang, H. et al. (2016). Therapeutic potential and functional interaction of carfilzomib and vorinostat in T-cell leukemia/lymphoma. Oncotarget 7: 29102–29115.
- Zinzani, P.L., Musuraca, G., Tani, M. et al. (2007). Phase II trial of proteasome inhibitor bortezomib in patients with relapsed or refractory cutaneous T-cell lymphoma. J Clin Oncol 25: 4293–4297.
- Tan, D., Phipps, C., Hwang, W.Y.K. et al. (2015). Panobinostat in combination with bortezomib in patients with relapsed or refractory peripheral T-cell lymphoma: an open-label, multicentre phase 2 trial. Lancet Haematol 2: e326–e333.
- Kim, S.J., Shin, D.Y., Kim, J.S. et al. (2016). A phase II study of everolimus (RAD001), an mTOR inhibitor plus CHOP for newly diagnosed peripheral T-cell lymphomas. Ann Oncol 27: 712–718.
- Oki, Y., Younes, A., Copeland, A. et al. (2013). Phase I study of vorinostat in combination with standard CHOP in patients with newly diagnosed peripheral T-cell lymphoma. Br J Haematol 162: 138–141.
- Mehta-Shah, N., Moskowitz, A.J., Lunning, M. et al. (2016). A phase Ib/IIa trial of the combination of romidepsin, lenalidomide and carfilzomib in patients with relapsed/refractory lymphoma shows complete responses in relapsed and refractory T-cell lymphomas. Blood 128: 2991–2991.
- O'Connor, O.A. (2019). Nurturing a diet rich in PTCL. Blood 134: 1367–1368.
- Khan, S. and Sawas, A. (2019). Antibody-directed therapies: toward a durable and tolerable treatment platform for CTCL. Front Oncol 9: 645.
- Barta, S.K., Zain, J., MacFarlane, A.W. et al. (2019). Phase II study of the PD-1 inhibitor pembrolizumab for the treatment of relapsed or refractory mature T-cell lymphoma. Clin Lymphoma Myeloma Leuk 19: 356–364.e3.
- Lesokhin, A.M., Ansell, S.M., Armand, P. et al. (2016). Nivolumab in patients with relapsed or refractory hematologic malignancy: preliminary results of a phase Ib study. J Clin Oncol 34: 2698–2704.
- Marchi, E., Ma, H., Montanari, F. et al. (2020). The integration of PD1 blockade with epigenetic therapy is highly active and safe in heavily treated patients with T-cell lymphoma. J Clin Oncol 38 (15): 8049–8049.
