Outcomes of Autologous Stem Cell Transplant for relapsed or refractory classic Hodgkin lymphoma in the era of PD-1 inhibitors
Main Article Content
Abstract
Classic Hodgkin lymphoma (cHL) is associated with excellent cure rates with front line therapy; however, relapses occur in about 10-20% of patients. Salvage therapy and autologous stem cell transplant is the standard of care treatment approach for relapsed/refractory cHL resulting in cure rates of 50-60%. Relapse rates are higher for patients with certain high-risk features. Addition of post-transplant consolidation brentuximab vedotin (BV) has led to significantly higher 5 year progression free survival rates of 60%. Patients who progressed after autologous stem cell transplant had overall survival of 2-3 years. cHL is remarkably sensitive to PD-1 inhibitors, due to overexpression of PD-L1 on Hodgkin Reed Sternberg cells that interact with PD-1 on immune effector cells in the tumor microenvironment. Studies have also shown that PD-1 inhibitors may increase naïve T cells in peripheral blood and recruit them to cHL tumor microenvironment to facilitate anti-tumor responses. PD-1 inhibitors containing salvage regimens have led to response rates approaching 90-100% in relapsed/refractory cHL. Patients who undergo autologous transplant immediately after PD-1 inhibitor-based therapy have 2 year progression free survival of ~93%, which is significantly higher than patients who undergo autologous transplant after chemotherapy or BV based regimens. Even in patients who undergo autologous transplant in complete response, PD-1 inhibitor-based therapy prior to autologous transplant is associated with post-transplant PFS of 97%, significantly higher than chemotherapy or BV. This finding raises the possibility that PD-1 inhibitors may induce cure in relapsed/refractory cHL, not just by improving depth of response but also by affecting post-transplant immune reconstitution. The remarkable outcomes of PD-1 inhibitors in relapsed/refractory cHL raises a question whether these patients can be cured without autologous transplant. Future large randomized clinical trials are needed to answer this question.
Keywords:
cHL, ASCT, PD-1 inhibitors, lymphoma
Article Details
How to Cite
MICALLEF, Ivana N. M.; DESAI, Sanjal H..
Outcomes of Autologous Stem Cell Transplant for relapsed or refractory classic Hodgkin lymphoma in the era of PD-1 inhibitors.
Medical Research Archives, [S.l.], v. 13, n. 2, mar. 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6234>. Date accessed: 16 mar. 2025.
doi: https://doi.org/10.18103/mra.v13i2.6234.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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2. Ansell SM, Radford J, Connors JM, et al. Overall Survival with Brentuximab Vedotin in Stage III or IV Hodgkin's Lymphoma. N Engl J Med. Jul 28 2022;387(4):310-320. doi:10.1056/NEJMoa2206125
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4. Desai S, Ansell SM. Future directions in Hodgkin lymphoma: checkpoint inhibitors and beyond. Leuk Lymphoma. Aug 2021;62(8):1795-1804. doi:10.1080/10428194.2021.1885667
5. Josting A, Franklin J, May M, et al. New prognostic score based on treatment outcome of patients with relapsed Hodgkin's lymphoma registered in the database of the German Hodgkin's lymphoma study group. J Clin Oncol. Jan 1 2002;20(1):221-30. doi:10.1200/JCO.2002.20.1.221
6. Moskowitz CH, Nimer SD, Zelenetz AD, et al. A 2-step comprehensive high-dose chemoradiotherapy second-line program for relapsed and refractory Hodgkin disease: analysis by intent to treat and development of a prognostic model. Blood. Feb 1 2001;97(3):616-23. doi:10.1182/blood.v97.3.616
7. Linch DC, Winfield D, Goldstone AH, et al. Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin's disease: results of a BNLI randomised trial. Lancet. Apr 24 1993;341(8852):1051-4. doi:10.1016/0140-6736(93)92411-l
8. Schmitz N, Pfistner B, Sextro M, et al. Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin's disease: a randomised trial. Lancet. Jun 15 2002;359(9323):2065-71. doi:10.1016/S0140-6736(02)08938-9
9. Shah GL, Yahalom J, Matasar MJ, et al. Risk factors predicting outcomes for primary refractory hodgkin lymphoma patients treated with salvage chemotherapy and autologous stem cell transplantation. Br J Haematol. Nov 2016;175(3):440-447. doi:10.1111/bjh.14245
10. Moskowitz CH, Walewski J, Nademanee A, et al. Five-year PFS from the AETHERA trial of brentuximab vedotin for Hodgkin lymphoma at high risk of progression or relapse. Blood. Dec 20 2018;132(25):2639-2642. doi:10.1182/blood-2018-07-861641
11. Sureda A, Constans M, Iriondo A, et al. Prognostic factors affecting long-term outcome after stem cell transplantation in Hodgkin's lymphoma autografted after a first relapse. Ann Oncol. Apr 2005;16(4):625-33. doi:10.1093/annonc/mdi119
12. Constans M, Sureda A, Terol MJ, et al. Autologous stem cell transplantation for primary refractory Hodgkin's disease: results and clinical variables affecting outcome. Ann Oncol. May 2003;14(5):745-51. doi:10.1093/annonc/mdg206
13. Josting A, Muller H, Borchmann P, et al. Dose intensity of chemotherapy in patients with relapsed Hodgkin's lymphoma. J Clin Oncol. Dec 1 2010;28(34):5074-80. doi:10.1200/JCO.2010.30.5771
14. Aparicio J, Segura A, Garcera S, et al. ESHAP is an active regimen for relapsing Hodgkin's disease. Ann Oncol. May 1999;10(5):593-5. doi:10.1023/a:1026454831340
15. Moskowitz AJ, Schoder H, Yahalom J, et al. PET-adapted sequential salvage therapy with brentuximab vedotin followed by augmented ifosamide, carboplatin, and etoposide for patients with relapsed and refractory Hodgkin's lymphoma: a non-randomised, open-label, single-centre, phase 2 study. Lancet Oncol. Mar 2015;16(3):284-92. doi:10.1016/S1470-2045(15)70013-6
16. LaCasce AS, Bociek RG, Sawas A, et al. Three-year outcomes with brentuximab vedotin plus bendamustine as first salvage therapy in relapsed or refractory Hodgkin lymphoma. Br J Haematol. May 2020;189(3):e86-e90. doi:10.1111/bjh.16499
17. Tun AM, Wang Y, Matin A, et al. Outcomes of Patients With Classic Hodgkin Lymphoma Who Relapsed After Autologous Stem Cell Transplant. Hemasphere. Apr 2023;7(4):e869. doi:10.1097/HS9.0000000000000869
18. Badar T, Epperla N, Szabo A, et al. Trends in postrelapse survival in classic Hodgkin lymphoma patients after experiencing therapy failure following auto-HCT. Blood Adv. Jan 14 2020;4(1):47-54. doi:10.1182/bloodadvances.2019000736
19. Baumeister SH, Freeman GJ, Dranoff G, Sharpe AH. Coinhibitory Pathways in Immunotherapy for Cancer. Annu Rev Immunol. May 20 2016;34:539-73. doi:10.1146/annurev-immunol-032414-112049
20. Wu R, Sattarzadeh A, Rutgers B, Diepstra A, van den Berg A, Visser L. The microenvironment of classical Hodgkin lymphoma: heterogeneity by Epstein-Barr virus presence and location within the tumor. Blood Cancer J. May 6 2016;6(5):e417. doi:10.1038/bcj.2016.26
21. Green MR, Monti S, Rodig SJ, et al. Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood. Oct 28 2010;116(17):3268-77. doi:10.1182/blood-2010-05-282780
22. Jalali S, Price-Troska T, Bothun C, et al. Reverse signaling via PD-L1 supports malignant cell growth and survival in classical Hodgkin lymphoma. Blood Cancer J. Feb 19 2019;9(3):22. doi:10.1038/s41408-019-0185-9
23. Ansell SM. PD-1 Blockade in Classic Hodgkin Lymphoma. JCO Oncol Pract. Feb 2021;17(2):72-73. doi:10.1200/OP.20.01020
24. Taylor JG, Truelove E, Clear A, Calaminici M, Gribben JG. PDL1 shapes the classical Hodgkin lymphoma microenvironment without inducing T-cell exhaustion. Haematologica. Apr 1 2023;108(4):1068-1082. doi:10.3324/haematol.2022.280014
25. Amarnath S, Mangus CW, Wang JC, et al. The PDL1-PD1 axis converts human TH1 cells into regulatory T cells. Sci Transl Med. Nov 30 2011;3(111):111ra120. doi:10.1126/scitranslmed.3003130
26. Kanamori M, Nakatsukasa H, Ito M, Chikuma S, Yoshimura A. Reprogramming of Th1 cells into regulatory T cells through rewiring of the metabolic status. Int Immunol. Jul 24 2018;30(8):357-373. doi:10.1093/intimm/dxy043
27. Chen X, Fosco D, Kline DE, et al. PD-1 regulates extrathymic regulatory T-cell differentiation. Eur J Immunol. Sep 2014;44(9):2603-16. doi:10.1002/eji.201344423
28. Francisco LM, Salinas VH, Brown KE, et al. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med. Dec 21 2009;206(13):3015-29. doi:10.1084/jem.20090847
29. Yost KE, Satpathy AT, Wells DK, et al. Clonal replacement of tumor-specific T cells following PD-1 blockade. Nat Med. Aug 2019;25(8):1251-1259. doi:10.1038/s41591-019-0522-3
30. Cader FZ, Hu X, Goh WL, et al. A peripheral immune signature of responsiveness to PD-1 blockade in patients with classical Hodgkin lymphoma. Nat Med. Sep 2020;26(9):1468-1479. doi:10.1038/s41591-020-1006-1
31. Yang ZZ, Kim HJ, Villasboas JC, et al. Mass Cytometry Analysis Reveals that Specific Intratumoral CD4(+) T Cell Subsets Correlate with Patient Survival in Follicular Lymphoma. Cell Rep. Feb 19 2019;26(8):2178-2193 e3. doi:10.1016/j.celrep.2019.01.085
32. Yang ZZ, Grote DM, Xiu B, et al. TGF-beta upregulates CD70 expression and induces exhaustion of effector memory T cells in B-cell non-Hodgkin's lymphoma. Leukemia. Sep 2014;28(9):1872-84. doi:10.1038/leu.2014.84
33. Yang ZZ, Grote DM, Ziesmer SC, et al. IL-12 upregulates TIM-3 expression and induces T cell exhaustion in patients with follicular B cell non-Hodgkin lymphoma. J Clin Invest. Apr 2012;122(4):1271-82. doi:10.1172/JCI59806
34. Wu H, Tang X, Kim HJ, et al. Expression of KLRG1 and CD127 defines distinct CD8(+) subsets that differentially impact patient outcome in follicular lymphoma. J Immunother Cancer. Jul 2021;9(7)doi:10.1136/jitc-2021-002662
35. Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med. Jan 22 2015;372(4):311-9. doi:10.1056/NEJMoa1411087
36. Armand P, Chen YB, Redd RA, et al. PD-1 blockade with pembrolizumab for classical Hodgkin lymphoma after autologous stem cell transplantation. Blood. Jul 4 2019;134(1):22-29. doi:10.1182/blood.2019000215
37. Kuruvilla J, Ramchandren R, Santoro A, et al. Pembrolizumab versus brentuximab vedotin in relapsed or refractory classical Hodgkin lymphoma (KEYNOTE-204): an interim analysis of a multicentre, randomised, open-label, phase 3 study. Lancet Oncol. Apr 2021;22(4):512-524. doi:10.1016/S1470-2045(21)00005-X
38. Advani RH, Moskowitz AJ, Bartlett NL, et al. Brentuximab vedotin in combination with nivolumab in relapsed or refractory Hodgkin lymphoma: 3-year study results. Blood. Aug 12 2021;138(6):427-438. doi:10.1182/blood.2020009178
39. Moskowitz AJ, Shah G, Schoder H, et al. Phase II Trial of Pembrolizumab Plus Gemcitabine, Vinorelbine, and Liposomal Doxorubicin as Second-Line Therapy for Relapsed or Refractory Classical Hodgkin Lymphoma. J Clin Oncol. Oct 1 2021;39(28):3109-3117. doi:10.1200/JCO.21.01056
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