Journal of Leukemia
Open Access

Allogeneic Hematopoietic Cell Transplantation: Treatment for Primary Mediastinal Large B cell Lymphoma

Stefano Carugo^{* *}Correspondence: Stefano Carugo, Department of Clinical Science and Oncology, University of Milan, Milano MI, Italy, Email:

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About the Study

The Herrera reported a multicenter retrospective data on outcomes after allogeneic Hematopoietic Cell Transplantation (allo-HCT) in Primary Mediastinal Large B Cell Lymphoma (PMBCL). PMBCL is a subtype of DLBCL with different morphological, immunohistochemical, genetic, and clinical features. While first-line therapy for PMBCL is currently excellent, outcomes are poor for patients with Relapsed and Refractory (R/R) disease and autologous or allogeneic hematopoietic cell transplantation is often considered. Before to 2019, the only published data on allo-HCT in R/R PMBCL was case reports or small case series, making this an important topic [1]. Furthermore, treatment options for PMBCL have changed in recent years as a result of increased use of the dose-adjusted REPOCH regimen, a shift away from involved field radiation [2,3] and recent reports demonstrating significant activity of PD-1 inhibitors [4,5] and Chimeric Antigen Receptor T Cell (CAR-T) therapy in heavily treated R/R PMBCL [6]. As a result, such as that reported by Herrera are particularly timely, as clinicians struggle to incorporate allo-HCT into this new treatment landscape.

First-line therapy for PMBCL has a high success rate, ranging from 70% to 93% depending on the regimen used [2,3]. However, once patients develop R/R PMBCL, the outcome becomes so much less. Historically, second-line platinum-based therapy with autologous Hematopoietic Cell Transplantation (auto-HCT) has been pursued for patients with R/R disease; involved-field radiation therapy is frequently integrated as well if it was not given during first-line therapy. Two retrospective studies have shown the patients with R/R PMBCL who undergo auto-HCT with chemo sensitive disease have a 64% to 70% Progression-Free Survival (PFS) at 4 to 5 years [7,8].

Unfortunately, second-line (salvage) therapy has a low response rate in PMBCL. Kuruvilla [9] observed that only 25% of patients achieved a Complete Response (CR) or Partial Response (PR) to second-line therapy. In that study, all PMBCL patients who developed R/R disease were included. Less than half of those who received second-line therapy eventually responded and went on to receive auto-HCT and the 2-year Overall Survival (OS) after the initial diagnosis of R/R disease was low, at 15% [9]. As a result, auto-HCT either fails to produce long-term remission or is invalid due to refractory disease in many R/R patients. As a result, allo-HCT is often considered for patients with R/R PMBCL, despite the reality that there is limited data on outcomes.

Herrera reports the findings of 28 patients with R/R PMBCL who underwent allo-HCT at five important US academic centers between 2000 and 2015. All patients had previously received rituximab, and 86% had previously received radiation. Only one of the 28 patients received DA-EPOCH-R as an induction regimen, and none had received a checkpoint inhibitor or CAR T cell therapy; however, 71% had progressed after previous auto- HCT. Before to allo-HCT, 21% of patients had refractory disease, with 75% in a PR and only 1 patient (4%) in a CR. Although the use of various conditioning regimens, all but 4 patients had reduced-intensity conditioning and 83% had a matched related or matched unrelated donor. The average duration of follow-up was 5 years. At 5 years, non-relapse mortality was 32%, and relapse was 33%. As a result, the 5-year PFS of 33% and the 5-year OS is 45%. PFS at 2 years was 50% (versus 0% in chemo refractory patients) and OS was 58%(versus 0% in chemo refractory patients) in patients with chemo sensitive disease before to allo-HCT. It is important to note that some patients with progressive or residual disease after allo-HCT responded to immunosuppressive reduction and/or donor lymphocyte infusion, suggesting a graft-versus-lymphoma effect in PMBCL.

The results by Herrera, et al. should be considered in combination with a recent study from the Japan Society for Hematopoietic Cell Transplantation registry published by Kondo [10] after a failed auto-HCT, 23 patients with R/R PMBCL underwent allo-HCT. The median patient age was 33 years, and PFS and OS at 3 years of 33% and 49%, respectively. Similar to Herrera, et al. notably, 6 of the 15 patients with refractory disease before to allo-HCT achieved a CR. The remission was lengthy in 3 of these patients. In contrast to Herrera, et al. this study suggests that long-term remission is possible in a small subset of patients with refractory PMBCL who undergo allo-HCT. However, there were some significant differences from the Herrera, et al. cohort. Different conditioning regimens were used (including 44% myeloablative), and alternative donors were used at a much higher rate (61%versus 18% by Herrera, et al). Kondo studies did not include regimens given before to allo-HCT.

It is possible that these differences account for the discrepancy in results between the two studies in individuals undergoing allo- HCT with refractory disease. Herrera results make an important contribution to the literature.

The results, as well as those of Kondo completely support the use of allo-HCT in patients with R/R PMBCL who have failed auto- HCT and obtained at least a PR before to allo-HCT. A Centre for International Blood and Marrow Transplant Research evaluating the outcomes of allo-HCT after a failed auto-HCT for the broader pathological entity of DLBCL also validates this procedure [11].

Conclusion

However, the results of Herrera suggest that allo-HCT is not beneficial for patients with truly refractory disease, and that such patients would be better served by alternative strategies such as PD-1 inhibitors (alone or in novel combinations), other checkpoint inhibitors, and/or CAR-T cell therapy. As more patients with R/R PMBCL undergo these alternative treatments in the future, an important future question will be the optimal sequencing of allo-HCT in relation to these new treatments.

References

1. AF Herrera, L Chen, S Khajavian, Chase M, Darrah J, Maloney D, et al. Allogeneic stem cell transplantation provides durable remission in patients with primary mediastinal large B-cell lymphoma. Biol Blood Marrow Transplant. 2019;25(12):2383-2387.

   [Crossref] [Google Scholar] [PubMed]

2. K Dunleavy, S Pittaluga, LS Maeda, Advani R, Chen CC, Hessler J. et al. Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma. N Engl J Med. 2013;368 (15):1408-1416.

   [Crossref] [Google Scholar] [PubMed]

3. NN Shah, A Szabo, SF Huntington, Epperla N, Reddy N, Ganguly S, et al. R-CHOP versus dose-adjusted R-EPOCH in frontline management of primary mediastinal B-cell lymphoma: a multi-centre analysis. Br J Haematol. 2018;180(4):534-544.

   [Crossref] [Google Scholar] [PubMed]

4. PL Zinzani, V Ribrag, CH Moskowitz, Michot JM, Kuruvilla J, Balakumaran A, et al. Safety and tolerability of pembrolizumab in patients with relapsed/refractory primary mediastinal large B-cell lymphoma. Blood. 2017;130(3):267-270.

   [Crossref] [Google Scholar] [PubMed]

5. PL Zinzani, A Santoro, G Gritti, Brice P, Barr PM, Kuruvilla J, et al. Nivolumab combined with brentuximab vedotin for relapsed/refractory primary mediastinal large B-cell lymphoma: efficacy and safety from the phase II CheckMate 436 study. J Clin Oncol. 2019;37(33):3081-3089.

   [Crossref] [Google Scholar] [PubMed]

6. FL Locke, A Ghobadi, CA Jacobson, Miklos DB, Lekakis LJ, Oluwole O, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 2019;20(1):31-42.

   [Crossref] [Google Scholar] [PubMed]

7. Avivi A, Boumendil H, Finel H, Nagler A, de Sousa AB, Santasusana JMR,  et al. Autologous stem cell transplantation for primary mediastinal B-cell lymphoma: long-term outcome and role of post-transplant radiotherapy. A report of the European Society for Blood and Marrow Transplantation. Bone Marrow Transplant. 2018;53(8):1001-1009.

   [Crossref] [Google Scholar] [PubMed]

8. T Aoki, K Shimada, R Suzuki, Izutsu K, Tomita A, Maeda Y, et al. High dose chemotherapy followed by autologous stem cell transplantation for relapsed/refractory primary mediastinal large B-cell lymphoma. Blood Cancer J. 2015;5(12):e372.

   [Crossref] [Google Scholar] [PubMed]

9. J Kuruvilla, M Pintilie, R Tsang, T Nagy, A Keating, M Crump. Salvage chemotherapy and autologous stem cell transplantation are inferior for relapsed or refractory primary mediastinal large B-cell lymphoma compared with diffuse large B-cell lymphoma. Leuk Lymphoma. 2008;49(7):1329-1336.

   [Crossref] [Google Scholar] [PubMed]

10. E Kondo, R Shimizu-Koresawa, D Chihara, Mizuta, S Izutsu, K Ikegame, et al. Allogeneic haematopoietic stem cell transplantation for primary mediastinal large B-cell lymphoma patients relapsing after high-dose chemotherapy with autologous stem cell transplantation: data from the Japan Society for Haematopoietic Cell Transplantation registry. Br J Haematol. 2019;186(6):e219-e223.  

    [Crossref] [Google Scholar] [PubMed]

11. TS Fenske, KW Ahn, TM Graff, DiGilio A, Bashir Q, Kamble RT, et al. Allogeneic transplantation provides durable remission in a subset of DLBCL patients relapsing after autologous transplantation. Br J Haematol. 2016;174(2):235-248.

    [Crossref] [Google Scholar] [PubMed]