- Email: [email protected]
Brentuximab vedotin as a salvage treatment for relapsed and refractory Hodgkin lymphoma patients in Taiwan
Journal of the Formosan Medical Association (2019) 118, 1466e1470
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.jfma-online.com
Short Communication
Brentuximab vedotin as a salvage treatment for relapsed and refractory Hodgkin lymphoma patients in Taiwan Feng-Ming Tien a,b, Cheng-Hong Tsai a,b,c,*, Jia-Hau Liu a,b, Chien-Ting Lin a,b a Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan b Tai-Cheng Stem Cell Therapy Center, National Taiwan University, Taipei, Taiwan c Genome and Systems Biology Degree Program, National Taiwan University, Taipei, Taiwan
Received 1 April 2019; received in revised form 11 June 2019; accepted 2 July 2019
KEYWORDS Brentuximab vedotin; Hodgkin lymphoma; Relapse; Transplantation
Hodgkin lymphoma (HL) is a highly curable hematologic malignancy. Relapsed/refractory (R/ R) HL is an important clinical challenge, despite advances in treatment. Brentuximab vedotin (BV) is highly effective in R/R HL in the western world. However, there are no real-world data on the use of BV in the Asian population. Our study aimed to evaluate the efficacy and safety of BV as salvage therapy in R/R HL patients in Taiwan. We recruited 20 R/R HL patients who received BV at National Taiwan University Hospital. BV was administered at 1.8 mg/kg once every 3 weeks. The median number of systemic treatment received before BV was three. The overall response rate was 73.7% with a complete remission rate of 21.1% in R/R HL. Overall survival was not reached and progression-free survival was 6.8 months. BV could strengthen disease control before transplantation and improve post-transplant outcomes, even among those heavily pretreated patients, without significant overlapping toxicities with prior therapies. Our data suggest that BV is well tolerated and effective in the treatment of Asian patients with R/R HL. BV may offer long-term disease control in selected patients. Copyright ª 2019, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ by-nc-nd/4.0/).
* Corresponding author. Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. E-mail address: [email protected] (C.-H. Tsai). https://doi.org/10.1016/j.jfma.2019.07.003 0929-6646/Copyright ª 2019, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Brentuximab vedotin in Hodgkin lymphoma
Introduction Hodgkin lymphoma (HL) is a B cell neoplasm with a high cure rate, and the 15-year survival reaches 83%.1 The occurrence of relapsed or refractory (R/R) disease after first-line therapy is not common but serves as a significant challenge for clinicians. Hodgkin ReedeSternberg (RS) cells express CD30. Brentuximab vedotin (BV; ADCETRIS) is an anti-CD30 antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E (MMAE). Once BV binds to CD30 on the Hodgkin RS cells, the antibodyedrug conjugate is internalized, and the linker is cleaved by lysosomal enzymes, allowing the release of MMAE inside the cells. MMAE then binds to tubulin, resulting in the apoptosis of CD30expressing cells.2 Reports from the pivotal phase 2 trial of BV demonstrated both significant efficacy and 3-year disease control in heavily treated R/R HL patients.3 Based on this study, BV was granted accelerated US Food and Drug Administration approval for the treatment of patients with R/R HL after autologous stem cell transplantation (autoSCT) or failure of more than two prior therapies. The incidences of HL vary in different geographic regions. HL accounts for more than 15% of all lymphomas in western countries but only 5.2%e8.6% in Asian lymphoma populations.4e6 Owing to relative low incidence, treatment data for HL among the Asian population are few. In this study, we aimed to present the clinical outcome of R/R HL patients treated with BV in Taiwan.
Methods and materials We retrospectively recruited 20 R/R HL patients treated with BV at the National Taiwan University Hospital (NTUH) from May 2016 to October 2018. Patients received BV at 1.8 mg/kg once every 3 weeks until transplantation, progression, toxicity, or death. This study was approved by the Institutional Review Board of the NTUH, and written informed consent was obtained from all the participants in accordance with the Declaration of Helsinki. The response was scored using standard criteria and was assessed by positron-emission tomography (PET) scans before cycle 4 and then on a regular interval at the discretion of the physician.7 Overall survival (OS) was measured from the date of BV use to the date of last follow-up or death from any cause. Progression-free survival (PFS) was measured from the date of BV use until treatment failure, relapse from complete remission (CR), or death from any cause, whichever occurred first. All analyses were performed using SPSS version 23 (SPSS Inc., Chicago, IL, USA).
Results Patients The characteristics of the patients are depicted in Table 1. The median age in this cohort was 28 years (range, 18e85 years). The median number of BV cycles received was 5.5 (range, 1e19). BV was administered as monotherapy in most
1467 patients (80%). Eight patients received BV as salvage treatment after failure of at least one prior therapy, and twelve patients received BV due to relapse after auto-SCT. These 20 patients had a median follow-up time of 49.7 months (range, 14.2e218.5 months) from initial diagnosis and 18.1 months (range, 1.5e26.3 months) from first BV dose. Fifteen patients (75%) were still alive at the end of follow-up.
BV treatment response and survival Treatment response was evaluable in 19 patients, and the initial response was assessed after 3 cycles of BV. We provided serial images of one patient who achieved CR under BV to illustrate the clinical response (Supplementary Fig. 1). The overall response rate (ORR) was 73.7%, including CR in 4 (21.1%) and partial remission (PR) in 10 (52.6%) (Fig. 1F). Among the 7 patients with refractory status before BV (defined as best response of stable disease or progressive disease to most recent prior therapy), the response rate was 67%. The median OS was not reached, and the median PFS was 6.8 months from the start of BV use (Fig. 1A). The outcome was better for patients who achieved CR to BV. The 2-year OS of patients who achieved CR, those who achieved PR, and nonresponders were 100%, 78%, and 60%, respectively (Fig. 1B). Next we stratified the result according to the timing of BV. In patients treated with BV after failure of at least one prior therapy (n Z 8), the response rate was 75%. The 2year OS and PFS were 60% and 31%, respectively. In patients treated with BV after auto-SCT (n Z 12), the response rate was 71.4%. The 2-year OS and PFS were 82% and 39%, respectively (Fig. 1C and D). The detailed treatment regimen and clinical outcome of each individual patient are shown in Fig. 1E and Supplementary Table 1. All of the 4 initial CR patients remained in CR and were still in follow-up: Two patient received consolidative auto-SCT after BV, while the other two continued on BV for a total of 12 and 19 cycles, respectively. For the 10 initial PR patients, one received consolidative auto-SCT, another one switched to nivolumab, and the other eight patients continued on BV. Finally, six patients (75%) developed progressive disease under BV, but two (25%) could achieved CR, with sustained BV use for a total of 15 and 17 cycles at the end of follow-up. For the 3 patients who initially progressed under BV, two received allogeneic stem cell transplantation (allo-SCT) at R/R status, and one died of disease. We also studied allo-SCT outcome after BV. Four patients received allo-SCT after BV, and two of them had active disease before transplant. The conditioning regimens were myeloablative in 3 patients and reduced intensity in one patient, and the donors were sibling (n Z 1) or haploidentical (n Z 3). With a median follow up of 4 months from allo-SCT, all of them were alive and free from disease relapse. One patient had grade III liver acute graft-versushost disease (GVHD), which was controlled by systemic steroid. Another one patient had grade I skin acute GVHD treated with only topical agents.
Safety BV was highly tolerated in all patients. No sepsis, fungal infection, or intensive care unit admission occurred during
1468 Table 1
F.-M. Tien et al. Demographics and baseline clinical characteristics of patients.
Variables Sexa Male Female Age (year)b Histology subtype Nodular sclerosis Mixed cellularity Lymphocyte rich Stage at diagnosis I II III IV Initial C/T regimen ABVD ABVD þ COMP Number of prior systemic therapy regimensb Disease status relative to most recent prior therapyc Relapse Refractory Prior radiotherapy Prior auto-SCT Prior allo-SCT BV combined C/T
Total (n Z 20)
Relapse after auto-SCT (n Z 12)
Relapse after chemotherapy (n Z 8)
10 (50) 10 (50) 28 (18e85)
6 (50) 6 (50) 26.5 (18e64)
4 (50) 4 (50) 42.5 (21e85)
13 (65) 6 (30) 1 (5)
8 (66.7) 3 (25) 1 (8.3)
5 (62.5) 3 (37.5) 0 (0)
0 8 4 8
0 6 3 3
0 2 1 5
P valued >0.999
0.057 0.628
0.245 (0) (40) (20) (40)
(0) (50) (25) (25)
(0) (25) (12.5) (62.5) >0.999
19 (95) 1 (5) 3 (1e7)
11 (91.7) 1 (8.3) 3 (2e4)
8 (100) 0 (0) 3 (1e7)
0.473 0.356
13 (65) 7 (35) 6 (30) 12 (60) 0 (0) 4 (20)
9 (75) 3 (25) 4 (33.3) 12 (100) 0 (0) 1 (8.3)
4 4 2 0 0 3
(50) (50) (25) (0) (0) (37.5)
e e e 0.255
Abbreviations: BV, Brentuximab vedotin; C/T: chemotherapy; SCT, stem cell transplantation. a Number of patients (%). b Median (range). c Relapse Z best response of CR or PR to most recent prior therapy; Refractory Z best response of SD or PD to most recent prior therapy. d Discrete variables were compared using the chi-square test. If the expected values of contingency tables were smaller than 5, Fisher’s exact test was used. ManneWhitney U test was used to compare continuous variables and medians of distributions.
BV treatment. The most common treatment-related adverse events were peripheral neuropathy (20%) and cytopenia (10%). BV therapy was delayed in only 1 (5%) patient. Cytopenia may occur even under BV monotherapy. One patient had grade 4 neutropenia after 5 cycles of BV. She responded promptly to granulocyte-colony stimulating factor and there was no infection episode during the neutropenia. The other patient, with pretreatment hemoglobin level 11.3 g/dL, developed grade 4 anemia (Hb 5.8 g/dL) after 5 cycles of BV.
Discussion This is the first study to explore BV effectiveness in HL patients in the Asian population. The ORR to BV was 73.7%. The result was similar to that of conventional salvage therapy, which typically produce an ORR of about 60%e80%.8,9 Excluding three patients treated with BV-based chemotherapy, the response rate to singleagent BV was 66.7%. These results were compatible with those of western studies, which showed a response rate to single-agent BV of 75%.10,11 Although BV
combined with chemotherapy showed higher response rate, 82%e100% in relapsed HL patients, chemotherapy inevitably confers more toxicity.12,13 Since there are no direct comparison between the outcome of single-agent BV and that of BV-based chemotherapy, it is not unreasonable to administer BV monotherapy in R/R patients. Patients who initially achieved CR after BV may possibly be cured without further transplantation. In Chen’s study, there were 34 R/R HL patients who achieved CR under BV after failing auto-SCT. About 13 (38%) of the 34 patients on BV treatment remained in remission for more than 5 years and may be cured. Interestingly, nine of the 13 patients remained in long-term remission without a consolidative allo-SCT.11 In accordance with the finding, two of the 4 initial CR patients, though not receiving further transplantation, remained in CR and were still under BV for a total of 12 and 19 cycles. However, it was difficult to determine who among those patients in CR status may benefit from allo-SCT. For patients with initial PR to BV, whether further BV may convert any patients from PR to CR remains a clinically relevant question. Previous literature reported the use of
Brentuximab vedotin in Hodgkin lymphoma
1469
Figure 1 Summary of BV treatment results. OS and PFS were measured from first BV dose using KaplaneMeier methodology and are shown (A) overall, (B) by best response, and (CeD) by BV timing. (E) Observation time for the subset of 19 patients with evaluable response. Patients are labeled according to their best response with BV. Fifteen patients are still alive at the end of follow up. (F) BV response is shown for patients who relapsed after auto-SCT (n Z 12) or who relapsed after chemotherapy (n Z 7).
1470 alternative salvage therapy or auto-SCT in patients who did not achieve CR after 4 cycles of BV.10 The 2-year PFS of patients in PR who proceeded to auto-SCT after treatment with BV alone was 75%. In our study, eight PR patients continued BV treatment. Finally, six patients under BV treatment developed progressive disease, while two achieved CR. We observed that BV may offer a deeper response in a minority of patients (25%), but the majority of patients had disease progression. In those patients with initial PR to BV, continuing BV might not be a recommended approach unless the patient is too frail for further salvage treatment. In conclusion, BV is a feasible treatment option for R/R HL with tolerable toxicity in Asian patients. The initial response to BV predicts survival, and even those patients who only achieved PR could possibly be cured without further transplantation.
Authorship Contribution: F.-M.T. was responsible for literature collection, data management and interpretation, statistical analysis and manuscript writing; J.-H.L., and C.-T.L was responsible for study coordination and data interpretation; C.-H.T. planned, designed, coordinated the study and wrote the manuscript.
Conflict of interest disclosure The authors have no conflicts of interest relevant to this article.
Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.jfma.2019.07.003.
References 1. Bessell EM, Bouliotis G, Armstrong S, Baddeley J, Haynes AP, O’Connor S, et al. Long-term survival after treatment for Hodgkin’s disease (1973e2002): improved survival with successive 10-year cohorts. Br J Cancer 2012;107:531e6. 2. Newland AM, Li JX, Wasco LE, Aziz MT, Lowe DK. Brentuximab vedotin: a CD30-directed antibody-cytotoxic drug conjugate. Pharmacotherapy 2013;33:93e104.
F.-M. Tien et al. 3. Younes A, Gopal AK, Smith SE, Ansell SM, Rosenblatt JD, Savage KJ, et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol e Offic J Am Soc Clin Oncol 2012;30:2183e9. 4. Miura Y, Fukuhara N, Yamamoto J, Kohata K, Ishizawa K, Ichinohasama R, et al. Clinicopathological features of malignant lymphoma in Japan: the Miyagi study. Tohoku J Exp Med 2011;224:151e60. 5. Chuang SS, Chen SW, Chang ST, Kuo YT. Lymphoma in Taiwan: Review of 1347 neoplasms from a single institution according to the 2016 revision of the world health organization classification. J Formosan Med Assoc Taiwan yi zhi 2017;116:620e5. 6. Sun J, Yang Q, Lu Z, He M, Gao L, Zhu M, et al. Distribution of lymphoid neoplasms in China: analysis of 4,638 cases according to the World Health Organization classification. Am J Clin Pathol 2012;138:429e34. 7. Mediwake H, Morris K, Curley C, Butler J, Kennedy G. Use of brentuximab vedotin as salvage therapy pre-allogeneic stem cell transplantation in relapsed/refractory CD30 positive lympho-proliferative disorders: a single centre experience. Intern Med J 2017;47:574e8. 8. Josting A, Rudolph C, Mapara M, Glossmann JP, Sieniawski M, Sieber M, et al. Cologne high-dose sequential chemotherapy in relapsed and refractory Hodgkin lymphoma: results of a large multicenter study of the German Hodgkin Lymphoma Study Group (GHSG). Ann Oncol e Offic J Eur Soc Med Oncol 2005;16:116e23. 9. Moskowitz CH, Bertino JR, Glassman JR, Hedrick EE, Hunte S, Coady-Lyons N, et al. Ifosfamide, carboplatin, and etoposide: a highly effective cytoreduction and peripheral-blood progenitor-cell mobilization regimen for transplant-eligible patients with non-Hodgkin’s lymphoma. J Clin Oncol e Offic J Am Soc Clin Oncol 1999;17:3776e85. 10. Herrera AF, Palmer J, Martin P, Armenian S, Tsai NC, Kennedy N, et al. Autologous stem-cell transplantation after second-line brentuximab vedotin in relapsed or refractory Hodgkin lymphoma. Ann Oncol e Offic J Eur Soc Med Oncol 2018;29:724e30. 11. Chen R, Gopal AK, Smith SE, Ansell SM, Rosenblatt JD, Savage kJ, et al. Five-year survival and durability results of brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma. Blood 2016;128:1562e6. 12. Garcia-Sanz R, Sureda A, Gonzalez AP, De la Cruz F, SanchezGonzalez B, Rodriguez A, et al. Brentuximab vedotin plus ESHAP (BRESHAP) is a highly effective combination for inducing remission in refractory and relapsed Hodgkin lymphoma patients prior to autologous stem cell transplant: a trial of the Spanish group of lymphoma and bone marrow transplantation (GELTAMO). Blood 2016;128. 1109-1109. 13. LaCasce AS, Bociek RG, Sawas A, Caimi P, Agura E, Matous J, et al. Brentuximab vedotin plus bendamustine: a highly active first salvage regimen for relapsed or refractory Hodgkin lymphoma. Blood 2018;132:40e8.
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.jfma-online.com
Short Communication
Brentuximab vedotin as a salvage treatment for relapsed and refractory Hodgkin lymphoma patients in Taiwan Feng-Ming Tien a,b, Cheng-Hong Tsai a,b,c,*, Jia-Hau Liu a,b, Chien-Ting Lin a,b a Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan b Tai-Cheng Stem Cell Therapy Center, National Taiwan University, Taipei, Taiwan c Genome and Systems Biology Degree Program, National Taiwan University, Taipei, Taiwan
Received 1 April 2019; received in revised form 11 June 2019; accepted 2 July 2019
KEYWORDS Brentuximab vedotin; Hodgkin lymphoma; Relapse; Transplantation
Hodgkin lymphoma (HL) is a highly curable hematologic malignancy. Relapsed/refractory (R/ R) HL is an important clinical challenge, despite advances in treatment. Brentuximab vedotin (BV) is highly effective in R/R HL in the western world. However, there are no real-world data on the use of BV in the Asian population. Our study aimed to evaluate the efficacy and safety of BV as salvage therapy in R/R HL patients in Taiwan. We recruited 20 R/R HL patients who received BV at National Taiwan University Hospital. BV was administered at 1.8 mg/kg once every 3 weeks. The median number of systemic treatment received before BV was three. The overall response rate was 73.7% with a complete remission rate of 21.1% in R/R HL. Overall survival was not reached and progression-free survival was 6.8 months. BV could strengthen disease control before transplantation and improve post-transplant outcomes, even among those heavily pretreated patients, without significant overlapping toxicities with prior therapies. Our data suggest that BV is well tolerated and effective in the treatment of Asian patients with R/R HL. BV may offer long-term disease control in selected patients. Copyright ª 2019, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ by-nc-nd/4.0/).
* Corresponding author. Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. E-mail address: [email protected] (C.-H. Tsai). https://doi.org/10.1016/j.jfma.2019.07.003 0929-6646/Copyright ª 2019, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Brentuximab vedotin in Hodgkin lymphoma
Introduction Hodgkin lymphoma (HL) is a B cell neoplasm with a high cure rate, and the 15-year survival reaches 83%.1 The occurrence of relapsed or refractory (R/R) disease after first-line therapy is not common but serves as a significant challenge for clinicians. Hodgkin ReedeSternberg (RS) cells express CD30. Brentuximab vedotin (BV; ADCETRIS) is an anti-CD30 antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E (MMAE). Once BV binds to CD30 on the Hodgkin RS cells, the antibodyedrug conjugate is internalized, and the linker is cleaved by lysosomal enzymes, allowing the release of MMAE inside the cells. MMAE then binds to tubulin, resulting in the apoptosis of CD30expressing cells.2 Reports from the pivotal phase 2 trial of BV demonstrated both significant efficacy and 3-year disease control in heavily treated R/R HL patients.3 Based on this study, BV was granted accelerated US Food and Drug Administration approval for the treatment of patients with R/R HL after autologous stem cell transplantation (autoSCT) or failure of more than two prior therapies. The incidences of HL vary in different geographic regions. HL accounts for more than 15% of all lymphomas in western countries but only 5.2%e8.6% in Asian lymphoma populations.4e6 Owing to relative low incidence, treatment data for HL among the Asian population are few. In this study, we aimed to present the clinical outcome of R/R HL patients treated with BV in Taiwan.
Methods and materials We retrospectively recruited 20 R/R HL patients treated with BV at the National Taiwan University Hospital (NTUH) from May 2016 to October 2018. Patients received BV at 1.8 mg/kg once every 3 weeks until transplantation, progression, toxicity, or death. This study was approved by the Institutional Review Board of the NTUH, and written informed consent was obtained from all the participants in accordance with the Declaration of Helsinki. The response was scored using standard criteria and was assessed by positron-emission tomography (PET) scans before cycle 4 and then on a regular interval at the discretion of the physician.7 Overall survival (OS) was measured from the date of BV use to the date of last follow-up or death from any cause. Progression-free survival (PFS) was measured from the date of BV use until treatment failure, relapse from complete remission (CR), or death from any cause, whichever occurred first. All analyses were performed using SPSS version 23 (SPSS Inc., Chicago, IL, USA).
Results Patients The characteristics of the patients are depicted in Table 1. The median age in this cohort was 28 years (range, 18e85 years). The median number of BV cycles received was 5.5 (range, 1e19). BV was administered as monotherapy in most
1467 patients (80%). Eight patients received BV as salvage treatment after failure of at least one prior therapy, and twelve patients received BV due to relapse after auto-SCT. These 20 patients had a median follow-up time of 49.7 months (range, 14.2e218.5 months) from initial diagnosis and 18.1 months (range, 1.5e26.3 months) from first BV dose. Fifteen patients (75%) were still alive at the end of follow-up.
BV treatment response and survival Treatment response was evaluable in 19 patients, and the initial response was assessed after 3 cycles of BV. We provided serial images of one patient who achieved CR under BV to illustrate the clinical response (Supplementary Fig. 1). The overall response rate (ORR) was 73.7%, including CR in 4 (21.1%) and partial remission (PR) in 10 (52.6%) (Fig. 1F). Among the 7 patients with refractory status before BV (defined as best response of stable disease or progressive disease to most recent prior therapy), the response rate was 67%. The median OS was not reached, and the median PFS was 6.8 months from the start of BV use (Fig. 1A). The outcome was better for patients who achieved CR to BV. The 2-year OS of patients who achieved CR, those who achieved PR, and nonresponders were 100%, 78%, and 60%, respectively (Fig. 1B). Next we stratified the result according to the timing of BV. In patients treated with BV after failure of at least one prior therapy (n Z 8), the response rate was 75%. The 2year OS and PFS were 60% and 31%, respectively. In patients treated with BV after auto-SCT (n Z 12), the response rate was 71.4%. The 2-year OS and PFS were 82% and 39%, respectively (Fig. 1C and D). The detailed treatment regimen and clinical outcome of each individual patient are shown in Fig. 1E and Supplementary Table 1. All of the 4 initial CR patients remained in CR and were still in follow-up: Two patient received consolidative auto-SCT after BV, while the other two continued on BV for a total of 12 and 19 cycles, respectively. For the 10 initial PR patients, one received consolidative auto-SCT, another one switched to nivolumab, and the other eight patients continued on BV. Finally, six patients (75%) developed progressive disease under BV, but two (25%) could achieved CR, with sustained BV use for a total of 15 and 17 cycles at the end of follow-up. For the 3 patients who initially progressed under BV, two received allogeneic stem cell transplantation (allo-SCT) at R/R status, and one died of disease. We also studied allo-SCT outcome after BV. Four patients received allo-SCT after BV, and two of them had active disease before transplant. The conditioning regimens were myeloablative in 3 patients and reduced intensity in one patient, and the donors were sibling (n Z 1) or haploidentical (n Z 3). With a median follow up of 4 months from allo-SCT, all of them were alive and free from disease relapse. One patient had grade III liver acute graft-versushost disease (GVHD), which was controlled by systemic steroid. Another one patient had grade I skin acute GVHD treated with only topical agents.
Safety BV was highly tolerated in all patients. No sepsis, fungal infection, or intensive care unit admission occurred during
1468 Table 1
F.-M. Tien et al. Demographics and baseline clinical characteristics of patients.
Variables Sexa Male Female Age (year)b Histology subtype Nodular sclerosis Mixed cellularity Lymphocyte rich Stage at diagnosis I II III IV Initial C/T regimen ABVD ABVD þ COMP Number of prior systemic therapy regimensb Disease status relative to most recent prior therapyc Relapse Refractory Prior radiotherapy Prior auto-SCT Prior allo-SCT BV combined C/T
Total (n Z 20)
Relapse after auto-SCT (n Z 12)
Relapse after chemotherapy (n Z 8)
10 (50) 10 (50) 28 (18e85)
6 (50) 6 (50) 26.5 (18e64)
4 (50) 4 (50) 42.5 (21e85)
13 (65) 6 (30) 1 (5)
8 (66.7) 3 (25) 1 (8.3)
5 (62.5) 3 (37.5) 0 (0)
0 8 4 8
0 6 3 3
0 2 1 5
P valued >0.999
0.057 0.628
0.245 (0) (40) (20) (40)
(0) (50) (25) (25)
(0) (25) (12.5) (62.5) >0.999
19 (95) 1 (5) 3 (1e7)
11 (91.7) 1 (8.3) 3 (2e4)
8 (100) 0 (0) 3 (1e7)
0.473 0.356
13 (65) 7 (35) 6 (30) 12 (60) 0 (0) 4 (20)
9 (75) 3 (25) 4 (33.3) 12 (100) 0 (0) 1 (8.3)
4 4 2 0 0 3
(50) (50) (25) (0) (0) (37.5)
e e e 0.255
Abbreviations: BV, Brentuximab vedotin; C/T: chemotherapy; SCT, stem cell transplantation. a Number of patients (%). b Median (range). c Relapse Z best response of CR or PR to most recent prior therapy; Refractory Z best response of SD or PD to most recent prior therapy. d Discrete variables were compared using the chi-square test. If the expected values of contingency tables were smaller than 5, Fisher’s exact test was used. ManneWhitney U test was used to compare continuous variables and medians of distributions.
BV treatment. The most common treatment-related adverse events were peripheral neuropathy (20%) and cytopenia (10%). BV therapy was delayed in only 1 (5%) patient. Cytopenia may occur even under BV monotherapy. One patient had grade 4 neutropenia after 5 cycles of BV. She responded promptly to granulocyte-colony stimulating factor and there was no infection episode during the neutropenia. The other patient, with pretreatment hemoglobin level 11.3 g/dL, developed grade 4 anemia (Hb 5.8 g/dL) after 5 cycles of BV.
Discussion This is the first study to explore BV effectiveness in HL patients in the Asian population. The ORR to BV was 73.7%. The result was similar to that of conventional salvage therapy, which typically produce an ORR of about 60%e80%.8,9 Excluding three patients treated with BV-based chemotherapy, the response rate to singleagent BV was 66.7%. These results were compatible with those of western studies, which showed a response rate to single-agent BV of 75%.10,11 Although BV
combined with chemotherapy showed higher response rate, 82%e100% in relapsed HL patients, chemotherapy inevitably confers more toxicity.12,13 Since there are no direct comparison between the outcome of single-agent BV and that of BV-based chemotherapy, it is not unreasonable to administer BV monotherapy in R/R patients. Patients who initially achieved CR after BV may possibly be cured without further transplantation. In Chen’s study, there were 34 R/R HL patients who achieved CR under BV after failing auto-SCT. About 13 (38%) of the 34 patients on BV treatment remained in remission for more than 5 years and may be cured. Interestingly, nine of the 13 patients remained in long-term remission without a consolidative allo-SCT.11 In accordance with the finding, two of the 4 initial CR patients, though not receiving further transplantation, remained in CR and were still under BV for a total of 12 and 19 cycles. However, it was difficult to determine who among those patients in CR status may benefit from allo-SCT. For patients with initial PR to BV, whether further BV may convert any patients from PR to CR remains a clinically relevant question. Previous literature reported the use of
Brentuximab vedotin in Hodgkin lymphoma
1469
Figure 1 Summary of BV treatment results. OS and PFS were measured from first BV dose using KaplaneMeier methodology and are shown (A) overall, (B) by best response, and (CeD) by BV timing. (E) Observation time for the subset of 19 patients with evaluable response. Patients are labeled according to their best response with BV. Fifteen patients are still alive at the end of follow up. (F) BV response is shown for patients who relapsed after auto-SCT (n Z 12) or who relapsed after chemotherapy (n Z 7).
1470 alternative salvage therapy or auto-SCT in patients who did not achieve CR after 4 cycles of BV.10 The 2-year PFS of patients in PR who proceeded to auto-SCT after treatment with BV alone was 75%. In our study, eight PR patients continued BV treatment. Finally, six patients under BV treatment developed progressive disease, while two achieved CR. We observed that BV may offer a deeper response in a minority of patients (25%), but the majority of patients had disease progression. In those patients with initial PR to BV, continuing BV might not be a recommended approach unless the patient is too frail for further salvage treatment. In conclusion, BV is a feasible treatment option for R/R HL with tolerable toxicity in Asian patients. The initial response to BV predicts survival, and even those patients who only achieved PR could possibly be cured without further transplantation.
Authorship Contribution: F.-M.T. was responsible for literature collection, data management and interpretation, statistical analysis and manuscript writing; J.-H.L., and C.-T.L was responsible for study coordination and data interpretation; C.-H.T. planned, designed, coordinated the study and wrote the manuscript.
Conflict of interest disclosure The authors have no conflicts of interest relevant to this article.
Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.jfma.2019.07.003.
References 1. Bessell EM, Bouliotis G, Armstrong S, Baddeley J, Haynes AP, O’Connor S, et al. Long-term survival after treatment for Hodgkin’s disease (1973e2002): improved survival with successive 10-year cohorts. Br J Cancer 2012;107:531e6. 2. Newland AM, Li JX, Wasco LE, Aziz MT, Lowe DK. Brentuximab vedotin: a CD30-directed antibody-cytotoxic drug conjugate. Pharmacotherapy 2013;33:93e104.
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