- Email: [email protected]
Lenalidomide in adult T-cell leukaemia-lymphoma
Comment
The acute and lymphoma subtypes of adult T-cell leukaemia-lymphoma are among the most difficult diseases to treat, largely due to the absence of highly effective therapies and their aggressive nature. This difficulty was shown in the International T-cell Lymphoma project, which reported a dismal 5-year overall survival of 14% for adult T-cell leukaemialymphoma, the lowest among the T-cell entities.1 Allogeneic stem-cell transplantation offers the potential for long-term remission for about 35% of patients who receive it; however many patients are unable to undergo such a procedure because of inadequate response to therapy.2 The poor outcomes reported with standard therapies such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone or prednisolone) led the Japan Clinical Oncology Group to develop the dose-intensified regimen VCAP (vincristine, cyclophosphamide, doxorubicin, prednisone), AMP (doxorubicin, ranimustine, prednisone), and VECP (vindesine, etoposide, carboplatin, prednisone). This regimen produced significantly improved proportions of patients achieving a complete response compared with dose-intense CHOP (40% vs 25%, p=0·02); however, the 3-year overall survival observed with VCAP-AMP-VECP was disappointing at 24%.3 In the past few years, new targeted agents seem promising for adult T-cell leukaemia-lymphoma. The almost universal expression of CCR4 on such tumour cells provided a rationale for assessment of mogamulizumab, an anti-CCR4 monoclonal antibody, in this disease. As a single-agent, mogamulizumab produced objective responses in 50% of patients with adult T-cell leukaemia-lymphoma and was subsequently assessed in a randomised phase 2 study in combination with VCAP-AMP-VECP.4 The addition of the monoclonal antibody to VCAP-AMP-VECP led to a non-statistically significant improvement in the proportion of patients achieving a complete response compared with chemotherapy alone (52% vs 33%), although this improvement was at the expense of increased incidence of often manageable infectious-related toxicities. Finally, antiviral therapy with zidovudine and interferon alfa seemed to provide benefit to patients with chronic, smouldering, and acute-type adult T-cell leukaemia-lymphoma in a large meta-analysis; however, it provided little benefit for www.thelancet.com/haematology Vol 3 March 2016
patients with lymphoma-type disease.5 Unfortunately, despite the availability of mogamulizumab and antiviral therapy, a substantial unmet need exists for effective and well-tolerated regimens for aggressive adult T-cell leukaemia-lymphoma. Many studies assessing new drugs in T-cell lymphoma either exclude patients with adult T-cell leukaemia-lymphoma or enrol few of them, and thus the efficacy of agents used in T-cell lymphoma, such as lenalidomide, romidepsin, belinostat, or pralatrexate, is not well understood. Among the studies assessing lenalidomide in T-cell lymphoma, the proportion of patients achieving a response ranges from 22% to 33%; however, no patients with adult T-cell leukaemia-lymphoma were enrolled.6,7 In The Lancet Haematology, Michinori Ogura and colleagues present the first study8 assessing the optimum dose and safety of lenalidomide in adult T-cell leukaemia-lymphoma, with efficacy as an exploratory endpoint. This phase 1 study enrolled 13 patients (nine with adult T-cell leukaemia-lymphoma and four with other T-cell lymphomas) to three sequential dosing cohorts. Cohort 1 received lenalidomide 25 mg/day for days 1–21 of a 28-day cycle, cohort 2 received lenalidomide 25 mg/day continuously, and cohort 3 received lenalidomide 35 mg/day continuously. Two dose-limiting toxicities were reported in the four patients in cohort 3 and one in the six patients in cohort 2, thus establishing lendaliomide 25 mg/day continuously as the maximum tolerated dose. Overall, the toxicity profile of lenalidomide was manageable and similar to that reported in other haematological malignancies. In 11 assessable patients, the overall proportion of patients achieving a response was 36% and the response in seven of these patients with adult T-cell leukaemia-lymphoma was 43%, including two compete responses and one partial response. Notably, the responses were durable, with median duration of response of 16·6 months (9·3–24·0). One potential bias was the requirement of a 4 week washout from previous treatments before enrolment, which might have led to selection of patients with less aggressive disease. Nevertheless, the results are encouraging. Building on this study, the authors recently completed a phase 2 study assessing
David M Phillips/Science Photo Library
Lenalidomide in adult T-cell leukaemia-lymphoma
Published Online February 11, 2016 http://dx.doi.org/10.1016/ S2352-3026(16)00009-0 See Articles page e107
e100
Comment
lenalidomide 25 mg/day continuously in adult T-cell leukaemia-lymphoma. At the 2015 American Society of Hematology meeting, they reported an overall response of 42% in 26 patients with adult T-cell leukaemia-lymphoma enrolled in the phase 2 study,9 thus confirming the efficacy observed in this phase 1 study. In view of the restricted treatment options available for adult T-cell leukaemia-lymphoma, investigations focused on development of new agents are much needed. These data support the use of lenalidomide as a single-agent in relapsed and refractory adult T-cell leukaemia-lymphoma; but more importantly, they pave the way for future combination studies that will hopefully improve on the efficacy of present regimens, and ultimately improve survival for this disease. Because lenalidomide is known to synergise with monoclonal antibodies by enhancing antibody-dependent cellular cytotoxicity, lenalidomide might synergise with mogamulizumab as well, which also functions primarily through antibody-dependent cellular cytotoxicity.10 Studies assessing lenalidomide plus mogamulizumab are therefore warranted. Anecdotal data from our institution showing activity of romidepsin in adult T-cell leukaemia-lymphoma led us to expand our phase 1/2 study assessing romidepsin plus lenalidomide to include a cohort for patients with adult T-cell leukaemia-lymphoma. This cohort is enrolling patients (NCT01755975). Additional studies evaluating lenalidomide plus chemotherapy in adult T-cell leukaemia-lymphoma should be explored and assessment of the role of maintenance lenalidomide for patients ineligible for allogeneic stem-cell transplantation is warranted as well. In view of its efficacy, favourable toxicity profile, and ability to be
e101
combined with other agents, lenalidomide has great potential for affecting the treatment paradigm of adult T-cell leukaemia-lymphoma. Hopefully outcomes will improve substantially as lenalidomide use is developed further in this disease. Alison J Moskowitz Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA [email protected] I declare no competing interests. 1
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Vose J, Armitage J, Weisenburger D. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol 2008; 26: 4124–30. Ishida T, Hishizawa M, Kato K, et al. Allogeneic hematopoietic stem cell transplantation for adult T-cell leukemia-lymphoma with special emphasis on preconditioning regimen: a nationwide retrospective study. Blood 2012; 120: 1734–41. Tsukasaki K, Utsunomiya A, Fukuda H, et al. VCAP-AMP-VECP compared with biweekly CHOP for adult T-cell leukemia-lymphoma: Japan Clinical Oncology Group Study JCOG9801. J Clin Oncol 2007; 25: 5458–64. Ishida T, Jo T, Takemoto S, et al. Dose-intensified chemotherapy alone or in combination with mogamulizumab in newly diagnosed aggressive adult T-cell leukaemia-lymphoma: a randomized phase II study. Br J Haematol 2015; 169: 672–82. Bazarbachi A, Plumelle Y, Carlos Ramos J, et al. Meta-analysis on the use of zidovudine and interferon-alfa in adult T-cell leukemia/lymphoma showing improved survival in the leukemic subtypes. J Clin Oncol 2010; 28: 4177–83. Toumishey E, Prasad A, Dueck G, et al. Final report of a phase 2 clinical trial of lenalidomide monotherapy for patients with T-cell lymphoma. Cancer 2015; 121: 716–23. Morschhauser F, Fitoussi O, Haioun C, et al. 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 2013; 49: 2869–76. Ogura M, Imaizumi Y, Uike N, et al. Lenalidomide in relapsed adult T-cell leukaemia-lymphoma or peripheral T-cell lymphoma (ATLL-001): a phase 1, multicentre, dose-escalation study. Lancet Haematol 2016; published online Feb 11. http://dx.doi.org/10.1016/S23523026(15)00284-7. Fujiwara H, Ishida T, Nosaka K, et al. Multicenter phase II study of lenalidomide in patients with relapsed adult T-cell leukemia-lymphoma. Blood 2015; 126: 181. Wu L, Adams M, Carter T, et al. Lenalidomide enhances natural killer cell and monocyte-mediated antibody-dependent cellular cytotoxicity of rituximab-treated CD20+ tumor cells. Clin Cancer Res 2008; 14: 4650–57.
www.thelancet.com/haematology Vol 3 March 2016
The acute and lymphoma subtypes of adult T-cell leukaemia-lymphoma are among the most difficult diseases to treat, largely due to the absence of highly effective therapies and their aggressive nature. This difficulty was shown in the International T-cell Lymphoma project, which reported a dismal 5-year overall survival of 14% for adult T-cell leukaemialymphoma, the lowest among the T-cell entities.1 Allogeneic stem-cell transplantation offers the potential for long-term remission for about 35% of patients who receive it; however many patients are unable to undergo such a procedure because of inadequate response to therapy.2 The poor outcomes reported with standard therapies such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone or prednisolone) led the Japan Clinical Oncology Group to develop the dose-intensified regimen VCAP (vincristine, cyclophosphamide, doxorubicin, prednisone), AMP (doxorubicin, ranimustine, prednisone), and VECP (vindesine, etoposide, carboplatin, prednisone). This regimen produced significantly improved proportions of patients achieving a complete response compared with dose-intense CHOP (40% vs 25%, p=0·02); however, the 3-year overall survival observed with VCAP-AMP-VECP was disappointing at 24%.3 In the past few years, new targeted agents seem promising for adult T-cell leukaemia-lymphoma. The almost universal expression of CCR4 on such tumour cells provided a rationale for assessment of mogamulizumab, an anti-CCR4 monoclonal antibody, in this disease. As a single-agent, mogamulizumab produced objective responses in 50% of patients with adult T-cell leukaemia-lymphoma and was subsequently assessed in a randomised phase 2 study in combination with VCAP-AMP-VECP.4 The addition of the monoclonal antibody to VCAP-AMP-VECP led to a non-statistically significant improvement in the proportion of patients achieving a complete response compared with chemotherapy alone (52% vs 33%), although this improvement was at the expense of increased incidence of often manageable infectious-related toxicities. Finally, antiviral therapy with zidovudine and interferon alfa seemed to provide benefit to patients with chronic, smouldering, and acute-type adult T-cell leukaemia-lymphoma in a large meta-analysis; however, it provided little benefit for www.thelancet.com/haematology Vol 3 March 2016
patients with lymphoma-type disease.5 Unfortunately, despite the availability of mogamulizumab and antiviral therapy, a substantial unmet need exists for effective and well-tolerated regimens for aggressive adult T-cell leukaemia-lymphoma. Many studies assessing new drugs in T-cell lymphoma either exclude patients with adult T-cell leukaemia-lymphoma or enrol few of them, and thus the efficacy of agents used in T-cell lymphoma, such as lenalidomide, romidepsin, belinostat, or pralatrexate, is not well understood. Among the studies assessing lenalidomide in T-cell lymphoma, the proportion of patients achieving a response ranges from 22% to 33%; however, no patients with adult T-cell leukaemia-lymphoma were enrolled.6,7 In The Lancet Haematology, Michinori Ogura and colleagues present the first study8 assessing the optimum dose and safety of lenalidomide in adult T-cell leukaemia-lymphoma, with efficacy as an exploratory endpoint. This phase 1 study enrolled 13 patients (nine with adult T-cell leukaemia-lymphoma and four with other T-cell lymphomas) to three sequential dosing cohorts. Cohort 1 received lenalidomide 25 mg/day for days 1–21 of a 28-day cycle, cohort 2 received lenalidomide 25 mg/day continuously, and cohort 3 received lenalidomide 35 mg/day continuously. Two dose-limiting toxicities were reported in the four patients in cohort 3 and one in the six patients in cohort 2, thus establishing lendaliomide 25 mg/day continuously as the maximum tolerated dose. Overall, the toxicity profile of lenalidomide was manageable and similar to that reported in other haematological malignancies. In 11 assessable patients, the overall proportion of patients achieving a response was 36% and the response in seven of these patients with adult T-cell leukaemia-lymphoma was 43%, including two compete responses and one partial response. Notably, the responses were durable, with median duration of response of 16·6 months (9·3–24·0). One potential bias was the requirement of a 4 week washout from previous treatments before enrolment, which might have led to selection of patients with less aggressive disease. Nevertheless, the results are encouraging. Building on this study, the authors recently completed a phase 2 study assessing
David M Phillips/Science Photo Library
Lenalidomide in adult T-cell leukaemia-lymphoma
Published Online February 11, 2016 http://dx.doi.org/10.1016/ S2352-3026(16)00009-0 See Articles page e107
e100
Comment
lenalidomide 25 mg/day continuously in adult T-cell leukaemia-lymphoma. At the 2015 American Society of Hematology meeting, they reported an overall response of 42% in 26 patients with adult T-cell leukaemia-lymphoma enrolled in the phase 2 study,9 thus confirming the efficacy observed in this phase 1 study. In view of the restricted treatment options available for adult T-cell leukaemia-lymphoma, investigations focused on development of new agents are much needed. These data support the use of lenalidomide as a single-agent in relapsed and refractory adult T-cell leukaemia-lymphoma; but more importantly, they pave the way for future combination studies that will hopefully improve on the efficacy of present regimens, and ultimately improve survival for this disease. Because lenalidomide is known to synergise with monoclonal antibodies by enhancing antibody-dependent cellular cytotoxicity, lenalidomide might synergise with mogamulizumab as well, which also functions primarily through antibody-dependent cellular cytotoxicity.10 Studies assessing lenalidomide plus mogamulizumab are therefore warranted. Anecdotal data from our institution showing activity of romidepsin in adult T-cell leukaemia-lymphoma led us to expand our phase 1/2 study assessing romidepsin plus lenalidomide to include a cohort for patients with adult T-cell leukaemia-lymphoma. This cohort is enrolling patients (NCT01755975). Additional studies evaluating lenalidomide plus chemotherapy in adult T-cell leukaemia-lymphoma should be explored and assessment of the role of maintenance lenalidomide for patients ineligible for allogeneic stem-cell transplantation is warranted as well. In view of its efficacy, favourable toxicity profile, and ability to be
e101
combined with other agents, lenalidomide has great potential for affecting the treatment paradigm of adult T-cell leukaemia-lymphoma. Hopefully outcomes will improve substantially as lenalidomide use is developed further in this disease. Alison J Moskowitz Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA [email protected] I declare no competing interests. 1
2
3
4
5
6
7
8
9
10
Vose J, Armitage J, Weisenburger D. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol 2008; 26: 4124–30. Ishida T, Hishizawa M, Kato K, et al. Allogeneic hematopoietic stem cell transplantation for adult T-cell leukemia-lymphoma with special emphasis on preconditioning regimen: a nationwide retrospective study. Blood 2012; 120: 1734–41. Tsukasaki K, Utsunomiya A, Fukuda H, et al. VCAP-AMP-VECP compared with biweekly CHOP for adult T-cell leukemia-lymphoma: Japan Clinical Oncology Group Study JCOG9801. J Clin Oncol 2007; 25: 5458–64. Ishida T, Jo T, Takemoto S, et al. Dose-intensified chemotherapy alone or in combination with mogamulizumab in newly diagnosed aggressive adult T-cell leukaemia-lymphoma: a randomized phase II study. Br J Haematol 2015; 169: 672–82. Bazarbachi A, Plumelle Y, Carlos Ramos J, et al. Meta-analysis on the use of zidovudine and interferon-alfa in adult T-cell leukemia/lymphoma showing improved survival in the leukemic subtypes. J Clin Oncol 2010; 28: 4177–83. Toumishey E, Prasad A, Dueck G, et al. Final report of a phase 2 clinical trial of lenalidomide monotherapy for patients with T-cell lymphoma. Cancer 2015; 121: 716–23. Morschhauser F, Fitoussi O, Haioun C, et al. 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 2013; 49: 2869–76. Ogura M, Imaizumi Y, Uike N, et al. Lenalidomide in relapsed adult T-cell leukaemia-lymphoma or peripheral T-cell lymphoma (ATLL-001): a phase 1, multicentre, dose-escalation study. Lancet Haematol 2016; published online Feb 11. http://dx.doi.org/10.1016/S23523026(15)00284-7. Fujiwara H, Ishida T, Nosaka K, et al. Multicenter phase II study of lenalidomide in patients with relapsed adult T-cell leukemia-lymphoma. Blood 2015; 126: 181. Wu L, Adams M, Carter T, et al. Lenalidomide enhances natural killer cell and monocyte-mediated antibody-dependent cellular cytotoxicity of rituximab-treated CD20+ tumor cells. Clin Cancer Res 2008; 14: 4650–57.
www.thelancet.com/haematology Vol 3 March 2016