- Email: [email protected]
Meeting an unmet need for peripheral T-cell lymphoma
Comment
The treatment outcome of patients with peripheral T-cell lymphoma, a heterogenous group of neoplasms, remains dismal compared with their B-cell counterparts after conventional cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP-like regimens. Even among patients with low-risk disease according to the International Prognostic Index, 5-year overall survival seldom exceeds 40–50%.1 No accepted regimen exists in the treatment of these diseases in the first-line setting. On the basis of the efficacy of romidepsin, a potent class I histone deacetylase inhibitor, as monotherapy in patients with relapsed or refractory peripheral T-cell lymphoma,2 Jehan Dupuis and colleagues assessed the feasibility of combination of romidepsin with eight cycles of standard CHOP chemotherapy in a phase 1b/2 study. The study recruited 37 patients, of whom 26 received all eight planned cycles. Severe toxicity led to the premature interruption of study treatment in six patients. Although no reported cases of grade 3–4 QTc prolongation occurred, three unexpected cases of acute cardiac toxicity developed after the first dose of romidepsin and CHOP. Nonetheless, no deaths were related to adverse events. Overall toxicity, especially grade 3–4 thrombocytopenia and grade 3–4 neutropenia, was increased with addition of romidepsin compared with CHOP alone but seemed manageable. In terms of activity, the authors reported that 18 (51%) of the 35 assessable patients had a complete response, based on 2007 PET-based response criteria. Although the numbers were small, complete responses were noted in five (36%) of 14 patients with angioimmunoblastic T-cell lymphoma and five (63%) of eight patients with peripheral T-cell lymphoma, not otherwise specified. Overall, estimated progression-free survival at 30 months was 41·0% (95% CI 24·7–57·3) and overall survival was 70·7% (52·3–83·1). On the basis of these results and the unmet medical need in the first-line treatment of peripheral T-cell lymphoma, a randomised phase 3 study comparing romidepsin and CHOP with CHOP alone is in progress (NCT01796002). This important study will provide definitive evidence as to the feasibility and benefit of this approach. It will also provide valuable information about whether responses differ according to the major disease subtypes. As a www.thelancet.com/haematology Vol 2 April 2015
comparison, the 3-year event-free survival and overall survival for the major subtypes treated with CHOP or CHOP plus etoposide within the trials of the German High-Grade Non-Hodgkin Lymphoma Study Group were 50·0% and 67·5%, respectively, for angioimmunoblastic T-cell lymphoma and 41·1% and 53·9% for peripheral T-cell lymphoma, not otherwise specified.4 Apart from romidepsin, several other drugs have emerged with promising activity in peripheral T-cell lymphoma: brentuximab vedotin (CD30-targeted antibody–drug conjugate), pralatrexate, and alisertib (an aurora A kinase inhibitor).5–7 Both brentuximab vedotin and pralatrexate are under investigation in firstline randomised trials with anthracycline-containing regimens as the backbone. However, in view of the modest activity of CHOP, whether it is the ideal backbone to test these combination regimens needs to be questioned. A large international retrospective analysis suggested that addition of anthracyclines do not benefit patients with peripheral T-cell lymphoma.1 Would a non-anthracycline containing regimen incorporating newer agents such as gemcitabine be a more suitable chemotherapy backbone? Unfortunately, no anthracycline-sparing regimen has been shown in prospective studies to be superior to anthracycline-based treatments and some were even more toxic. Thus, CHOP, although unsatisfactory, is a reasonable chemotherapy backbone with which to test the efficacy of new drugs. Despite the fact that peripheral T-cell lymphoma is a heterogeneous disease, most trials continue to recruit patients with different histological subtypes. Thus, a fundamental question is whether this one-sizefits-all approach is the right one. Our understanding of the molecular pathogenesis of the disease has improved substantially in recent years. Although the existing classification lacks prognostic and therapeutic relevance, high-throughput genomic studies have helped identify biological and prognostic subgroups in peripheral T-cell lymphoma and identify potentially actionable genetic defects in the disease.8–10 One recent gene expression study identified enriched oncogenic pathways associated with the different peripheral T-cell lymphoma entities.8 The study suggested that patients with angioimmunoblastic T-cell lymphoma might
Ramon Andrade 3dciencia/Science Photo Library
Meeting an unmet need for peripheral T-cell lymphoma
Published Online March 17, 2015 http://dx.doi.org/10.1016/ S2352-3026(15)00042-3 See Articles page e160
e134
Comment
benefit from drugs that target the NF-κB pathway whereas patients with ALK-negative anaplastic large cell lymphoma could benefit from aurora kinase inhibitors in combination with drugs that target the PI3K/AKT pathway. Whole-exome sequencing analysis showed that angioimmunoblastic T-cell lymphoma and some subsets of peripheral T-cell lymphoma, not otherwise specified, with surface markers of follicular helper T cells share a similar spectrum of epigenetic alterations centred on pathways that aberrantly disrupt DNA methylation.9,10 These alterations, which include TET2, DNMT3A, and IDH2, are potentially targetable with IDH1 inhibitors. Present classification of peripheral T-cell lymphoma could conceivably undergo a substantial refinement in the next few years, paving the way for a personalised approach. Future clinical trials in this cancer will need to focus on targeting of biologically active pathways. Nonetheless, creation of new approaches for targeted combination therapy as first-line therapy is challenging and will require international collaboration considering the relative rarity of this subset of lymphoma.
I declare no competing interests. 1
2
3
4
5
6
7
8
9
10
International T-Cell Lymphoma Project. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol 2008; 26: 4124–30. Coiffier B, Pro B, Prince HM, et al. 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 2012; 30: 631–36. Dublius J, Morschhauser F, Ghesquieres H, et al. 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 2015; published online March 17. http://dx.doi.org/10.1016/S2352-3026(15)00042-3. Schmitz N, Trümper L, Ziepert M, et al. Treatment and prognosis of mature T-cell and NK-cell lymphoma: an analysis of patients with T-cell lymphoma treated in studies of the German High-Grade Non-Hodgkin Lymphoma Study Group. Blood 2010; 116: 3418–25. Horwitz SM, Advani RH, Bartlett NL, et al. Objective responses in relapsed T-cell lymphomas with single-agent brentuximab vedotin. Blood 2014; 123: 3095–100. O’Connor OA, Pro B, Pinter-Brown L, et al. Pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma: results from the pivotal PROPEL study. J Clin Oncol 2011; 29: 1182–89. Friedberg JW, Mahadevan D, Cebula E, et al. Phase II study of alisertib, a selective Aurora A kinase inhibitor, in relapsed and refractory aggressive Band T-cell non-Hodgkin lymphomas. J Clin Oncol 2014; 32: 44–50. Iqbal J, Wright G, Wang C, et al. Gene expression signatures delineate biologic and prognostic subgroups in peripheral T-cell lymphomas. Blood 2014; 123: 2915–23. Palomero T, Couronné L, Khiabanian H, et al. Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas. Nat Genet 2014; 46: 166–70. Ahearne MJ, Allchin RL, Fox CP, et al. Follicular helper T-cells: expanding roles in T-cell lymphoma and targets for treatment. Br J Haematol 2014; 166: 326–35.
Soon Thye Lim National Cancer Centre, Medical Oncology, 11 Hospital Drive, Singapore, Singapore [email protected]
e135
www.thelancet.com/haematology Vol 2 April 2015
The treatment outcome of patients with peripheral T-cell lymphoma, a heterogenous group of neoplasms, remains dismal compared with their B-cell counterparts after conventional cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP-like regimens. Even among patients with low-risk disease according to the International Prognostic Index, 5-year overall survival seldom exceeds 40–50%.1 No accepted regimen exists in the treatment of these diseases in the first-line setting. On the basis of the efficacy of romidepsin, a potent class I histone deacetylase inhibitor, as monotherapy in patients with relapsed or refractory peripheral T-cell lymphoma,2 Jehan Dupuis and colleagues assessed the feasibility of combination of romidepsin with eight cycles of standard CHOP chemotherapy in a phase 1b/2 study. The study recruited 37 patients, of whom 26 received all eight planned cycles. Severe toxicity led to the premature interruption of study treatment in six patients. Although no reported cases of grade 3–4 QTc prolongation occurred, three unexpected cases of acute cardiac toxicity developed after the first dose of romidepsin and CHOP. Nonetheless, no deaths were related to adverse events. Overall toxicity, especially grade 3–4 thrombocytopenia and grade 3–4 neutropenia, was increased with addition of romidepsin compared with CHOP alone but seemed manageable. In terms of activity, the authors reported that 18 (51%) of the 35 assessable patients had a complete response, based on 2007 PET-based response criteria. Although the numbers were small, complete responses were noted in five (36%) of 14 patients with angioimmunoblastic T-cell lymphoma and five (63%) of eight patients with peripheral T-cell lymphoma, not otherwise specified. Overall, estimated progression-free survival at 30 months was 41·0% (95% CI 24·7–57·3) and overall survival was 70·7% (52·3–83·1). On the basis of these results and the unmet medical need in the first-line treatment of peripheral T-cell lymphoma, a randomised phase 3 study comparing romidepsin and CHOP with CHOP alone is in progress (NCT01796002). This important study will provide definitive evidence as to the feasibility and benefit of this approach. It will also provide valuable information about whether responses differ according to the major disease subtypes. As a www.thelancet.com/haematology Vol 2 April 2015
comparison, the 3-year event-free survival and overall survival for the major subtypes treated with CHOP or CHOP plus etoposide within the trials of the German High-Grade Non-Hodgkin Lymphoma Study Group were 50·0% and 67·5%, respectively, for angioimmunoblastic T-cell lymphoma and 41·1% and 53·9% for peripheral T-cell lymphoma, not otherwise specified.4 Apart from romidepsin, several other drugs have emerged with promising activity in peripheral T-cell lymphoma: brentuximab vedotin (CD30-targeted antibody–drug conjugate), pralatrexate, and alisertib (an aurora A kinase inhibitor).5–7 Both brentuximab vedotin and pralatrexate are under investigation in firstline randomised trials with anthracycline-containing regimens as the backbone. However, in view of the modest activity of CHOP, whether it is the ideal backbone to test these combination regimens needs to be questioned. A large international retrospective analysis suggested that addition of anthracyclines do not benefit patients with peripheral T-cell lymphoma.1 Would a non-anthracycline containing regimen incorporating newer agents such as gemcitabine be a more suitable chemotherapy backbone? Unfortunately, no anthracycline-sparing regimen has been shown in prospective studies to be superior to anthracycline-based treatments and some were even more toxic. Thus, CHOP, although unsatisfactory, is a reasonable chemotherapy backbone with which to test the efficacy of new drugs. Despite the fact that peripheral T-cell lymphoma is a heterogeneous disease, most trials continue to recruit patients with different histological subtypes. Thus, a fundamental question is whether this one-sizefits-all approach is the right one. Our understanding of the molecular pathogenesis of the disease has improved substantially in recent years. Although the existing classification lacks prognostic and therapeutic relevance, high-throughput genomic studies have helped identify biological and prognostic subgroups in peripheral T-cell lymphoma and identify potentially actionable genetic defects in the disease.8–10 One recent gene expression study identified enriched oncogenic pathways associated with the different peripheral T-cell lymphoma entities.8 The study suggested that patients with angioimmunoblastic T-cell lymphoma might
Ramon Andrade 3dciencia/Science Photo Library
Meeting an unmet need for peripheral T-cell lymphoma
Published Online March 17, 2015 http://dx.doi.org/10.1016/ S2352-3026(15)00042-3 See Articles page e160
e134
Comment
benefit from drugs that target the NF-κB pathway whereas patients with ALK-negative anaplastic large cell lymphoma could benefit from aurora kinase inhibitors in combination with drugs that target the PI3K/AKT pathway. Whole-exome sequencing analysis showed that angioimmunoblastic T-cell lymphoma and some subsets of peripheral T-cell lymphoma, not otherwise specified, with surface markers of follicular helper T cells share a similar spectrum of epigenetic alterations centred on pathways that aberrantly disrupt DNA methylation.9,10 These alterations, which include TET2, DNMT3A, and IDH2, are potentially targetable with IDH1 inhibitors. Present classification of peripheral T-cell lymphoma could conceivably undergo a substantial refinement in the next few years, paving the way for a personalised approach. Future clinical trials in this cancer will need to focus on targeting of biologically active pathways. Nonetheless, creation of new approaches for targeted combination therapy as first-line therapy is challenging and will require international collaboration considering the relative rarity of this subset of lymphoma.
I declare no competing interests. 1
2
3
4
5
6
7
8
9
10
International T-Cell Lymphoma Project. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol 2008; 26: 4124–30. Coiffier B, Pro B, Prince HM, et al. 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 2012; 30: 631–36. Dublius J, Morschhauser F, Ghesquieres H, et al. 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 2015; published online March 17. http://dx.doi.org/10.1016/S2352-3026(15)00042-3. Schmitz N, Trümper L, Ziepert M, et al. Treatment and prognosis of mature T-cell and NK-cell lymphoma: an analysis of patients with T-cell lymphoma treated in studies of the German High-Grade Non-Hodgkin Lymphoma Study Group. Blood 2010; 116: 3418–25. Horwitz SM, Advani RH, Bartlett NL, et al. Objective responses in relapsed T-cell lymphomas with single-agent brentuximab vedotin. Blood 2014; 123: 3095–100. O’Connor OA, Pro B, Pinter-Brown L, et al. Pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma: results from the pivotal PROPEL study. J Clin Oncol 2011; 29: 1182–89. Friedberg JW, Mahadevan D, Cebula E, et al. Phase II study of alisertib, a selective Aurora A kinase inhibitor, in relapsed and refractory aggressive Band T-cell non-Hodgkin lymphomas. J Clin Oncol 2014; 32: 44–50. Iqbal J, Wright G, Wang C, et al. Gene expression signatures delineate biologic and prognostic subgroups in peripheral T-cell lymphomas. Blood 2014; 123: 2915–23. Palomero T, Couronné L, Khiabanian H, et al. Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas. Nat Genet 2014; 46: 166–70. Ahearne MJ, Allchin RL, Fox CP, et al. Follicular helper T-cells: expanding roles in T-cell lymphoma and targets for treatment. Br J Haematol 2014; 166: 326–35.
Soon Thye Lim National Cancer Centre, Medical Oncology, 11 Hospital Drive, Singapore, Singapore [email protected]
e135
www.thelancet.com/haematology Vol 2 April 2015