- Email: [email protected]
A novel clinicogenetic prognostic score for follicular lymphoma
Comment
Mohamed A Kharfan-Dabaja Department of Blood and Marrow Transplantation, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA Mohamed.Kharfan-Dabaja@Moffitt.org I have participated in an advisory board meeting for GlaxoSmithKline and in a speaker bureau for Incyte, both outside this work. I declare no competing interests. 1
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Bejar R, Stevenson K, Abdel-Wahab O, et al. Clinical effect of point mutations in myelodysplastic syndromes. N Engl J Med 2011; 364: 2496–506. Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood 2012; 120: 2454–65. Patel JP, Gonen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 2012; 366: 1079–89. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol 2009; 10: 223–32.
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Kantarjian H, Issa JP, Rosenfeld CS, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer 2006; 106: 1794–803. Kharfan-Dabaja MA, Labopin M, Bazarbachi A, et al. Comparing i.v. BU dose intensity between two regimens (FB2 vs FB4) for allogeneic HCT for AML in CR1: a report from the Acute Leukemia Working Party of EBMT. Bone Marrow Transplant 2014; 49: 1170–75. Issa J-PJ, Roboz G RD, Jabbour E, et al. Safety and biologically effective dose of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: a multicentre, randomised, dose-escalation phase 1 study. Lancet Oncol 2015; published online Aug 19. http://dx.doi. org/10.1016/S1470-2045(15)00038-8. Shen L, Kantarjian H, Guo Y, et al. DNA methylation predicts survival and response to therapy in patients with myelodysplastic syndromes. J Clin Oncol 2010; 28: 605–13.
In The Lancet Oncology, Pastore and colleagues1 introduce a new prognostic score (m7-FLIPI) for patients with follicular lymphoma based on specific gene mutations found in tumour cells, together with standard clinical features. This score is the first attempt to incorporate key genetic information to the clinical setting, at least as a prognostic tool. Although follicular lymphoma usually has an indolent behaviour, it is still considered incurable in most cases, since the majority of patients eventually relapse or progress. Nevertheless, about a third of patients do not need treatment at diagnosis or can be managed with less intensive treatment, such as rituximab monotherapy. For patients needing treatment, immunochemotherapy is the gold standard. However, some patients become refractory to chemotherapy or their disease transforms to an aggressive lymphoma. Early relapsed patients or those with histological transformation have a poor outcome with standard treatments and clearly represent an unmet need. Thus, the assessment of prognosis in specific situations might be of paramount importance in the decision-making process in follicular lymphoma.2 Prognosis of patients with follicular lymphoma is currently based on clinical scores, namely FLIPI3 and FLIPI-2.4 With easily obtainable variables, both scores are able to predict progression-free survival and overall survival. However, such scores are not used to establish the need for therapy and their ability to predict response to a specific treatment, particularly targeted therapies, is low. The proposed www.thelancet.com/oncology Vol 16 September 2015
score, m7-FLIPI, incorporates information on the mutational status of seven genes and is able to predict failure-free survival more accurately than FLIPI.1 However, the clinical significance of this refinement remains doubtful as, strictly in terms of prognosis, m7-FLIPI seems to be marginally better than FLIPI2 in selecting high-risk patients. Additionally, a caveat of FLIPI, namely, the inability to select asymptomatic patients needing treatment, has not been tested for m7-FLIPI. Nevertheless, m7-FLIPI could potentially provide benefit as a predictor of response to specific or targeted therapies. The concept is attractive, since m7-FLIPI incorporates potentially relevant genetic information, but this remains to be shown in prospective clinical trials. Crucial aspects before using m7-FLIPI as a standard score are feasibility, reproducibility under different circumstances (ie, different treatments), and ease of application in clinical practice at a reasonable cost. During the last decade, next generation sequencing has allowed mutations and other genetic abnormalities to be assessed in malignant diseases, including lymphomas. The amount of data is enormous and the determination of genetic drivers of tumourigenesis to better understand the biology of the tumour, to develop novel prognostic tools and, to guide the use of the therapy remains a challenge. The prognostic role of mutations in genes such as TP53, TNFRSF14, STAT6, or BCL2 has previously been demonstrated for follicular lymphoma.5–7 The
Tek Image/Science Photo Library
A novel clinicogenetic prognostic score for follicular lymphoma
Published Online August 7, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)00142-4 See Articles page 1111
1011
Comment
present study is the first to select a high number of genes with prognostic purpose. Although the genes in this study have been rationally selected, the existence of mutations in genes different from the 74 analysed with prognostic relevance remains a possibility. On the other hand, the only criterion used to incorporate mutations to the m7-FLIPI score was their prognostic weight, with no consideration of the biological function of the mutated genes. This method avoids any a-priori selection, but is somewhat contradictory to the classic assumption that only clinically relevant variables should be incorporated to prognostic scores. An alternative to this type of analysis could be the study of sets of genes grouped by signalling pathways. This approach could improve the usefulness of biological scores to predict response to targeted treatments. Among the genes used in the m7-FLIPI score, EZH2 deserves specific mention, since expression of this gene was enriched in patients with favourable outcome irrespective of their risk group. Moreover, tumours with EZH2 mutations harbour a distinct transcriptional profile and importantly, EZH2 is a potential therapeutic target.8 In summary, Pastore and colleagues1 present interesting data on how to use the new biological
information in the clinical setting. The clinicogenetic m7-FLIPI score represents the first step towards a bioscore in follicular lymphoma that is clinically relevant, reproducible, and feasible in clinical practice. Armando López-Guillermo Department of Hematology, Hospital Clínic, Barcelona, Spain [email protected] I declare no competing interests. 1
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Pastore A, Jurinovic V, Kridel R, et al. Integration of gene mutations in risk prognostication for patients receiving first-line immunochemotherapy for follicular lymphoma: a retrospective analyisis of a prospective clinical trial and validation in a population-based registry. Lancet Oncol 2015; published online Aug 7. http://dx.doi.org/10.1016/S1470-2045(15)00169-2. Hiddemann W, Cheson BD. How we manage follicular lymphoma. Leukemia 2014; 28: 1388–95. Solal-Celigny P, Roy P, Colombat P, et al. Follicular lymphoma international prognostic index. Blood 2004; 104: 1258–65. Federico M, Bellei M, MArcheselli L, et al. Follicular lymphoma international prognostic index 2: a new prognostic index for follicular lymphoma developed by the International Follicular Lymphoma Prognostic Factor Project. J Clin Oncol 2009; 27: 4555–62. Launay E, Pangault C, Bertrand P, et al. High rate of TNFRSF14 gene alterations related to 1p36 region in de novo follicular lymphoma and impact on prognosis. Leukemia 2012; 26: 559–62. Morin RD, Johnson NA, Severson TM, et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet 2010; 42: 181–85. Correia C, Schneider PA, Dai H, et al. BCL2 mutations are associated with increased risk of transformation and shortened survival in follicular lymphomas. Blood 2015; 125: 658–67. McCabe MT, Ott HM, Ganji G, et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 2013; 492: 108–12.
Science Photo Library
The UK Age Trial: screening women in their forties
Published Online July 21, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)00057-1 This online publication has been corrected. The corrected version first appeared at thelancet.com/ oncology on November 2, 2015 See Articles page 1123
1012
The age of 50 years was first imbued with false importance in breast cancer screening when, in a retrospective review of their data, the investigators of the first randomised trial of screening (the Health Insurance Plan of New York trial) decided to see whether menopause had an effect on their results, and used the age of 50 years as a surrogate for menopause. Several randomised trials1 have shown a benefit from breast cancer screening for women starting at the age of 40 years, and this is confirmed by observational studies. Over time, the benefits of screening women aged 40–49 years became irrefutable, but those who disagreed with screening women at this age sought ways to claim that the benefit was not as great for younger women as for women aged 50 years and older. Efforts have been made to make the age of 50 years seem to be a legitimate threshold for screening through the use of unplanned retrospective subgroup analyses of
trials that did not have sufficient statistical power,2 and by grouping women and averaging the data to make it seem as if there was a major jump in cancer detection at the age of 50 years although no data show that any of the variables of screening change abruptly at any age.3 No biological or scientific evidence supports the use of the age of 50 years as a threshold for screening.4 The Health Insurance Plan trial showed that for women aged 50–64 years, breast cancer mortality began to drop almost immediately after the start of screening, whereas for women aged 40–49 years, the mortality reduction was delayed for 5–7 years. Length bias sampling predicts that a delayed benefit is expected in this circumstance; however, the apparent immediate decrease in breast cancer deaths for women aged 50–64 years was not explained.5 This finding was almost certainly due to statistical fluctuation from low numbers of deaths from cancer in the early years of the trial. Nevertheless, www.thelancet.com/oncology Vol 16 September 2015
Mohamed A Kharfan-Dabaja Department of Blood and Marrow Transplantation, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA Mohamed.Kharfan-Dabaja@Moffitt.org I have participated in an advisory board meeting for GlaxoSmithKline and in a speaker bureau for Incyte, both outside this work. I declare no competing interests. 1
2 3 4
Bejar R, Stevenson K, Abdel-Wahab O, et al. Clinical effect of point mutations in myelodysplastic syndromes. N Engl J Med 2011; 364: 2496–506. Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood 2012; 120: 2454–65. Patel JP, Gonen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 2012; 366: 1079–89. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol 2009; 10: 223–32.
5
6
7
8
Kantarjian H, Issa JP, Rosenfeld CS, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer 2006; 106: 1794–803. Kharfan-Dabaja MA, Labopin M, Bazarbachi A, et al. Comparing i.v. BU dose intensity between two regimens (FB2 vs FB4) for allogeneic HCT for AML in CR1: a report from the Acute Leukemia Working Party of EBMT. Bone Marrow Transplant 2014; 49: 1170–75. Issa J-PJ, Roboz G RD, Jabbour E, et al. Safety and biologically effective dose of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: a multicentre, randomised, dose-escalation phase 1 study. Lancet Oncol 2015; published online Aug 19. http://dx.doi. org/10.1016/S1470-2045(15)00038-8. Shen L, Kantarjian H, Guo Y, et al. DNA methylation predicts survival and response to therapy in patients with myelodysplastic syndromes. J Clin Oncol 2010; 28: 605–13.
In The Lancet Oncology, Pastore and colleagues1 introduce a new prognostic score (m7-FLIPI) for patients with follicular lymphoma based on specific gene mutations found in tumour cells, together with standard clinical features. This score is the first attempt to incorporate key genetic information to the clinical setting, at least as a prognostic tool. Although follicular lymphoma usually has an indolent behaviour, it is still considered incurable in most cases, since the majority of patients eventually relapse or progress. Nevertheless, about a third of patients do not need treatment at diagnosis or can be managed with less intensive treatment, such as rituximab monotherapy. For patients needing treatment, immunochemotherapy is the gold standard. However, some patients become refractory to chemotherapy or their disease transforms to an aggressive lymphoma. Early relapsed patients or those with histological transformation have a poor outcome with standard treatments and clearly represent an unmet need. Thus, the assessment of prognosis in specific situations might be of paramount importance in the decision-making process in follicular lymphoma.2 Prognosis of patients with follicular lymphoma is currently based on clinical scores, namely FLIPI3 and FLIPI-2.4 With easily obtainable variables, both scores are able to predict progression-free survival and overall survival. However, such scores are not used to establish the need for therapy and their ability to predict response to a specific treatment, particularly targeted therapies, is low. The proposed www.thelancet.com/oncology Vol 16 September 2015
score, m7-FLIPI, incorporates information on the mutational status of seven genes and is able to predict failure-free survival more accurately than FLIPI.1 However, the clinical significance of this refinement remains doubtful as, strictly in terms of prognosis, m7-FLIPI seems to be marginally better than FLIPI2 in selecting high-risk patients. Additionally, a caveat of FLIPI, namely, the inability to select asymptomatic patients needing treatment, has not been tested for m7-FLIPI. Nevertheless, m7-FLIPI could potentially provide benefit as a predictor of response to specific or targeted therapies. The concept is attractive, since m7-FLIPI incorporates potentially relevant genetic information, but this remains to be shown in prospective clinical trials. Crucial aspects before using m7-FLIPI as a standard score are feasibility, reproducibility under different circumstances (ie, different treatments), and ease of application in clinical practice at a reasonable cost. During the last decade, next generation sequencing has allowed mutations and other genetic abnormalities to be assessed in malignant diseases, including lymphomas. The amount of data is enormous and the determination of genetic drivers of tumourigenesis to better understand the biology of the tumour, to develop novel prognostic tools and, to guide the use of the therapy remains a challenge. The prognostic role of mutations in genes such as TP53, TNFRSF14, STAT6, or BCL2 has previously been demonstrated for follicular lymphoma.5–7 The
Tek Image/Science Photo Library
A novel clinicogenetic prognostic score for follicular lymphoma
Published Online August 7, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)00142-4 See Articles page 1111
1011
Comment
present study is the first to select a high number of genes with prognostic purpose. Although the genes in this study have been rationally selected, the existence of mutations in genes different from the 74 analysed with prognostic relevance remains a possibility. On the other hand, the only criterion used to incorporate mutations to the m7-FLIPI score was their prognostic weight, with no consideration of the biological function of the mutated genes. This method avoids any a-priori selection, but is somewhat contradictory to the classic assumption that only clinically relevant variables should be incorporated to prognostic scores. An alternative to this type of analysis could be the study of sets of genes grouped by signalling pathways. This approach could improve the usefulness of biological scores to predict response to targeted treatments. Among the genes used in the m7-FLIPI score, EZH2 deserves specific mention, since expression of this gene was enriched in patients with favourable outcome irrespective of their risk group. Moreover, tumours with EZH2 mutations harbour a distinct transcriptional profile and importantly, EZH2 is a potential therapeutic target.8 In summary, Pastore and colleagues1 present interesting data on how to use the new biological
information in the clinical setting. The clinicogenetic m7-FLIPI score represents the first step towards a bioscore in follicular lymphoma that is clinically relevant, reproducible, and feasible in clinical practice. Armando López-Guillermo Department of Hematology, Hospital Clínic, Barcelona, Spain [email protected] I declare no competing interests. 1
2 3 4
5
6
7
8
Pastore A, Jurinovic V, Kridel R, et al. Integration of gene mutations in risk prognostication for patients receiving first-line immunochemotherapy for follicular lymphoma: a retrospective analyisis of a prospective clinical trial and validation in a population-based registry. Lancet Oncol 2015; published online Aug 7. http://dx.doi.org/10.1016/S1470-2045(15)00169-2. Hiddemann W, Cheson BD. How we manage follicular lymphoma. Leukemia 2014; 28: 1388–95. Solal-Celigny P, Roy P, Colombat P, et al. Follicular lymphoma international prognostic index. Blood 2004; 104: 1258–65. Federico M, Bellei M, MArcheselli L, et al. Follicular lymphoma international prognostic index 2: a new prognostic index for follicular lymphoma developed by the International Follicular Lymphoma Prognostic Factor Project. J Clin Oncol 2009; 27: 4555–62. Launay E, Pangault C, Bertrand P, et al. High rate of TNFRSF14 gene alterations related to 1p36 region in de novo follicular lymphoma and impact on prognosis. Leukemia 2012; 26: 559–62. Morin RD, Johnson NA, Severson TM, et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet 2010; 42: 181–85. Correia C, Schneider PA, Dai H, et al. BCL2 mutations are associated with increased risk of transformation and shortened survival in follicular lymphomas. Blood 2015; 125: 658–67. McCabe MT, Ott HM, Ganji G, et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 2013; 492: 108–12.
Science Photo Library
The UK Age Trial: screening women in their forties
Published Online July 21, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)00057-1 This online publication has been corrected. The corrected version first appeared at thelancet.com/ oncology on November 2, 2015 See Articles page 1123
1012
The age of 50 years was first imbued with false importance in breast cancer screening when, in a retrospective review of their data, the investigators of the first randomised trial of screening (the Health Insurance Plan of New York trial) decided to see whether menopause had an effect on their results, and used the age of 50 years as a surrogate for menopause. Several randomised trials1 have shown a benefit from breast cancer screening for women starting at the age of 40 years, and this is confirmed by observational studies. Over time, the benefits of screening women aged 40–49 years became irrefutable, but those who disagreed with screening women at this age sought ways to claim that the benefit was not as great for younger women as for women aged 50 years and older. Efforts have been made to make the age of 50 years seem to be a legitimate threshold for screening through the use of unplanned retrospective subgroup analyses of
trials that did not have sufficient statistical power,2 and by grouping women and averaging the data to make it seem as if there was a major jump in cancer detection at the age of 50 years although no data show that any of the variables of screening change abruptly at any age.3 No biological or scientific evidence supports the use of the age of 50 years as a threshold for screening.4 The Health Insurance Plan trial showed that for women aged 50–64 years, breast cancer mortality began to drop almost immediately after the start of screening, whereas for women aged 40–49 years, the mortality reduction was delayed for 5–7 years. Length bias sampling predicts that a delayed benefit is expected in this circumstance; however, the apparent immediate decrease in breast cancer deaths for women aged 50–64 years was not explained.5 This finding was almost certainly due to statistical fluctuation from low numbers of deaths from cancer in the early years of the trial. Nevertheless, www.thelancet.com/oncology Vol 16 September 2015