- Email: [email protected]
Childhood leukaemia: towards improved tailored therapy
Reflection and Reaction
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Daubine F, Le Gall C, Gasser J, Green J, Clezardin P. Antitumor effects of clinical dosing regimens of bisphosphonates in experimental breast cancer bone metastasis. J Natl Cancer Inst 2007; 99: 322–30. Coleman RE, Minter MC, Cameron D, et al. The effects of adding zoledronic acid to neoadjuvant chemotherapy on tumour response: exploratory evidence for direct anti-tumour activity in breast cancer. Br J Cancer 2010; 102: 1099–105. Gnant M. Bisphosphonates in the prevention of disease recurrence: current results and ongoing trials. Current Cancer Drug Targets 2009; 9: 824–33. Gnant M. The evolving role of zoledronic acid in early breast cancer. Onco Targets Therapy 2009; 2: 95–104.
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Paget S. The distribution of secondary growths in cancer of the breast. Lancet 1889; 133: 571–73. Shiozawa Y, Havens AM, Pienta KJ, Taichman RS. The bone marrow niche: habitat to hematopoietic and mesenchymal stem cells, and unwitting host to molecular parasites. Leukemia 2008; 22: 941–50. Gnant M, Mlineritsch B, Schippinger W, et al. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med 2009; 360: 679–91.
In this issue of The Lancet Oncology, Moorman and colleagues1 describe the association between cytogenetic abnormalities and risk of relapse in childhood acute lymphoblastic leukaemia (ALL). Numerous studies have addressed this issue but are usually limited because they analyse one or few genetic abnormalities or only selected subsets of patients with ALL. By contrast, this study analyses a large number of recurrent abnormalities in more than 1700 patients who were uniformly treated and have a long follow-up. Two abnormalities were associated with a favourable outcome (ETV6–RUNX1 and high hyperdiploidy) and four with a worse outcome (intrachromosomal amplification of chromosome 21 [iAMP21], t(9;22), loss of chromosome 13q, and abnormalities of chromosome 17p). The authors propose a classification into three risk groups using these abnormalities with event-free survival (EFS) at 5 years of 86% for the good-risk group, 76% for the intermediaterisk group, and 45% for the high-risk group. Early response to therapy correlated with the cytogenetic risk group, with proportions of patients deemed to be slow responders of 7%, 10%, and 28% in the three groups, respectively. These results confirm the findings of many smaller studies and illustrate the importance of genetics for outcome prediction in childhood ALL; they also raise two questions: how can these findings be used in clinical practice and which mechanisms explain these associations between cytogenetics and outcome? Although the prognostic relevance of the genetic abnormalities is highly significant, the absolute numbers of patients in the three genetic risk groups are very different. Of all the patients classified by genetic abnormalities, 60% are in the good-risk group, 30% in the intermediate-risk group, and only 10% in the high-risk group. Of all relapses, only 26% occurred in the high-risk group whereas 42% occurred in the www.thelancet.com/oncology Vol 11 May 2010
so-called good-risk group. It is thus difficult to consider therapy reduction for the good-risk patients: a high number of relapses occur in these patients and their EFS is not high enough to justify therapy reduction, which risks increasing the number of relapses. The favourable outcome of patients with ETV6–RUNX1 or high hyperdiploidy may be due to the higher sensitivity of ALL cells carrying these abnormalities. ETV6–RUNX1 is associated with sensitivity to L-asparaginase2 and high hyperdiplody with sensitivity to mercaptopurine and methotrexate.3 If changes to chemotherapy are considered, it seems inadvisable to reduce these drugs in these specific subclasses. If therapy needs to be increased for patients with a high risk of relapse, how should this be done? The primary reflex is to use allogeneic haematopoietic stem-cell transplantation for these patients. For BCR–ABL-positive patients this seems a good option,4 although the addition of imatinib to intensive chemotherapy might reduce the need for transplantation in these patients.5 MLL gene rearrangements were also classified in the high-risk group by Moorman and colleagues, although in their multivariate analysis it did not retain its significance for effect on relapse risk. However, data suggest that patients with a MLL rearrangement do not benefit from allogeneic stem-cell transplantation.6 In practice, in many treatment protocols, high-risk patients with a risk of relapse of about 50% are exposed to very intensive chemotherapy followed by transplantation in selected cases. The use of targeted therapy is at present limited to BCR–ABL-positive ALL patients, for whom imatinib, dasatinib, and nilotinib are available. Clofarabine-based combination chemotherapies will probably gain a more prominent role in treatment of high-risk patients in the near future. Also, several high-risk groups, such as infants with MLL gene rearrangements7 and BCR–ABL-positive
National Cancer Institute/Science Photo Library
Childhood leukaemia: towards improved tailored therapy
Published Online April 20, 2010 DOI:10.1016/S14702045(10)70101-7 See Articles page 429
403
Reflection and Reaction
patients, are currently treated with separate international protocols, such as Interfant and EsPhALL. Measuring minimal residual disease (MRD) during the first weeks or months of therapy is used for risk stratification in many protocols because it is the strongest predictor of relapse risk in childhood ALL. MRD is a powerful tool to predict relapse because it measures overall therapy response, irrespective of underlying genetic abnormality. However, the disadvantage of using MRD is that adaptations in therapy can not be made in the first weeks or months of therapy. Because details of genetic abnormalities are readily available in the first few days after diagnosis, these can be used, for instance, to determine in which patients the use of anthracyclines can be reduced in the induction course— especially relevant since a large proportion of patients can be cured without this class of drugs, thus avoiding their cardiotoxic side-effects.8 One should note that the strongest predictive factor for relapse in patients with ALL is the administered treatment itself. If low intensive treatment is given, many abnormalities have prognostic relevance, whereas intensification of therapy over-rides many of the differences in outcome associated with genetic abnormalities. With increasing therapy, the number of relapses have—fortunately—decreased and the survival of children with ALL has increased from less than 10% in the early 1960s to more than 80% now. It is inevitable that new genetic abnormalities with predictive value will continue to be discovered. Genome-wide techniques recently identified a new type of very high-risk ALL characterised by a BCR–ABL-like gene expression profile and showed abnormalities in the Ikaros gene as a poor prognostic factor.9,10 However, long-term follow-up and large numbers of patients are necessary to firmly establish which genetic abnormalities have independent
prognostic value. As Moorman and colleagues1 show here, genetic abnormalities are strong predictors of outcome in childhood ALL, and will be used increasingly in the stratification of children with ALL in current and future protocols. The findings of Moorman and colleagues1 will contribute to further refinements of therapy so that every child with ALL receives the most appropriate intensity of therapy. Rob Pieters Department of Pediatric Oncology/Hematology, Erasmus MC—Sophia Childrens Hospital, Rotterdam, Netherlands [email protected] The author declared no conflicts of interest. 1
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Moorman AV, Ensor HM, Richards SM, et al. Prognostic effect of chromosomal abnormalities in childhood B-cell precursor acute lymphoblastic leukaemia: results from the UK Medical Research Council ALL97/99 randomised trial. Lancet Oncol 2010; published online Apr 20. DOI:10.1016/S1470-2045(10)70066-8. Stams WA, den Boer ML, Holleman A, et al. Asparagine synthetase expression is linked with L-asparaginase resistance in TEL-AML1-negative but not TEL-AML1-positive pediatric acute lymphoblastic leukemia. Blood 2005; 105: 4223–25. Kaspers GJ, Smets LA, Pieters R, et al. Favorable prognosis of hyperdiploid common acute lymphoblastic leukemia may be explained by sensitivity to antimetabolites and other drugs: results of an in vitro study. Blood 1995; 85: 751–56. Aricò M, Valsecchi MG, Camitta B, et al. Outcome of treatment in children with Philadelphia chromosome-positive acute lymphoblastic leukemia. N Engl J Med 2000; 342: 998–1006. Schultz KR, Bowman WP, Aledo A, et al. Improved early event free survival with imatinib in Philadelphia chromosome positive acute lymphoblastic leukaemia: a Childrens Oncology Group study. J Clin Oncol 2009; 27: 5121–23. Pui CH, Gaynon PS, Boyett JM, et al. Outcome of treatment in childhood acute lymphoblastic leukaemia with rearrangements of the 11q23 chromosomal region. Lancet 2002; 359: 1909–15. Pieters R, Schrappe M, De Lorenzo P, et al. A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial. Lancet 2007; 370: 240–50. Childhood Acute Lymphoblastic Leukaemia Collaborative Group. Beneficial and harmful effects of anthracyclines in the treatment of childhood acute lymphoblastic leukaemia: a systematic review and meta-analysis. Br J Haematol 2009; 145: 376–88. den Boer ML, van Slegtenhorst M, De Menezes RX, et al. A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study. Lancet Oncol 2009; 10: 125–34. Mullighan CG, Su X, Zhang J, et al. Deletion of IKZF1 and prognosis in acute lymphoblastic leukaemia. New Engl J Med 2009; 360: 470–80.
Extended follow-up after extended lymphadenectomy for gastric cancer: was it worth the wait? Published Online April 20, 2010 DOI:10.1016/S14702045(10)70098-X See Articles page 439
404
Studies show that D2 (extended) lymphadenectomy improves the accuracy of locoregional staging and might reduce disease recurrence in patients with advanced gastric adenocarcinoma.1,2 When expert surgeons perform D2 lymphadenectomy and avoid routine
distal pancreatectomy and splenectomy, perioperative morbidity and mortality can be kept to a minimum.3 At present, surgical resection is seldom the only treatment for patients with advanced disease. The use of multimodal therapies is supported by a series of trials substantiating www.thelancet.com/oncology Vol 11 May 2010
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Daubine F, Le Gall C, Gasser J, Green J, Clezardin P. Antitumor effects of clinical dosing regimens of bisphosphonates in experimental breast cancer bone metastasis. J Natl Cancer Inst 2007; 99: 322–30. Coleman RE, Minter MC, Cameron D, et al. The effects of adding zoledronic acid to neoadjuvant chemotherapy on tumour response: exploratory evidence for direct anti-tumour activity in breast cancer. Br J Cancer 2010; 102: 1099–105. Gnant M. Bisphosphonates in the prevention of disease recurrence: current results and ongoing trials. Current Cancer Drug Targets 2009; 9: 824–33. Gnant M. The evolving role of zoledronic acid in early breast cancer. Onco Targets Therapy 2009; 2: 95–104.
6 7
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Paget S. The distribution of secondary growths in cancer of the breast. Lancet 1889; 133: 571–73. Shiozawa Y, Havens AM, Pienta KJ, Taichman RS. The bone marrow niche: habitat to hematopoietic and mesenchymal stem cells, and unwitting host to molecular parasites. Leukemia 2008; 22: 941–50. Gnant M, Mlineritsch B, Schippinger W, et al. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med 2009; 360: 679–91.
In this issue of The Lancet Oncology, Moorman and colleagues1 describe the association between cytogenetic abnormalities and risk of relapse in childhood acute lymphoblastic leukaemia (ALL). Numerous studies have addressed this issue but are usually limited because they analyse one or few genetic abnormalities or only selected subsets of patients with ALL. By contrast, this study analyses a large number of recurrent abnormalities in more than 1700 patients who were uniformly treated and have a long follow-up. Two abnormalities were associated with a favourable outcome (ETV6–RUNX1 and high hyperdiploidy) and four with a worse outcome (intrachromosomal amplification of chromosome 21 [iAMP21], t(9;22), loss of chromosome 13q, and abnormalities of chromosome 17p). The authors propose a classification into three risk groups using these abnormalities with event-free survival (EFS) at 5 years of 86% for the good-risk group, 76% for the intermediaterisk group, and 45% for the high-risk group. Early response to therapy correlated with the cytogenetic risk group, with proportions of patients deemed to be slow responders of 7%, 10%, and 28% in the three groups, respectively. These results confirm the findings of many smaller studies and illustrate the importance of genetics for outcome prediction in childhood ALL; they also raise two questions: how can these findings be used in clinical practice and which mechanisms explain these associations between cytogenetics and outcome? Although the prognostic relevance of the genetic abnormalities is highly significant, the absolute numbers of patients in the three genetic risk groups are very different. Of all the patients classified by genetic abnormalities, 60% are in the good-risk group, 30% in the intermediate-risk group, and only 10% in the high-risk group. Of all relapses, only 26% occurred in the high-risk group whereas 42% occurred in the www.thelancet.com/oncology Vol 11 May 2010
so-called good-risk group. It is thus difficult to consider therapy reduction for the good-risk patients: a high number of relapses occur in these patients and their EFS is not high enough to justify therapy reduction, which risks increasing the number of relapses. The favourable outcome of patients with ETV6–RUNX1 or high hyperdiploidy may be due to the higher sensitivity of ALL cells carrying these abnormalities. ETV6–RUNX1 is associated with sensitivity to L-asparaginase2 and high hyperdiplody with sensitivity to mercaptopurine and methotrexate.3 If changes to chemotherapy are considered, it seems inadvisable to reduce these drugs in these specific subclasses. If therapy needs to be increased for patients with a high risk of relapse, how should this be done? The primary reflex is to use allogeneic haematopoietic stem-cell transplantation for these patients. For BCR–ABL-positive patients this seems a good option,4 although the addition of imatinib to intensive chemotherapy might reduce the need for transplantation in these patients.5 MLL gene rearrangements were also classified in the high-risk group by Moorman and colleagues, although in their multivariate analysis it did not retain its significance for effect on relapse risk. However, data suggest that patients with a MLL rearrangement do not benefit from allogeneic stem-cell transplantation.6 In practice, in many treatment protocols, high-risk patients with a risk of relapse of about 50% are exposed to very intensive chemotherapy followed by transplantation in selected cases. The use of targeted therapy is at present limited to BCR–ABL-positive ALL patients, for whom imatinib, dasatinib, and nilotinib are available. Clofarabine-based combination chemotherapies will probably gain a more prominent role in treatment of high-risk patients in the near future. Also, several high-risk groups, such as infants with MLL gene rearrangements7 and BCR–ABL-positive
National Cancer Institute/Science Photo Library
Childhood leukaemia: towards improved tailored therapy
Published Online April 20, 2010 DOI:10.1016/S14702045(10)70101-7 See Articles page 429
403
Reflection and Reaction
patients, are currently treated with separate international protocols, such as Interfant and EsPhALL. Measuring minimal residual disease (MRD) during the first weeks or months of therapy is used for risk stratification in many protocols because it is the strongest predictor of relapse risk in childhood ALL. MRD is a powerful tool to predict relapse because it measures overall therapy response, irrespective of underlying genetic abnormality. However, the disadvantage of using MRD is that adaptations in therapy can not be made in the first weeks or months of therapy. Because details of genetic abnormalities are readily available in the first few days after diagnosis, these can be used, for instance, to determine in which patients the use of anthracyclines can be reduced in the induction course— especially relevant since a large proportion of patients can be cured without this class of drugs, thus avoiding their cardiotoxic side-effects.8 One should note that the strongest predictive factor for relapse in patients with ALL is the administered treatment itself. If low intensive treatment is given, many abnormalities have prognostic relevance, whereas intensification of therapy over-rides many of the differences in outcome associated with genetic abnormalities. With increasing therapy, the number of relapses have—fortunately—decreased and the survival of children with ALL has increased from less than 10% in the early 1960s to more than 80% now. It is inevitable that new genetic abnormalities with predictive value will continue to be discovered. Genome-wide techniques recently identified a new type of very high-risk ALL characterised by a BCR–ABL-like gene expression profile and showed abnormalities in the Ikaros gene as a poor prognostic factor.9,10 However, long-term follow-up and large numbers of patients are necessary to firmly establish which genetic abnormalities have independent
prognostic value. As Moorman and colleagues1 show here, genetic abnormalities are strong predictors of outcome in childhood ALL, and will be used increasingly in the stratification of children with ALL in current and future protocols. The findings of Moorman and colleagues1 will contribute to further refinements of therapy so that every child with ALL receives the most appropriate intensity of therapy. Rob Pieters Department of Pediatric Oncology/Hematology, Erasmus MC—Sophia Childrens Hospital, Rotterdam, Netherlands [email protected] The author declared no conflicts of interest. 1
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Moorman AV, Ensor HM, Richards SM, et al. Prognostic effect of chromosomal abnormalities in childhood B-cell precursor acute lymphoblastic leukaemia: results from the UK Medical Research Council ALL97/99 randomised trial. Lancet Oncol 2010; published online Apr 20. DOI:10.1016/S1470-2045(10)70066-8. Stams WA, den Boer ML, Holleman A, et al. Asparagine synthetase expression is linked with L-asparaginase resistance in TEL-AML1-negative but not TEL-AML1-positive pediatric acute lymphoblastic leukemia. Blood 2005; 105: 4223–25. Kaspers GJ, Smets LA, Pieters R, et al. Favorable prognosis of hyperdiploid common acute lymphoblastic leukemia may be explained by sensitivity to antimetabolites and other drugs: results of an in vitro study. Blood 1995; 85: 751–56. Aricò M, Valsecchi MG, Camitta B, et al. Outcome of treatment in children with Philadelphia chromosome-positive acute lymphoblastic leukemia. N Engl J Med 2000; 342: 998–1006. Schultz KR, Bowman WP, Aledo A, et al. Improved early event free survival with imatinib in Philadelphia chromosome positive acute lymphoblastic leukaemia: a Childrens Oncology Group study. J Clin Oncol 2009; 27: 5121–23. Pui CH, Gaynon PS, Boyett JM, et al. Outcome of treatment in childhood acute lymphoblastic leukaemia with rearrangements of the 11q23 chromosomal region. Lancet 2002; 359: 1909–15. Pieters R, Schrappe M, De Lorenzo P, et al. A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial. Lancet 2007; 370: 240–50. Childhood Acute Lymphoblastic Leukaemia Collaborative Group. Beneficial and harmful effects of anthracyclines in the treatment of childhood acute lymphoblastic leukaemia: a systematic review and meta-analysis. Br J Haematol 2009; 145: 376–88. den Boer ML, van Slegtenhorst M, De Menezes RX, et al. A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study. Lancet Oncol 2009; 10: 125–34. Mullighan CG, Su X, Zhang J, et al. Deletion of IKZF1 and prognosis in acute lymphoblastic leukaemia. New Engl J Med 2009; 360: 470–80.
Extended follow-up after extended lymphadenectomy for gastric cancer: was it worth the wait? Published Online April 20, 2010 DOI:10.1016/S14702045(10)70098-X See Articles page 439
404
Studies show that D2 (extended) lymphadenectomy improves the accuracy of locoregional staging and might reduce disease recurrence in patients with advanced gastric adenocarcinoma.1,2 When expert surgeons perform D2 lymphadenectomy and avoid routine
distal pancreatectomy and splenectomy, perioperative morbidity and mortality can be kept to a minimum.3 At present, surgical resection is seldom the only treatment for patients with advanced disease. The use of multimodal therapies is supported by a series of trials substantiating www.thelancet.com/oncology Vol 11 May 2010