The
n e w e ng l a n d j o u r na l
to genetic testing; interpreting complex results, including incidental findings; and communicating about risk.2,3 Genetic counselors also assist in obtaining third-party reimbursement for tests and provide an ongoing resource for reanalysis of negative results or interpretation of unknown variants. Implementation of CGES provides important opportunities for fruitful partnerships between physicians and genetic counselors. Such partnerships, which warrant explicit attention, support physicians and enhance patient satisfaction with care.4 Alice Virani, Ph.D. Jehannine Austin, Ph.D. University of British Columbia Vancouver, BC, Canada [email protected] No potential conflict of interest relevant to this letter was reported. 1. Resta R, Biesecker BB, Bennett RL, et al. A new definition of
genetic counseling: National Society of Genetic Counselors’ Task Force report. J Genet Couns 2006;15:77-83. 2. Davey A, Rostant K, Harrop K, Goldblatt J, O’Leary P. Evaluating genetic counseling: client expectations, psychological adjustment and satisfaction with service. J Genet Couns 2005; 14:197-206. 3. McAllister M, Payne K, Macleod R, Nicholls S, Donnai D, Davies L. Patient empowerment in clinical genetics services. J Health Psychol 2008;13:895-905. 4. Waxler JL, Cherniske EM, Dieter K, Herd P, Pober BR. Hearing from parents: the impact of receiving the diagnosis of Williams syndrome in their child. Am J Med Genet A 2013;161A: 534-41. DOI: 10.1056/NEJMc1408914
of
m e dic i n e
forms routine evaluation of the ACMG 56 genes, with an optional extended panel of additional “disease” genes. The ACMG has appointed a standing committee to evaluate suggestions that additional genes and conditions be added or subtracted from the original list, and we support the suggestion that HNF1A-related late-onset diabetes be evaluated. Virani and Austin rightly underscore the importance of the role of the genetic counselor in CGES. We strongly support genetic counselors, some of whom are indispensable members of our clinical and research teams. Our omission of the role of genetic counselors was deliberate, and we also did not emphasize the role of the clinical geneticist. We took a different approach, which was to delineate the specific tasks and objectives for the appropriate care of patients who undergo sequencing, without specifying which health professional should perform those tasks. Indeed, we believe that it would be appropriate for any clinician with the necessary training and skills in genomics to perform these tasks. At present, very few clinicians outside the fields of medical genetics and genetic counseling have these skills, and so it will often be necessary and appropriate to involve such professionals in the care of patients. In the future, genomic analysis will be a common component of health care that will be ordered, interpreted, and managed by many health professionals. Leslie G. Biesecker, M.D. National Human Genome Research Institute
The Authors Reply: Westerink et al. thought- Bethesda, MD fully question the genes selected by the ACMG [email protected] for evaluation as secondary findings.1 Both of us Robert C. Green, M.D., M.P.H. participated in the selection of the genes for that Harvard Medical School recommendation. That list of genes was short be- Boston, MA Since publication of their article, the authors report no furcause the initial recommendation was for routine ther potential conflict of interest. evaluation and return of such variants. If analysis 1. Green RC, Berg JS, Grody WW, et al. ACMG recommendaof secondary findings is routine, it is appropriate tions for reporting of incidental findings in clinical exome and to return only the most medically compelling genome sequencing. Genet Med 2013;15:565-74. variants. At least one clinical exome service per- DOI: 10.1056/NEJMc1408914
Resistance to Therapy in Acute Promyelocytic Leukemia to the editor: Acute promyelocytic leukemia (PML) and retinoic acid receptor alpha (RARA) (APL) is driven by an oncogenic chromosomal genes. APL responds to two targeted therapies: translocation fusing the promyelocytic leukemia all-trans retinoic acid (ATRA) and arsenic trioxide.
1170
n engl j med 371;12 nejm.org september 18, 2014
The New England Journal of Medicine Downloaded from nejm.org at NORTHWESTERN UNIVERSITY on February 9, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
correspondence
Arsenic binds to the PML moiety of the PMLRARA fusion, whereas ATRA binds to its RARA portion; each drug initiates biochemically independent degradation pathways. Degradation of RARA (or PML-RARA) follows transcriptional activation by ATRA. Arsenic trioxide initiates degradation of PML (or PML-RARA) by promoting PML aggregation into subnuclear domains implicated in senescence and apoptosis. Several studies in humans and mice have shown that ATRA and arsenic trioxide dramatically synergize for eradication of APL,1,2 presumably because this therapeutic association degrades PML-RARA more efficiently than either treatment alone. We recently found in a mouse model that therapy-induced degradation of PMLRARA allowed the unfused PML protein to activate a senescence checkpoint that ultimately enforced eradication of APL.3 In this model, genetic inactivation of PML precluded clearance of APL by an otherwise curative ATRA–arsenic trioxide regimen. In studies involving patients who had not received the frontline ATRA–arsenic trioxide combination, resistance to ATRA was associated with mutations in the RARA moiety of PML-RARA, and resistance to arsenic trioxide was associated with highly clustered mutations in the PML moiety4; both types of mutations impeded degradation of PML-RARA. Here we describe the clinical course of a patient with standard-risk APL who presented with a history of multiple relapses after conventional treatments (ATRA plus chemotherapy, three courses of arsenic trioxide, and finally allogeneic stem-cell transplantation) (Fig. 1A). The distinctly uncommon clinical course in this patient was associated with a mutation in the PML allele that was not rearranged, but this mutation was not present in the PML moiety of the PMLRARA fusion (Fig. 1B). This mutation was undetectable at initial diagnosis. Remarkably, the PML mutation (A216V, immediately adjacent to the arsenic-binding site) is identical to the one most commonly encountered in the PML-RARA fusion when resistance to arsenic develops.4 Like the C212S mutant of the arsenic-binding site, PML A216V does not organize functional and arsenic trioxide–responsive PML nuclear bodies. These findings provide an example of the same mutation interfering with the response to therapy when present in the oncogene (PML-RARA) or
A ATRA plus idarubicin– cytarabine
ATO 20 mo
Allogeneic SCT 27 mo
R1
36 mo
R2 Analyses of PML and PML-RARA mutation
B R B1 B2
PML * A216V
PMLRARA
DNA
ATRA
Figure 1. Resistance to Therapy through a Mutation Present in the Promyelocytic Leukemia (PML) Allele That Is Not Rearranged but Not Present in the PML– Retinoic Acid Receptor Alpha (RARA) Oncogenic Driver. In Panel A, the clinical course of the patient is shown. The patient had molecular remissions between relapses. ATO denotes arsenic trioxide, ATRA all-trans retinoic acid, R1 the first clinical relapse, R2 the second clinical relapse, and SCT stem-cell transplantation. In Panel B, the results of the genetic analysis of PML and PML-RARA messenger RNA at R2 are shown. RARA sequences are in shown in gray. The asterisk indicates the PML mutation, which was undetectable at diagnosis. B1 and B2 denote the B-box zinc-finger domains, and R the RING zinc-finger domain.
the antioncogene (PML). The dual action of arsenic trioxide to degrade PML-RARA and enforce formation of PML nuclear bodies (before the ultimate degradation of PML) most likely explains why single-agent arsenic trioxide cures more than 70% of patients with APL,5 whereas ATRA alone is only rarely curative. Jacqueline Lehmann-Che, Pharm.D., Ph.D. Université Paris Diderot Paris, France
Cecile Bally, M.D. Hôpital Saint-Louis Paris Paris, France
Hugues de Thé, M.D., Ph.D INSERM Unité 944 Paris, France [email protected] Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
n engl j med 371;12 nejm.org september 18, 2014
The New England Journal of Medicine Downloaded from nejm.org at NORTHWESTERN UNIVERSITY on February 9, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
1171
The
n e w e ng l a n d j o u r na l
of
m e dic i n e
1. Shen ZX, Shi ZZ, Fang J, et al. All-trans retinoic acid/As2O3
combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A 2004;101:5328-35. 2. Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med 2013;369:111-21. 3. Ablain J, Rice K, Soilihi H, de Reynies A, Minucci S, de Thé H. Activation of a promyelocytic leukemia-tumor protein 53 axis underlies acute promyelocytic leukemia cure. Nat Med 2014;20: 167-74. 4. Zhu HH, Qin YZ, Huang XJ. Resistance to arsenic therapy in acute promyelocytic leukemia. N Engl J Med 2014;370:18646. 5. Mathews V, George B, Chendamarai E, et al. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: long-term follow-up data. J Clin Oncol 2010;28:3866-71.
correction A Phase 3 Trial of Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis (May 29, 2014;370:2083-92). In Results, in the second paragraph of the Primary Efficacy Analysis subsection (page 2086), the final sentence should have read, “The linear slope of decline in FVC at week 52 was −164 ml in the pirfenidone group and −280 ml in the placebo group (absolute difference, 116 ml; relative difference, 41.5%; P
n e w e ng l a n d j o u r na l
to genetic testing; interpreting complex results, including incidental findings; and communicating about risk.2,3 Genetic counselors also assist in obtaining third-party reimbursement for tests and provide an ongoing resource for reanalysis of negative results or interpretation of unknown variants. Implementation of CGES provides important opportunities for fruitful partnerships between physicians and genetic counselors. Such partnerships, which warrant explicit attention, support physicians and enhance patient satisfaction with care.4 Alice Virani, Ph.D. Jehannine Austin, Ph.D. University of British Columbia Vancouver, BC, Canada [email protected] No potential conflict of interest relevant to this letter was reported. 1. Resta R, Biesecker BB, Bennett RL, et al. A new definition of
genetic counseling: National Society of Genetic Counselors’ Task Force report. J Genet Couns 2006;15:77-83. 2. Davey A, Rostant K, Harrop K, Goldblatt J, O’Leary P. Evaluating genetic counseling: client expectations, psychological adjustment and satisfaction with service. J Genet Couns 2005; 14:197-206. 3. McAllister M, Payne K, Macleod R, Nicholls S, Donnai D, Davies L. Patient empowerment in clinical genetics services. J Health Psychol 2008;13:895-905. 4. Waxler JL, Cherniske EM, Dieter K, Herd P, Pober BR. Hearing from parents: the impact of receiving the diagnosis of Williams syndrome in their child. Am J Med Genet A 2013;161A: 534-41. DOI: 10.1056/NEJMc1408914
of
m e dic i n e
forms routine evaluation of the ACMG 56 genes, with an optional extended panel of additional “disease” genes. The ACMG has appointed a standing committee to evaluate suggestions that additional genes and conditions be added or subtracted from the original list, and we support the suggestion that HNF1A-related late-onset diabetes be evaluated. Virani and Austin rightly underscore the importance of the role of the genetic counselor in CGES. We strongly support genetic counselors, some of whom are indispensable members of our clinical and research teams. Our omission of the role of genetic counselors was deliberate, and we also did not emphasize the role of the clinical geneticist. We took a different approach, which was to delineate the specific tasks and objectives for the appropriate care of patients who undergo sequencing, without specifying which health professional should perform those tasks. Indeed, we believe that it would be appropriate for any clinician with the necessary training and skills in genomics to perform these tasks. At present, very few clinicians outside the fields of medical genetics and genetic counseling have these skills, and so it will often be necessary and appropriate to involve such professionals in the care of patients. In the future, genomic analysis will be a common component of health care that will be ordered, interpreted, and managed by many health professionals. Leslie G. Biesecker, M.D. National Human Genome Research Institute
The Authors Reply: Westerink et al. thought- Bethesda, MD fully question the genes selected by the ACMG [email protected] for evaluation as secondary findings.1 Both of us Robert C. Green, M.D., M.P.H. participated in the selection of the genes for that Harvard Medical School recommendation. That list of genes was short be- Boston, MA Since publication of their article, the authors report no furcause the initial recommendation was for routine ther potential conflict of interest. evaluation and return of such variants. If analysis 1. Green RC, Berg JS, Grody WW, et al. ACMG recommendaof secondary findings is routine, it is appropriate tions for reporting of incidental findings in clinical exome and to return only the most medically compelling genome sequencing. Genet Med 2013;15:565-74. variants. At least one clinical exome service per- DOI: 10.1056/NEJMc1408914
Resistance to Therapy in Acute Promyelocytic Leukemia to the editor: Acute promyelocytic leukemia (PML) and retinoic acid receptor alpha (RARA) (APL) is driven by an oncogenic chromosomal genes. APL responds to two targeted therapies: translocation fusing the promyelocytic leukemia all-trans retinoic acid (ATRA) and arsenic trioxide.
1170
n engl j med 371;12 nejm.org september 18, 2014
The New England Journal of Medicine Downloaded from nejm.org at NORTHWESTERN UNIVERSITY on February 9, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
correspondence
Arsenic binds to the PML moiety of the PMLRARA fusion, whereas ATRA binds to its RARA portion; each drug initiates biochemically independent degradation pathways. Degradation of RARA (or PML-RARA) follows transcriptional activation by ATRA. Arsenic trioxide initiates degradation of PML (or PML-RARA) by promoting PML aggregation into subnuclear domains implicated in senescence and apoptosis. Several studies in humans and mice have shown that ATRA and arsenic trioxide dramatically synergize for eradication of APL,1,2 presumably because this therapeutic association degrades PML-RARA more efficiently than either treatment alone. We recently found in a mouse model that therapy-induced degradation of PMLRARA allowed the unfused PML protein to activate a senescence checkpoint that ultimately enforced eradication of APL.3 In this model, genetic inactivation of PML precluded clearance of APL by an otherwise curative ATRA–arsenic trioxide regimen. In studies involving patients who had not received the frontline ATRA–arsenic trioxide combination, resistance to ATRA was associated with mutations in the RARA moiety of PML-RARA, and resistance to arsenic trioxide was associated with highly clustered mutations in the PML moiety4; both types of mutations impeded degradation of PML-RARA. Here we describe the clinical course of a patient with standard-risk APL who presented with a history of multiple relapses after conventional treatments (ATRA plus chemotherapy, three courses of arsenic trioxide, and finally allogeneic stem-cell transplantation) (Fig. 1A). The distinctly uncommon clinical course in this patient was associated with a mutation in the PML allele that was not rearranged, but this mutation was not present in the PML moiety of the PMLRARA fusion (Fig. 1B). This mutation was undetectable at initial diagnosis. Remarkably, the PML mutation (A216V, immediately adjacent to the arsenic-binding site) is identical to the one most commonly encountered in the PML-RARA fusion when resistance to arsenic develops.4 Like the C212S mutant of the arsenic-binding site, PML A216V does not organize functional and arsenic trioxide–responsive PML nuclear bodies. These findings provide an example of the same mutation interfering with the response to therapy when present in the oncogene (PML-RARA) or
A ATRA plus idarubicin– cytarabine
ATO 20 mo
Allogeneic SCT 27 mo
R1
36 mo
R2 Analyses of PML and PML-RARA mutation
B R B1 B2
PML * A216V
PMLRARA
DNA
ATRA
Figure 1. Resistance to Therapy through a Mutation Present in the Promyelocytic Leukemia (PML) Allele That Is Not Rearranged but Not Present in the PML– Retinoic Acid Receptor Alpha (RARA) Oncogenic Driver. In Panel A, the clinical course of the patient is shown. The patient had molecular remissions between relapses. ATO denotes arsenic trioxide, ATRA all-trans retinoic acid, R1 the first clinical relapse, R2 the second clinical relapse, and SCT stem-cell transplantation. In Panel B, the results of the genetic analysis of PML and PML-RARA messenger RNA at R2 are shown. RARA sequences are in shown in gray. The asterisk indicates the PML mutation, which was undetectable at diagnosis. B1 and B2 denote the B-box zinc-finger domains, and R the RING zinc-finger domain.
the antioncogene (PML). The dual action of arsenic trioxide to degrade PML-RARA and enforce formation of PML nuclear bodies (before the ultimate degradation of PML) most likely explains why single-agent arsenic trioxide cures more than 70% of patients with APL,5 whereas ATRA alone is only rarely curative. Jacqueline Lehmann-Che, Pharm.D., Ph.D. Université Paris Diderot Paris, France
Cecile Bally, M.D. Hôpital Saint-Louis Paris Paris, France
Hugues de Thé, M.D., Ph.D INSERM Unité 944 Paris, France [email protected] Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
n engl j med 371;12 nejm.org september 18, 2014
The New England Journal of Medicine Downloaded from nejm.org at NORTHWESTERN UNIVERSITY on February 9, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
1171
The
n e w e ng l a n d j o u r na l
of
m e dic i n e
1. Shen ZX, Shi ZZ, Fang J, et al. All-trans retinoic acid/As2O3
combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A 2004;101:5328-35. 2. Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med 2013;369:111-21. 3. Ablain J, Rice K, Soilihi H, de Reynies A, Minucci S, de Thé H. Activation of a promyelocytic leukemia-tumor protein 53 axis underlies acute promyelocytic leukemia cure. Nat Med 2014;20: 167-74. 4. Zhu HH, Qin YZ, Huang XJ. Resistance to arsenic therapy in acute promyelocytic leukemia. N Engl J Med 2014;370:18646. 5. Mathews V, George B, Chendamarai E, et al. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: long-term follow-up data. J Clin Oncol 2010;28:3866-71.
correction A Phase 3 Trial of Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis (May 29, 2014;370:2083-92). In Results, in the second paragraph of the Primary Efficacy Analysis subsection (page 2086), the final sentence should have read, “The linear slope of decline in FVC at week 52 was −164 ml in the pirfenidone group and −280 ml in the placebo group (absolute difference, 116 ml; relative difference, 41.5%; P
