The
n e w e ng l a n d j o u r na l
of
m e dic i n e
Resistance to Arsenic Therapy in Acute Promyelocytic Leukemia To the Editor: Acute promyelocytic leukemia (APL) is a highly curable disease. Recently, two randomized trials conducted by Lo-Coco et al.1 and our group2 provided strong evidence supporting front-line treatment with arsenic trioxide and all-trans retinoic acid (ATRA) for APL. This treatment has been adopted by the most recent National Comprehensive Cancer Network guidelines.1 The direct-binding targets of arsenic trioxide in the promyelocytic leukemia protein (PML) B2 domain are required to induce a molecular response in APL.3,4 Mutant PML-C212/213 has been shown to lead to resistance to arsenic trioxide in an ex vivo model, but this association has not been observed in patients with APL.4 Thus far, only mutations in PML resulting in the amino acid substitutions of A216V and L218P have been detected in two patients with APL that was resistant to arsenic trioxide.5 The effect of PML mutations on resistance to arsenic and the incidence of these mutations in patients who have disease with clinical resistance to arsenic remain unclear. Using direct sequencing, we screened PML– retinoic acid receptor alpha (RARA) transcripts obtained from 35 patients with relapsed APL who previously had received arsenic. Patients who did not have remission after arsenic-based induction therapy were categorized as having arsenic-resistant disease. Thirteen patients with arsenic-resistant disease received ATRA plus chemotherapy as induction therapy, chemotherapy as consolidation therapy, and ATRA and arsenic trioxide as maintenance therapy before relapse. Nine of these patients harbored PML mutations; these patients included the previously reported 3 patients with an A216V mutation and 4 new patients with A216T, S214L, L217F, and S220G mutations (1 patient had both the S214L and A216T mutations) (Fig. 1A). Furthermore, 7 patients with arsenic-resistant disease simultaneously harbored RARA mutations (Fig. 1A). No PML mutations were detected in the 22 patients with disease that was not resistant to arsenic. We also examined another 24 samples obtained from 13 patients before their most recent relapse. Patients with only a RARA mutation could have a second remission when they were
1864
Figure 1 (facing page). Promyelocytic Leukemia Protein (PML)–Retinoic Acid Receptor Alpha (RARA) Mutations in Patients with Relapsed Acute Promyelocytic Leukemia (APL), Longitudinal Analysis Involving 4 Patients with Mutations, and the Outcomes of 35 Patients with Relapsed APL in this Study. In Panel A, data at the top show the PML and RARA mutations that were reported in other studies,3-5 and those at the bottom were detected in the 35 patients in our study with relapsed APL. The mutations in red were reported in our study, and the numbers in parentheses indicate the number of patients harboring the mutation. In Panel B, data on 4 patients in whom longitudinal studies were technically feasible are shown. The percentages near the asterisks represent the relative percentage of the mutated genes as compared with the nonmutated genes. ATRA denotes all-trans retinoic acid, CR complete remission, HSCT hematopoietic stem-cell transplantation, and NR no remission. In Panel C, the outcomes of 35 patients with relapsed APL according to the presence or absence of arsenic resistance and PML mutation status are shown.
treated with arsenic and ATRA together. However, we were unable to induce second remissions in patients with both PML and RARA mutations (Fig. 1B). The PML mutations, which were usually detectable after the RARA mutations were detected, were seldom observed before the first relapse. A total of 11 of 13 patients with arsenic-resistant disease and 5 of 22 patients with disease that was not resistant to arsenic died. Among the 13 patients with arsenic-resistant disease, 8 of 9 patients with PML mutations and 3 of 4 patients without the PML mutation died (Fig. 1C). The presence of a mutation in the arsenicbinding domain of PML-RARA led to arsenic resistance in patients in an ex vivo model.4 Our clinical observations provide evidence to substantiate this finding in vivo and validate the presence of a PML mutational hot-spot domain (C212-S220). Detection of PML-RARA mutations may be helpful in guiding treatment choices. Hong-Hu Zhu, M.D. Ya-Zhen Qin, M.D. Xiao-Jun Huang, M.D. Peking University People’s Hospital Beijing, China [email protected]
n engl j med 370;19 nejm.org may 8, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF LEEDS on August 19, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
correspondence
A PML Previous Studies
C212A C213A
R
B
Our S214L Study (1)
RARA A216V (1)
B2
A216T (4)
L218P (1)
∆207–208 R217H L224P K238E R272Q R276W T285A G289R ∆412–414 I273F R276Q S287L G289E Y208N S287W
CC
B
A216V L217F S220G (3) (1) (1)
C
D
G197E (1)
E (LBD)
L224P (2)
F
R276Q (6)
R2831 S287L G289R (2) (1) (1) M284V D288E (1) (1)
B CR
−− Date of Diagnosis
Relapse 1
07/2003
CR
− −
01/2006
CR
Relapse 1
08/2007
CR
05/2004
−− 11/2006
12/2007
04/2008
01/2008
02/2008
02/2012
Death
03/2008
Allogeneic-HSCT Death 01/2012
NR Relapse 1 100% * * 100% 100% *
− −
10/2010
NR Relapse 3 NR * 100% 100% * * 100%
03/2010
CR
Date of Diagnosis
− − 10% *
NR Relapse 2 100% * * 100%
− * 100% Date of Diagnosis
CR
Relapse 2
01/2013
PML
NR * 100%
Death
03/2013
06/2013
RARA *
Mutation
−
No mutation ATRA
CR
Date of Diagnosis
Relapse 1
− * 40%
09/2007
11/2009
−
CR * 80%
Relapse 2 100% *
12/2009
NR * 100%
07/2010
Chemotherapy Death
Arsenic
10/2010
C 35 Patients had relapse
13 Had arsenic-resistant disease
9 Had PML mutation 8 Died 1 Survived
22 Did not have arsenic-resistant disease
4 Did not have PML mutation 3 Died 1 Survived
n engl j med 370;19
nejm.org
22 Did not have PML mutation 5 Died 17 Survived
may 8, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF LEEDS on August 19, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
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notices Drs. Zhu and Qin contributed equally to this letter. Supported by grants from the National Natural Science Foundation of China (No. 81370639), the 100 Leading Talents Training Project of Science and Technology of Beijing (Z121107002612035), and the Beijing Municipal Science and Technology Commission (Z111107067311070). Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org. 1. 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. 2. Zhu HH, Wu DP, Jin J, et al. Oral tetra-arsenic tetra-sulfide formula versus intravenous arsenic trioxide as first-line treatment of acute promyelocytic leukemia: a multicenter randomized controlled trial. J Clin Oncol 2013;31:4215-21. 3. Zhang XW, Yan XJ, Zhou ZR, et al. Arsenic trioxide controls the fate of the PML-RARalpha oncoprotein by directly binding PML. Science 2010;328:240-3. [Erratum, Science 2010;328:974.] 4. Jeanne M, Lallemand-Breitenbach V, Ferhi O, et al. PML/ RARA oxidation and arsenic binding initiate the antileukemia response of As2O3. Cancer Cell 2010;18:88-98. 5. Goto E, Tomita A, Hayakawa F, Atsumi A, Kiyoi H, Naoe T. Missense mutations in PML-RARA are critical for the lack of responsiveness to arsenic trioxide treatment. Blood 2011;118: 1600-9.
corrections Case 4-2014: A 39-Year-Old Man with Night Sweats and Abdominal Pain (January 30, 2014;370:467-73). In Table 1 (page 470), the penultimate entry under Signs should have read, “Positive test for hepatitis B virus surface antibodies . . . ,” rather than “. . . surface antigen . . . .” The article is correct at NEJM.org. Variant GADL1 and Response to Lithium Therapy in Bipolar I Disorder (January 9, 2014;370:119-28). In Table 2 (page 125), the values for “Odds ratio (95% CI)” under “Combined Cohorts” should have read, “88.5 (41.4−198.4),” rather than “82.2 (36.2−195.6).” The article is correct at NEJM.org. Cardiovascular Effects of Intensive Lifestyle Intervention in Type 2 Diabetes (July 11, 2013;369:145-54). In the stub column of Table 2 (page 150), under Secondary outcomes, the second entry should have read, “Death from any cause, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for angina,” rather than “Death from any cause, nonfatal myocardial infarction, or nonfatal stroke.” The article is correct at NEJM.org.
DOI: 10.1056/NEJMc1316382
notices
Correspondence Copyright © 2014 Massachusetts Medical Society.
instructions for letters to the editor
Letters to the Editor are considered for publication, subject to editing and abridgment, provided they do not contain material that has been submitted or published elsewhere. Please note the following: • Letters in reference to a Journal article must not exceed 175 words (excluding references) and must be received within 3 weeks after publication of the article. • Letters not related to a Journal article must not exceed 400 words. • A letter can have no more than five references and one figure or table. • A letter can be signed by no more than three authors. • Financial associations or other possible conflicts of interest must be disclosed. Disclosures will be published with the letters. (For authors of Journal articles who are responding to letters, we will only publish new relevant relationships that have developed since publication of the article.) • Include your full mailing address, telephone number, fax number, and e-mail address with your letter. • All letters must be submitted at authors.NEJM.org. Letters that do not adhere to these instructions will not be considered. We will notify you when we have made a decision about possible publication. Letters regarding a recent Journal article may be shared with the authors of that article. We are unable to provide prepublication proofs. Submission of a letter constitutes permission for the Massachusetts Medical Society, its licensees, and its assignees to use it in the Journal’s various print and electronic publications and in collections, revisions, and any other form or medium.
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Notices submitted for publication should contain a mailing address and telephone number of a contact person or department. We regret that we are unable to publish all notices received. Notices also appear on the Journal’s website (NEJM.org/medical-conference). The listings can be viewed in their entirety or filtered by specialty, location, or month. University of Minnesota Colon & Rectal Surgery Principles Course The course will be offered in Minneapolis, Oct. 8–11. Contact Mary Pat McGlynn, Minnesota Colon & Rectal Foundation, 5353 Wayzata Blvd., Suite 350, Minneapolis, MN 55416; or call (952) 564-3062; or e-mail [email protected]; or see http://www.colonrectalcourse.org.
CHEMOTHERAPY FOUNDATION SYMPOSIUM: Innovative Cancer Therapy for Tomorrow The symposium will be held in New York, Nov. 5–7. It is jointly presented by the Icahn School of Medicine at Mount Sinai and the Chemotherapy Foundation. Contact the Mount Sinai Medical Center, 1 Gustave L. Levy Place, Box 1193, New York , NY 10029; or call (212) 866-2813; or fax (646) 215-7589; or e-mail [email protected]; or see http://www.chemotherapyfoundationsymposium.org/CMS/. the journal’s web and e-mail addresses:
For letters to the Editor: authors.NEJM.org For information about the status of a submitted manuscript: authors.NEJM.org To submit a meeting notice: [email protected] The Journal’s web pages: NEJM.org
n engl j med 370;19 nejm.org may 8, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF LEEDS on August 19, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
n e w e ng l a n d j o u r na l
of
m e dic i n e
Resistance to Arsenic Therapy in Acute Promyelocytic Leukemia To the Editor: Acute promyelocytic leukemia (APL) is a highly curable disease. Recently, two randomized trials conducted by Lo-Coco et al.1 and our group2 provided strong evidence supporting front-line treatment with arsenic trioxide and all-trans retinoic acid (ATRA) for APL. This treatment has been adopted by the most recent National Comprehensive Cancer Network guidelines.1 The direct-binding targets of arsenic trioxide in the promyelocytic leukemia protein (PML) B2 domain are required to induce a molecular response in APL.3,4 Mutant PML-C212/213 has been shown to lead to resistance to arsenic trioxide in an ex vivo model, but this association has not been observed in patients with APL.4 Thus far, only mutations in PML resulting in the amino acid substitutions of A216V and L218P have been detected in two patients with APL that was resistant to arsenic trioxide.5 The effect of PML mutations on resistance to arsenic and the incidence of these mutations in patients who have disease with clinical resistance to arsenic remain unclear. Using direct sequencing, we screened PML– retinoic acid receptor alpha (RARA) transcripts obtained from 35 patients with relapsed APL who previously had received arsenic. Patients who did not have remission after arsenic-based induction therapy were categorized as having arsenic-resistant disease. Thirteen patients with arsenic-resistant disease received ATRA plus chemotherapy as induction therapy, chemotherapy as consolidation therapy, and ATRA and arsenic trioxide as maintenance therapy before relapse. Nine of these patients harbored PML mutations; these patients included the previously reported 3 patients with an A216V mutation and 4 new patients with A216T, S214L, L217F, and S220G mutations (1 patient had both the S214L and A216T mutations) (Fig. 1A). Furthermore, 7 patients with arsenic-resistant disease simultaneously harbored RARA mutations (Fig. 1A). No PML mutations were detected in the 22 patients with disease that was not resistant to arsenic. We also examined another 24 samples obtained from 13 patients before their most recent relapse. Patients with only a RARA mutation could have a second remission when they were
1864
Figure 1 (facing page). Promyelocytic Leukemia Protein (PML)–Retinoic Acid Receptor Alpha (RARA) Mutations in Patients with Relapsed Acute Promyelocytic Leukemia (APL), Longitudinal Analysis Involving 4 Patients with Mutations, and the Outcomes of 35 Patients with Relapsed APL in this Study. In Panel A, data at the top show the PML and RARA mutations that were reported in other studies,3-5 and those at the bottom were detected in the 35 patients in our study with relapsed APL. The mutations in red were reported in our study, and the numbers in parentheses indicate the number of patients harboring the mutation. In Panel B, data on 4 patients in whom longitudinal studies were technically feasible are shown. The percentages near the asterisks represent the relative percentage of the mutated genes as compared with the nonmutated genes. ATRA denotes all-trans retinoic acid, CR complete remission, HSCT hematopoietic stem-cell transplantation, and NR no remission. In Panel C, the outcomes of 35 patients with relapsed APL according to the presence or absence of arsenic resistance and PML mutation status are shown.
treated with arsenic and ATRA together. However, we were unable to induce second remissions in patients with both PML and RARA mutations (Fig. 1B). The PML mutations, which were usually detectable after the RARA mutations were detected, were seldom observed before the first relapse. A total of 11 of 13 patients with arsenic-resistant disease and 5 of 22 patients with disease that was not resistant to arsenic died. Among the 13 patients with arsenic-resistant disease, 8 of 9 patients with PML mutations and 3 of 4 patients without the PML mutation died (Fig. 1C). The presence of a mutation in the arsenicbinding domain of PML-RARA led to arsenic resistance in patients in an ex vivo model.4 Our clinical observations provide evidence to substantiate this finding in vivo and validate the presence of a PML mutational hot-spot domain (C212-S220). Detection of PML-RARA mutations may be helpful in guiding treatment choices. Hong-Hu Zhu, M.D. Ya-Zhen Qin, M.D. Xiao-Jun Huang, M.D. Peking University People’s Hospital Beijing, China [email protected]
n engl j med 370;19 nejm.org may 8, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF LEEDS on August 19, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
correspondence
A PML Previous Studies
C212A C213A
R
B
Our S214L Study (1)
RARA A216V (1)
B2
A216T (4)
L218P (1)
∆207–208 R217H L224P K238E R272Q R276W T285A G289R ∆412–414 I273F R276Q S287L G289E Y208N S287W
CC
B
A216V L217F S220G (3) (1) (1)
C
D
G197E (1)
E (LBD)
L224P (2)
F
R276Q (6)
R2831 S287L G289R (2) (1) (1) M284V D288E (1) (1)
B CR
−− Date of Diagnosis
Relapse 1
07/2003
CR
− −
01/2006
CR
Relapse 1
08/2007
CR
05/2004
−− 11/2006
12/2007
04/2008
01/2008
02/2008
02/2012
Death
03/2008
Allogeneic-HSCT Death 01/2012
NR Relapse 1 100% * * 100% 100% *
− −
10/2010
NR Relapse 3 NR * 100% 100% * * 100%
03/2010
CR
Date of Diagnosis
− − 10% *
NR Relapse 2 100% * * 100%
− * 100% Date of Diagnosis
CR
Relapse 2
01/2013
PML
NR * 100%
Death
03/2013
06/2013
RARA *
Mutation
−
No mutation ATRA
CR
Date of Diagnosis
Relapse 1
− * 40%
09/2007
11/2009
−
CR * 80%
Relapse 2 100% *
12/2009
NR * 100%
07/2010
Chemotherapy Death
Arsenic
10/2010
C 35 Patients had relapse
13 Had arsenic-resistant disease
9 Had PML mutation 8 Died 1 Survived
22 Did not have arsenic-resistant disease
4 Did not have PML mutation 3 Died 1 Survived
n engl j med 370;19
nejm.org
22 Did not have PML mutation 5 Died 17 Survived
may 8, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF LEEDS on August 19, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
1865
notices Drs. Zhu and Qin contributed equally to this letter. Supported by grants from the National Natural Science Foundation of China (No. 81370639), the 100 Leading Talents Training Project of Science and Technology of Beijing (Z121107002612035), and the Beijing Municipal Science and Technology Commission (Z111107067311070). Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org. 1. 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. 2. Zhu HH, Wu DP, Jin J, et al. Oral tetra-arsenic tetra-sulfide formula versus intravenous arsenic trioxide as first-line treatment of acute promyelocytic leukemia: a multicenter randomized controlled trial. J Clin Oncol 2013;31:4215-21. 3. Zhang XW, Yan XJ, Zhou ZR, et al. Arsenic trioxide controls the fate of the PML-RARalpha oncoprotein by directly binding PML. Science 2010;328:240-3. [Erratum, Science 2010;328:974.] 4. Jeanne M, Lallemand-Breitenbach V, Ferhi O, et al. PML/ RARA oxidation and arsenic binding initiate the antileukemia response of As2O3. Cancer Cell 2010;18:88-98. 5. Goto E, Tomita A, Hayakawa F, Atsumi A, Kiyoi H, Naoe T. Missense mutations in PML-RARA are critical for the lack of responsiveness to arsenic trioxide treatment. Blood 2011;118: 1600-9.
corrections Case 4-2014: A 39-Year-Old Man with Night Sweats and Abdominal Pain (January 30, 2014;370:467-73). In Table 1 (page 470), the penultimate entry under Signs should have read, “Positive test for hepatitis B virus surface antibodies . . . ,” rather than “. . . surface antigen . . . .” The article is correct at NEJM.org. Variant GADL1 and Response to Lithium Therapy in Bipolar I Disorder (January 9, 2014;370:119-28). In Table 2 (page 125), the values for “Odds ratio (95% CI)” under “Combined Cohorts” should have read, “88.5 (41.4−198.4),” rather than “82.2 (36.2−195.6).” The article is correct at NEJM.org. Cardiovascular Effects of Intensive Lifestyle Intervention in Type 2 Diabetes (July 11, 2013;369:145-54). In the stub column of Table 2 (page 150), under Secondary outcomes, the second entry should have read, “Death from any cause, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for angina,” rather than “Death from any cause, nonfatal myocardial infarction, or nonfatal stroke.” The article is correct at NEJM.org.
DOI: 10.1056/NEJMc1316382
notices
Correspondence Copyright © 2014 Massachusetts Medical Society.
instructions for letters to the editor
Letters to the Editor are considered for publication, subject to editing and abridgment, provided they do not contain material that has been submitted or published elsewhere. Please note the following: • Letters in reference to a Journal article must not exceed 175 words (excluding references) and must be received within 3 weeks after publication of the article. • Letters not related to a Journal article must not exceed 400 words. • A letter can have no more than five references and one figure or table. • A letter can be signed by no more than three authors. • Financial associations or other possible conflicts of interest must be disclosed. Disclosures will be published with the letters. (For authors of Journal articles who are responding to letters, we will only publish new relevant relationships that have developed since publication of the article.) • Include your full mailing address, telephone number, fax number, and e-mail address with your letter. • All letters must be submitted at authors.NEJM.org. Letters that do not adhere to these instructions will not be considered. We will notify you when we have made a decision about possible publication. Letters regarding a recent Journal article may be shared with the authors of that article. We are unable to provide prepublication proofs. Submission of a letter constitutes permission for the Massachusetts Medical Society, its licensees, and its assignees to use it in the Journal’s various print and electronic publications and in collections, revisions, and any other form or medium.
1866
Notices submitted for publication should contain a mailing address and telephone number of a contact person or department. We regret that we are unable to publish all notices received. Notices also appear on the Journal’s website (NEJM.org/medical-conference). The listings can be viewed in their entirety or filtered by specialty, location, or month. University of Minnesota Colon & Rectal Surgery Principles Course The course will be offered in Minneapolis, Oct. 8–11. Contact Mary Pat McGlynn, Minnesota Colon & Rectal Foundation, 5353 Wayzata Blvd., Suite 350, Minneapolis, MN 55416; or call (952) 564-3062; or e-mail [email protected]; or see http://www.colonrectalcourse.org.
CHEMOTHERAPY FOUNDATION SYMPOSIUM: Innovative Cancer Therapy for Tomorrow The symposium will be held in New York, Nov. 5–7. It is jointly presented by the Icahn School of Medicine at Mount Sinai and the Chemotherapy Foundation. Contact the Mount Sinai Medical Center, 1 Gustave L. Levy Place, Box 1193, New York , NY 10029; or call (212) 866-2813; or fax (646) 215-7589; or e-mail [email protected]; or see http://www.chemotherapyfoundationsymposium.org/CMS/. the journal’s web and e-mail addresses:
For letters to the Editor: authors.NEJM.org For information about the status of a submitted manuscript: authors.NEJM.org To submit a meeting notice: [email protected] The Journal’s web pages: NEJM.org
n engl j med 370;19 nejm.org may 8, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF LEEDS on August 19, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
