- Email: [email protected]
Cardiotoxicity in African–American patients treated with arsenic trioxide for acute promyelocytic leukemia
Leukemia Research 30 (2006) 362–364
Letter to the Editor Young age MDS: Differences between Western and Eastern countries [4]
Dear Editor, I read with great interest of the paper published by Breccia et al. [1]. As stressed by the authors the most interesting point of this study is the young age in MDS; median age was found to be 43 years. It is known that in Western countries MDS is seen after the seventh decade of the life. However, MDS in younger age has been reported many times from Asian countries including Japan, China, Korea, India, Thailand, India and also from Turkey [2–7]. Median age in these series was between 40 and 50. These results show that MDS is seen one to two decades earlier in Eastern countries than Western countries. The exact cause of this young age is not known, but there are some speculations for this status. Certain environmental factors such as exposure to some toxins including pesticides or environmental pollutions and some infectious agents have been accussed. Uncontrolled pesticide using in these countries and some other environmental factors such as benzen exposure in some professions may cause bone marrow disturbances. A trend of younger age has been reported in rural regions where insecticide exposure is much higher and also higher Hepatitis B virus infection has been reported in Chinese patients [3]. MDS is seen as de novo or as secondary to other factors such as anti-neoplastic agents or some toxins. Therapy-related MDS is most commonly seen in developed countries. Is it possible to name this entity as toxic MDS seen in underdeveloped and/or developing countries? This is very important and it is necessary to analyse the biology and differences of clinical outcome of this MDS. It is very important to analyse and to compare the biology and also the clinical outcome of MDS seen in Eastern and Western countries and also developed and underdeveloped countries. References [1] Breccia M, Mengarelli A, Mancini M, Biondo F, Gentilini F, Latagliata R, et al. Myelodysplastic syndromes in patients under 50 years old: a single institution experience. Leuk Res 2005;29:749–54. [2] Oguma S, Yoshida Y, Uchino H, Maekawa T, Nomura T, Mizoguchi H. Clinical characteristics of Japanese patients with primary myelodysplastic syndrome: a co-operative study based on 838 cases. Anemia Study Group of the Ministry of Health and Welfare. Leuk Res 1995;19:219–25. [3] Chen B, Zhao WL, Jin J, Xue YQ, Cheng X, Chen XT, et al. Clinical and cytogenetic features of 508 patients with myelodysplastic 0145-2126/$ – see front matter © 2005 Elsevier Ltd. All rights reserved.
[5]
[6]
[7]
syndrome and comparison with those in Western countries. Leukemia 2005;19:767–75. Lee JH, Shin YR, Lee JS, Kim WK, Chi HS, Park CJ, et al. Application of different prognostic scoring systems and comparison of the FAB and WHO classifications in Korean patients with myelodysplastic syndrome. Leukemia 2003;17:305–13. Intragumtornchai T, Prayoonwiwat W, Swasdikul D, Suwanwela N, Chaimongkol B, Jootar S, et al. Myelodysplastic syndromes in Thailand: a retrospective pathologic and clinical analysis of 117 cases. Leuk Res 1998;22:453–60. Chatterjee T, Ashish D, Mohapatra M, Tyagi S, Gupta PK, Mishra P, et al. Clinical, hematological and histomorphological profiel of adult myelodysplastic syndrome. Study of 96 cases in single institute. Eur J Haematol 2004;73:93–7. Paydas S, Kocak R. Myelodysplastic syndrome in young age. Ann Intern Med 1994;3:29–32.
Semra Paydas ∗ Cukurova University, Faculty of Medicine Department of Oncology, 01330 Adana, Turkey ∗ Tel.:
+90 322 3386060; fax: +90 322 3386153 E-mail address: [email protected] 15 July 2005 Available online 24 August 2005
doi:10.1016/j.leukres.2005.07.005
Cardiotoxicity in African–American patients treated with arsenic trioxide for acute promyelocytic leukemia Keywords: Cardiotoxicity; Arsenic trioxide; African–American; Arrhythmia; Acute promyelocytic leukaemia
To the Editor, Arsenic trioxide (ATO) is an effective therapy for acute promyelocytic leukemia (APL), but has toxicity. In particular, cardiac side effects have occurred during treatment, especially in young (<40 years old) African–Americans despite weekly ECG monitoring of the QTc interval [1]. The latter observation prompted us to review the charts of all 77 patients given ATO at M.D. Anderson from 1998 to present. Our objectives were to: (1) identify patients at relatively high risk of developing arrhythmias after receiving ATO and (2) evaluate the sensitivity and specificity of the electrocardiographic QTc interval in predicting subsequent arrhythmias. The median age of the patients was 54 years. Five percent were African–American. Seventy percent received ATO for treatment of APL, 18% for myelodysplastic syndrome,
Letter to the Editor / Leukemia Research 30 (2006) 362–364
and 12% for other hematological malignancies. Patients were ineligible to receive ATO if they had a history of documented arrhythmias. The dose of ATO was 0.15 mg/kg daily for 60 days. ATO was not combined with any known cardiotoxic drugs, e.g. anthracyclines, or any other drugs that might induce arrhythmias. If, after 60 days, response was observed 0.15 mg/kg ATO was given five times a week for an additional 6 months, on a 2 weeks on, 2 weeks off schedule. The dose was not increased if response was not observed, but was lowered from 0.15 mg/kg in the event of acute cardiotoxicity; however the African–American patients discussed here were on the standard 0.15 mg/kg dose when they experienced arrhythmias. Arrhythmias were observed in 4 of the 77 patients (5%, exact 95% CI 1–13%). Of these four patients, two developed ventricular tachycardia and two atrial tachycardia. In three of the four patients, these arrhythmias led to discontinuation of ATO and its replacement by gemtuzumab ozogamycin (“mylotarg”). Three of the four African–Americans given ATO developed arrhythmias versus only 1/73 nonAfrican–Americans (Fisher exact p-value, 0.002). The patients who developed arrhythmias were younger (median age = 32) than those who did not (median age = 57) and had no history of cardiac disease, electrolyte abnormalities, or use of medications that would alter their response to ATO relative to the other patients. African–Americans tended to be younger than non-African–Americans: 3/4 were age <40 versus 19/73 non-African–Americans. However, since the incidence of arrhythmias in patients age <40 was 3/3 for African–Americans versus 0/19 for others (p = 0.0006), it seems that race, not age, is the principal predictor of arrhythmias. Similarly, although all four African–Americans had APL versus 50/73 others, the respective incidence of arrhythmias in African–American APL patients was 3/4 versus 1/50 in non-African–American APL patients (p = 0.0006). Furthermore, arrhythmias were seen on average 8 days after ATO induction in the three African–Americans, while the Caucasian patient did not develop arrhythmias until 45 days after ATO induction. Although all patients were on weekly to bimonthly ECG monitoring, QTc interval prolongation (>430 ms) was not observed in the patients who developed serious cardiac arrhythmias. None of the three patients with QTc prolongation had a documented arrhythmia. Thus, QTc monitoring had zero sensitivity and zero specificity as a barometer for eventual arrhythmia development. The precise mechanism leading to African–Americans’ increased susceptibility to ATO-induced cardiac arrhythmias is unknown; however numerous highly polymorphic candidate genes involved in arsenic metabolism are known. MTHFR (metylenetetrahydrofolate reductase) has a specific set of polymorphisms in African–Americans versus other populations [2]. HNP (human purine nucleoside phosphorylase) and hGSTO1-1 (human glutathione-S-transferase omega 1–1) are two other candidate genes that are polymorphic in European and Native American populations and
363
are involved in arsenic metabolism—indicating that further study into the polymorphic nature of this pathway might elucidate the differential response of African–Americans to arsenic trioxide [3]. Despite uncertainty as to mechanism, physicians should be aware that ATO may cause arrhythmias in young African–Americans. Our data also calls into question the value of QTc monitoring, atleast in patients given ATO. Acknowledgements This study was partially supported by grant R21 CA101341 from the National Cancer Institute. The authors thank Sherry A. Pierce for her technical assistance and expertise. Contributions. Sandip Patel contributed for chart review, data collection, initial statistical analysis and manuscript writing. Elihu Estey contributed for statistical analysis and manuscript writing. Guillermo Garcia-Manero, Alexandra Ferrajoli, Stefan Faderl, Serge Verstovek and Hagop Kantarjian contributed for patient care and providing data regarding patients. References [1] Westervelt, P, Brown, RA, Adkins, DR, et al. Sudden death among patients with acute promyelocytic leukemia treated with arsenic trioxide. Blood 2001;98:266–71. [2] Keku T, Millikan R, Worley K, et al., 5,10-Methylenetetrahydrofolate reductase codon 677 and 1298 polymorphisms and colon cancer in African–Americans and Whites. Cancer Epidemiol Biomark Prevent 2005;11:1611–21. [3] Yu L, Kalla K, Guthrie E, Vidrine A, Klimecki WT. Genetic variation in genes associated with arsenic metabolism: glutathione-Stransferase omega 1-1 and purine nucleoside phosphorylase polymorphisms in European and indigenous Americans. Environ Health Perspect 2003;111:1421-7.
Sandip P. Patel Baylor College of Medicine, Houston, TX, USA Guillermo Garcia-Manero Alexandra Ferrajoli Stefan Faderl Serge Verstovek Hagop Kantarjian Elihu Estey ∗ Department of Leukemia, Unit 428, UT-MD Anderson Cancer Center, 1515 Holcome Boulevard, P.O. Box 301402, Houston, TX 77230-1402, USA ∗ Corresponding
author. Tel.: +1 713 792 7544 E-mail address: [email protected] (E. Estey) 11 July 2005 Available online 13 September 2005
doi:10.1016/j.leukres.2005.08.002
Letter to the Editor Young age MDS: Differences between Western and Eastern countries [4]
Dear Editor, I read with great interest of the paper published by Breccia et al. [1]. As stressed by the authors the most interesting point of this study is the young age in MDS; median age was found to be 43 years. It is known that in Western countries MDS is seen after the seventh decade of the life. However, MDS in younger age has been reported many times from Asian countries including Japan, China, Korea, India, Thailand, India and also from Turkey [2–7]. Median age in these series was between 40 and 50. These results show that MDS is seen one to two decades earlier in Eastern countries than Western countries. The exact cause of this young age is not known, but there are some speculations for this status. Certain environmental factors such as exposure to some toxins including pesticides or environmental pollutions and some infectious agents have been accussed. Uncontrolled pesticide using in these countries and some other environmental factors such as benzen exposure in some professions may cause bone marrow disturbances. A trend of younger age has been reported in rural regions where insecticide exposure is much higher and also higher Hepatitis B virus infection has been reported in Chinese patients [3]. MDS is seen as de novo or as secondary to other factors such as anti-neoplastic agents or some toxins. Therapy-related MDS is most commonly seen in developed countries. Is it possible to name this entity as toxic MDS seen in underdeveloped and/or developing countries? This is very important and it is necessary to analyse the biology and differences of clinical outcome of this MDS. It is very important to analyse and to compare the biology and also the clinical outcome of MDS seen in Eastern and Western countries and also developed and underdeveloped countries. References [1] Breccia M, Mengarelli A, Mancini M, Biondo F, Gentilini F, Latagliata R, et al. Myelodysplastic syndromes in patients under 50 years old: a single institution experience. Leuk Res 2005;29:749–54. [2] Oguma S, Yoshida Y, Uchino H, Maekawa T, Nomura T, Mizoguchi H. Clinical characteristics of Japanese patients with primary myelodysplastic syndrome: a co-operative study based on 838 cases. Anemia Study Group of the Ministry of Health and Welfare. Leuk Res 1995;19:219–25. [3] Chen B, Zhao WL, Jin J, Xue YQ, Cheng X, Chen XT, et al. Clinical and cytogenetic features of 508 patients with myelodysplastic 0145-2126/$ – see front matter © 2005 Elsevier Ltd. All rights reserved.
[5]
[6]
[7]
syndrome and comparison with those in Western countries. Leukemia 2005;19:767–75. Lee JH, Shin YR, Lee JS, Kim WK, Chi HS, Park CJ, et al. Application of different prognostic scoring systems and comparison of the FAB and WHO classifications in Korean patients with myelodysplastic syndrome. Leukemia 2003;17:305–13. Intragumtornchai T, Prayoonwiwat W, Swasdikul D, Suwanwela N, Chaimongkol B, Jootar S, et al. Myelodysplastic syndromes in Thailand: a retrospective pathologic and clinical analysis of 117 cases. Leuk Res 1998;22:453–60. Chatterjee T, Ashish D, Mohapatra M, Tyagi S, Gupta PK, Mishra P, et al. Clinical, hematological and histomorphological profiel of adult myelodysplastic syndrome. Study of 96 cases in single institute. Eur J Haematol 2004;73:93–7. Paydas S, Kocak R. Myelodysplastic syndrome in young age. Ann Intern Med 1994;3:29–32.
Semra Paydas ∗ Cukurova University, Faculty of Medicine Department of Oncology, 01330 Adana, Turkey ∗ Tel.:
+90 322 3386060; fax: +90 322 3386153 E-mail address: [email protected] 15 July 2005 Available online 24 August 2005
doi:10.1016/j.leukres.2005.07.005
Cardiotoxicity in African–American patients treated with arsenic trioxide for acute promyelocytic leukemia Keywords: Cardiotoxicity; Arsenic trioxide; African–American; Arrhythmia; Acute promyelocytic leukaemia
To the Editor, Arsenic trioxide (ATO) is an effective therapy for acute promyelocytic leukemia (APL), but has toxicity. In particular, cardiac side effects have occurred during treatment, especially in young (<40 years old) African–Americans despite weekly ECG monitoring of the QTc interval [1]. The latter observation prompted us to review the charts of all 77 patients given ATO at M.D. Anderson from 1998 to present. Our objectives were to: (1) identify patients at relatively high risk of developing arrhythmias after receiving ATO and (2) evaluate the sensitivity and specificity of the electrocardiographic QTc interval in predicting subsequent arrhythmias. The median age of the patients was 54 years. Five percent were African–American. Seventy percent received ATO for treatment of APL, 18% for myelodysplastic syndrome,
Letter to the Editor / Leukemia Research 30 (2006) 362–364
and 12% for other hematological malignancies. Patients were ineligible to receive ATO if they had a history of documented arrhythmias. The dose of ATO was 0.15 mg/kg daily for 60 days. ATO was not combined with any known cardiotoxic drugs, e.g. anthracyclines, or any other drugs that might induce arrhythmias. If, after 60 days, response was observed 0.15 mg/kg ATO was given five times a week for an additional 6 months, on a 2 weeks on, 2 weeks off schedule. The dose was not increased if response was not observed, but was lowered from 0.15 mg/kg in the event of acute cardiotoxicity; however the African–American patients discussed here were on the standard 0.15 mg/kg dose when they experienced arrhythmias. Arrhythmias were observed in 4 of the 77 patients (5%, exact 95% CI 1–13%). Of these four patients, two developed ventricular tachycardia and two atrial tachycardia. In three of the four patients, these arrhythmias led to discontinuation of ATO and its replacement by gemtuzumab ozogamycin (“mylotarg”). Three of the four African–Americans given ATO developed arrhythmias versus only 1/73 nonAfrican–Americans (Fisher exact p-value, 0.002). The patients who developed arrhythmias were younger (median age = 32) than those who did not (median age = 57) and had no history of cardiac disease, electrolyte abnormalities, or use of medications that would alter their response to ATO relative to the other patients. African–Americans tended to be younger than non-African–Americans: 3/4 were age <40 versus 19/73 non-African–Americans. However, since the incidence of arrhythmias in patients age <40 was 3/3 for African–Americans versus 0/19 for others (p = 0.0006), it seems that race, not age, is the principal predictor of arrhythmias. Similarly, although all four African–Americans had APL versus 50/73 others, the respective incidence of arrhythmias in African–American APL patients was 3/4 versus 1/50 in non-African–American APL patients (p = 0.0006). Furthermore, arrhythmias were seen on average 8 days after ATO induction in the three African–Americans, while the Caucasian patient did not develop arrhythmias until 45 days after ATO induction. Although all patients were on weekly to bimonthly ECG monitoring, QTc interval prolongation (>430 ms) was not observed in the patients who developed serious cardiac arrhythmias. None of the three patients with QTc prolongation had a documented arrhythmia. Thus, QTc monitoring had zero sensitivity and zero specificity as a barometer for eventual arrhythmia development. The precise mechanism leading to African–Americans’ increased susceptibility to ATO-induced cardiac arrhythmias is unknown; however numerous highly polymorphic candidate genes involved in arsenic metabolism are known. MTHFR (metylenetetrahydrofolate reductase) has a specific set of polymorphisms in African–Americans versus other populations [2]. HNP (human purine nucleoside phosphorylase) and hGSTO1-1 (human glutathione-S-transferase omega 1–1) are two other candidate genes that are polymorphic in European and Native American populations and
363
are involved in arsenic metabolism—indicating that further study into the polymorphic nature of this pathway might elucidate the differential response of African–Americans to arsenic trioxide [3]. Despite uncertainty as to mechanism, physicians should be aware that ATO may cause arrhythmias in young African–Americans. Our data also calls into question the value of QTc monitoring, atleast in patients given ATO. Acknowledgements This study was partially supported by grant R21 CA101341 from the National Cancer Institute. The authors thank Sherry A. Pierce for her technical assistance and expertise. Contributions. Sandip Patel contributed for chart review, data collection, initial statistical analysis and manuscript writing. Elihu Estey contributed for statistical analysis and manuscript writing. Guillermo Garcia-Manero, Alexandra Ferrajoli, Stefan Faderl, Serge Verstovek and Hagop Kantarjian contributed for patient care and providing data regarding patients. References [1] Westervelt, P, Brown, RA, Adkins, DR, et al. Sudden death among patients with acute promyelocytic leukemia treated with arsenic trioxide. Blood 2001;98:266–71. [2] Keku T, Millikan R, Worley K, et al., 5,10-Methylenetetrahydrofolate reductase codon 677 and 1298 polymorphisms and colon cancer in African–Americans and Whites. Cancer Epidemiol Biomark Prevent 2005;11:1611–21. [3] Yu L, Kalla K, Guthrie E, Vidrine A, Klimecki WT. Genetic variation in genes associated with arsenic metabolism: glutathione-Stransferase omega 1-1 and purine nucleoside phosphorylase polymorphisms in European and indigenous Americans. Environ Health Perspect 2003;111:1421-7.
Sandip P. Patel Baylor College of Medicine, Houston, TX, USA Guillermo Garcia-Manero Alexandra Ferrajoli Stefan Faderl Serge Verstovek Hagop Kantarjian Elihu Estey ∗ Department of Leukemia, Unit 428, UT-MD Anderson Cancer Center, 1515 Holcome Boulevard, P.O. Box 301402, Houston, TX 77230-1402, USA ∗ Corresponding
author. Tel.: +1 713 792 7544 E-mail address: [email protected] (E. Estey) 11 July 2005 Available online 13 September 2005
doi:10.1016/j.leukres.2005.08.002