Editorial Comment Acta Haematol 2015;134:57–58 DOI: 10.1159/000370098
Received: November 24, 2014 Accepted: November 24, 2014 Published online: April 11, 2015
The Importance of Body Surface Area at Baseline and during Treatment in Chronic Myeloid Leukemia Patients Treated with Imatinib Massimo Breccia Matteo Molica Gioia Colafigli Giuliana Alimena Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy
© 2015 S. Karger AG, Basel 0001–5792/15/1341–0057$39.50/0 E-Mail [email protected] www.karger.com/aha
efficacy of imatinib [7]. Kawaguchi et al. [9] reported the clinical outcome of 31 patients, 13 of whom were treated with 400 mg/day and 9 of whom received 300 mg/day. The mean trough levels of the two groups were not significantly different and exceeded the effective plasma threshold. The BSA was significantly smaller in patients receiving the reduced dose compared to those receiving the standard dose, and a significant association with age and gender was found [9]. Another Japanese group reported that a Japanese population experienced increased hematologic toxicity with standard-dose imatinib due to low BSA [10]. Seventy-three patients were treated with imatinib, achieving responses similar to those reported in the IRIS study, but the median dose intensity administered was lower compared to the other study. The measurement of the plasma imatinib through level was comparable to that reported in other studies, showing a significant relationship between the dose administered and a low BSA. A Korean group reported 9 patients who started with the standard dose and then reduced to 200–300 mg/day due to toxicity, but all patients had a low BSA [6]. The Japanese group reported the impact of low-dose imatinib as follows: an MMR was observed in all patients with a low Sokal score treated with 300-mg or lower dosages. Achievement of an MMR was also reported for intermediate and high Sokal risks, but there was an increased rate of relapse and the MMR was maintained only with timely increases in dose [11]. Our group also reported the effects of low-dose imaMassimo Breccia, MD Department of Cellular Biotechnologies and Hematology, Sapienza University Via Benevento 6 IT–00161 Rome (Italy) E-Mail breccia @ bce.uniroma1.it
Downloaded by: Freie Universität Berlin 130.133.8.114 - 5/12/2015 3:43:03 PM
The established dose of imatinib for chronic myeloid leukemia (CML) patients in the chronic phase (CP) is 400 mg/day [1]. This dose is required to obtain a clinical benefit based on the relationship between the pharmacokinetics and pharmacodynamics of the drug at a steady state, indicating that clinical responses are dependent on the administered dose [2]. Picard et al. [3] showed that trough imatinib plasma levels at a steady state exceed 1,002 ng/ml and that this value correlates with the best clinical outcome. It was demonstrated, in the 5-year follow-up of the IRIS trial, that maintenance of plasma trough levels above 1,002 ng/ml is associated with achievement of a major molecular response (MMR) [4]. With the standard dose, some patients experienced severe toxicity including myelosuppression, skin rash, edema, and gastrointestinal side effects. In routine clinical practice, usually to avoid these complications and the low rate of adherence to imatinib, the standard dose is reduced to less than 400 mg/day [5–8]. Several reports have indicated that an inverse correlation exists between body surface area (BSA) and plasma imatinib trough level. A Japanese group reported the role of body weight in 89 evaluable patients with a median weight of 62.8 kg. The drug was withheld in 45% of patients due to grade 3/4 toxicity, but it was resumed gradually in 62 out of 89 patients. In that study, patients with an older age and a lower body weight were less likely to achieve a complete cytogenetic response (CCyR), suggesting that BSA had a significant influence on the toxicity and
tinib in 45 CML patients in the early (17 patients) or late CP (28 patients) who reduced the dose after experiencing side effects after a median of 58 days. We showed that also with low doses 58% of patients achieved CCyR, but these were prevalently patients with a low Sokal risk and in early CP. We suggested that the increased toxicity could be associated with low BSA and that the standard dose of imatinib may be too high as the effective dose for a proportion of patients with a low BSA and that such patients can be optimally managed with reduced doses of the drug [12]. We also evaluated the impact of BMI in a subsequent study which correlated increased BMI at baseline with suboptimal molecular and delayed cytogenetic responses, with imatinib but not nilotinib tested as frontline treatment [13]. In this issue of Acta Haematologica, Sung et al. [14] referred to this aspect in order to correctly manage CML patients during first-line treatment with imatinib. They created an important index to evaluate the incidence
of patients with a 12-month probability of CCyR, with a ratio between the imatinib effective dose and BSA. Patients with a ratio above 206.7 mg/m2 showed a higher probability of CCyR, and a positive and significant correlation was also found between the ratio and the plasma trough imatinib concentration [14]. Several other variables that may influence the pharmacokinetics of imatinib and responses deserve consideration. Previous reports have demonstrated an association between the pharmacokinetics of imatinib and ABC transporters (ABCB1, ABCC1, and ABCG2), the human organic cation transporter (OCT1), and cytochrome P450 isoenzymes, such as CYP2C9 and CYP3A4/5 [15]. The role of the genetic variants and race differences in interindividual variability in the pharmacokinetics of the drug remains controversial, and further investigations are needed to determine the relative role of genetic polymorphisms and BSA variability in the effective dose of imatinib.
References
58
7 Kanda Y, Okamoto S, Tauchi T, Kizaki M, Inokuchi K, Yabe M, Yokoyama K, Ito Y, Kimura Y, Hihashihara M, Bessho M, Ando K, Chiba S, Kurokawa M, Oshimi K, Dan K, Ohyashiki K, Ikeda Y: Multicenter prospective trial evaluating the tolerability of imatinib for Japanese patients with chronic myelogenous leukemia in the chronic phase: dose body weight matter? Am J Hematol 2008; 83: 835–839. 8 Ohnishi K, Nakaseko C, Takeuchi J, Fujisawa S, Nagai T, Yamazaki H, Tauchi T, Imai K, Mori N, Yagasaki F, Maeda Y, Usui N, Miyazaki Y, Miyamura K, Kiyoi H, Ohtake S, Naoe T: Long-term outcome following imatinib therapy for chronic myelogenous leukemia, with assessment of dosage and blood levels: the JALSG CML02 study. Cancer Sci 2012; 103:1071–1078. 9 Kawaguchi T, Hamada A, Hirayama C, Nakashima R, Nambu T, Yamakawa Y, Watanabe H, Horikawa K, Mitsuya H, Saito H: Relationship between an effective dose of imatinib, body surface area, and trough drug levels in patients with chronic myeloid leukemia. Int J Hematol 2009;89:642–648. 10 Sakai M, Miyazaki Y, Matsuo E, Moriuchi Y, Hata T, Fukushima T, Imaizumi Y, Imanishi D, Taguchi J, Iwanaga M, Tsushima H, Inoue Y, Takasaki Y, Tsuchiya T, Komoda M, Ando K, Horio K, Moriwaki Y, Tominaga S, Itonaga H, Nagai K, Tsukasaki K, Tsutsumi C, Sawayama Y, Yamasaki R, Ogawa D, Kawaguchi Y, Ikeda S, Yoshida S, Onimaru Y, Tawara M, Atogami S, Koida S, Joh T, Yamamura M, Matsuo Y, Soda H, Nonaka H, Jinnai I, Kuriyama K, Tomonaga M: Long-term efficacy of
Acta Haematol 2015;134:57–58 DOI: 10.1159/000370098
11
12
13
14
15
imatinib in a practical setting is correlated with imatinib trough concentration that is influenced by body size: a report by the Nagasaki CML Study Group. Int J Hematol 2009; 89:319–325. Kobayashi S, Kimura E, Kobavashi A, Sato K, Motoyoshi K: Efficacy of low-dose imatinib in chronic-phase chronic myelogenous leukemia patients. Ann Hematol 2009; 88: 311– 315. Breccia M, Cannella L, Stefanizzi C, Latagliata R, Nanni M, Diverio D, Santopietro M, Federico V, Alimena G: Cytogenetic and molecular responses in chronic phase chronic myeloid leukaemia patients receiving low dose of imatinib for intolerance to standard dose. Hematol Oncol 2010;28:89–92. Breccia M, Loglisci G, Salaroli A, Serrao A, Mancini M, Diverio D, Latagliata R, Alimena G: Delayed cytogenetic and major molecular responses associated to increate BMI at baseline in chronic myeloid leukemia patients treated with imatinib. Cancer Lett 2013; 333: 32–35. Sung JH, Lee S, Choi IK, Park Y, Choi CW, Kim H-J, Yhim H-Y, Kim BS: Imatinib mesylate dose adjustment based on body surface area for CML chronic phase patients intolerance to standard dosage. Acta Haematol 2015; 134:59–68. Gardner ER, Burger H, van Schaik RH, van Oosterom AT, de Bruijn EA, Guetens G, Prenen H, de Jong FA, Baker SD, Bates SE, Figg WD, Verweij J, Sparreboom A, Nooter K: Association of enzyme and transporter genotypes with the pharmacokinetics of imatinib. Clin Pharmacol Ther 2006;80:192–201.
Breccia/Molica/Colafigli/Alimena
Downloaded by: Freie Universität Berlin 130.133.8.114 - 5/12/2015 3:43:03 PM
1 O’Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, Cornelissen JJ, Fischer T, Hochhaus A, Hughes T, Lechner K, Nielsen JL, Rousselot P, Reiffers J, Saglio G, Shepherd J, Simonsson B, Gratwohl A, Goldman JM, Kantarjian H, Taylor K, Verhoef G, Bolton AE, Capdeville R, Druker BJ: Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003;348:994–1004. 2 Peng B, Lloyd P, Schran H: Clinical pharmacokinetics of imatinib. Clin Pharmacokinet 2005;44:879–894. 3 Picard S, Titier K, Etienne G, Teilhet E, Ducint D, Bernard MA, Lassalle R, Marit G, Reiffers J, Begaud B, Moore N, Molimard M, Mahon FX: Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood 2007; 109: 3496–3499. 4 Larson RA, Druker BJ, Guilhot FA, O’Brien SG, Riviere GJ, Krahnke T, Gathmann I, Wang Y: Imatinib pharmacokinetics and its correlation with response and safety in chronic phase chronic myeloid leukemia: a subanalysis of the IRIS study. Blood 2008;111:4022–4028. 5 Horikoshi A, Takei K, Sawada S: Effects of lower dose of imatinib to CML patients. Leuk Res 2003;27:1167. 6 Park SJ, Choi IK, Seo HY, Sung HJ, Park KH, Kim SJ, Oh SC, Seo JH, Choi CW, Kim BS, Shin SW, Kim YH, Kim JS: Reduced dose of imatinib for patients with chronic myeloid leukemia and low body surface area. Acta Haematol 2007;118:219–221.
Received: November 24, 2014 Accepted: November 24, 2014 Published online: April 11, 2015
The Importance of Body Surface Area at Baseline and during Treatment in Chronic Myeloid Leukemia Patients Treated with Imatinib Massimo Breccia Matteo Molica Gioia Colafigli Giuliana Alimena Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy
© 2015 S. Karger AG, Basel 0001–5792/15/1341–0057$39.50/0 E-Mail [email protected] www.karger.com/aha
efficacy of imatinib [7]. Kawaguchi et al. [9] reported the clinical outcome of 31 patients, 13 of whom were treated with 400 mg/day and 9 of whom received 300 mg/day. The mean trough levels of the two groups were not significantly different and exceeded the effective plasma threshold. The BSA was significantly smaller in patients receiving the reduced dose compared to those receiving the standard dose, and a significant association with age and gender was found [9]. Another Japanese group reported that a Japanese population experienced increased hematologic toxicity with standard-dose imatinib due to low BSA [10]. Seventy-three patients were treated with imatinib, achieving responses similar to those reported in the IRIS study, but the median dose intensity administered was lower compared to the other study. The measurement of the plasma imatinib through level was comparable to that reported in other studies, showing a significant relationship between the dose administered and a low BSA. A Korean group reported 9 patients who started with the standard dose and then reduced to 200–300 mg/day due to toxicity, but all patients had a low BSA [6]. The Japanese group reported the impact of low-dose imatinib as follows: an MMR was observed in all patients with a low Sokal score treated with 300-mg or lower dosages. Achievement of an MMR was also reported for intermediate and high Sokal risks, but there was an increased rate of relapse and the MMR was maintained only with timely increases in dose [11]. Our group also reported the effects of low-dose imaMassimo Breccia, MD Department of Cellular Biotechnologies and Hematology, Sapienza University Via Benevento 6 IT–00161 Rome (Italy) E-Mail breccia @ bce.uniroma1.it
Downloaded by: Freie Universität Berlin 130.133.8.114 - 5/12/2015 3:43:03 PM
The established dose of imatinib for chronic myeloid leukemia (CML) patients in the chronic phase (CP) is 400 mg/day [1]. This dose is required to obtain a clinical benefit based on the relationship between the pharmacokinetics and pharmacodynamics of the drug at a steady state, indicating that clinical responses are dependent on the administered dose [2]. Picard et al. [3] showed that trough imatinib plasma levels at a steady state exceed 1,002 ng/ml and that this value correlates with the best clinical outcome. It was demonstrated, in the 5-year follow-up of the IRIS trial, that maintenance of plasma trough levels above 1,002 ng/ml is associated with achievement of a major molecular response (MMR) [4]. With the standard dose, some patients experienced severe toxicity including myelosuppression, skin rash, edema, and gastrointestinal side effects. In routine clinical practice, usually to avoid these complications and the low rate of adherence to imatinib, the standard dose is reduced to less than 400 mg/day [5–8]. Several reports have indicated that an inverse correlation exists between body surface area (BSA) and plasma imatinib trough level. A Japanese group reported the role of body weight in 89 evaluable patients with a median weight of 62.8 kg. The drug was withheld in 45% of patients due to grade 3/4 toxicity, but it was resumed gradually in 62 out of 89 patients. In that study, patients with an older age and a lower body weight were less likely to achieve a complete cytogenetic response (CCyR), suggesting that BSA had a significant influence on the toxicity and
tinib in 45 CML patients in the early (17 patients) or late CP (28 patients) who reduced the dose after experiencing side effects after a median of 58 days. We showed that also with low doses 58% of patients achieved CCyR, but these were prevalently patients with a low Sokal risk and in early CP. We suggested that the increased toxicity could be associated with low BSA and that the standard dose of imatinib may be too high as the effective dose for a proportion of patients with a low BSA and that such patients can be optimally managed with reduced doses of the drug [12]. We also evaluated the impact of BMI in a subsequent study which correlated increased BMI at baseline with suboptimal molecular and delayed cytogenetic responses, with imatinib but not nilotinib tested as frontline treatment [13]. In this issue of Acta Haematologica, Sung et al. [14] referred to this aspect in order to correctly manage CML patients during first-line treatment with imatinib. They created an important index to evaluate the incidence
of patients with a 12-month probability of CCyR, with a ratio between the imatinib effective dose and BSA. Patients with a ratio above 206.7 mg/m2 showed a higher probability of CCyR, and a positive and significant correlation was also found between the ratio and the plasma trough imatinib concentration [14]. Several other variables that may influence the pharmacokinetics of imatinib and responses deserve consideration. Previous reports have demonstrated an association between the pharmacokinetics of imatinib and ABC transporters (ABCB1, ABCC1, and ABCG2), the human organic cation transporter (OCT1), and cytochrome P450 isoenzymes, such as CYP2C9 and CYP3A4/5 [15]. The role of the genetic variants and race differences in interindividual variability in the pharmacokinetics of the drug remains controversial, and further investigations are needed to determine the relative role of genetic polymorphisms and BSA variability in the effective dose of imatinib.
References
58
7 Kanda Y, Okamoto S, Tauchi T, Kizaki M, Inokuchi K, Yabe M, Yokoyama K, Ito Y, Kimura Y, Hihashihara M, Bessho M, Ando K, Chiba S, Kurokawa M, Oshimi K, Dan K, Ohyashiki K, Ikeda Y: Multicenter prospective trial evaluating the tolerability of imatinib for Japanese patients with chronic myelogenous leukemia in the chronic phase: dose body weight matter? Am J Hematol 2008; 83: 835–839. 8 Ohnishi K, Nakaseko C, Takeuchi J, Fujisawa S, Nagai T, Yamazaki H, Tauchi T, Imai K, Mori N, Yagasaki F, Maeda Y, Usui N, Miyazaki Y, Miyamura K, Kiyoi H, Ohtake S, Naoe T: Long-term outcome following imatinib therapy for chronic myelogenous leukemia, with assessment of dosage and blood levels: the JALSG CML02 study. Cancer Sci 2012; 103:1071–1078. 9 Kawaguchi T, Hamada A, Hirayama C, Nakashima R, Nambu T, Yamakawa Y, Watanabe H, Horikawa K, Mitsuya H, Saito H: Relationship between an effective dose of imatinib, body surface area, and trough drug levels in patients with chronic myeloid leukemia. Int J Hematol 2009;89:642–648. 10 Sakai M, Miyazaki Y, Matsuo E, Moriuchi Y, Hata T, Fukushima T, Imaizumi Y, Imanishi D, Taguchi J, Iwanaga M, Tsushima H, Inoue Y, Takasaki Y, Tsuchiya T, Komoda M, Ando K, Horio K, Moriwaki Y, Tominaga S, Itonaga H, Nagai K, Tsukasaki K, Tsutsumi C, Sawayama Y, Yamasaki R, Ogawa D, Kawaguchi Y, Ikeda S, Yoshida S, Onimaru Y, Tawara M, Atogami S, Koida S, Joh T, Yamamura M, Matsuo Y, Soda H, Nonaka H, Jinnai I, Kuriyama K, Tomonaga M: Long-term efficacy of
Acta Haematol 2015;134:57–58 DOI: 10.1159/000370098
11
12
13
14
15
imatinib in a practical setting is correlated with imatinib trough concentration that is influenced by body size: a report by the Nagasaki CML Study Group. Int J Hematol 2009; 89:319–325. Kobayashi S, Kimura E, Kobavashi A, Sato K, Motoyoshi K: Efficacy of low-dose imatinib in chronic-phase chronic myelogenous leukemia patients. Ann Hematol 2009; 88: 311– 315. Breccia M, Cannella L, Stefanizzi C, Latagliata R, Nanni M, Diverio D, Santopietro M, Federico V, Alimena G: Cytogenetic and molecular responses in chronic phase chronic myeloid leukaemia patients receiving low dose of imatinib for intolerance to standard dose. Hematol Oncol 2010;28:89–92. Breccia M, Loglisci G, Salaroli A, Serrao A, Mancini M, Diverio D, Latagliata R, Alimena G: Delayed cytogenetic and major molecular responses associated to increate BMI at baseline in chronic myeloid leukemia patients treated with imatinib. Cancer Lett 2013; 333: 32–35. Sung JH, Lee S, Choi IK, Park Y, Choi CW, Kim H-J, Yhim H-Y, Kim BS: Imatinib mesylate dose adjustment based on body surface area for CML chronic phase patients intolerance to standard dosage. Acta Haematol 2015; 134:59–68. Gardner ER, Burger H, van Schaik RH, van Oosterom AT, de Bruijn EA, Guetens G, Prenen H, de Jong FA, Baker SD, Bates SE, Figg WD, Verweij J, Sparreboom A, Nooter K: Association of enzyme and transporter genotypes with the pharmacokinetics of imatinib. Clin Pharmacol Ther 2006;80:192–201.
Breccia/Molica/Colafigli/Alimena
Downloaded by: Freie Universität Berlin 130.133.8.114 - 5/12/2015 3:43:03 PM
1 O’Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, Cornelissen JJ, Fischer T, Hochhaus A, Hughes T, Lechner K, Nielsen JL, Rousselot P, Reiffers J, Saglio G, Shepherd J, Simonsson B, Gratwohl A, Goldman JM, Kantarjian H, Taylor K, Verhoef G, Bolton AE, Capdeville R, Druker BJ: Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003;348:994–1004. 2 Peng B, Lloyd P, Schran H: Clinical pharmacokinetics of imatinib. Clin Pharmacokinet 2005;44:879–894. 3 Picard S, Titier K, Etienne G, Teilhet E, Ducint D, Bernard MA, Lassalle R, Marit G, Reiffers J, Begaud B, Moore N, Molimard M, Mahon FX: Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood 2007; 109: 3496–3499. 4 Larson RA, Druker BJ, Guilhot FA, O’Brien SG, Riviere GJ, Krahnke T, Gathmann I, Wang Y: Imatinib pharmacokinetics and its correlation with response and safety in chronic phase chronic myeloid leukemia: a subanalysis of the IRIS study. Blood 2008;111:4022–4028. 5 Horikoshi A, Takei K, Sawada S: Effects of lower dose of imatinib to CML patients. Leuk Res 2003;27:1167. 6 Park SJ, Choi IK, Seo HY, Sung HJ, Park KH, Kim SJ, Oh SC, Seo JH, Choi CW, Kim BS, Shin SW, Kim YH, Kim JS: Reduced dose of imatinib for patients with chronic myeloid leukemia and low body surface area. Acta Haematol 2007;118:219–221.
