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Successful Treatment of Relapsed Acute Promyelocytic Leukemia in a Patient Receiving Continuous Ambulatory Peritoneal Dialysis With Oral Arsenic Trioxide

Successful Treatment of Relapsed Acute Promyelocytic Leukemia in a Patient Receiving Continuous... Serious medical comorbidities generally preclude curative therapies for patients with leukemia. Arsenic trioxide (As2O3), both intravenous and oral, is highly effective for acute promyelocytic leukemia (APL).1 As arsenic is eliminated mainly by renal excretion, uremic patients are considered unsuitable for arsenic trioxide therapy. To our knowledge, there are no data on arsenic clearance during dialysis. A patient with APL who was receiving continuous ambulatory peritoneal dialysis (CAPD) was successfully treated with oral arsenic trioxide. We took this unique opportunity to study arsenic clearance during CAPD. Report of a Case A 65-year-old woman with diabetes mellitus, ischemic heart disease, and chronic renal failure who was receiving CAPD had a relapse of APL 18 months after a first complete remission (CR) that had been induced with all trans-retinoic acid. She achieved a second CR (CR2) after 23 days of oral arsenic trioxide therapy (5 mg/d).2 There were no significant adverse effects (normal liver function; maximum QT interval, 0.48 seconds; peak leukocyte count, 6.8 × 103/μL; and stable diabetic control). Six consolidation courses of oral arsenic trioxide (5 mg/d ×14 every 2 months) were administered. The patient remained in CR2 but died of diabetic leg gangrene 24 months later. The results of molecular detection of PML/RARA, which is characteristic of APL, became persistently negative 4 months after CR2. Comment Plasma, blood cell, and peritoneal dialysate arsenic levels were measured by inductively coupled plasma mass spectroscopy.3 To evaluate CAPD as a renal replacement for arsenic excretion, we studied 15 control patients with relapsed APL and normal renal function who were treated with the same oral arsenic trioxide regimen, but at a higher dosage (10 mg/d) (Figure). During induction, although arsenic trioxide was administered at half the standard dosage, our patient’s plasma arsenic concentration still accumulated gradually. After induction, her plasma arsenic levels were about 6 times those of the control patients’, who were receiving twice the dosage of oral arsenic trioxide. During consolidation, her plasma arsenic levels fluctuated but were generally several times those of the control patients’. After consolidation, her plasma arsenic levels gradually declined to baseline. Figure. View LargeDownload Plasma and cellular arsenic levels during oral arsenic trioxide treatment for relapsed acute promyelocytic leukemia (to convert arsenic values to micromoles per liter, multiply by 0.0133). A, Study patient, who received continuous ambulatory peritoneal dialysis. Blood samples were obtained 2 hours after each arsenic trioxide treatment and at follow-up after cessation of treatment. Asterisks indicate time points at which concomitant plasma and peritoneal dialysate (PD) arsenic levels were measured. B, Fifteen patients with normal renal function. Error bars show median values and range. Monitoring of blood cell arsenic levels showed intriguing findings. In the control patients, blood cells consistently accumulated more arsenic than plasma, implying that there were mechanisms leading to more avid cellular uptake. In our patient, however, cellular arsenic levels did not exceed the high plasma levels during induction, maintaining a level comparable with the levels in the controls. Therefore, cellular uptake of arsenic was regulated, preventing uncontrolled arsenic entry. Arsenic membrane trafficking may be mediated via aquaglyceroporin 9, although the exact kinetics and regulatory mechanisms have not been defined.4 Interestingly, the cellular arsenic levels gradually increased after consolidation, in contrast to decreasing plasma arsenic levels, ultimately peaking at about 8 times those of the control levels 6 months after consolidation. This increase probably reflected a redistribution of arsenic that had accumulated in bodily tissues, with a preferential late partition into blood cells. The protracted maintenance of high cellular arsenic concentrations might have accounted for the durable remission. Our patient’s peritoneal dialysate levels were assayed at 4 time points. On each occasion, the dialysate arsenic level was almost identical to that of the plasma level. This finding indicated that arsenic did not bind appreciably to any plasma proteins. Furthermore, peritoneal dialysis was effective in clearing arsenic. With a 2-L exchange of peritoneal dialysate 4 times daily, the peritoneal arsenic clearance was calculated as 5.5 mL/min. In addition to providing data on arsenic pharmacology during CAPD, we showed that arsenic trioxide could be used therapeutically in uremic patients. Owing to slow gastrointestinal absorption, oral arsenic trioxide achieves a lower peak plasma arsenic concentration than intravenous arsenic trioxide,5 an advantage in uremic patients with impaired arsenic excretion. The highest plasma arsenic level in our patient after 23 days of oral arsenic trioxide was about 301 μg/L (4 μmol/L), much lower than the estimated lethal level of 1805 μg/L (24 μmol/L) in arsenic poisoning.6 Because hemodialysis removes arsenic more efficiently than peritoneal dialysis, arsenic trioxide may be administered with an even bigger safety margin to patients who are undergoing hemodialysis. Therefore, uremic patients who are receiving dialysis should not be excluded from arsenic trioxide therapy. However, dose reduction and monitoring of plasma and cellular arsenic levels are needed. Back to top Article Information Correspondence: Dr Kwong, University Department of Medicine, Professorial Block, Queen Mary Hospital, Pokfulam Road, Hong Kong (ylkwong@hkucc.hku.hk). Financial Disclosure: None. Acknowledgment: We thank the S. K. Yee Medical Foundation, Hong Kong, for funding support and Kar N. Lai, MD, for helpful discussion. References 1. Kwong YL Arsenic trioxide in the treatment of haematological malignancies. Expert Opin Drug Saf 2004;3589- 597PubMedGoogle ScholarCrossref 2. Au WYKumana CRKou M et al. Oral arsenic trioxide in the treatment of relapsed acute promyelocytic leukemia. Blood 2003;102407- 408PubMedGoogle ScholarCrossref 3. Nixon DEMoyer TP Routine clinical determination of lead, arsenic, cadmium, and thallium in urine and whole blood by inductively coupled plasma mass spectrometry. Spectrochimica Acta 1996;51B13- 25Google ScholarCrossref 4. Liu ZShen JCarbrey JMMukhopadhyay RAgre PRosen BP Arsenite transport by mammalian aquaglyceroporins AQP7 and AQP9. Proc Natl Acad Sci U S A 2002;996053- 6058PubMedGoogle ScholarCrossref 5. Kumana CRAu WYLee NS et al. Systemic availability of arsenic from oral arsenic-trioxide used to treat patients with hematological malignancies. Eur J Clin Pharmacol 2002;58521- 526PubMedGoogle ScholarCrossref 6. Stephanopoulos DEWillman DAShevlin DPinter LGummin DD Treatment and toxicokinetics of acute pediatric arsenic ingestion: danger of arsenic insecticides in children. Pediatr Crit Care Med 2002;374- 80PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Internal Medicine American Medical Association

Successful Treatment of Relapsed Acute Promyelocytic Leukemia in a Patient Receiving Continuous Ambulatory Peritoneal Dialysis With Oral Arsenic Trioxide

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Publisher
American Medical Association
Copyright
Copyright © 2005 American Medical Association. All Rights Reserved.
ISSN
0003-9926
eISSN
1538-3679
DOI
10.1001/archinte.165.9.1067
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Abstract

Serious medical comorbidities generally preclude curative therapies for patients with leukemia. Arsenic trioxide (As2O3), both intravenous and oral, is highly effective for acute promyelocytic leukemia (APL).1 As arsenic is eliminated mainly by renal excretion, uremic patients are considered unsuitable for arsenic trioxide therapy. To our knowledge, there are no data on arsenic clearance during dialysis. A patient with APL who was receiving continuous ambulatory peritoneal dialysis (CAPD) was successfully treated with oral arsenic trioxide. We took this unique opportunity to study arsenic clearance during CAPD. Report of a Case A 65-year-old woman with diabetes mellitus, ischemic heart disease, and chronic renal failure who was receiving CAPD had a relapse of APL 18 months after a first complete remission (CR) that had been induced with all trans-retinoic acid. She achieved a second CR (CR2) after 23 days of oral arsenic trioxide therapy (5 mg/d).2 There were no significant adverse effects (normal liver function; maximum QT interval, 0.48 seconds; peak leukocyte count, 6.8 × 103/μL; and stable diabetic control). Six consolidation courses of oral arsenic trioxide (5 mg/d ×14 every 2 months) were administered. The patient remained in CR2 but died of diabetic leg gangrene 24 months later. The results of molecular detection of PML/RARA, which is characteristic of APL, became persistently negative 4 months after CR2. Comment Plasma, blood cell, and peritoneal dialysate arsenic levels were measured by inductively coupled plasma mass spectroscopy.3 To evaluate CAPD as a renal replacement for arsenic excretion, we studied 15 control patients with relapsed APL and normal renal function who were treated with the same oral arsenic trioxide regimen, but at a higher dosage (10 mg/d) (Figure). During induction, although arsenic trioxide was administered at half the standard dosage, our patient’s plasma arsenic concentration still accumulated gradually. After induction, her plasma arsenic levels were about 6 times those of the control patients’, who were receiving twice the dosage of oral arsenic trioxide. During consolidation, her plasma arsenic levels fluctuated but were generally several times those of the control patients’. After consolidation, her plasma arsenic levels gradually declined to baseline. Figure. View LargeDownload Plasma and cellular arsenic levels during oral arsenic trioxide treatment for relapsed acute promyelocytic leukemia (to convert arsenic values to micromoles per liter, multiply by 0.0133). A, Study patient, who received continuous ambulatory peritoneal dialysis. Blood samples were obtained 2 hours after each arsenic trioxide treatment and at follow-up after cessation of treatment. Asterisks indicate time points at which concomitant plasma and peritoneal dialysate (PD) arsenic levels were measured. B, Fifteen patients with normal renal function. Error bars show median values and range. Monitoring of blood cell arsenic levels showed intriguing findings. In the control patients, blood cells consistently accumulated more arsenic than plasma, implying that there were mechanisms leading to more avid cellular uptake. In our patient, however, cellular arsenic levels did not exceed the high plasma levels during induction, maintaining a level comparable with the levels in the controls. Therefore, cellular uptake of arsenic was regulated, preventing uncontrolled arsenic entry. Arsenic membrane trafficking may be mediated via aquaglyceroporin 9, although the exact kinetics and regulatory mechanisms have not been defined.4 Interestingly, the cellular arsenic levels gradually increased after consolidation, in contrast to decreasing plasma arsenic levels, ultimately peaking at about 8 times those of the control levels 6 months after consolidation. This increase probably reflected a redistribution of arsenic that had accumulated in bodily tissues, with a preferential late partition into blood cells. The protracted maintenance of high cellular arsenic concentrations might have accounted for the durable remission. Our patient’s peritoneal dialysate levels were assayed at 4 time points. On each occasion, the dialysate arsenic level was almost identical to that of the plasma level. This finding indicated that arsenic did not bind appreciably to any plasma proteins. Furthermore, peritoneal dialysis was effective in clearing arsenic. With a 2-L exchange of peritoneal dialysate 4 times daily, the peritoneal arsenic clearance was calculated as 5.5 mL/min. In addition to providing data on arsenic pharmacology during CAPD, we showed that arsenic trioxide could be used therapeutically in uremic patients. Owing to slow gastrointestinal absorption, oral arsenic trioxide achieves a lower peak plasma arsenic concentration than intravenous arsenic trioxide,5 an advantage in uremic patients with impaired arsenic excretion. The highest plasma arsenic level in our patient after 23 days of oral arsenic trioxide was about 301 μg/L (4 μmol/L), much lower than the estimated lethal level of 1805 μg/L (24 μmol/L) in arsenic poisoning.6 Because hemodialysis removes arsenic more efficiently than peritoneal dialysis, arsenic trioxide may be administered with an even bigger safety margin to patients who are undergoing hemodialysis. Therefore, uremic patients who are receiving dialysis should not be excluded from arsenic trioxide therapy. However, dose reduction and monitoring of plasma and cellular arsenic levels are needed. Back to top Article Information Correspondence: Dr Kwong, University Department of Medicine, Professorial Block, Queen Mary Hospital, Pokfulam Road, Hong Kong (ylkwong@hkucc.hku.hk). Financial Disclosure: None. Acknowledgment: We thank the S. K. Yee Medical Foundation, Hong Kong, for funding support and Kar N. Lai, MD, for helpful discussion. References 1. Kwong YL Arsenic trioxide in the treatment of haematological malignancies. Expert Opin Drug Saf 2004;3589- 597PubMedGoogle ScholarCrossref 2. Au WYKumana CRKou M et al. Oral arsenic trioxide in the treatment of relapsed acute promyelocytic leukemia. Blood 2003;102407- 408PubMedGoogle ScholarCrossref 3. Nixon DEMoyer TP Routine clinical determination of lead, arsenic, cadmium, and thallium in urine and whole blood by inductively coupled plasma mass spectrometry. Spectrochimica Acta 1996;51B13- 25Google ScholarCrossref 4. Liu ZShen JCarbrey JMMukhopadhyay RAgre PRosen BP Arsenite transport by mammalian aquaglyceroporins AQP7 and AQP9. Proc Natl Acad Sci U S A 2002;996053- 6058PubMedGoogle ScholarCrossref 5. Kumana CRAu WYLee NS et al. Systemic availability of arsenic from oral arsenic-trioxide used to treat patients with hematological malignancies. Eur J Clin Pharmacol 2002;58521- 526PubMedGoogle ScholarCrossref 6. Stephanopoulos DEWillman DAShevlin DPinter LGummin DD Treatment and toxicokinetics of acute pediatric arsenic ingestion: danger of arsenic insecticides in children. Pediatr Crit Care Med 2002;374- 80PubMedGoogle ScholarCrossref

Journal

Archives of Internal Medicine – American Medical Association

Published: May 9, 2005

Keywords: acute promyelocytic leukemia,peritoneal dialysis, continuous ambulatory,arsenic trioxide

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