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Case Report
Use of arsenic trioxide in a hemodialysisdependent patient with relapsed acute promyelocytic leukemia
J Oncol Pharm Practice 0(0) 1–6 ! The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1078155215586235 opp.sagepub.com
Sarah Perreault1, Julie Moeller1, Kejal Patel1, Rachel Eyler2, Trinh Pham2, Kerry Russell3 and Nikolai Podoltsev4
Abstract Arsenic trioxide has been established for use in both relapsed and front-line treatment of acute promyelocytic leukemia. Dose adjustments are recommended to be considered in severe renal impairment although dosage reduction guidelines are not provided. In addition, toxicities of arsenic are significant. The use of arsenic trioxide has not been well studied in dialysis patients and there is a paucity of data in the literature to support the use in such a situation. We describe an 81year-old relapsed acute promyelocytic leukemia hemodialysis-dependent patient with a pre-existing cardiac condition who was treated with 10 mg arsenic trioxide three times weekly after dialysis. These findings provide support along with the marginal amount of currently published data for an arsenic trioxide dosing regimen in hemodialysis patients.
Keywords Arsenic trioxide, hemodialysis, acute promyelocytic leukemia
Introduction Acute promyelocytic leukemia (APL), characterized by an arrest in normal hematopoietic cell differentiation at the promyelocyte stage, is a reciprocal chromosomal translocation between the promyelocytic leukemia (PML) gene on chromosome 15 and the retinoic acid receptor-a (RAR-a) gene on chromosome 17, in more than 98% of cases.1 The resulting PML-RARa gene fusion produces an oncoprotein that deregulates the expression of genes in hematopoietic cells, blocking differentiation and causing accumulation of undifferentiated promyelocytes and eventual development of leukemia.2 APL is a particularly aggressive but highly curable subtype of acute myeloid leukemia. APL is rare in adults, accounting for only 10–15% of all AML diagnoses.3 Eighty to ninety percent of patients who survive induction therapy achieve a complete remission (CR) with cure rates exceeding 80%.4–6 Initial high mortality is due to disseminated intravascular coagulation and differential syndrome. Relapsed APL occurs in 20–30% of patients. Arsenic trioxide (ATO) proved to be efficacious and safe in achieving CR in patients with relapsed disease.7–12 During induction, ATO is given
daily at 0.15 mg/kg until remission with recommendations of at least weekly monitoring of EKGs and QTc interval. ATO is eliminated via urinary excretion and limited data exists regarding ATO pharmacokinetics, dosing and timing in patients with renal impairment or requiring hemodialysis.13–16 In this report, we describe a case of an 81-year-old man with multiple comorbidities including cardiac and renal disease requiring hemodialysis who was treated with ATO therapy for relapsed APL.
1 Department of Pharmacy, Yale New Haven Hospital, New Haven, CT, USA 2 University of Connecticut, School of Pharmacy, Storrs, CT, USA 3 Department of Cardiovascular and Metabolism, Novartis Institutes for BioMedical Research, Inc., Cambridge, MA, USA 4 Department of Internal Medicine, Hematology Section, Yale University School of Medicine, New Haven, CT, USA
Corresponding author: Sarah Perreault, Yale New Haven Hospital, 20 York Street, New Haven, CT 06510 United States. Email: [email protected]
Downloaded from opp.sagepub.com at NORTH DAKOTA STATE UNIV LIB on May 20, 2015
XML Template (2015) [8.5.2015–9:44am] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/OPPJ/Vol00000/150032/APPFile/SG-OPPJ150032.3d
(OPP)
[1–6] [INVALID Stage]
2
Journal of Oncology Pharmacy Practice 0(0)
Case presentation An 81-year-old Caucasian male originally presented in February 2011 with persistent pancytopenia. APL was diagnosed by bone marrow evaluation showing 50% promyelocytes with fluorescence in-situ hybridization (FISH) positive for t(15;17) in 91% of cells. His comorbid conditions included type II diabetes mellitus, hypertension, coronary artery disease (status post percutaneous coronary intervention without a stent in 2000), benign prostatic hyperplasia and gastroesophageal reflux disease. His baseline ECHO showed an LVEF of 65%. The patient received inpatient induction therapy with idarubicin and all-trans retinoic acid (ATRA) according to low-risk Sanz protocol and had a complete morphologic remission (CR).17 During induction, he developed hypotension secondary to sepsis and required transfer to the intensive care unit. This event resulted in renal failure, and he subsequently required chronic hemodialysis. His consolidation therapy was modified due to end-stage renal disease (ESRD) and he received idarubicin and ATRA from May through July 2011 and maintenance therapy with ATRA from October through December 2011.17 In June 2012, the patient was diagnosed with relapsed APL when he again presented with pancytopenia. Bone marrow evaluation showed hypercellular marrow with 43% promyelocytes, cytogenetics revealed FISH for t(15;17) in seven out of 15 cells, and FISH was positive in 28.5% cells. A fixed dose of ATO 10 mg in 250 mL of D5W infused over 2 hours twice weekly was selected for re-induction therapy due to his cardiac history and hemodialysis-dependent renal dysfunction. A pretreatment ECHO showed a LVEF of 69% and an EKG was obtained which demonstrated sinus rhythm with 1st degree AV block, incomplete right bundle branch block (RBBB) and left anterior fascicular block (LAFB). A cardiologist was consulted, and based on the risk/benefit ratio, a decision was agreed upon to proceed with treatment with additional monitoring by EKGs. After the second dose of ATO, the patient’s EKG demonstrated sinus rhythm with progression of AV block to 2nd degree AV block (Mobitz type I), and persistent RBBB and LAFB. The patient remained asymptomatic and hemodynamically stable. ATO was held and Cardiology evaluation agreed that the 2nd degree AV heart block could be related to ATO administration. After discussion with the patient and team regarding the risk/benefit ratio, a decision was reached to continue treatment with ATO with continuous EKG monitoring in a telemetry unit. Over the next seven weeks, 11 doses of ATO were administered. The patient experienced fluctuations between 1st degree AV block and 2nd degree AV block felt to be due to ATO administration.
Placement of a pacemaker was considered. However, this was unable to be performed percutaneously due to multiple venous obstructions, and the risk of performing an open placement of an epicardial-lead pacemaker was considered very high risk due to the patient’s thrombocytopenia and neutropenia. In addition, the patient remained hemodynamically stable despite these rhythm disturbances, thus the risk of open procedure was considered to outweigh the potential benefit of pacing. A repeat bone marrow evaluation revealed hypercellular marrow with 50% promyelocytes, cytogenetics revealed t(15;17) in eight out of 15 cells, and FISH for t(15;17) was positive in 88% of cells. Due to persistence of the disease as well as the patient’s overall tolerance of ATO therapy, the treatment interval was changed to 10 mg IV three times weekly given after dialysis. After an additional 10 doses were given, a repeat bone marrow evaluation demonstrated hypercellular marrow containing 33% promyelocytes, cytogenetics revealed a t(15;17) in two out of 16 cells and FISH for t(15;17) was positive in 52% of cells. Re-induction ATO therapy was continued based on favorable response and a total of 47 ATO doses were given during the re-induction phase before a bone marrow evaluation which showed morphologic CR, normal karyotype and negative FISH for t(15;17). Three weeks after the completion of re-induction therapy, two cycles of consolidation therapy, three weeks apart, were given in the outpatient setting. Each consolidation cycle consisted of 25 doses of ATO given as 10 mg IV three times weekly postdialysis. Bone marrow evaluation was done 1 month after completion of the second consolidation and was consistent with morphologic remission with normal karyotype but positive FISH for t(15;17) in 1.5% of cells. He was considered for therapy with gemtuzumab ozogamicin on an extended access program but 2 months after second consolidation, he developed a hemorrhagic stroke and passed away.
ATO whole blood concentration monitoring Total arsenic whole blood concentration assays were performed by Mayo Medical Laboratories using an inductively coupled plasma-mass spectrometer. Prior to the initiation of treatment, the whole blood concentration of arsenic was 0 ng/mL. After the first dose of ATO was administered arsenic whole blood concentrations were drawn immediately post-dose (68 ng/mL) at 2.6 hours (43 ng/mL), 44.2 hours (74 ng/mL), and 61.4 hours (81 ng/mL). This demonstrated an infusional peak with distribution of arsenic into the tissues and later redistribution of arsenic back into the blood.
Downloaded from opp.sagepub.com at NORTH DAKOTA STATE UNIV LIB on May 20, 2015
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The patient received dialysis after the first dose of ATO at hour 62. The arsenic concentration prior to dialysis was 81 ng/mL and then 1 hour after was 36 ng/mL and 8 hours after was 40 ng/mL (Figure 1). The percentage of arsenic removed by dialysis at hour 1 was 55.5% and at hour 8 was 38.3%. Arsenic removal by dialysis was also calculated with the second dose to measure consistency. The levels were again drawn prior to dialysis (96 ng/mL) and 5.7 hours after dialysis (59 ng/mL). The percentage of arsenic removed by dialysis after the second dose was 38.5%. The dialysis sessions were approximately 165 minutes in duration and were performed on a Fresenius 2008k2 machine using a polyarylethersulfone polyvinylpyrrolidone dialyzer (Reveclear, Gambro). Blood and dialysate flow rates were 400 mL/min and 600 mL/min, respectively. Other serial arsenic levels were obtained prior to and post-administration from the first dose to the eleventh dose. This collection of levels confirmed initial observation of arsenic distribution with hemodialysis with peak infusion effect, followed by redistribution of arsenic from blood into the tissue and back into the blood. Over time, a slight accumulation of arsenic concentrations occurred despite regularly administered dialysis. As a result, an elimination half-life was not possible to calculate; therefore weekly pre-dialysis ATO levels were obtained starting with the 12th dose which yielded a median concentration of 114 ng/mL (range 83–205 ng/mL). Twenty-three days elapsed between the completion of the first cycle of consolidation and the start of the second cycle. During this time-period no doses of ATO were administered. An arsenic concentration at the completion of the first cycle of consolidation was 176 ng/mL and prior to the initiation of the second
Arsenic Concentration (ng/mL)
Arsenic Removal from Hemodialysis 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0
7/21 Dose 3 and HD
7/17 Dose 2 and HD
NOTE: No pre and post dialysis levels were drawn for HD 7/19,thus no dip in level.
0
20
40
60
cycle of consolidation was 45 ng/mL. These levels confirm the known prolonged elimination of ATO from the body. To reconfirm this observation an additional level was obtained 38 days after the final completion of all doses of arsenic, showing a concentration of 30 ng/mL.
ATO toxicity monitoring Complete blood count with differential, serum creatinine, blood urea nitrogen, potassium, magnesium, aspartate aminotransferase, alanine aminotransferase, bilirubin was monitored daily during admission for re-induction and drawn at hemodialysis prior to every ATO dose during consolidation. While admitted during re-induction, our patient was monitored on a telemetry floor with daily EKGs, and EKGs were obtained before each ATO dose during outpatient consolidation. Magnesium and potassium serum concentrations were maintained above 2 mg/dL and 4 mmol/L; respectively. Concomitant medications known to prolong QTc were avoided during therapy. Manual calculation by cardiology of QTc interval using Bazett’s formula revealed the QTc interval was 10% lower compared to the automated calculations obtained from the EKG report. Therefore, the goal QTc interval was conservatively adjusted to be maintained at
(OPP)
[1–6] [INVALID Stage]
Case Report
Use of arsenic trioxide in a hemodialysisdependent patient with relapsed acute promyelocytic leukemia
J Oncol Pharm Practice 0(0) 1–6 ! The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1078155215586235 opp.sagepub.com
Sarah Perreault1, Julie Moeller1, Kejal Patel1, Rachel Eyler2, Trinh Pham2, Kerry Russell3 and Nikolai Podoltsev4
Abstract Arsenic trioxide has been established for use in both relapsed and front-line treatment of acute promyelocytic leukemia. Dose adjustments are recommended to be considered in severe renal impairment although dosage reduction guidelines are not provided. In addition, toxicities of arsenic are significant. The use of arsenic trioxide has not been well studied in dialysis patients and there is a paucity of data in the literature to support the use in such a situation. We describe an 81year-old relapsed acute promyelocytic leukemia hemodialysis-dependent patient with a pre-existing cardiac condition who was treated with 10 mg arsenic trioxide three times weekly after dialysis. These findings provide support along with the marginal amount of currently published data for an arsenic trioxide dosing regimen in hemodialysis patients.
Keywords Arsenic trioxide, hemodialysis, acute promyelocytic leukemia
Introduction Acute promyelocytic leukemia (APL), characterized by an arrest in normal hematopoietic cell differentiation at the promyelocyte stage, is a reciprocal chromosomal translocation between the promyelocytic leukemia (PML) gene on chromosome 15 and the retinoic acid receptor-a (RAR-a) gene on chromosome 17, in more than 98% of cases.1 The resulting PML-RARa gene fusion produces an oncoprotein that deregulates the expression of genes in hematopoietic cells, blocking differentiation and causing accumulation of undifferentiated promyelocytes and eventual development of leukemia.2 APL is a particularly aggressive but highly curable subtype of acute myeloid leukemia. APL is rare in adults, accounting for only 10–15% of all AML diagnoses.3 Eighty to ninety percent of patients who survive induction therapy achieve a complete remission (CR) with cure rates exceeding 80%.4–6 Initial high mortality is due to disseminated intravascular coagulation and differential syndrome. Relapsed APL occurs in 20–30% of patients. Arsenic trioxide (ATO) proved to be efficacious and safe in achieving CR in patients with relapsed disease.7–12 During induction, ATO is given
daily at 0.15 mg/kg until remission with recommendations of at least weekly monitoring of EKGs and QTc interval. ATO is eliminated via urinary excretion and limited data exists regarding ATO pharmacokinetics, dosing and timing in patients with renal impairment or requiring hemodialysis.13–16 In this report, we describe a case of an 81-year-old man with multiple comorbidities including cardiac and renal disease requiring hemodialysis who was treated with ATO therapy for relapsed APL.
1 Department of Pharmacy, Yale New Haven Hospital, New Haven, CT, USA 2 University of Connecticut, School of Pharmacy, Storrs, CT, USA 3 Department of Cardiovascular and Metabolism, Novartis Institutes for BioMedical Research, Inc., Cambridge, MA, USA 4 Department of Internal Medicine, Hematology Section, Yale University School of Medicine, New Haven, CT, USA
Corresponding author: Sarah Perreault, Yale New Haven Hospital, 20 York Street, New Haven, CT 06510 United States. Email: [email protected]
Downloaded from opp.sagepub.com at NORTH DAKOTA STATE UNIV LIB on May 20, 2015
XML Template (2015) [8.5.2015–9:44am] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/OPPJ/Vol00000/150032/APPFile/SG-OPPJ150032.3d
(OPP)
[1–6] [INVALID Stage]
2
Journal of Oncology Pharmacy Practice 0(0)
Case presentation An 81-year-old Caucasian male originally presented in February 2011 with persistent pancytopenia. APL was diagnosed by bone marrow evaluation showing 50% promyelocytes with fluorescence in-situ hybridization (FISH) positive for t(15;17) in 91% of cells. His comorbid conditions included type II diabetes mellitus, hypertension, coronary artery disease (status post percutaneous coronary intervention without a stent in 2000), benign prostatic hyperplasia and gastroesophageal reflux disease. His baseline ECHO showed an LVEF of 65%. The patient received inpatient induction therapy with idarubicin and all-trans retinoic acid (ATRA) according to low-risk Sanz protocol and had a complete morphologic remission (CR).17 During induction, he developed hypotension secondary to sepsis and required transfer to the intensive care unit. This event resulted in renal failure, and he subsequently required chronic hemodialysis. His consolidation therapy was modified due to end-stage renal disease (ESRD) and he received idarubicin and ATRA from May through July 2011 and maintenance therapy with ATRA from October through December 2011.17 In June 2012, the patient was diagnosed with relapsed APL when he again presented with pancytopenia. Bone marrow evaluation showed hypercellular marrow with 43% promyelocytes, cytogenetics revealed FISH for t(15;17) in seven out of 15 cells, and FISH was positive in 28.5% cells. A fixed dose of ATO 10 mg in 250 mL of D5W infused over 2 hours twice weekly was selected for re-induction therapy due to his cardiac history and hemodialysis-dependent renal dysfunction. A pretreatment ECHO showed a LVEF of 69% and an EKG was obtained which demonstrated sinus rhythm with 1st degree AV block, incomplete right bundle branch block (RBBB) and left anterior fascicular block (LAFB). A cardiologist was consulted, and based on the risk/benefit ratio, a decision was agreed upon to proceed with treatment with additional monitoring by EKGs. After the second dose of ATO, the patient’s EKG demonstrated sinus rhythm with progression of AV block to 2nd degree AV block (Mobitz type I), and persistent RBBB and LAFB. The patient remained asymptomatic and hemodynamically stable. ATO was held and Cardiology evaluation agreed that the 2nd degree AV heart block could be related to ATO administration. After discussion with the patient and team regarding the risk/benefit ratio, a decision was reached to continue treatment with ATO with continuous EKG monitoring in a telemetry unit. Over the next seven weeks, 11 doses of ATO were administered. The patient experienced fluctuations between 1st degree AV block and 2nd degree AV block felt to be due to ATO administration.
Placement of a pacemaker was considered. However, this was unable to be performed percutaneously due to multiple venous obstructions, and the risk of performing an open placement of an epicardial-lead pacemaker was considered very high risk due to the patient’s thrombocytopenia and neutropenia. In addition, the patient remained hemodynamically stable despite these rhythm disturbances, thus the risk of open procedure was considered to outweigh the potential benefit of pacing. A repeat bone marrow evaluation revealed hypercellular marrow with 50% promyelocytes, cytogenetics revealed t(15;17) in eight out of 15 cells, and FISH for t(15;17) was positive in 88% of cells. Due to persistence of the disease as well as the patient’s overall tolerance of ATO therapy, the treatment interval was changed to 10 mg IV three times weekly given after dialysis. After an additional 10 doses were given, a repeat bone marrow evaluation demonstrated hypercellular marrow containing 33% promyelocytes, cytogenetics revealed a t(15;17) in two out of 16 cells and FISH for t(15;17) was positive in 52% of cells. Re-induction ATO therapy was continued based on favorable response and a total of 47 ATO doses were given during the re-induction phase before a bone marrow evaluation which showed morphologic CR, normal karyotype and negative FISH for t(15;17). Three weeks after the completion of re-induction therapy, two cycles of consolidation therapy, three weeks apart, were given in the outpatient setting. Each consolidation cycle consisted of 25 doses of ATO given as 10 mg IV three times weekly postdialysis. Bone marrow evaluation was done 1 month after completion of the second consolidation and was consistent with morphologic remission with normal karyotype but positive FISH for t(15;17) in 1.5% of cells. He was considered for therapy with gemtuzumab ozogamicin on an extended access program but 2 months after second consolidation, he developed a hemorrhagic stroke and passed away.
ATO whole blood concentration monitoring Total arsenic whole blood concentration assays were performed by Mayo Medical Laboratories using an inductively coupled plasma-mass spectrometer. Prior to the initiation of treatment, the whole blood concentration of arsenic was 0 ng/mL. After the first dose of ATO was administered arsenic whole blood concentrations were drawn immediately post-dose (68 ng/mL) at 2.6 hours (43 ng/mL), 44.2 hours (74 ng/mL), and 61.4 hours (81 ng/mL). This demonstrated an infusional peak with distribution of arsenic into the tissues and later redistribution of arsenic back into the blood.
Downloaded from opp.sagepub.com at NORTH DAKOTA STATE UNIV LIB on May 20, 2015
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(OPP)
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The patient received dialysis after the first dose of ATO at hour 62. The arsenic concentration prior to dialysis was 81 ng/mL and then 1 hour after was 36 ng/mL and 8 hours after was 40 ng/mL (Figure 1). The percentage of arsenic removed by dialysis at hour 1 was 55.5% and at hour 8 was 38.3%. Arsenic removal by dialysis was also calculated with the second dose to measure consistency. The levels were again drawn prior to dialysis (96 ng/mL) and 5.7 hours after dialysis (59 ng/mL). The percentage of arsenic removed by dialysis after the second dose was 38.5%. The dialysis sessions were approximately 165 minutes in duration and were performed on a Fresenius 2008k2 machine using a polyarylethersulfone polyvinylpyrrolidone dialyzer (Reveclear, Gambro). Blood and dialysate flow rates were 400 mL/min and 600 mL/min, respectively. Other serial arsenic levels were obtained prior to and post-administration from the first dose to the eleventh dose. This collection of levels confirmed initial observation of arsenic distribution with hemodialysis with peak infusion effect, followed by redistribution of arsenic from blood into the tissue and back into the blood. Over time, a slight accumulation of arsenic concentrations occurred despite regularly administered dialysis. As a result, an elimination half-life was not possible to calculate; therefore weekly pre-dialysis ATO levels were obtained starting with the 12th dose which yielded a median concentration of 114 ng/mL (range 83–205 ng/mL). Twenty-three days elapsed between the completion of the first cycle of consolidation and the start of the second cycle. During this time-period no doses of ATO were administered. An arsenic concentration at the completion of the first cycle of consolidation was 176 ng/mL and prior to the initiation of the second
Arsenic Concentration (ng/mL)
Arsenic Removal from Hemodialysis 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0
7/21 Dose 3 and HD
7/17 Dose 2 and HD
NOTE: No pre and post dialysis levels were drawn for HD 7/19,thus no dip in level.
0
20
40
60
cycle of consolidation was 45 ng/mL. These levels confirm the known prolonged elimination of ATO from the body. To reconfirm this observation an additional level was obtained 38 days after the final completion of all doses of arsenic, showing a concentration of 30 ng/mL.
ATO toxicity monitoring Complete blood count with differential, serum creatinine, blood urea nitrogen, potassium, magnesium, aspartate aminotransferase, alanine aminotransferase, bilirubin was monitored daily during admission for re-induction and drawn at hemodialysis prior to every ATO dose during consolidation. While admitted during re-induction, our patient was monitored on a telemetry floor with daily EKGs, and EKGs were obtained before each ATO dose during outpatient consolidation. Magnesium and potassium serum concentrations were maintained above 2 mg/dL and 4 mmol/L; respectively. Concomitant medications known to prolong QTc were avoided during therapy. Manual calculation by cardiology of QTc interval using Bazett’s formula revealed the QTc interval was 10% lower compared to the automated calculations obtained from the EKG report. Therefore, the goal QTc interval was conservatively adjusted to be maintained at
