CASE REPORT Carfilzomib-Associated Tumor Lysis Syndrome Ryan N. Shely, and Patrick D. Ratliff* Department of Pharmacy Services, Saint Joseph Hospital, Lexington, Kentucky
Multiple myeloma is the second most common type of hematologic malignancy. It is a B-cell malignancy that affects the bone marrow and often results in thrombocytopenia as well as renal dysfunction. Treatment options range from oral and intravenous chemotherapy to bone marrow transplantation and supportive care. Carfilzomib was approved by the U.S. Food and Drug Administration in 2012 as a treatment option for patients with refractory multiple myeloma who have received at least two previous therapies and have demonstrated recent disease progression. According to the product labeling, the frequency of tumor lysis syndrome (TLS) is less than 1% in patients treated with carfilzomib. To our knowledge, no postmarketing events of TLS have been reported or published. We describe a 55-year-old man with relapsed multiple myeloma who developed a case of TLS that occurred after he received his first two doses of carfilzomib therapy on days 1 and 2; he also had chronic kidney disease secondary to his neoplastic disease. Beginning on day 4, his uric acid levels spiked to critical levels, prompting the use of rasburicase, which returned the levels to within normal limits. His phosphorus and creatinine levels increased during days 5 and 6. On day 8, the patient died, likely due to a combination of disease progression and the adverse effects of treatment. Use of the Naranjo adverse drug reaction probability scale indicated a probable relationship (score of 6) between the patient’s development of TLS and carfilzomib therapy. The Hill criteria were used as a secondary measure to ensure causality, which also suggested a link between the patient’s development of TLS and the administration of carfilzomib. This case report shows that even the most unlikely of adverse events may occur with medications, especially in the case of a new or recently approved medication. Caution must be taken when deciding to treat and when choosing hydration and premedications with regard to biologic and chemotherapeutic medications. In this case, additional hydration may have been considered. Although given the extent of the adverse reaction combined with the patient’s underlying renal dysfunction, extra fluid may or may not have proven beneficial. The use of prophylactic rasburicase or allopurinol could have been considered, but these measures are not typically used with multiple myeloma due to the low incidence of TLS. All things considered, this unlikely adverse reaction may occur in certain patients. If other cases such as this occur, it may be advisable to use TLS prophylaxis in the future in certain patient populations, including those with renal dysfunction or worsening disease states. KEY WORDS multiple myeloma, oncology, hematology, carfilzomib, tumor lysis syndrome. (Pharmacotherapy 2014;34(5):e34–e37) doi: 10.1002/phar.1397
Multiple myeloma is the second most common hematologic malignancy, trailing only nonHodgkin lymphoma, and it represents ~1% of The authors have no disclosures or conflicts of interest. *Author for correspondence: Patrick D. Ratliff, Department of Pharmacy Services, Saint Joseph Hospital, One Saint Joseph Drive, Lexington, KY 40504, e-mail: [email protected]. Ó 2014 Pharmacotherapy Publications, Inc.
neoplastic diseases.1 Multiple myeloma is a cancer of the B cells, affecting the bone marrow and often resulting in thrombocytopenia. Another complication seen with multiple myeloma is kidney dysfunction as a result of prolonged elevations of myeloma protein levels.2 Several treatment options exist for multiple myeloma; however, disease progression is common; the average 5-year survival is ~68%.3
CARFILZOMIB-ASSOCIATED TLS Shely and Ratliff Carfilzomib, approved by the U.S. Food and Drug Administration in July 2012, is a new treatment option for patients with multiple myeloma who have been exposed to both an immunomodulating agent and bortezomib, and they must also have had disease progression on or within 60 days of completing previous therapy.4 This new medication shows positive results in the refractory setting. In a multicenter singlearm study of carfilzomib therapy in 266 patients who failed a median of five prior therapies, the overall response rate was 23.7%, median response duration was 7.8 months, and median overall survival was 15.6 months.5, 6 The beneficial effects of carfilzomib may be due in part to its mechanism of action. Carfilzomib functions as an irreversible proteasome inhibitor that may be more selective for the chymotrypsin protease enzyme than previous agents.4 Proteasomes function to remove abnormal or mutated proteins, which improves cellular function. Tumor cells are much more heavily reliant on proteasomes than normal cells, and inhibition of this function leads to apoptosis and halts cell proliferation in malignant cells.7, 8 The adverse-effect profile of carfilzomib is significant and is notable for causing thrombocytopenia (36% of patients), pulmonary complications (dyspnea [35%]), elevations in serum creatinine concentration (24%), and peripheral neuropathies (14%).4 Of note, the incidence of tumor lysis syndrome (TLS) is listed as less than 1% in the package insert.4 TLS is considered an oncologic emergency that results in a rapid shift in several electrolyte concentrations secondary to the lysing of tumor cells. Upon lysing, the intracellular contents of the tumor cells are spilled into the extracellular space, causing alterations in phosphorus, calcium, potassium, and uric acid levels.8 TLS is commonly delineated by the Cairo-Bishop definition and may be expressed as laboratorydefined or clinically defined TLS.9 To fulfill the criteria for laboratory-defined TLS, two or more laboratory changes must occur within 3 days before or 7 days after cytotoxic therapy. Table 1 shows the specific criteria for laboratory-defined TLS. Clinically defined TLS is a combination of
e35
evidence of laboratory-defined TLS plus one of the following: serum creatinine concentration greater than 1.5 times the upper normal limit, cardiac arrhythmias, sudden death, or seizures.10 The incidence of TLS varies with tumor type, tumor burden, type of chemotherapy, and tumor sensitivity to chemotherapy.11 The average incidence of TLS in patients with multiple myeloma is ~1%, with high-risk patients only having a slightly higher incidence of 1.4%.11 Complications of TLS include renal failure, arrhythmias, seizures, and death.9 Renal failure is largely due to uric acid crystallization and calcium-phosphate precipitation, which can be damaging to the kidney. Arrhythmias and seizures are principally attributable to rapid fluctuations in potassium and calcium levels. Prevention of TLS focuses primarily on three modalities: hydration, use of sodium bicarbonate, and medicinal prophylaxis with allopurinol and/or rasburicase. The benefit of hydration focuses on renal protection. Increased fluid volume allows for improved renal perfusion, optimizing excretion. Hydration also acts as a diluent to decrease serum solute concentrations, possibly making calcium-phosphate precipitants and uric acid crystals less nephrotoxic.9 The recommended fluid for prevention of TLS is 5% dextrose in 0.225% normal saline given throughout the course of therapy.9 The use of sodium bicarbonate is based on the methodology of urinary alkalization. On one hand, a higher pH allows for uric acid to be converted to a more soluble urate salt. On the other hand, the increase in pH promotes calcium-phosphate precipitation, which may offset the benefit of this approach. One study examined the effectiveness of hydration compared with the use of urinary alkalization and found no significant difference between the two therapies.9 Medicinal prevention with allopurinol and/or rasburicase is common practice depending on the patient’s risk factors. However, both medications only affect uric acid levels and have no effect on electrolyte dysfunction. Allopurinol is a
Table 1. Cairo-Bishop Criteria for Laboratory-Defined Tumor Lysis Syndrome10 Criteria Uric acid Potassium Phosphorus Calcium
Critical threshold ≥ ≥ ≥ ≤
8 mg/dl 6 mEq/L 4.5 mg/dl 7 mg/dl
Change from baseline 25% 25% 25% 25%
increase increase increase decrease
Normal range 3.4–7 mg/dl 3.5–5.1 mEq/L 2.4–5.1 mg/dl 8.5–10.2 mg/dl
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PHARMACOTHERAPY Volume 34, Number 5, 2014
xanthine oxidase inhibitor that prevents the formation of uric acid from xanthine and hypoxanthine.9 As such, allopurinol does not decrease existing elevated uric acid levels. Rasburicase is an exogenous urate oxidase enzyme that degrades uric acid to a more water-soluble compound and works to decrease existing serum concentrations.9 Case Report A 55-year-old man with a 5-year history of multiple myeloma and chronic kidney disease secondary to his neoplastic disease presented to the hospital with the chief complaint of lower extremity weakness and urinary retention. His myeloma had been treated aggressively with both chemotherapy and radiation over the past 5 years. Several combinations of medications had been used in the past, with the latest including bortezomib, lenalidomide, dexamethasone, and liposomal doxorubicin. He was evaluated for potential bone marrow transplant twice; however, a transplant was not feasible due to the medication-refractory nature of his disease. During this admission, the patient was found to have a tumor of the spinal canal, causing cord compression. The patient underwent spinal surgery as a palliative measure. Two weeks later, magnetic resonance imaging of the spine showed a return of the mass along with other signs of disease progression. Once the patient had stabilized, the decision was made to initiate therapy with carfilzomib. The patient was hydrated and premedicated with the appropriate antiemetic agents prior to therapy. The first two doses of carfilzomib 44 mg (20 mg/m2 on days 1 and 2) were administered; Table 2 shows the patient’s baseline laboratory results. Beginning on day 4, the patient’s
uric acid levels spiked to critical levels, prompting the use of rasburicase, which returned the levels to within normal limits. His phosphorus and creatinine levels increased during days 5 and 6. Table 2 shows the progression of the patient’s laboratory results after carfilzomib treatment. On day 8, the patient died, likely due to a combination of disease progression and the adverse effects of treatment. At that point, no postmortem examination was performed. It was speculated, however, that exsanguination was the likely cause of death. Discussion According to the Cairo-Bishop criteria for TLS, the patient did have laboratory-defined TLS because two of the four markers were above the breakpoint values (phosphorus and uric acid levels). Furthermore, it appears clinically defined TLS was also present as was evident by the patient’s rise in serum creatinine concentration. Confounding factors exist that need to be addressed when discussing whether this case was definitively TLS. One confounding factor is whether the rise in serum creatinine concentration was due to TLS or was an adverse event from carfilzomib therapy. As previously noted, an increase in serum creatinine concentration was seen in 24% of patients receiving carfilzomib in clinical trials.4 A second issue to consider is the patient’s baseline renal function. The Cairo-Bishop definition for clinically defined TLS focuses on an increase in serum creatinine concentration of 1.5 times the upper limit of normal or greater. In this case, the patient was initially above this threshold, making quantitative identification more difficult. One final confounding factor to address is the lack of a true
Table 2. Laboratory Results at Baseline and After Carfilzomib Administration Criteria Potassium, mEq/L Creatinine, mg/dl Calcium, mg/ dl Phosphorus, mg/dl Uric acid, mg/dl
Baseline (normal range)
Day 4
Day 5
4.8 (3.5–5.1)
4.3
4.7
4.7
≥6
3.3 (0.6–1.4)
3.2
3.8
4.7
8.2 (8.5–10.2)
ND
7.6
7.1
6.3 (2.4–5.1)
ND
6.8
10.4
ND (3.4–7)
15.9 0.3
0.3
UNL = upper normal limit; ND = not done.
Day 6
Breakpoint
% Difference from baseline
Positive marker for tumor lysis syndrome
2% decrease
No
≥ 1.5 9 ULN
42% increase
Yes
≤7
13% decrease
No
≥ 4.5
65% increase
Yes
≥8
Not applicable
Yes
CARFILZOMIB-ASSOCIATED TLS Shely and Ratliff baseline uric acid level. After treatment with carfilzomib, the patient’s uric acid level was measured at 15.9 mg/dl, almost double the established breakpoint value for TLS, but a true baseline value was not known. Use of the Naranjo adverse drug reaction probability scale12 indicated a probable link, with a score of 6, between the development of TLS and the administration of carfilzomib. Because it is a rather subjective rating system, the link was further evaluated by the Hill criteria.13 The strength of association, frequency, and replicability of this adverse reaction could not be determined with a single event. However, there is the plausibility of a temporal relationship and coherence within the case to support a causal link. The patient was neither alive long enough for medication rechallenge nor was it known if the development of TLS was dose dependent. The only alternative explanation is that disease progression was responsible for the events due to worsened renal function and thereby a limited ability to regulate electrolytes. This does not exactly explain, however, the cause of the dramatic increases in the previously mentioned blood chemistries. Conclusion This case shows that even the most unlikely of adverse events may occur with medications, especially in the case of a new or recently approved medication. Caution must be taken when deciding to treat and when choosing hydration and premedications with regard to biologic and chemotherapeutic medications. In this case, additional hydration may have been considered. Although given the extent of the adverse reaction combined with the patient’s underlying renal dysfunction, extra fluid may or may not have proven beneficial. The use of pro-
e37
phylactic rasburicase or allopurinol could have been considered, but these measures are not typically used with multiple myeloma due to the low incidence of TLS. All things considered, this unlikely adverse reaction may occur in certain patients. If other cases such as this occur, it may be advisable to use TLS prophylaxis in the future in certain patient populations including those with renal dysfunction or worsening disease states. References 1. Raab MS, Podar K, Breitkreutz I, Richardson PG, Anderson KC. Multiple myeloma. Lancet 2009;147:324–39. 2. Palumbo A, Anderson K. Multiple myeloma. N Engl J Med 2011;364:1046–60. 3. Wirth SM, Steinke DT, Lawson AP, et al. Predictors for severe tumor lysis syndrome. J Hematol Oncol Pharm 2012;2:47–53. 4. Onyx Pharmaceuticals. Kyprolis (carfilzomib) package insert. South San Francisco, CA; 2012. 5. Redic K. Carfilzomib: a novel agent for multiple myeloma. J Pharm Pharmacol 2013;65:1095–106. 6. Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood 2012;120:2817–25. 7. Targeted Oncology. Novel Proteasome Inhibitors for Multiple Myeloma. June 2013. Available from http://www.targetedonc.com/publications/targeted-therapies-cancer/2013/June2013/Novel-Proteasome-Inhibitors-for-Multiple-Myeloma. Accessed October 9, 2013. 8. Salvia Jain S, Diefenbach C, Zain J, O’Connor OA. Emerging role of carfilzomib in treatment of relapsed and refractory lymphoid neoplasms and multiple myeloma. Core Evid 2011;6:43– 57. 9. Coiffier B, Altman A, Pui C, Younes A, Cairo MS. Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol 2008;26:2767– 78. 10. Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol 2004;127:3–11. 11. Brenner H, Gondos A, Pulte D. Expected long-term survival of patients diagnosed with multiple myeloma in 2006–2010. Hematologica 2009;94:270–5. 12. Naranjo CA, Busto U, Sellers EM, et al. A method of estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239–45. 13. Hill AB. The environment and disease: association or causation? Proc R Soc Med 1965;58:295–300.
Multiple myeloma is the second most common type of hematologic malignancy. It is a B-cell malignancy that affects the bone marrow and often results in thrombocytopenia as well as renal dysfunction. Treatment options range from oral and intravenous chemotherapy to bone marrow transplantation and supportive care. Carfilzomib was approved by the U.S. Food and Drug Administration in 2012 as a treatment option for patients with refractory multiple myeloma who have received at least two previous therapies and have demonstrated recent disease progression. According to the product labeling, the frequency of tumor lysis syndrome (TLS) is less than 1% in patients treated with carfilzomib. To our knowledge, no postmarketing events of TLS have been reported or published. We describe a 55-year-old man with relapsed multiple myeloma who developed a case of TLS that occurred after he received his first two doses of carfilzomib therapy on days 1 and 2; he also had chronic kidney disease secondary to his neoplastic disease. Beginning on day 4, his uric acid levels spiked to critical levels, prompting the use of rasburicase, which returned the levels to within normal limits. His phosphorus and creatinine levels increased during days 5 and 6. On day 8, the patient died, likely due to a combination of disease progression and the adverse effects of treatment. Use of the Naranjo adverse drug reaction probability scale indicated a probable relationship (score of 6) between the patient’s development of TLS and carfilzomib therapy. The Hill criteria were used as a secondary measure to ensure causality, which also suggested a link between the patient’s development of TLS and the administration of carfilzomib. This case report shows that even the most unlikely of adverse events may occur with medications, especially in the case of a new or recently approved medication. Caution must be taken when deciding to treat and when choosing hydration and premedications with regard to biologic and chemotherapeutic medications. In this case, additional hydration may have been considered. Although given the extent of the adverse reaction combined with the patient’s underlying renal dysfunction, extra fluid may or may not have proven beneficial. The use of prophylactic rasburicase or allopurinol could have been considered, but these measures are not typically used with multiple myeloma due to the low incidence of TLS. All things considered, this unlikely adverse reaction may occur in certain patients. If other cases such as this occur, it may be advisable to use TLS prophylaxis in the future in certain patient populations, including those with renal dysfunction or worsening disease states. KEY WORDS multiple myeloma, oncology, hematology, carfilzomib, tumor lysis syndrome. (Pharmacotherapy 2014;34(5):e34–e37) doi: 10.1002/phar.1397
Multiple myeloma is the second most common hematologic malignancy, trailing only nonHodgkin lymphoma, and it represents ~1% of The authors have no disclosures or conflicts of interest. *Author for correspondence: Patrick D. Ratliff, Department of Pharmacy Services, Saint Joseph Hospital, One Saint Joseph Drive, Lexington, KY 40504, e-mail: [email protected]. Ó 2014 Pharmacotherapy Publications, Inc.
neoplastic diseases.1 Multiple myeloma is a cancer of the B cells, affecting the bone marrow and often resulting in thrombocytopenia. Another complication seen with multiple myeloma is kidney dysfunction as a result of prolonged elevations of myeloma protein levels.2 Several treatment options exist for multiple myeloma; however, disease progression is common; the average 5-year survival is ~68%.3
CARFILZOMIB-ASSOCIATED TLS Shely and Ratliff Carfilzomib, approved by the U.S. Food and Drug Administration in July 2012, is a new treatment option for patients with multiple myeloma who have been exposed to both an immunomodulating agent and bortezomib, and they must also have had disease progression on or within 60 days of completing previous therapy.4 This new medication shows positive results in the refractory setting. In a multicenter singlearm study of carfilzomib therapy in 266 patients who failed a median of five prior therapies, the overall response rate was 23.7%, median response duration was 7.8 months, and median overall survival was 15.6 months.5, 6 The beneficial effects of carfilzomib may be due in part to its mechanism of action. Carfilzomib functions as an irreversible proteasome inhibitor that may be more selective for the chymotrypsin protease enzyme than previous agents.4 Proteasomes function to remove abnormal or mutated proteins, which improves cellular function. Tumor cells are much more heavily reliant on proteasomes than normal cells, and inhibition of this function leads to apoptosis and halts cell proliferation in malignant cells.7, 8 The adverse-effect profile of carfilzomib is significant and is notable for causing thrombocytopenia (36% of patients), pulmonary complications (dyspnea [35%]), elevations in serum creatinine concentration (24%), and peripheral neuropathies (14%).4 Of note, the incidence of tumor lysis syndrome (TLS) is listed as less than 1% in the package insert.4 TLS is considered an oncologic emergency that results in a rapid shift in several electrolyte concentrations secondary to the lysing of tumor cells. Upon lysing, the intracellular contents of the tumor cells are spilled into the extracellular space, causing alterations in phosphorus, calcium, potassium, and uric acid levels.8 TLS is commonly delineated by the Cairo-Bishop definition and may be expressed as laboratorydefined or clinically defined TLS.9 To fulfill the criteria for laboratory-defined TLS, two or more laboratory changes must occur within 3 days before or 7 days after cytotoxic therapy. Table 1 shows the specific criteria for laboratory-defined TLS. Clinically defined TLS is a combination of
e35
evidence of laboratory-defined TLS plus one of the following: serum creatinine concentration greater than 1.5 times the upper normal limit, cardiac arrhythmias, sudden death, or seizures.10 The incidence of TLS varies with tumor type, tumor burden, type of chemotherapy, and tumor sensitivity to chemotherapy.11 The average incidence of TLS in patients with multiple myeloma is ~1%, with high-risk patients only having a slightly higher incidence of 1.4%.11 Complications of TLS include renal failure, arrhythmias, seizures, and death.9 Renal failure is largely due to uric acid crystallization and calcium-phosphate precipitation, which can be damaging to the kidney. Arrhythmias and seizures are principally attributable to rapid fluctuations in potassium and calcium levels. Prevention of TLS focuses primarily on three modalities: hydration, use of sodium bicarbonate, and medicinal prophylaxis with allopurinol and/or rasburicase. The benefit of hydration focuses on renal protection. Increased fluid volume allows for improved renal perfusion, optimizing excretion. Hydration also acts as a diluent to decrease serum solute concentrations, possibly making calcium-phosphate precipitants and uric acid crystals less nephrotoxic.9 The recommended fluid for prevention of TLS is 5% dextrose in 0.225% normal saline given throughout the course of therapy.9 The use of sodium bicarbonate is based on the methodology of urinary alkalization. On one hand, a higher pH allows for uric acid to be converted to a more soluble urate salt. On the other hand, the increase in pH promotes calcium-phosphate precipitation, which may offset the benefit of this approach. One study examined the effectiveness of hydration compared with the use of urinary alkalization and found no significant difference between the two therapies.9 Medicinal prevention with allopurinol and/or rasburicase is common practice depending on the patient’s risk factors. However, both medications only affect uric acid levels and have no effect on electrolyte dysfunction. Allopurinol is a
Table 1. Cairo-Bishop Criteria for Laboratory-Defined Tumor Lysis Syndrome10 Criteria Uric acid Potassium Phosphorus Calcium
Critical threshold ≥ ≥ ≥ ≤
8 mg/dl 6 mEq/L 4.5 mg/dl 7 mg/dl
Change from baseline 25% 25% 25% 25%
increase increase increase decrease
Normal range 3.4–7 mg/dl 3.5–5.1 mEq/L 2.4–5.1 mg/dl 8.5–10.2 mg/dl
e36
PHARMACOTHERAPY Volume 34, Number 5, 2014
xanthine oxidase inhibitor that prevents the formation of uric acid from xanthine and hypoxanthine.9 As such, allopurinol does not decrease existing elevated uric acid levels. Rasburicase is an exogenous urate oxidase enzyme that degrades uric acid to a more water-soluble compound and works to decrease existing serum concentrations.9 Case Report A 55-year-old man with a 5-year history of multiple myeloma and chronic kidney disease secondary to his neoplastic disease presented to the hospital with the chief complaint of lower extremity weakness and urinary retention. His myeloma had been treated aggressively with both chemotherapy and radiation over the past 5 years. Several combinations of medications had been used in the past, with the latest including bortezomib, lenalidomide, dexamethasone, and liposomal doxorubicin. He was evaluated for potential bone marrow transplant twice; however, a transplant was not feasible due to the medication-refractory nature of his disease. During this admission, the patient was found to have a tumor of the spinal canal, causing cord compression. The patient underwent spinal surgery as a palliative measure. Two weeks later, magnetic resonance imaging of the spine showed a return of the mass along with other signs of disease progression. Once the patient had stabilized, the decision was made to initiate therapy with carfilzomib. The patient was hydrated and premedicated with the appropriate antiemetic agents prior to therapy. The first two doses of carfilzomib 44 mg (20 mg/m2 on days 1 and 2) were administered; Table 2 shows the patient’s baseline laboratory results. Beginning on day 4, the patient’s
uric acid levels spiked to critical levels, prompting the use of rasburicase, which returned the levels to within normal limits. His phosphorus and creatinine levels increased during days 5 and 6. Table 2 shows the progression of the patient’s laboratory results after carfilzomib treatment. On day 8, the patient died, likely due to a combination of disease progression and the adverse effects of treatment. At that point, no postmortem examination was performed. It was speculated, however, that exsanguination was the likely cause of death. Discussion According to the Cairo-Bishop criteria for TLS, the patient did have laboratory-defined TLS because two of the four markers were above the breakpoint values (phosphorus and uric acid levels). Furthermore, it appears clinically defined TLS was also present as was evident by the patient’s rise in serum creatinine concentration. Confounding factors exist that need to be addressed when discussing whether this case was definitively TLS. One confounding factor is whether the rise in serum creatinine concentration was due to TLS or was an adverse event from carfilzomib therapy. As previously noted, an increase in serum creatinine concentration was seen in 24% of patients receiving carfilzomib in clinical trials.4 A second issue to consider is the patient’s baseline renal function. The Cairo-Bishop definition for clinically defined TLS focuses on an increase in serum creatinine concentration of 1.5 times the upper limit of normal or greater. In this case, the patient was initially above this threshold, making quantitative identification more difficult. One final confounding factor to address is the lack of a true
Table 2. Laboratory Results at Baseline and After Carfilzomib Administration Criteria Potassium, mEq/L Creatinine, mg/dl Calcium, mg/ dl Phosphorus, mg/dl Uric acid, mg/dl
Baseline (normal range)
Day 4
Day 5
4.8 (3.5–5.1)
4.3
4.7
4.7
≥6
3.3 (0.6–1.4)
3.2
3.8
4.7
8.2 (8.5–10.2)
ND
7.6
7.1
6.3 (2.4–5.1)
ND
6.8
10.4
ND (3.4–7)
15.9 0.3
0.3
UNL = upper normal limit; ND = not done.
Day 6
Breakpoint
% Difference from baseline
Positive marker for tumor lysis syndrome
2% decrease
No
≥ 1.5 9 ULN
42% increase
Yes
≤7
13% decrease
No
≥ 4.5
65% increase
Yes
≥8
Not applicable
Yes
CARFILZOMIB-ASSOCIATED TLS Shely and Ratliff baseline uric acid level. After treatment with carfilzomib, the patient’s uric acid level was measured at 15.9 mg/dl, almost double the established breakpoint value for TLS, but a true baseline value was not known. Use of the Naranjo adverse drug reaction probability scale12 indicated a probable link, with a score of 6, between the development of TLS and the administration of carfilzomib. Because it is a rather subjective rating system, the link was further evaluated by the Hill criteria.13 The strength of association, frequency, and replicability of this adverse reaction could not be determined with a single event. However, there is the plausibility of a temporal relationship and coherence within the case to support a causal link. The patient was neither alive long enough for medication rechallenge nor was it known if the development of TLS was dose dependent. The only alternative explanation is that disease progression was responsible for the events due to worsened renal function and thereby a limited ability to regulate electrolytes. This does not exactly explain, however, the cause of the dramatic increases in the previously mentioned blood chemistries. Conclusion This case shows that even the most unlikely of adverse events may occur with medications, especially in the case of a new or recently approved medication. Caution must be taken when deciding to treat and when choosing hydration and premedications with regard to biologic and chemotherapeutic medications. In this case, additional hydration may have been considered. Although given the extent of the adverse reaction combined with the patient’s underlying renal dysfunction, extra fluid may or may not have proven beneficial. The use of pro-
e37
phylactic rasburicase or allopurinol could have been considered, but these measures are not typically used with multiple myeloma due to the low incidence of TLS. All things considered, this unlikely adverse reaction may occur in certain patients. If other cases such as this occur, it may be advisable to use TLS prophylaxis in the future in certain patient populations including those with renal dysfunction or worsening disease states. References 1. Raab MS, Podar K, Breitkreutz I, Richardson PG, Anderson KC. Multiple myeloma. Lancet 2009;147:324–39. 2. Palumbo A, Anderson K. Multiple myeloma. N Engl J Med 2011;364:1046–60. 3. Wirth SM, Steinke DT, Lawson AP, et al. Predictors for severe tumor lysis syndrome. J Hematol Oncol Pharm 2012;2:47–53. 4. Onyx Pharmaceuticals. Kyprolis (carfilzomib) package insert. South San Francisco, CA; 2012. 5. Redic K. Carfilzomib: a novel agent for multiple myeloma. J Pharm Pharmacol 2013;65:1095–106. 6. Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood 2012;120:2817–25. 7. Targeted Oncology. Novel Proteasome Inhibitors for Multiple Myeloma. June 2013. Available from http://www.targetedonc.com/publications/targeted-therapies-cancer/2013/June2013/Novel-Proteasome-Inhibitors-for-Multiple-Myeloma. Accessed October 9, 2013. 8. Salvia Jain S, Diefenbach C, Zain J, O’Connor OA. Emerging role of carfilzomib in treatment of relapsed and refractory lymphoid neoplasms and multiple myeloma. Core Evid 2011;6:43– 57. 9. Coiffier B, Altman A, Pui C, Younes A, Cairo MS. Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol 2008;26:2767– 78. 10. Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol 2004;127:3–11. 11. Brenner H, Gondos A, Pulte D. Expected long-term survival of patients diagnosed with multiple myeloma in 2006–2010. Hematologica 2009;94:270–5. 12. Naranjo CA, Busto U, Sellers EM, et al. A method of estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239–45. 13. Hill AB. The environment and disease: association or causation? Proc R Soc Med 1965;58:295–300.
