Rapid Onset of Fatal Tumor Lysis Syndrome in a Patient With Acute Myeloid Leukemia Receiving Azacitidine and Venetoclax Without a Ramp-Up Schedule: A Case Report

Venetoclax is an oral, highly selective BCL-2 inhibitor that is FDA-approved for the treatment of chronic lymphocytic leukemia (CLL) or acute myeloid leukemia (AML) in patients with comorbidities that preclude the use of intensive induction chemotherapy, including age ≥75 years.¹ BCL-2 is one of a family of proteins that exert an antiapoptotic function by blocking the translocation of proapoptotic factors across mitochondrial membranes to halt the permeabilization of mitochondrial membranes, leading to cell survival.^1,2 BCL-2 inhibition has been shown in preclinical models and clinical trials to restore dysregulated apoptosis in cancer cells and lead to clinical improvements in patients with specific hematologic malignancies.^3,4 In patients with AML, treatment with venetoclax coupled with low-dose cytarabine or a hypomethylating agent, such as azacitidine or decitabine, leads to rapid and durable responses relative to venetoclax monotherapy while maintaining a favorable adverse event (AE) profile.^5-7

A serious AE of venetoclax treatment that was identified early in clinical development is tumor lysis syndrome (TLS), a metabolic disorder in which high numbers of intracellular ions from lysed cells enter the plasma, leading to potentially fatal electrolyte imbalances.⁸ TLS is most frequent in patients with hematologic malignancies.⁹ Laboratory findings of electrolyte abnormalities beyond the defined thresholds for uric acid, potassium, phosphorus, and calcium are the defining characteristics of laboratory TLS. These electrolyte imbalances can lead to AEs, including kidney injury, seizures, cardiac arrhythmias, and sudden death, the presence of any of which, in addition to laboratory abnormalities, meets the definition of clinical TLS.¹⁰

The risk for TLS and the resultant serious clinical sequelae were realized early in the dose-escalation stage of the phase 1b trial investigating venetoclax in CLL.¹¹ Of 56 patients in the dose-escalation study cohort, 10 had TLS, even after initiating a ramp-up dosing schedule, as well as careful monitoring and prophylaxis.¹¹ Of the 10 patients with TLS, 3 patients had clinical TLS, including 2 who had serious sequelae and 1 who died.¹¹ When evaluating venetoclax combination therapy in patients with AML, a modified ramp-up schedule was developed⁶ and was propagated forward in the large-scale VIALE-A7 and VIALE-C5 trials, which was in concert with prophylactic measures, monitoring, and cytoreduction.

The ramp-up dosing schedule for venetoclax in patients with AML is 100 mg on day 1, 200 mg on day 2, 400 mg on day 3, and 400 mg daily on day 4 and thereafter when used with azacitidine or decitabine or 600 mg daily when used with low-dose cytarabine.¹² When venetoclax is administered with a strong CYP3A4 inhibitor (such as azole antifungals), a modified ramp up to a reduced target dose is defined to achieve comparable drug exposure despite the altered metabolism. The length of the treatment cycle for venetoclax is 28 days, and azacitidine can be administered intravenously or subcutaneously. The prescribing information for venetoclax gives risk stratification in patients with CLL based on tumor burden, coupled with specific recommendations for monitoring the level of care based on the patient’s risk for TLS. Unfortunately, there is not a similar risk stratification available for AML, but instead is usually evaluated based on provider discretion and institutional protocols. There are general recommendations in the prescribing information for venetoclax, including cytoreduction to a white blood cell (WBC) count <25×10⁹/L, adequate hydration, and antihyperuricemic measures for all patients. Regular laboratory monitoring during the ramp-up phase and dose changes, and aggressive correction of electrolyte abnormalities are also recommended.¹²

Case Report

An 85-year-old man presented to our institution with a 10-year history of polycythemia vera that was initially managed with aspirin and periodic phlebotomy. His medical history included hyperlipidemia and iron deficiency anemia for which he received atorvastatin and oral iron supplementation, respectively. The patient did not have any significant cardiac or renal history. Eight years after the initial diagnosis, splenomegaly and anemia suggested progression to myelofibrosis and led to the initiation of treatment with ruxolitinib. Two years later, a complete blood count showed 20% blasts, and a bone marrow biopsy showed hypercellular marrow with stage 3 fibrosis and 40% blasts on morphology, confirming the patient’s disease progression to AML. Despite otherwise good health, the patient’s age was disqualifying for allogeneic bone marrow transplant, and intensive induction chemotherapy has increased risk for severe cytopenias and subsequent infection and hospitalization. After consultation with the patient’s family, treatment with subcutaneous azacitidine and oral venetoclax was pursued.

Six days before the event, laboratory values showed uric acid of 6.5 mg/dL, lactate dehydrogenase of 743 mg/dL, serum creatinine of 1.17 mg/dL, and blood urea nitrogen of 40 mg/dL, with WBC 15.1×10⁹/L and 43% blasts in the peripheral blood. The patient started treatment with hydroxyurea 500 mg orally twice daily and allopurinol 300 mg orally twice daily to cytoreduce and decrease the risk for TLS, respectively, and was given instructions to increase hydration because of a potential for renal dysfunction resulting from tumor lysis from progressive disease. Three days before the event, the provider planned to titrate up the hydroxyurea dose to lower the patient’s WBCs (Figure) and delay the start of venetoclax treatment a few days after cycle 1 day 1 of azacitidine therapy to allow for more significant cytoreduction. Insurance authorization for posaconazole therapy was initiated at this time, but because the patient was not neutropenic, treatment with posaconazole was held to be reconsidered if his absolute neutrophil count were to drop to <1000 neutrophils/µL.

The venetoclax prescription was routed to the retail pharmacy 3 days before the event and the patient received directions that stated, “Take 4 tablets by mouth daily” of the 100-mg venetoclax tablets. The clinical pharmacist was scheduled to provide the ramp-up instructions during the chemotherapy teach before cycle 1 day 1 of therapy, but was postponed by the provider to align more closely to the new venetoclax treatment start date.

Two days before the event, the patient’s caregiver reported that the patient had a fever of 101.1°F without other signs or symptoms of infection. The patient was told to come to the clinic for hydration and evaluation. On arrival, he was afebrile, but cultures were drawn, a 14-day course of levofloxacin was ordered, and intravenous hydration was given. Cultures did not result in growth from any of the sites that were sampled (peripheral blood and urine). Hydroxyurea was not increased as initially planned, because the WBCs were trending slightly downward, and the patient had mouth sores that could be attributed to hydroxyurea. The patient obtained levofloxacin and venetoclax from the outpatient pharmacy and went home.

On the day of the event, a travel nurse saw the patient for a laboratory test review appointment and for the administration of treatment with azacitidine. The patient asked if he could take the first venetoclax dose in the presence of the nurse during his azacitidine and hydration appointment. The nurse checked the medical record and did not see a note indicating a delay in starting the venetoclax, because the start date adjustment was communicated by email and was not captured in the medical record. Without any evidence to suggest otherwise, the nurse agreed, and the patient took 400 mg of venetoclax rather than the planned 100 mg on day 1 of the ramp-up schedule. The patient was discharged home at the conclusion of the hydration appointment ambulatory and in stable condition.

Approximately 6 hours later, the patient had a syncopal episode at home and was transported to a nearby hospital. On arrival, he presented with hyperkalemia (8.1 mEq/L), hyperphosphatemia (11.1 mg/dL), and hypocalcemia (6.6 mEq/L; Table). His blood pressure was 120/40 mm Hg, his pulse was 40 bpm, and an electrocardiogram (ECG) was remarkable for low voltage and a wide QRS complex. The patient then received bicarbonate, insulin, calcium carbonate, and 1 L of normal saline. Because the patient’s uric acid level on admission to the emergency department was 4 mg/dL, treatment with rasburicase was not initiated. Despite the patient’s normal uric acid level, the administration of the high dose of venetoclax that morning, the electrolyte imbalances, and syncope with ECG changes leading to hemodynamic instability, the patient met the criteria for grade 4 clinical TLS.¹³

Despite an initial potassium shift with insulin and an attempted correction of other electrolytes, the patient’s pulse and blood pressure continued to decrease, and dopamine treatment was started. A second ECG showed atrial fibrillation with no P waves and the same low-amplitude QRS complex. The patient was intubated given his decreased consciousness and poor oxygenation. Repeat laboratory testing showed increased potassium and slightly decreased blood urea nitrogen despite receiving 1 L of fluid, and he had virtually no urine output. He went into cardiac arrest and received cardiopulmonary resuscitation, which was able to return a weak pulse but not a high enough blood pressure to sufficiently support oxygenation. The patient died approximately 2.75 hours after the initial syncopal episode.

Discussion

To date, such a rapid and fatal progression of TLS after a dose of venetoclax has not been reported and should be realized as a risk in the outpatient management of venetoclax-containing chemotherapy regimens. The patient’s disease and initial WBC count of <25×10⁹/L would be categorized as having a low risk for TLS.¹³ However, the patient’s need for cytoreduction before treatment initiation, elevated lactate dehydrogenase, and recent mild kidney dysfunction may have increased his risk for TLS-related complications. Although the patient’s age and course of levofloxacin treatment increased his risk for QTc prolongation, he had no other significant cardiac history and the emergency department’s monitoring did not show evidence of torsades de pointes. Collectively, the combination of positive and negative risk factors in this patient, particularly when combined with a medication error and his progressing disease, leaves the cause of his rapid health deterioration and death unclear despite receiving prophylactic treatment.

Although initial reports of TLS were the motivation for intense monitoring and careful dose escalation in CLL, the incidence of TLS in patients with AML remains relatively infrequent.¹⁴ In the phase 1b and phase 2 CLL trials, all patients were hospitalized for dose increases as a precaution; they also received TLS prophylaxis with an antihyperuricemic agent and hydration before the initiation of treatment.⁴ These precautions, as well as cytoreduction to a WBC count of <25×10⁹/L, were carried forward in the VIALE-A and VIALE-C trials.^5,7,15 In each of these trials, the incidence of TLS remained very low; there were no cases of TLS in the dose-finding trial, and the rates of TLS were 1% and 6% in the VIALE-A and VIALE-C trials, respectively.^5-7,16 In VIALE-A, the 3 cases of TLS were all transient laboratory abnormalities that were corrected with uricosuric agents and calcium supplementation without interrupting treatment.⁷ Some evidence suggests that the rate of TLS in real-world clinical practice is higher than the rate of TLS in seminal trials.¹⁷ There are some emerging case reports of clinical TLS in patients,^18,19 although these cases are not as severe as the case presented here. Currently, the prescribing information for venetoclax and the current National Comprehensive Cancer Network (NCCN) guidelines describe a ramp-up dosing schedule and careful monitoring as well as TLS prophylaxis considerations.^12,20

However, there is a growing body of evidence that suggests that venetoclax can be safely prescribed without a ramp-up schedule in certain patients with AML.^21-23 Further, several recent retrospective analyses have compared the outcomes, efficacy, and safety of patients who receive outpatient care or who have modified (or omitted) ramp-up strategies.^24-28 This variability is reflected in the current NCCN guidelines for venetoclax with low-dose cytarabine or hypomethylating agent therapy, which clarify that “treatment in [the] outpatient setting may be considered per institutional practice or treatment preference.”²⁰ Ultimately, although the ramp up in this case was omitted by mistake, it inadvertently mirrored a growing trend in clinical practice of dialing back some of the safety features described in earlier trials.^5,7

In response to this event, our institution has implemented systemic changes in our oral chemotherapy processes to prevent this error from recurring. The patient instructions for all venetoclax therapy now include “Do not take until instructed by your care team,” as well as the full ramp-up schedule. Counseling is provided by retail pharmacists on dispensing to reiterate checking in with the care team before starting the medication. Furthermore, changes in the start date for oral chemotherapy must now be documented in the treatment plan in the electronic medical record, and orders for delayed oral chemotherapy are released closer to the true start date of the medication and are not related to the start of the cycle.

We now have a separate treatment plan for high-risk patients who require more careful monitoring and care to prevent TLS. This high-risk treatment plan is available for selection by providers, using an individualized approach that considers renal function, disease burden, and anticipated tolerability as a result of physiologic frailty. This approach also includes scheduling phases for nursing follow-up and pharmacy education to ensure that important monitoring and instruction steps are scheduled appropriately before and after the initiation of oral chemotherapy.

Although the advantages of treatment with venetoclax in combination with hypomethylating agents or low-dose cytarabine are evident, this case serves as an important reminder of ensuring clinical and logistical safeguards are in place to minimize the risk for medication errors. Further, this case offers a cautionary tale that the omission of a medication ramp-up schedule in the outpatient setting can rapidly lead to a serious risk for TLS, even with appropriate cytoreduction and antihyperuricemic agents. This case also shows that the threshold of inpatient admission for medication ramp up should be quite low, and that, despite its rarity, TLS can happen and progress rapidly even in patients without significant medical comorbidities. This case also emphasizes the lack of well-defined, guideline-directed, evidence-based risk stratification for a more effective use of this agent in patients with AML and shows that a better understanding of the risk factors that are truly predictive of TLS in patients with AML is needed.

Author Disclosure Statement
Dr Eaton has received research support for Mirati Therapeutics; and Mr Schonrock, Mr Ma, Dr Momin, and Dr Ghuman have no conflicts of interest to report.

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