ABSTRACT
Venetoclax with hypomethylating agents (HMA) is the standard of care for acute myeloid leukemia (AML) in patients ineligible for intensive chemotherapy and is associated with tumor lysis syndrome (TLS). TLS prophylaxis and the use of Cairo Bishop versus Howard diagnostic criteria are not standardized. Here we report TLS prophylaxis and incidence in a retrospective cohort of 100 consecutive AML patients treated with venetoclax and HMA. Thirty four patients developed laboratory Cairo Bishop TLS; 8 of these met criteria for clinical Cairo Bishop TLS. Only 6 of patients met Howard TLS criteria. Fourteen patients had spontaneous TLS. Ninety two out of 100 patients had a white blood cell count (WBC) < 25 000 cells/μL at treatment start. Prophylaxis like the original venetoclax trial with allopurinol (56%), intravenous fluids (21%), and frequent lab monitoring (56%) was less common. There was a trend toward increased Cairo Bishop TLS in patients with WBC ≥ 15 000 cells/μL. In our study Howard TLS criteria better identified patients with significant TLS. Aggressive TLS prophylaxis was uncommon in our cohort and is likely unnecessary for most patients at low risk of TLS.
Keywords: acute myeloid leukemia, Leukoreduction, prophylaxis, tumor lysis syndrome, Venetoclax
1. Introduction
Acute myeloid leukemia (AML) most commonly affects adults over the age of 65 who are often ineligible or respond poorly to standard induction chemotherapy regimens due to co‐morbidities, poor functional status, and high risk genomic features [1, 2]. Venetoclax is a small molecule inhibitor of B‐cell lymphoma 2 (BCL‐2) which, in combination with hypomethylating agents (HMA) or low dose cytarabine, has been shown to improve remission and survival rates in AML patients who are ineligible for standard chemotherapy and can be used as an induction regimen this patient population [3, 4, 5].
Venetoclax has been associated with tumor lysis syndrome (TLS), which is characterized by hyperuricemia, hyperphosphatemia, hyperkalemia, and/or hypocalcemia resulting from the death of malignant cells [6]. TLS can be further classified as laboratory or clinical TLS, with clinical TLS defined by the presence of acute kidney injury (AKI), seizure, cardiac arrhythmia, or sudden death in addition to laboratory abnormalities. There are two main sets of criteria used to diagnose TLS: Cairo Bishop criteria and Howard criteria (Table 1) [6, 7]. They differ in that Howard criteria do not include ≥ 25% changes in electrolytes/uric acid from baseline, use calcium corrected for hypoalbuminemia, and require that the two laboratory abnormalities be present within the same 24 hour period. For both criteria, the laboratory abnormalities must occur within 3 days prior to or up to 7 days following the initiation of treatment to constitute TLS.
TABLE 1.
TLS diagnostic criteria.
| Cairo Bishop criteria [6] | Howard criteria [7] | |
|---|---|---|
| Laboratory TLS: must meet two or more criteria within 3 days before the start of therapy and up to 7 days afterward |
|
Abnormalities must occur within the same 24 hour time frame |
| Clinical TLS: must meet at least one criteria in addition to laboratory TLS criteria |
|
|
Abbreviations: AKI, acute kidney injury; TLS, tumor lysis syndrome.
TLS related to venetoclax was first seen in patients with chronic lymphocytic leukemia (CLL). A phase I study in this population found laboratory TLS in 7/56 patients and clinical TLS in 3/56 patients including one case of sudden death and one case of renal failure requiring dialysis [8]. Due to this experience, the phase 1b trial of venetoclax (DiNardo et al., 2018) with HMA in AML patients took strict precautions to mitigate the risk of TLS [4, 9]. The first group of patients started allopurinol at least 72 hours prior to starting treatment and received intravenous (IV) fluids starting the night prior to the first dose of venetoclax with a goal of 2 L per day. All patients also had frequent TLS laboratory tests, had WBC count < 25 × 109 cells/L prior to treatment, and underwent a daily dose ramp‐up of venetoclax. There were no cases of clinical or laboratory TLS by Howard criteria in the phase 1b trial [4]. The phase 3 clinical trial of venetoclax and azacitidine for previously untreated AML did not have as strict TLS prophylaxis guidelines as the phase 1b trial. It reported 3 cases of laboratory TLS by Howard criteria out of 283 patients in the venetoclax group [10]. None of these patients required interruption of treatment.
Estimates of laboratory TLS occurrence in real world populations of AML patients receiving venetoclax with HMA vary from 0% and 40% and prophylactic measures are not well defined [11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23]. Cheng et al. found no cases of laboratory or clinical TLS by Cairo Bishop criteria in a cohort of 45 patients treated with venetoclax 100 mg daily plus posaconazole without dose ramp‐up. Shahswar et al. described a cohort of 42 patients who similarly received venetoclax 100 mg plus a cytochrome 3A4 (CYP3A4) inhibitor without dose ramp‐up and showed a 12% rate of laboratory TLS by Cairo Bishop criteria. In contrast, 59 out of 148 patients (40%) in a larger cohort study demonstrated laboratory TLS by Cairo Bishop criteria [12]. Only 5.4% of patients had values outside of reference ranges and only 2.7% met criteria for clinical TLS.
The existing literature therefore raises questions about the necessity of stringent TLS prophylaxis including hospitalization for frequent labs and aggressive IV hydration. Some centers administer venetoclax and HMA on an outpatient basis to eligible patients. One cohort of 39 patients and another cohort of 47 patients who received outpatient venetoclax each had only one patient develop laboratory TLS by Howard criteria requiring inpatient admission [14, 15].
Furthermore, the optimal TLS prophylaxis regimen in AML patients receiving venetoclax and HMA is not clear. Prior studies have reported the incidence of TLS using different sets of criteria, making it difficult to compare outcomes. Our work aims to identify the incidence of TLS as defined by both Cairo Bishop and Howard criteria in AML patients treated with venetoclax and HMA at our institution. It also aims to describe the TLS prophylaxis received by these patients and identify risk factors for TLS.
2. Materials & Methods
2.1. Patient Cohort
This study, performed with the approval of the Institutional Review Board of the University of Pennsylvania, was designed as a retrospective chart review of patients who received venetoclax with azacitidine or decitabine as up front treatment of AML. We identified 100 consecutive patients who were ≥ 18 years of age and started treatment at the University of Pennsylvania between January 2017 and August 2022.
All patients started venetoclax and azacitidine or decitabine on the same day. Patients who received at least one dose of venetoclax were included although the vast majority completed the first cycle of venetoclax as intended; only 13 patients in the cohort had an interruption in venetoclax dosing during the 7 days of treatment.
2.2. Definition of TLS and TLS Prophylaxis
TLS was defined using both Cairo Bishop and Howard criteria as outlined in Table 1. TLS laboratory values 3 days prior to initiating treatment were used as the patient's baseline unless the first available data was closer to the start of venetoclax. Laboratory values, if available, were trended through the seventh day after starting venetoclax. Of the patients who received inpatient treatment, 72.6% had 7 days of laboratory data and 91.6% had five or more days of laboratory data. Our cohort included a subset of patients treated in the ambulatory setting, 50% of whom only had TLS laboratory values measured every 2–4 days. TLS prophylaxis was at the discretion of the treating team.
2.3. Statistical Analysis
Statistics were performed using Mann–Whitney U tests, 2‐sided Fisher's exact tests, and 2‐sided Fisher–Freeman–Halton exact tests using SPSS Statistics for Macintosh, version 28.0 (Armonk, NY), with a significant p value of < 0.05.
3. Results
3.1. Cohort Characteristics
In this retrospective cohort of 100 consecutive AML patients receiving venetoclax and HMA the median age was 72 years (range 42–91 years), 67% were male, and most were White and non‐Hispanic/Latino (Table 2). Most patients had an ECOG score of 1. The average WBC count at the start of treatment was 9300 cells/μL. Most patients had adverse risk AML as defined by European LeukemiaNet (ELN) genetic risk classification. Sixteen (16%) of patients were treated in an outpatient setting.
TABLE 2.
Baseline characteristics.
| All patients (n = 100) | No TLS (n = 66) | Laboratory or clinical TLS by Cairo Bishop (n = 34) | p | |
|---|---|---|---|---|
| Sex (%) | 0.181 | |||
| Female | 33 (33) | 25 (38) | 8 (24) | |
| Male | 67 (67) | 41 (62) | 26 (76) | |
| Race (%) | 0.732 | |||
| White | 81 (81) | 53 (80) | 28 (82) | |
| Black | 9 (9) | 7 (11) | 2 (6) | |
| Asian | 1 (1) | 1 (2) | 0 (0) | |
| Other | 3 (3) | 1 (2) | 2 (6) | |
| Unknown | 6 (6) | 4 (6) | 2 (6) | |
| Ethnicity (%) | 1.000 | |||
| Non‐Hispanic/Latino | 96 (96) | 63 (96) | 33 (97) | |
| Hispanic/Latino | 1 (1) | 1 (2) | 0 (0) | |
| Unknown | 3 (3) | 2 (3) | 1 (3) | |
| Age (years) | 72 (mean) | 72 (mean) | 73 (mean) | 0.482 |
| 72 (median) | ||||
| Range 42–91 | ||||
| ECOG score at diagnosis (%) | < 0.001 | |||
| 0 | 8/64 (13) | 6/42 (14) | 2/22 (9) | |
| 1 | 30/64 (47) | 26/42 (62) | 4/22 (18) | |
| 2 | 18/64 (28) | 9/42 (21) | 9/22 (41) | |
| 3 | 8/64 (13) | 1/42 (2) | 7/22 (32) | |
| Creatinine (mean) | 1.08 mg/dL | 0.94 mg/dL | 1.35 mg/dL | 0.163 |
| Lactate dehydrogenase (u/L) | 541 (mean) | 416 (n = 58) | 757 (n = 34) | 0.002 |
| 317 (median) Range 121–4612 (n = 92) | ||||
| Treatment setting (%) | 0.010 | |||
| Inpatient | 84 (84) | 51 (77) | 33 (97) | |
| Outpatient | 16 (16) | 15 (23) | 1 (3) | |
| HMA Agent (%) | 0.397 | |||
| Azacitidine | 84 (84) | 57 (86) | 27 (79) | |
| Decitabine | 16 (16) | 9 (14) | 7 (21) | |
| Peripheral blast % (mean) | 26.9 | 21.9 | 36.5 | 0.008 |
| Bone marrow blast % (mean) | 46.9 (n = 92) | 42.8 (n = 64) | 56.7 (n = 28) | 0.028 |
| ELN risk classification (%) | 0.093 | |||
| Favorable | 10/89 (11) | 4/57 (7) | 6/32 (19) | |
| Intermediate | 17/89 (19) | 10/57 (18) | 7/32 (22) | |
| Adverse | 62/89 (70) | 43/57 (75) | 19/32 (59) | |
| Disease associated mutations (%) | ||||
| TP53 | 25/94 (27) | 18/61 (30) | 7/33 (21) | 0.468 |
| FLT3‐ITD | 13/96 (14) | 4/62 (6) | 9/34 (26) | 0.011 |
| FLT3‐TKD | 6/95 (6) | 1/61 (2) | 5/34 (15) | 0.021 |
| IDH1 | 7/97 (7) | 5/63 (8) | 2/34 (6) | 1.000 |
| IDH2 | 13/97 (13) | 9/63 (14) | 4/34 (12) | 1.000 |
| NPM1 | 17/95 (18) | 7/62 (11) | 10/33 (30) | 0.027 |
| CLL or CLL type MBL (%) | 6/95 (6) | 5/61 (8) | 1/34 (3) | 0.415 |
| CYP3A4 inhibitors at treatment start | 0.922 | |||
| Posaconazole | 5 (5) | 5 (8) | 3 (9) | |
| Voriconazole | 6 (6) | 3 (5) | 3 (9) | |
| Fluconazole | 2 (2) | 2 (3) | 0 (0) | |
| Amiodarone | 1 (1) | 1 (2) | 0 (0) | |
| Diltiazem or verapamil | 3 (3) | 2 (3) | 1 (3) | |
| None | 83 (83) | 56 (85) | 27 (79) |
Note: All pts. in cohort had data available for all variables unless noted in denominator or n = in parentheses. LDH reference range 98–192 u/L. Bold indicates p < 0.05.
Abbreviations: CLL, chronic lymphocytic leukemia; ECOG, Eastern Cooperative Oncology Group; ELN, European LeukemiaNet; HMA, hypomethylating agent; MBL, monoclonal B cell lymphocytosis; TLS, tumor lysis syndrome.
Eighty four (84%) patients received azacitidine and 16 (16%) received decitabine in combination with venetoclax. The majority of patients completed a 3 day dose escalation of venetoclax up to 400 mg (Table 3). Seventeen patients were on concomitant moderate or strong CYP3A4 inhibitors at the time they started venetoclax.
TABLE 3.
TLS prophylaxis in patients with and without evidence of TLS.
| No TLS (n = 66) | Laboratory or clinical TLS by Cairo Bishop (n = 34) | p | |
|---|---|---|---|
| WBC count at treatment start (mean) | 9.1 | 12.9 | 0.039 |
| ≥ 25 000 cells/μL (%) | 4 (6) | 4 (12) | 0.439 |
| ≥ 15 000 cells/μL (%) | 8 (12) | 10 (29) | 0.052 |
| Leukoreduction (%) | 9 (14) | 20 (59) | < 0.001 |
| Any venetoclax ramp‐up (%) | 56 (85) | 28 (82) | 0.778 |
| Venetoclax dosing strategy (%) | 0.694 | ||
| 100 mg > 200 mg > 400 mg by day 3 | 49 (74) | 26 (76) | |
| Slower ramp‐up or lower target dose without CYP3A4 inhibitors | 4 (6) | 1 (3) | |
| Other ramp‐up with CYP3A4 inhibitors | 3 (5) | 1 (3) | |
| 100 mg daily with posaconazole or voriconazole (no ramp‐up) | 7 (11) | 6 (18) | |
| 400 mg daily without CYP3A4 inhibitor | 3 (5) | 0 (0) | |
| (no ramp‐up) | |||
| Allopurinol start (%) | 0.065 | ||
| ≥ 72 h before venetoclax start | 32 (48) | 24 (71) | |
| 0–71 h before venetoclax start | 33 (50) | 10 (29) | |
| None | 1 (2) | 0 (0) | |
| Allopurinol end (%) | 0.593 | ||
| Day 3–6 of treatment cycle | 22 (33) | 15 (44) | |
| Day ≥ 7 of treatment cycle | 43 (65) | 19 (56) | |
| None | 1 (2) | 0 (0) | |
| TLS laboratories drawn every 8–12 h on days 1–3 of treatment cycle (%) | 29 (44) | 27 (79) | < 0.001 |
| IV fluid strategy (%) | < 0.001 | ||
| Continuous fluids | 42 (64) | 32 (94) | |
| Bolus fluids | 6 (9) | 2 (6) | |
| None | 18 (27) | 0 (0) | |
| Timing of maintenance IV fluid start (%) | 0.050 | ||
| Day before venetoclax start or earlier | 17/42 (40) | 20/32 (63) | |
| Day of venetoclax start or after | 25/42 (60) | 12/32 (38) | |
| Timing of maintenance IV fluid end (%) | 0.863 | ||
| Before day 3 of tx cycle | 8/42 (19) | 7/32 (22) | |
| Day 3–6 of tx cycle | 31/42 (74) | 22/32 (69) | |
| Day ≥ 7 of tx cycle | 3/42 (7) | 3/32 (9) | |
| Mean maintenance IV fluid duration (hour) | 103 | 124 | 0.034 |
| Maintenance IV fluid rate | 0.183 | ||
| < 100 cc/h | 20/42 (48) | 11/32 (34) | |
| ≥ 100 cc/h | 22/42 (52) | 21/32 (65) | |
| IV fluid prophylaxis as described in DiNardo et al., 2018 (%) | 7 (11) | 14 (41) | < 0.001 |
Note: Bold indicates p < 0.05.
Abbreviations: IV, intravenous; TLS, tumor lysis syndrome; WBC, white blood cell.
Thirty four patients met criteria for laboratory TLS by Cairo Bishop criteria; 8 of these patients also met criteria for clinical TLS due to AKI (Figure 1). There were no events of seizure, cardiac arrhythmia attributable to hyperkalemia, or sudden death in the cohort. Only 6 patients with Cairo Bishop TLS met the more stringent Howard criteria for TLS; 5 of these had clinical TLS due to AKI. Of the 3 patients who met criteria for clinical Cairo Bishop TLS only, 2 were found to have hypotension associated AKI rather than TLS. The other patient would have met clinical Howard TLS criteria if applied at the onset of their lab abnormalities rather than ≤ 3 days prior to venetoclax start when the formal time frame for defining TLS begins. Fourteen patients developed TLS prior to receiving venetoclax (including 4 patients who developed TLS again after receiving venetoclax). TLS that developed after receiving venetoclax most commonly occurred on day 2 (Figure 2).
FIGURE 1.
TLS subtypes. All patients with clinical TLS had acute kidney injury. CB‐TLS, Cairo Bishop TLS; H‐TLS, Howard TLS.
FIGURE 2.
Timing of TLS onset. 4 patients who experienced TLS spontaneously and after starting venetoclax are counted at both time points. 3 patients whose lab abnormalities were attributed to another pathology are excluded from this graph. CB‐TLS, Cairo Bishop TLS; H‐TLS, Howard TLS.
3.2. Clinical Predictors of TLS
Patients with Cairo Bishop TLS had higher ECOG scores and lactate dehydrogenase (LDH) than patients without Cairo Bishop TLS (Table 2). Higher peripheral blast percentage and bone marrow blast percentage were both associated with Cairo Bishop TLS. Patients with Cairo Bishop TLS were more likely to receive inpatient treatment. There was no difference in the presence of CLL or CLL type monoclonal B‐cell lymphocytosis (MBL).
Patients who developed TLS by Cairo Bishop criteria had a higher mean WBC count at the start of treatment but there was no difference in the proportion of patients who had WBC counts higher than 25 000 cells/μL. There was a trend towards increased Cairo Bishop TLS in patients with WBC counts ≥ 15 000 cells/μL; this reached statistical significance when excluding patients with spontaneous TLS (32% vs. 12%, p = 0.049). Other prophylactic measures as stringent as the original venetoclax trial were less common; 56 patients received allopurinol, 56 patients received frequent lab monitoring, and 21 patients received IV fluids similar to Di Nardo et al., 2018 (Table 3). Patients who developed Cairo Bishop TLS were more likely to have received aggressive IV fluid prophylaxis and frequent laboratory monitoring in line with the original trial.
Overall, there was a statistically significant increased relative risk of developing Cairo Bishop TLS with ECOG ≥ 2 (RR 3.9, 95% CI 1.8–8.6) and FLT3‐ITD (RR 2.3, 95% CI 1.4–3.8), FLT3‐TKD (2.6, 95% CI 1.6–4.1), and NPM1 mutations (RR 2.0, 95% CI 1.2–3.4) (Figure 3). FLT3‐TKD and FLT3‐ITD mutations were also associated with higher ECOG scores in our cohort, however the association between Cairo Bishop TLS and higher ECOG scores remained significant when excluding FLT3 mutated patients. While WBC ≥ 15 000 cells/μL only had a trend toward Cairo Bishop TLS using Fisher's exact test, it did show a statistically significantly increased relative risk (RR 1.9, 95% CI 1.1–3.2).
FIGURE 3.
Forest plot showing relative risk (RR) with 95% confidence interval (CI) for Cairo‐Bishop TLS.
3.3. Severity of TLS
To characterize the severity of TLS in the cohort, we categorized patients with any TLS into three groups: insignificant TLS, significant TLS, and those whose laboratory abnormalities were explained by a different pathology (Figure 4). We defined significant TLS as patients who required hospitalization (if started treatment outpatient) or ICU transfer, received rasburicase, developed an AKI, or had treatment held due to TLS. Seventeen patients had insignificant TLS, 14 had significant TLS, and 3 were ultimately felt not to have TLS. Of the 3 patients were felt not to have TLS, one patient had a gastrointestinal bleed with AKI and two patients developed AKIs attributed to hypotension. All 6 of the patients who met Howard criteria had significant TLS. Of the 8 patients with significant TLS who only met Cairo Bishop criteria, 6 had spontaneous TLS that began more than 3 days prior to starting venetoclax. These patients would have met Howard criteria at the onset of their TLS however by the time the formal time frame for defining TLS started, the laboratory abnormalities had improved and they only met Cairo Bishop criteria.
FIGURE 4.
TLS significance as defined by requiring hospitalization (if started treatment outpatient) or ICU transfer, receiving rasburicase, developing an AKI, or having treatment held due to TLS. *Six of these patients met laboratory or clinical Howard criteria at the onset of their spontaneous TLS. Their laboratory abnormalities were not as severe by ≤ 3 days prior to venetoclax start when the formal time frame for defining TLS begins. CB‐TLS, Cairo Bishop TLS; H‐TLS, Howard TLS.
Among the 14 patients with significant TLS, 9 had the onset of their TLS prior to receiving venetoclax, 4 had the onset after receiving venetoclax, and 1 patient experienced significant TLS both before and after receiving their first dose of venetoclax. Of the 5 patients with significant TLS after receiving venetoclax, one was an outpatient who developed hyperkalemia and required admission, one was an intermittent hemodialysis patient who required continuous renal replacement therapy in the ICU after the onset of TLS, one developed a respiratory decompensation after the first dose of venetoclax requiring ICU transfer and received rasburicase for TLS, and two had doses of venetoclax held due to TLS without other complications.
4. Discussion
In this university referral center cohort of 100 AML patient undergoing induction with venetoclax and HMA, we defined the rate of significant TLS and identified clinical variables associated with TLS development. Most patients did not develop significant TLS despite less aggressive prophylaxis than the original venetoclax trials. We found that Howard TLS criteria better identify patients who develop significant TLS. Our study suggests that significant TLS is uncommon and that a risk‐adapted approach could be identified to guide the intensity of TLS prophylaxis.
TLS occurred more frequently in our group than most previously published cohorts with a 34% rate of laboratory TLS by Cairo Bishop criteria (6% by laboratory Howard criteria) and an 8% rate of clinical TLS by Cairo Bishop criteria (5% by clinical Howard criteria). Only 17 patients had significant TLS, and most of the significant TLS in our cohort occurred prior to starting venetoclax. The high rate of laboratory TLS by Cairo Bishop criteria in our cohort may be in part attributable to the acuity of the patient population in our university referral center. Twenty nine patients (29%) required leukoreduction and 41 (41%) had an ECOG score of 2 or 3. Our cohort also had a high incidence of spontaneous TLS (14 out of 34 patients), which contributed to the high overall TLS rate. Additionally, most of our patients had 5–7 days of TLS labs available for analysis starting from the first day of venetoclax dosing of TLS labs available, which allowed us to detect small changes in laboratory values that met criteria for laboratory Cairo Bishop TLS.
Higher ECOG score was associated with laboratory TLS by Cairo Bishop criteria in our cohort. This may be reflective of underlying comorbidities that contribute to poor functional status in our patient population. Mutations in FLT3 and NPM1 were also associated with laboratory TLS by Cairo Bishop criteria. These mutations have not previously been identified with an increased risk of TLS. FLT3 mutated AML is associated with leukocytosis, which may affect its association with TLS in our cohort [24]. Other cohorts have shown an increased risk of TLS in patients with IDH2 mutations likely due to these patients' good response rates with venetoclax [12]. Interestingly, we did not find this association in our cohort. IDH mutations were present at expected rates and there were no differences in the TLS prophylaxis received by these patients [25].
Similarly to Abernathy et al., the average WBC count at treatment initiation was higher in patients who developed TLS (12.9 × 109 cells/L vs. 9.1 × 109 cells/L), although these averages were far below the WBC count guideline for venetoclax initiation of 25 × 109 cells/L [23]. Our entire cohort had a higher average WBC count at treatment initiation than many other cohorts that reported average WBC counts from 2 and 5 × 109 cells/L. [11, 12, 13, 15, 16, 19] Additionally, our data suggest an association of a WBC count < 15 × 109 cells/L with lower TLS risk. This may suggest that more aggressive leukoreduction further reduces the risk of TLS.
Using Howard TLS criteria excluded all patients with insignificant TLS as well as the patients who met Cairo Bishop TLS criteria but who ultimately were felt not to have TLS; this includes 2 patients who met clinical Cairo Bishop criteria. If applied at the onset of spontaneous TLS rather than 3 days before starting venetoclax, Howard criteria would have identified 12/14 patients with significant TLS. Of the two patients with significant TLS who did not meet Howard criteria, one had a dose of venetoclax held after meeting laboratory Cairo Bishop criteria and then resumed the following day without complications; the other received rasburicase for laboratory Cairo Bishop TLS after being transferred to the ICU for a respiratory decompensation following the first dose of venetoclax although it was not clear that TLS was the ultimate driver of the decompensation. This suggests that the Howard criteria for TLS may be more clinically meaningful than the Cairo Bishop criteria and should be used in future studies.
These results suggest patient, disease, and laboratory characteristics that can be used to identify patients at higher risk of significant TLS (Figure 5). Patients with poor functional status (ECOG ≥ 2) were at higher risk of laboratory Cairo Bishop TLS. Disease characteristics such as high LDH (mean 416 u/L vs. 757 u/L, p = 0.002), high blast percentage in the periphery (mean 21.9% vs. 36.5%, p = 0.008) and bone marrow (mean 42.8% vs. 56.7%, p = 0.028), and FLT3 and NPM1 mutations were also associated with laboratory Cairo Bishop TLS. We also saw that patients with significant TLS were more likely to have experienced spontaneous TLS and to have met Howard TLS criteria. All of these factors can be taken into account to identify patients at risk of significant TLS who are likely appropriate for more aggressive TLS prophylaxis.
FIGURE 5.
Proposed algorithm for identifying patients at increased risk of significant TLS. Images from www.flaticon.com.
Limitations of our study include its single center, retrospective design. Our cohort was predominantly male, White, and non‐Hispanic/Latino. Further study is needed to determine if these findings are replicated in a more diverse patient population. Not all patients had TLS laboratory data available through the seventh day after starting venetoclax, though over 90% of patients who received inpatient treatment had at least 5 days of data. More frequent data, particularly for outpatients, might increase the incidence of TLS in our cohort although such TLS would be unlikely to be significant.
5. Conclusion
In summary, our work shows a higher rate of Cairo Bishop laboratory TLS and higher rate of spontaneous TLS than commonly reported. Aggressive prophylaxis with allopurinol, leukoreduction, IV fluids, and frequent laboratory monitoring as outlined in the original trial of venetoclax and HMA was uncommon in our university referral center cohort but likely is not necessary for most patients. Howard criteria for TLS, particularly when used at the onset of spontaneous TLS even if > 3 days before starting venetoclax, more accurately identify patients who will suffer clinical consequences from TLS and should be included in future studies.
Author Contributions
M.R. designed the study, collected and analyzed the data, and wrote the manuscript. X.J.B. designed and supervised the study and wrote the manuscript. A.C. identified patients for data collection. D.B., M.C., N.F., S.G., E.H., R.H., N.H., C.L., A.L., S.L., I.M., S.M., A.M., M.E.M., V.R.P., A.P., D.P., K.P., and E.S. edited the manuscript.
Conflicts of Interest
MR, DB, EH, RH, NH, AL, SM, AM, MEM, VRP: None. MC: Cartography Bioscences: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Consultancy. NF: Kite Pharma: Consultancy; Sana Biotechnology: Consultancy. SG: Kite Pharma: Consultancy; Carisma Therapeutics: Current equity holder in publicly‐traded company, Current holder of stock options in a privately‐held company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: patents, Research Funding; Interius Biotherapeutics: Current equity holder in private company, Current holder of stock options in a privately‐held company, Membership on an entity's Board of Directors or advisory committees, Research Funding; Asher: Research Funding; Currus: Membership on an entity's Board of Directors or advisory committees; Inndura: Membership on an entity's Board of Directors or advisory committees; Mission Bio: Membership on an entity's Board of Directors or advisory committees; NKILT: Membership on an entity's Board of Directors or advisory committees; Vor Bio: Membership on an entity's Board of Directors or advisory committees, Research Funding. CL: Novartis: Consultancy; Rigel: Consultancy; Astellas: Consultancy; AbbVie: Consultancy; BMS: Consultancy; Genentech: Consultancy; Daiichi: Consultancy; Taiho: Consultancy; Pfizer: Consultancy; Jazz: Consultancy, Research Funding. SL: Onconova: Research Funding; Bristol‐Myers Squibb: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Marker Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Astellas: Honoraria. IM: Garuda Therapeutics: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Regeneron: Research Funding. AP: Forma: Consultancy; Rigel: Honoraria; Actinium: Honoraria; Aptose: Honoraria; BerGen Bio: Honoraria; Genentech: Honoraria; Foghorn: Consultancy; FujiFilm: Research Funding; Syndax: Research Funding; Immunogen: Honoraria; BMS: Honoraria; Beat AML: Other: Participation on a Data Safety Monitoring Board or Advisory Board; Bayer: Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi‐Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. DP: Sana Therapeutics: Consultancy, Current equity holder in publicly‐traded company; Tmunity: Patents & Royalties; Wiley and Sons Publishing: Honoraria; Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Mirror Biologics: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Genentech: Current equity holder in publicly‐traded company; DeCart: Membership on an entity's Board of Directors or advisory committees; Capstan Bio: Honoraria; BMS: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees; Angiocrine Bio: Membership on an entity's Board of Directors or advisory committees. KP: Roche: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Jazz Pharamceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol‐Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Research Funding; AbbVie: Consultancy, Research Funding. ES: Amgen: Consultancy; Janssen: Consultancy; BMS: Consultancy; Abbvie: Consultancy, Research Funding; genmab: Consultancy.
Acknowledgments
The authors have nothing to report.
Funding: The authors received no specific funding for this work.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.