Venetoclax is a B-cell lymphoma 2 (BCL2) inhibitor that leads to apoptosis in BCL2-driven tumours, such as chronic lymphocytic leukaemia (CLL) and acute myeloid leukaemia (AML). Venetoclax has clinical activity in combination with either hypomethylating agents (HMAs) or low-dose cytarabine (LDAC) in newly diagnosed older (≥75 years) and unfit AML patients with overall complete remission (CR) rates of 73% and 54%, respectively (DiNardo et al, 2019; Wei et al, 2019). Venetoclax can lead to rapid tumour lysis syndrome (TLS) in CLL patients and is therefore administered in a weekly dose ramp-up to minimize toxicity (Roberts et al, 2016). A modified dose ramp-up of venetoclax over 3–4 days in combination with HMAs has been investigated in AML trials without any reported cases of TLS (DiNardo et al, 2019). Here, we present three AML patients who developed TLS whilst receiving treatment with venetoclax and azacitidine. Notably, two of these patients shared similar genomic characteristics.
Case 1 is a 71-year-old male with AML who received front-line treatment with azacitidine and venetoclax 100 mg daily (with concomitant posaconazole prophylaxis starting on day 1). Disease characteristics and laboratory values are listed in Tables I and II, respectively. He developed laboratory TLS by Cairo-Bishop criteria (Cairo & Bishop, 2004) by Day 2 (Table II). Sevelamer and intravenous fluids (IVFs) were initiated with TLS resolution by day 4. Posaconazole was held (days 2–4) due to liver function abnormalities. He achieved a CR after Cycle 1 and completed three subsequent cycles of therapy without TLS.
Table I.
Patient characteristics.
| Case | Treatment history | Bone marrow/blood pathology | Cytogenetics | Flow cytometry | Mutation panel | Venetoclax dose | Posaconazole prophylaxis start | Response |
|---|---|---|---|---|---|---|---|---|
| 1 | Newly diagnosed AML with prior cytopenias | Hypercellular marrow (95% cellular) with 92% blasts, monocytic differentiation and 5% plasma cells | Abnormal karyotype: 46,XY,der(12)t(11;12) (q23;q24·3)[20] | 78% blasts with CD4+, CD11c+, CD33+, CD45 dim, CD56+, CD64+, CD117+dim/partial, HLA-DR+, CD14−, CD34−, CD123−, Tdt- | ASXL1, RUNX1, SRSF2, TET2 on bone marrow | 100 mg PO daily | Day 1 | CR |
| 2 | Refractory AML | Normocellular marrow (40% cellular) with 70% blasts | Abnormal karyotype: 45,XY,-7[13]/46,sl,+22 [4]/46,XY[3] | 2% blasts with CD13+, CD34+, CD45 dim, D117+, HLA-DR+, CD11c−/+, CD33−/+, TdT −/+, CD4−, CD14−, CD56− CD64− | ASXL1, RUNX1, TET2 on bone marrow | 100 mg PO daily | Day 1 | Refractory |
| 3 | Secondary AML | 21% circulating blasts | Normal karyotype: 46,XY[20] | 36% blasts with CD4+/−, CD11c+, CD13+, CD33+, CD45 dim, CD64+, CD117+/−, CD14−, CD34−, CD56− | DNMT3, CEBPA, JAK2, STAG2, TET2 on peripheral blood | Ramp-up: Days 1–2: 100 mg; Days 3–4: 200 mg; Day 5 and beyond: 400 mg | No azole use | Refractory |
AML, acute myeloid leukaemia; CR, complete remission; PO, orally.
Table II.
Medications and tumour lysis laboratory results.
| Before treatment | Day 1 | Day 2 | Day 3 | Day 4 | Day 5 | |
|---|---|---|---|---|---|---|
| Case 1 | ||||||
| Azacitidine | 75 mg/m2 | 75 mg/m2 | 75 mg/m2 | 75 mg/m2 | 75 mg/m2 | |
| Venetoclax | 100 mg | 100 mg | 100 mg | 100 mg | 100 mg | |
| Posaconazole | 300 mg | 300 mg | ||||
| Allopurinol | 300 mg | 300 mg | 300 mg | 300 mg | 300 mg | 300 mg |
| IV Fluids (0·9% sodium chloride) | 1 l | 500 ml | 500 ml | 500 ml | ||
| Phosphate binder (sevelamer 1600 mg TID) | 4800 mg | 4800 mg | ||||
| Rasburicase | ||||||
| Uric acid (μmol/l) | 393 | 428 | 399 | 339 | 303 | |
| Potassium (mmol/l) | 4·3 | 4·8 | 4·7 | 4·8 | 4·8 | 4·5 |
| Phosphorus (mmol/l) | 1·45 | 1·94 | 1·52 | 1·23 | 0·97 | |
| Calcium (mmol/l) | 2·15 | 2·10 | 1·65 | 2·10 | 2·02 | 1·95 |
| Corrected calcium mmol/l | 2·15 | 1·9 | 2·15 | 2·15 | 2·10 | |
| Creatinine (μmol/l) | 90 | 188 | 146 | 126 | 96 | 96 |
| LDH (μkat/l) | 28 | 53 | 122 | 77 | 61 | |
| WBC (×109/l) | 3·8 | 1·5 | 0·5 | 0·2 | 0·2 | 0·2 |
| Case 2 | ||||||
| Azacitidine | 75 mg/m2 | 75 mg/m2 | 75 mg/m2 | 75 mg/m2 | ||
| Venetoclax | 100 mg | 100 mg | 100 mg | 100 mg | 100 mg | |
| Posaconazole | 300 mg | 300 mg | 300 mg | 300 mg | 300 mg | |
| Allopurinol | 300 mg | 300 mg | 300 mg | 300 mg | ||
| IV Fluids (0·9% sodium chloride) | 1 l | 1 l | 1 l | 1 l | ||
| Phosphate binder (sevelamer 1600 mg TID) | 2400 mg | 2400 mg | 2400 mg | |||
| Rasburicase | ||||||
| Uric acid (μmol/l) | 309 | 440 | 393 | 315 | 250 | |
| Potassium (mmol/l) | 4 | 4·4 | 4·8 | 3·7 | 4·1 | 4·1 |
| Phosphorus (mmol/l) | 1·29 | 1·81 | 1·71 | 1·52 | 1·36 | |
| Calcium (mmol/l) | 2·17 | 2·23 | 2·17 | 2·20 | 2·13 | 2·15 |
| Corrected calcium mmol/l | 2·33 | 2·25 | 2·33 | 2·35 | 2·30 | 2·30 |
| Creatinine (μmol/l) | 63 | 56 | 63 | 69 | 70 | 66 |
| LDH (μkat/l) | 14 | 36 | 31 | 19 | 16 | |
| WBC (×109/l) | 8·1 | 6·3 | 3·2 | 1 | 0·7 | 0·7 |
| Case 3 | ||||||
| Azacitidine | 75 mg/m2 | 75 mg/m2 | 75 mg/m2 | 75 mg/m2 | 75 mg/m2 | |
| Venetoclax | 100 mg | 100 mg | 200 mg | 200 mg | 400 mg | |
| Posaconazole | ||||||
| Allopurinol | 300 mg | 300 mg | 300 mg | 300 mg | ||
| IV Fluids (0·9% sodium chloride) | 1 l | 1 l | 1 l | 1 l | ||
| Phosphate binder (sevelamer 1600 mg TID) | ||||||
| Rasburicase | 6 mg | |||||
| Uric acid (μmol/l) | 440 | 625 | 42 | 36 | 54 | |
| Potassium (mmol/l) | 3·9 | 3·6 | 4 | 3·5 | 3·6 | 3·8 |
| Phosphorus (mmol/l) | 1·49 | 1·78 | 1·71 | 1·55 | 1·45 | |
| Calcium (mmol/l) | 2·52 | 2·38 | 2·13 | 2·10 | 2·05 | 2·13 |
| Corrected calcium mmol/l | 2·52 | 2·38 | 2·17 | 2·17 | 2·13 | 2·17 |
| Creatinine (μmol/l) | 118 | 155 | 156 | 176 | 169 | 144 |
| LDH (μkat/l) | 69 | 121 | 185 | 157 | 90 | |
| WBC (×109/l) | 18·5 | 23 | 16 | 8·9 | 7·3 | 4·3 |
IV, intravenous; LDH, lactate dehydrogenase; TID, 3 times a day; WBC, white blood cell count.
Normal ranges: uric acid, 240–540 μmol/l; potassium, 3·5–5 mmol/l; phosphorus, 0·94–1·52 mmol/l; calcium, 2·13–2·55 mmol/l; creatinine, 62–115 μmol/l; LDH, 5·64–10·19 μkat/l; WBC, 4·5–11 × 109/l.
Tumour lysis syndrome (TLS) risk was determined using the criteria of Cairo et al. (2010) and laboratory and clinical TLS was determined using Cairo-Bishop and Howard criteria (Cairo & Bishop, 2004; Howard et al., 2011). Case 1 had intermediate risk, with WBC < 25 × 109/l and LDH > 2× upper limit of normal (ULN) and met laboratory TLS (Cairo & Bishop, 2004) with phosphorus ≥1·45 mmol/l and calcium ≤1·75 mmol/l. Case 2 had low risk for TLS with WBC < 25 × 109/l and LDH < 2× ULN and met laboratory TLS by Cairo Bishop criteria (Cairo & Bishop, 2004) with uric acid increase by 25% and phosphorus >1·45 mmol/l. Case 3 had intermediate risk for TLS with WBC < 25 × 109/l and LDH > 2× ULN and met laboratory and clinical TLS by Cairo-Bishop and Howard criteria (Cairo & Bishop, 2004; Howard et al., 2011) with uric acid >476 μmol/l, phosphorus >1·45 mmol/l and creatinine ×1·5 ULN.
Case 2 is a 69-year-old male with refractory AML after CPX-351 induction followed by one cycle of azacitidine (Table I). Posaconazole was held one week prior to adding venetoclax. On Cycle 2 Day 1, he began venetoclax 100 mg/day with posaconazole prophylaxis. On Day 2, he developed laboratory TLS according to the criteria developed by Cairo and Bishop (2004) (Table II). He received allopurinol, sevelamer, and IVFs with TLS resolution by Day 4. He completed three additional cycles of azacitidine and venetoclax without TLS complications, but has not achieved a response.
Case 3 is a 79-year-old male initially diagnosed with myelodysplastic syndrome/myeloproliferative neoplasm, but developed 21% circulating blasts, demonstrating progression to AML (Table I). He received azacitidine and venetoclax ramp-up according to package insert (Table II) without azole prophylaxis. On Day 2, he was hospitalized after developing signs of laboratory and clinical TLS by recommended criteria (Cairo & Bishop, 2004; Howard et al, 2011) (Table II). He received rasburicase and IVFs, ramped up to venetoclax 400 mg without complications, and kidney injury resolution after 2 weeks. He had no TLS during Cycle 2, but this regimen was discontinued for disease progression.
To our knowledge, these are the first published reports of venetoclax-induced TLS in combination with HMAs in AML. Clinical trials of venetoclax alone or in combination with HMAs have not reported any incidence of venetoclax-induced TLS (Kanopleva et al, 2016; DiNardo et al, 2019), though there were two reported cases of laboratory TLS with venetoclax plus LDAC (Wei et al, 2019). Although rare, our institutional incidence of venetoclax-induced TLS (3/45 = 7%) suggests this may be more common in clinical practice than clinical trial populations. Possible explanations for the lack of TLS in the phase 1b trials with HMAs are that patients were administered TLS prophylaxis 72 h prior to therapy, received a short venetoclax ramp-up, and could not receive moderate/strong cytochrome P4503A (CYP3A) inducers/inhibitors (DiNardo et al, 2019). In our patients, only Case 1 received allopurinol >72 h prior to venetoclax and Cases 1 and 2 received a strong CYP3A inhibitor, which may have contributed to TLS in these cases.
Posaconazole, a strong CYP3A inhibitor, is recommended as anti-fungal prophylaxis for neutropenic AML patients (Minetto et al, 2013). Venetoclax is metabolized by CYP3A4 and concurrent treatment with CYP3A inhibitors can lead to significantly elevated levels of venetoclax by 7·1- to 8·8-fold (Agarwal et al, 2017). Thus, reducing the venetoclax dose by ≥75% is recommended when administered with strong CYP3A inhibitors.
Updated guidelines for venetoclax with strong CYP3A inhibitors recommend ramp-up from 10 to 70 mg over 4 days, followed by 70 mg/day (https://www.rxabbvie.com/pdf/venclexta.pdf), however, these have not been reported in clinical trials to date (DiNardo et al, 2019) and pose practical challenges. For example, the 10 and 50 mg pills, packaged in 7 day “wallet-packs” designed for ramp-up in CLL, require a separate co-pay. Given these challenges and the lack of prior TLS with AML, our practice is to start venetoclax and posaconazole on the same day to allow time to reach posaconazole steady state levels (half-life = ~30 h) (Agarwal et al, 2017) as an artificial dose ramp-up of venetoclax. This may have, in part, accounted for the TLS observed in Cases 1 and 2, though posaconazole would not have reached steady state by Day 2. Nonetheless, these patients may have been exposed to higher levels of venetoclax than expected.
Two patients (Case 1 and 2) who developed venetoclax-induced TLS had similar genomic profiles (ASXL1, RUNX1, TET2 mutations). The significance of this shared mutational profile, albeit rare in AML with an institutional prevalence of 4%, is unclear (Papaemmanuil et al, 2016). Further investigation of this mutational spectrum as a potential predictor of venetoclax sensitivity and proclivity for TLS is warranted.
In conclusion, this report highlights three cases of TLS after venetoclax initiation with azacitidine. Comparison of the management in phase 1b studies with our institutional experience suggests that TLS prophylaxis with allopurinol >72 h prior to venetoclax initiation is beneficial and that further investigation of dose ramp-up of venetoclax in combination with strong CYP3A inhibitors is warranted. Based on our findings, our recommendation is to attempt a venetoclax dose ramp-up without concomitant strong CYP3A inhibitors. Once venetoclax dose ramp-up is complete, azole prophylaxis can be added, if necessary, with appropriate venetoclax dose reduction in order to reduce potential TLS complications. As venetoclax becomes standard management for newly diagnosed older and unfit AML patients, vigilant monitoring is required to mitigate the possible TLS complications and ensure the safety of patients on these therapeutic agents.
Acknowledgments
Conflict of interest
Joshua F. Zeidner has received honoraria from AbbVie, Agios, Daiichi Sankyo, Celgene, Pfizer, and Tolero Pharmaceuticals. He has served as a consultant for AsystBio Laboratories and Covance. He received research funding from Celgene, Merck, Takeda, and Tolero. Benyam Muluneh has served as a consultant for Heron Therapeutics. Catherine C. Coombs has received honoraria from AbbVie, Loxo, H3 Biomedicine, Octapharma, and Pharmacyclics. She has served as a consultant for Abbvie, Covance, and Cowen & Co. She received institutional research funding from AROG, Gilead, Loxo, H3 Biomedicine, and Incyte. She received travel funding from AROG and Incyte. All other authors including Sonia Esparza, Jonathan Galeotti, Melissa Matson, Daniel R. Richardson, Nathan D. Montgomery, Katarzyna Jamieson, and Matthew C. Foster have no conflicts of interest.
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