Venetoclax with Azacitidine Induced Tumor Lysis Syndrome in an Elderly Patient with Acute Myeloid Leukemia: A Case Report

Abstract LBH589 (Novartis) is a potent histone deacetylase inhibitor (HDACi) currently in early phase clinical development. Preliminary data suggests biological activity in a range of malignant hematological disorders including acute myeloid leukemia (AML). To-date, laboratory tumor lysis syndrome (LTLS) has not been described as a complication of LBH589 therapy. We report a case of a 60 year-old man who developed LTLS following treatment for AML with oral LBH589. The patient was diagnosed with refractory anemia with excess blasts (RAEB) in July 2005. Cytogenetic analysis demonstrated trisomy 8 and del(20q). He was initially treated with standard dose cytarabine and idarubicin (7 + 3). Post-induction bone marrow examination revealed ongoing dysplasia but no excess of myeloblasts. He subsequently received further cytarabine and idarubicin as consolidation. This was complicated by prolonged pancytopenia and subsequently by rapid progression to overt AML. Salvage therapy with fludarabine/cytarabine/G-CSF (FLAG) failed and he was referred to our institution for investigational therapy with LBH589. The patient was enrolled in a Phase IA/II trial of oral LBH589 for patients with advanced hematological malignancies and commenced intermittent oral LBH589 (30mg orally Monday, Wednesday and Friday on alternate weeks). He re-presented on day 14 with deteriorating renal function - creatinine 0.28mM/L (baseline 0.12mmol/L) and hyperleukocytosis (WBC 68 × 109/L). He recommenced LBH589 and was also commenced on hydroxyurea 1g bd, allopurinol and hydration. Within 24 hours, associated with a fall in his WBC to 9 × 109/L, he developed LTLS - corrected calcium 1.91mM/L (2.23 – 2.50), phosphate 2.99mM/L (0.70 – 1.30) and uric acid 0.8mM/L (0.15 – 0.50). He recovered uneventfully with the administration of rasburicase, intravenous fluid and electrolytes. Hydroxyurea was ceased and he continued LBH589 as per schedule. On day 28 with a WBC of 60 × 109/L and with prophylactic rasburicase and hyper-hydration, LTLS again recurred within 24 hours of LBH589 administration - WBC fell to 6 × 109/L accompanied by corrected calcium of 2.1 mM/L and serum phosphate of 1.91 mM/L. The patient again recovered uneventfully. This first reported case of LTLS with LBH589 therapy clearly demonstrates the potent anti-leukemic potential of LBH589 and mandates that caution be taken with LBH589 treatment of AML patients exhibiting highly proliferative and/or a high tumor burden disease.

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Tumor Lysis Syndrome Risk in Outpatient Versus Inpatient Administration of Venetoclax and Hypomethlators for Acute Myeloid Leukemia

10.21203/rs.3.rs-160517/v1 ◽

2021 ◽

Author(s):

Ari Pelcovits ◽

Jozal Moore ◽

Brianna Bakow ◽

Rabin Niroula ◽

Pamela Egan ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Tumor Lysis Syndrome ◽

Outpatient Setting ◽

Lymphocytic Leukemia ◽

Inpatient Setting ◽

Close Monitoring ◽

Hypomethylating Agents ◽

Tumor Lysis ◽

Acute Myeloid

Abstract IntroductionVenetoclax along with hypomethylating agents (HMAs) is the new standard therapy for older patients with acute myeloid leukemia (AML) not fit for intensive frontline induction chemotherapy. Venetoclax is associated with fatal episodes of tumor lysis syndrome (TLS) in chronic lymphocytic leukemia (CLL), and recommendations are for its initiation for CLL and AML in the inpatient setting with close monitoring. Herein, we evaluated the safety of outpatient venetoclax ramp up when given in addition to HMAs for the treatment of AML. Methods We conducted a retrospective review of patients diagnosed with AML at our institution from 12/1/2016 until 7/1/2020. We identified patients who received HMAs and venetoclax for AML, either as frontline or relapsed/refractory therapy. Records were reviewed for evidence of laboratory or clinical tumor lysis episodes in all patients. Results Between 12/1/2016 and 7/1/2020 43 patients at our institution received venetoclax/HMA for the treatment of AML. Thirty-nine patients (91%) had venetoclax initiation and ramp up in the outpatient setting. One episode of laboratory TLS (2.5%) was identified. This patient required admission to the hospital for rasburicase and IV fluids with resolution of the laboratory effects without resultant clinical TLS. There were no episodes of clinical TLS in either group. 30-day mortality from venetoclax initiation was 0% in both groups. Conclusion Our experience with HMAs and venetoclax showed that outpatient ramp up of venetoclax is safe with a very low risk of laboratory TLS (2.5%) and no evidence of clinical TLS within our cohort.

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Tumor Lysis Syndrome Risk in Outpatient Versus Inpatient Administration of Venetoclax and Hypomethlators for Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2020-133880 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 6-7

Author(s):

Aryeh Pelcovits ◽

Brianna Bakow ◽

Jozal Waroich ◽

Pamela C Egan ◽

Rabin Niroula ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Uric Acid ◽

Salvage Therapy ◽

Myeloid Leukemia ◽

Research Funding ◽

Tumor Lysis Syndrome ◽

Outpatient Setting ◽

Tumor Lysis ◽

Wbc Count ◽

Acute Myeloid

Introduction Venetoclax (VEN), a BCL-2 inhibitor, along with hypomethylating agents (HMAs) has become standard therapy for older patients (pts) with acute myeloid leukemia (AML) not fit for intensive frontline therapy based on recent Phase 3 data reporting a median overall survival (OS) of 14.7 months. Initially used in CLL, VEN is associated with fatal episodes of tumor lysis syndrome (TLS). Package insert and expert opinion recommendations are for its initiation in the inpatient setting, with a dose escalation of 100mg day 1, 200mg day 2, and 400mg day 3 with IV hydration and close monitoring of TLS markers. In the initial phase 1b trial that resulted in its approval for use in pts with AML all pts were admitted to the hospital for initial venetoclax ramp up and received at least 72 hours of prior TLS prophylaxis, as well as initiation of venetoclax only if the white blood cell count was less than 25,000. No episodes of TLS were documented. Herein, we evaluated the safety of outpatient VEN ramp up when given in addition to HMAs for the treatment of AML. Methods We conducted a retrospective review of pts diagnosed with AML at our institution from 12/1/2016 until 7/1/2020. We identified pts who received HMAs and VEN, either as up-front treatment for newly diagnosed AML or as salvage therapy for relapsed or refractory disease, and stratified pts based on whether venetoclax was initiated in the inpatient or outpatient setting. We then examined baseline AML characteristics including initial blast count, cytogenetics and molecular profiles as well as baseline TLS markers prior to the initiation of VEN. Finally, using the Cairo-Bishop Criteria we examined the number of episodes of laboratory or clinical tumor lysis in all pts. Fisher's exact test and Wilcoxon rank-sum tests were performed to examine differences in categorical and continuous variables. Results Between 12/1/2016 and 7/1/2020 43 pts at received VEN in addition to an HMA for the treatment of AML (Table 1). 39 pts (91%) had VEN initiation and ramp up in the outpatient setting. Amongst all pts 24 received azacitadine, 11 decitabine, and 8 received both HMAs at some point during therapy. Twenty-two pts received HMA and VEN as frontline treatment while the other 21 received it as salvage therapy. There were 28 pts who received venetoclax within 28 days of starting the HMA, 25 of whom received it as an outpatient and 3 as an inpatient. Pretreatment labs were notable for median normal values of potassium, phosphate, uric acid, calcium and creatinine (Table 1). The median pretreatment creatinine levels between the two groups were not significantly different. Median pre-treatment WBC count was noted to be significantly higher in the inpatient cohort (37.9 vs 5.5, p-value of 0.01). Cytogenetic and molecular characteristics are included in the table with the only significant difference being a larger percentage of DNMT3A mutation in the inpatient group. While identification of TLS was somewhat limited by incomplete data on all pts, there was only one identified episode of laboratory TLS (2.5%) with an elevated phosphate and uric acid. This occurred in the outpatient group in a patient whose pretreatment WBC count was greater than 25,000. This pt required admission to the hospital for rasburicase and IV fluids with resolution of the laboratory effects without resultant clinical TLS. There were no episodes of clinical TLS in either group. 30-day mortality from starting VEN was 0% in both groups. While the Cairo-Bishop Criteria require the presence of 2 lab abnormalities to diagnose TLS we did a further analysis to evaluate for the presence of even a single lab abnormality associated with TLS. We identified 3 additional pts (7.5%) in the outpatient cohort who had the presence of only one lab abnormality associated with TLS within the 7 days after initiating treatment. None of these pts required any further TLS directed treatment or hospitalization. Conclusion Our experience with HMAs and VEN showed that outpatient ramp up of venetoclax is safe with a very low risk of laboratory TLS (2.5%) and no evidence of clinical TLS within our cohort. Even with an expanded definition of TLS we only identified 3 additional pts who developed laboratory abnormalities associated with TLS. Our results suggest that, in addition to HMA, VEN ramp up can be safely delivered with monitoring to pts with a WBC count less than 25,000 in the outpatient setting. Disclosures Olszewski: Genentech, Inc.: Research Funding; Spectrum Pharmaceuticals: Research Funding; TG Therapeutics: Research Funding; Adaptive Biotechnologies: Research Funding.

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Clinical Features and Cytoreduction Therapy in Children with Newly Diagnosed Acute Myeloid Leukemia and Hyperleukocytosis

Blood ◽

10.1182/blood-2021-151045 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2295-2295

Author(s):

Georgios E. Christakopoulos ◽

Kendra N Walker ◽

Lei Wang ◽

Clifford Takemoto ◽

Yan Zheng ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Adverse Events ◽

Blood Cell ◽

Myeloid Leukemia ◽

Low Dose ◽

Tumor Lysis Syndrome ◽

Newly Diagnosed ◽

Tumor Lysis ◽

Low Dose Chemotherapy ◽

Acute Myeloid

Abstract Background Hyperleukocytosis is observed in 5% to 20% of patients with newly diagnosed acute myeloid leukemia (AML) and is associated with an increased risk of early complications and mortality. While being used frequently in patients with AML and hyperleukocytosis, the clinical utility of leukapheresis has not been conclusive. Low-dose chemotherapy has also been used recently as a cytoreduction method in these patients, but the data are limited. Objectives: To describe and compare the clinical and laboratory characteristics, early adverse events, and outcomes of children with newly diagnosed AML and hyperleukocytosis according to cytoreductive methods; leukapheresis, low dose chemotherapy (cytarabine), or no intervention. Methods: We studied patients with newly diagnosed AML treated on three multi-institutional St. Jude protocols, AML97, AML02, and AML08, between 1997 and 2017. Hyperleukocytosis was defined as white blood cell (WBC) counts of 100 x 10 9/L or higher at diagnosis. The decision of cytoreductive treatment was made as the discretion of the treating physician. Leukoreduction was used in the AML97 and AML02 studies, and cytarabine (100mg/m 2/dose every 12 hours) was the first choice for AML08 study. We reviewed baseline clinical characteristics and laboratory data (complete blood cell counts [CBC], chemistries, coagulation) and adverse effects (grade 3 or higher on neurologic, renal, respiratory, and hemorrhagic complications based on Common Terminology Criteria for Adverse Events) from diagnosis to day 14 of protocol-based chemotherapy. Cairo-Bishop criteria was used for laboratory/clinical tumor lysis syndrome. The time from the first CBC to administration of protocol-based chemotherapy was calculated. Results: A total of 49 patients were identified: 8 patients in AML97, 19 in AML02, and 22 in AML08) (Table). The age at diagnosis was 10.8 years with a median initial WBC count of 157.6 x 10 9/L; CNS (CNS 2, 3 or traumatic lumbar puncture with blasts) was seen in 29 (59.2%) cases. FAB M4 or M5 subtype was found in 30 patients (61.2%), 11q23 abnormalities in 15 (30.6%) and inv(16) in 8 (16.3%). In regards to leukoreduction method, 16 patients received leukapheresis (14 patients in AML97/02 and 2 in AML08), 18 cytarabine (all in AML08) and 1 hydroxyurea (in AML08); 14 did not receive leukoreduction (13 patients in AML97/02 and 1 in AML08). Leukapheresis was used more often in patients with higher diagnostic WBC counts (218.7 x 10 9/L) than those treated with cytarabine (152.9 x 10 9/L) or without intervention (127.3 x 10 9/L) (P<0.001). The decrease of WBC counts (%) before and after intervention was more pronounced among patients treated with cytarabine than those treated with leukapheresis (75% vs. 48.5%, P=0.03). When decreases in WBC counts were evaluated from the first CBC to the initiation of protocol therapy, cytarabine treatment was associated with more decreases in WBC counts from baseline (84.8%) than leukapheresis (46.7%) or no intervention (1.8%) (P<0.001). Patients who received cytarabine intervention had a longer median time from the first CBC to initiation of protocol therapy (95.2 hours) compared to those who received leukapheresis (28.1 hours) and no intervention (20.4 hours) (P<0.001). No early deaths were observed from the time of diagnosis to two weeks after initiation of protocol chemotherapy, and no statistically significant differences were noted in the incidences of neurologic, pulmonary, renal, hemorrhagic events, or laboratory/clinical tumor lysis syndrome among these three groups. Conclusion: Low-dose cytarabine treatment appears to be a safe and effective mean of cytoreduction for patients with AML and hyperleukocytosis. Further studies are needed to determine if this approach is preferable among patients treated with contemporary treatment. Figure 1 Figure 1. Disclosures Pui: Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Data Monitoring Committee.

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A Rare t(5;11)(q35;q13) Translocation in an Elderly Patient With Acute Myeloid Leukemia With Maturation: A Case Report

Journal of Hematology ◽

10.14740/jh394w ◽

2018 ◽

Vol 7 (2) ◽

pp. 79-82

Author(s):

Masahiro Manabe ◽

Yuuji Hagiwara ◽

Reiko Asada ◽

Dai Momose ◽

Yasuyoshi Sugano ◽

...

Keyword(s):

Elderly Patient ◽

Acute Myeloid Leukemia ◽

Case Report ◽

Myeloid Leukemia ◽

Acute Myeloid

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Venetoclax-induced tumor lysis syndrome in acute myeloid leukemia: Real world experience.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e19542 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e19542-e19542

Author(s):

Amany Keruakous ◽

Rabia Saleem ◽

Adam Steven Asch

Keyword(s):

Acute Myeloid Leukemia ◽

Real World ◽

Myeloid Leukemia ◽

Bone Marrow Involvement ◽

Tumor Lysis Syndrome ◽

Lymphocytic Leukemia ◽

Weekly Dose ◽

Newly Diagnosed ◽

Tumor Lysis ◽

Acute Myeloid

e19542 Background: Venetoclax in combination with hypomethylating agents (HMAs) has become standard management for newly diagnosed older and unfit acute myeloid leukemia (AML) patients and an option for relapsed/refractory disease in cases unfit for aggressive therapy. Although venetoclax can lead to rapid tumor lysis syndrome (TLS) in chronic lymphocytic leukemia and therefore administrated in a weekly dose ramp-up to minimize toxicity, 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). Notably, this trial prohibited azole fungal prophylaxis because of the known potentiation of venetoclax activity in that setting. Rare cases have been reported for venetoclax induced TLS in the context of CYP3A inhibition. This study presents cases with AML who developed TLS whilst receiving azacitidine/venetoclax combination. Notably, they shared similar pattern of disease progression. Methods: All AML patients who are unfit to receive induction chemotherapy, treated with venetoclax combination either upfront or in the salvage setting starting January 2019 until November 2019 were reviewed retrospectively. TLS was reported using Cairo-Bishop criteria (Cairo & Bishop, 2004), AML risk stratification and response evaluation by ELN-Leukemia NET. Results: We report fourteen cases treated with azacitidine/venetoclax combination, three cases developed venetoclax induced TLS despite following the TLS protocol per the phase 1b trial (administering allopurinol > 72 hours prior to initiation of venetoclax). All cases had intermediate to poor risk AML; all had WBCs < 25 k before starting venetoclax, 2 of 3 patients received CYP3A inhibitors for fungal prophylaxis. Disease burden, defined as per-cent of bone marrow involvement and peripheral circulating blasts, did not increase the risk of TLS. We observed TLS in newly diagnosed (n = 1) and in relapsed AML (n = 2). Also, with first initiation of venetoclax as well as with delayed onset and more prominent with azole fungal prophylaxis. All the cases of venetoclax induced TLS we observed, proved to be refractory to venetoclax combination after resumption of therapy. Conclusions: Venetoclax induced TLS is reportedly rare in AML. In our experience, TLS is more common in real world experience than has been previously reported. More prominent with azole fungal prophylaxis. Additionally, it appears to be associated with disease that proved ultimately refractory to venetoclax combination.

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