Abstract
LBH589 is a novel cinnamic hydroxamic acid analog (HAA) pan-histone deacetylase inhibitor (HDACi) currently in early phase clinical development.Preliminary data about LBH589 suggests significant biological activity (both in vitro and in vivo) in solid tumor cell lines1 and more recently, in a range of malignant hematological disorders including acute myeloid leukemia (AML).2,3 To-date, laboratory tumor lysis syndrome4 (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).5 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 FLAG6 failed and the patient 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 (30 mg orally three times per week on alternate weeks [one cycle = 28 days]). The patient presented on day 14 of cycle 1 with hyperleukocytosis (WBC 68×10/L) and acute renal failure: creatinine 280 μmol/L (baseline 120 μmol/L). He was administered LBH589 according to protocol and was also commenced on hydroxyurea 1g b.d., allopurinol and hyper-hydration. Within 24 hours, associated with a fall in his WBC to 9×10/L, he developed LTLS - corrected calcium 1.91 mmol/L (2.23–2.50), phosphate 2.99 mmol/L (0.70–1.30) and uric acid 0.8 mmol/L (0.15–0.50) (Figure 1 and 2). He recovered uneventfully following the administration of single dose of 13.5mg of rasburicase, intravenous fluid and electrolytes. Treatment with hydroxyurea was ceased and he continued LBH589 as per schedule. On day 28 (day 1 of cycle 2) with a WBC of 60x10/L, LTLS again recurred within 24 hours of LBH589 administration despite pro-phylactic rasburicase therapy (single dose of 12 mg) and hyper-hydration - WBC fell to 6×10/L, corrected calcium 2.1 mmol/L, phosphate 1.91 mmol/L and uric acid <0.02 mmol/L (from 0.66mmol/L) (Figure 1 and 2). Notably, the patient was not on hydroxyurea therapy at this time, unlike the first episode of LTLS. The patient again recovered uneventfully but was taken off trial following completion of 1.5 cycles due to disease progression. He died not long after due to complications of his disease.
This first reported case of laboratory tumor lysis syndrome with LBH589 therapy clearly demonstrates the potent anti-leukemia potential of LBH589 and mandates that caution be taken with LBH589 treatment of AML patients, particularly those exhibiting highly proliferative and/or high tumor burden disease.
References
- Beck J, Fischer T, Rowinsky E. Phase 1 pharmacokinetic (PK) and pharmacodynamic (PD) study of LBH589: a novel histone deacetylase inhibitor [abstract]. Proc Amer Soc Clin Oncol. 2004; 23:20. Google Scholar
- George P, Bali P, Annavarapu S, Scuto A, Fiskus W, Guo F. Combination of the histone deacetylase inhibitor LBH589 and the hsp90 inhibitor 17-AAG is highly active against human CML-BC cells and AML cells with activating mutation of FLT-3. Blood. 2005; 104:1768-1776. Google Scholar
- Bali P, Pranpat M, Bradner J, Balasis M, Fiskus W, Guo F. Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90: a novel basis for antileukemia activity of histone deacetylase inhibitors. J Biol Chem. 2005; 280:26729-34. Google Scholar
- Cairo M, Bishop M. Tumour Lysis syndrome: new therapeutic strategies and classification. Br J Haematol. 2004; 127:3-11. Google Scholar
- Wiernik PH, Banks PL, Case DC. Cytarabine plus idarubicin or daunorubicin as induction and consolidation therapy for previously untreated adult patients with acute myeloid leukemia. Blood. 1995; 79:313-9. Google Scholar
- Visani G, Tosi P, Zinzani PL, Manfroi S, Ottaviani E, Testoni N. FLAG (fludarabine + high-dose cytarabine + G-CSF): an effective and tolerable protocol for the treatment of ‘poor risk’ acute myeloid leukemias. Leukemia. 1994; 8:1842-6. Google Scholar