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Severe tumor lysis syndrome during treatment with STI 571in a patient with chronic myelogenous leukemia accelerated phase

2002; Elsevier BV; Volume: 13; Issue: 11 Linguagem: Inglês

10.1093/annonc/mdf304

1569-8041

Amish Vora, Manisha Bhutani, Atul Sharma, V. Raina,

Acute Lymphoblastic Leukemia research

Signal transduction inhibitor 571 (STI 571), a potent and selective inhibitor of the tyrosine kinase activity of BCR–ABL, is an important advance in the treatment of chronic myelogenous leukemia (CML) patients in the advanced phase of disease or those with chronic phase (CP) intolerant or resistant to interferon (IFN) therapy [1.Mauro M.J. O’Dwyer M. Heinrich M.C. Druker B.J. STI571: a paradigm of new agents for cancer therapeutics.J Clin Oncol. 2002; 20: 325-334Crossref PubMed Scopus (198) Google Scholar, 2.Talpaz M. Silver R.T. Druker B.J. et al.Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study.Blood. 2002; 99: 1928-1937Crossref PubMed Scopus (956) Google Scholar, 3.Sawyers C.L. Hochhaus A. Feldman E. et al.Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study.Blood. 2002; 99: 3530-3539Crossref PubMed Scopus (1064) Google Scholar]. Given at the dose of 400–600 mg p.o. daily, STI 571 is generally well tolerated. Common adverse effects include mild to moderate myelosuppression, nausea, vomiting, diarrhea, edema, myalgia, arthralgia and skin rash [2.Talpaz M. Silver R.T. Druker B.J. et al.Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study.Blood. 2002; 99: 1928-1937Crossref PubMed Scopus (956) Google Scholar, 3.Sawyers C.L. Hochhaus A. Feldman E. et al.Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study.Blood. 2002; 99: 3530-3539Crossref PubMed Scopus (1064) Google Scholar]. Tumor lysis syndrome (TLS) with this drug is not so common. An 18-year-old boy was diagnosed with Philadelphia chromosome (Ph) positive CML-CP in September 1994. He did not have an HLA-identical sibling and was started on IFN‐α. Treatment with IFN was continued until August 2001, when he was diagnosed as having accelerated disease. The spleen was palpable 12 cm below the left costal margin (LCM), white blood cell (WBC) count was 8.9 × 109/l, platelet count 100 × 109/l and bone-marrow examination revealed grade 3 myelofibrosis with 12% blasts. STI 571 400 mg p.o. daily was started; within 2 weeks his symptoms improved and spleen regressed to 8 cm. The patient did not continue STI 571 beyond 1 month. Two months later STI 571 was restarted at the dose of 400 mg p.o. daily along with allopurinol supplementation. At that time his WBC count had increased to 114 × 109/l. On day 5 of therapy, he was admitted with severe pain in the suprapubic region. He was afebrile, had mild dehydration, severe pallor and spleen measured 15 cm below LCM. The laboratory parameters were hemoglobin 5.6 g/dl, platelet count 77 × 109/l, WBC count 77.6 × 109/l, blood urea 233 mg/dl, serum creatinine 12.7 mg/dl, calcium 7.2 mg/dl, uric acid38.4 mg/dl, phosphorus 7.2 mg/dl and potassium 8 mEq/l. On the basis of these findings a diagnosis of TLS and acute renal failure was made. Notably, he had adequate renal and hepatic functions and was not exposed to any contrast agent or nephrotoxic drug prior to starting STI 571. With vigorous supportive care and hemodialysis his biochemical parameters improved and finally normalised after 7 days. Treatment with STI 571 was continued through the episode without any dose modification. At last follow-up, a month later, his spleen had regressed to 2 cm, WBC count was 6.5 × 109/l, renal functions were normal and he continued to take STI 571. Despite the propensity of STI 571 to produce early responses (lowering of WBC count within 2–3 weeks), TLS has not been specifically observed with its use. In a phase I trial, one of 58 patients treated for Ph positive CML-blast crisis or acute lymphoblastic leukemia (ALL) developed this complication; details are not available [4.Druker B.J. Sawyers C.L. Kantarjian H. et al.Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome.N Engl J Med. 2001; 344: 1038-1042Crossref PubMed Scopus (2442) Google Scholar]. A recent report from Israel describes a patient with Ph positive ALL with WBC count 41 × 109/l; he received STI 571 600 mg/day for2 days and on day 5 was diagnosed as having TLS [5.Dann E.J. Fineman R. Rowe J.M. Tumor lysis syndrome after STI 571 in Philadelphia chromosome positive acute lymphoblastic leukemia.J Clin Oncol. 2002; 20: 354-355Crossref PubMed Scopus (18) Google Scholar]. Following vigorous hydration and continued hemodialysis, the renal function returned to normal on day 14 and STI 571 was resumed at half the dose. Preliminary data indicates that cells from patients treated with STI 571 undergo rapid apoptosis [4.Druker B.J. Sawyers C.L. Kantarjian H. et al.Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome.N Engl J Med. 2001; 344: 1038-1042Crossref PubMed Scopus (2442) Google Scholar]. This probably results in rapid release of intracellular contents into the blood stream, producing a pattern of features consistent with TLS. Patients with CML in accelerated phase/blast crisis with WBC counts >20 × 109/l should routinely be prescribed allopurinol and hydration and observed closely for TLS. They should be hospitalized at the earliest sign of this complication and treated with intravenous hydration, forced diuresis, correction of acid–base status and hemodialysis if worsening renal failure ensues.