Correspondence

Adverse Events after Imatinib Mesylate Therapy

N Engl J Med 2002; 346:712-713February 28, 2002

Article

To the Editor:

Chronic myelomonocytic leukemia and myelofibrosis with myeloid metaplasia are hematopoietic stem-cell disorders for which there is no effective drug therapy. Imatinib mesylate (Gleevec, Novartis, Basel, Switzerland), formerly known as STI571, is an orally bioavailable derivative of 2-phenylaminopyrimidine that stabilizes an inactive conformation of BCR-ABL and related kinases.1 One of these kinases is the platelet-derived growth factor receptor.2 Because the pathogenesis of both chronic myelomonocytic leukemia and myelofibrosis with myeloid metaplasia may involve signal transduction mediated by platelet-derived growth factor, we initiated two independent pilot studies of imatinib mesylate in these two disorders. We report 3 cases of splenic rupture: 2 occurred among 3 patients with chronic myelomonocytic leukemia, and 1 occurred among 23 patients with myelofibrosis with myeloid metaplasia who were enrolled in phase 2 trials that had been approved by the institutional review boards of participating institutions.

Patient 1, a 61-year-old woman with chronic myelomonocytic leukemia, was treated with 600 mg of imatinib mesylate per day for 12 days before the agent was discontinued because of gastrointestinal symptoms and abnormal results on liver-function tests. Before treatment, the patient's spleen had been palpated 5 cm below the left costal margin and blood studies revealed a leukocyte count of 34.1×10⁹ per liter and a platelet count of 392×10⁹ per liter. Five days after treatment was discontinued, computed tomography (CT) performed to evaluate pain in the left upper quadrant demonstrated a splenic rupture (Figure 1AFigure 1CT Scans Showing Splenic Rupture in Patient 1 (Arrow in Panel A) and Splenomegaly and a Contained Splenic Rupture in Patient 2 (Arrow in Panel B).). Splenectomy was performed, and histopathological analysis confirmed the occurrence of splenic rupture with extramedullary hematopoiesis and without evidence of leukemic transformation.

In Patient 2, a 71-year-old woman with chronic myelomonocytic leukemia, treatment with 600 mg of imatinib mesylate per day was stopped after eight days because of the appearance of constitutional symptoms. Before treatment, her spleen had not been palpable and she had had a leukocyte count of 16.8×10⁹ per liter and a platelet count of 50×10⁹ per liter. Treatment was resumed at a lower dose (300 mg per day) after the symptoms resolved. Treatment was again stopped one month later because of increasing splenomegaly and constitutional symptoms. Continued deterioration in the patient's condition during the next month led to a CT scan, which demonstrated splenomegaly with a contained splenic rupture (Figure 1B).

Patient 3, a 51-year-old woman with myelofibrosis with myeloid metaplasia and massive splenomegaly, received 400 mg of imatinib mesylate per day for 20 days. The daily dose was then decreased to 200 mg because of lower-extremity edema, and treatment was discontinued 15 days thereafter because of drug-induced thrombocytosis. Spontaneous splenic rupture necessitating splenectomy occurred 50 days later.

One review of splenic rupture in hematologic cancers found that 136 such cases have been reported since 1861.3 Our findings suggest but do not prove a causal relation in these disease states. Communication with Novartis disclosed that there have been 3 reported cases of splenic rupture among the more than 10,000 patients with chronic myelogenous leukemia who have been treated with imatinib mesylate.

Michelle A. Elliott, M.D.
Ruben A. Mesa, M.D.
Ayalew Tefferi, M.D.
Mayo Clinic, Rochester, MN 55905
elliott.michelle@mayo.edu

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To the Editor:

Imatinib mesylate has recently been licensed for the treatment of selected patients with chronic myelogenous leukemia (CML).1 We report a case of bone marrow necrosis secondary to imatinib mesylate therapy in a patient with accelerated-phase CML.

A 73-year-old man was given a diagnosis of high-risk chronic-phase CML in September 1999. He was treated with hydroxyurea and then interferon, and his blood counts became normal. In March 2001, bone marrow examination and cytogenetic analysis demonstrated progression to accelerated-phase CML. Treatment with imatinib mesylate was commenced at a dose of 600 mg per day. After three weeks of treatment, high fevers and rigors developed. The following week, the patient reported having severe pain in the lower back and legs. He became wheelchair-bound over a period of a few days. At this time he had a white-cell count of 4.4×10⁹ per liter, a hemoglobin level of 92 g per liter, and a platelet count of 395×10⁹ per liter. Biochemical analysis demonstrated an alkaline phosphatase level of 398 U per liter. Examination of bone marrow aspirate and biopsy specimens obtained with a trephine revealed extensive bone marrow necrosis and osteonecrosis, with no evidence of transformation to blast crisis.

Bone marrow necrosis is defined pathologically by the loss of the normal bone marrow architecture; the degeneration of bone marrow cells results in indistinct cellular margins and pyknotic nuclei on an amorphous eosinophilic background. Bone marrow necrosis results from cellular hypoxia that is due to ischemia of the bone microcirculation as a consequence of inflammatory damage or mechanical obstruction. This may, in turn, be due to the release of prothrombotic toxins, cytokines, and vasoactive substances from damaged cells, particularly tumor necrosis factor α.2 The most prominent symptoms of bone marrow necrosis are bone pain and fever, usually with anemia and thrombocytopenia. The white-cell count usually declines, but it can increase or remain unchanged.

In retrospective reviews of unselected biopsy specimens of bone marrow, the incidence of bone marrow necrosis ranges from 0.15 percent to 0.32 percent.3 The majority of cases are caused by cancer, two thirds of which are hematologic cancers and one third of which are solid tumors. CML is the cause in 5 percent of cases, and bone marrow necrosis has been reported in 12 patients with CML.4 In these patients there was a strong association between bone marrow necrosis and blast transformation. Bone marrow necrosis has also been associated with the use of interferon alfa.5 Our patient had no evidence of disease progression that could account for the bone marrow necrosis. This case suggests that imatinib mesylate, perhaps by accelerating the rate of apoptosis and release of prothrombotic cellular material, may lead to bone marrow necrosis.

Catherine Burton, M.B., B.Chir., M.R.C.P.
Anthony Azzi, M.B., B.S.
Ian Kerridge, F.R.A.C.P., F.R.C.P.A.
Newcastle Mater Hospital, Newcastle, NSW 2298, Australia
cathyhburton@hotmail.com

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   Yavuz Aras, Mehmet Osman Akcakaya, Seher N. Unal, Bilge Bilgic, Omer Faruk Unal. (2011) Bone marrow necrosis secondary to imatinib usage, mimicking spinal metastasis on magnetic resonance imaging and FDG-PET/CT. Journal of Neurosurgery: Spine1-4
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