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Journal of Clinical Oncology, Vol 24, No 24 (August 20), 2006: pp. 4028-4029 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.05.5608
Isolated Blast Crisis in CNS in a Patient With Chronic Myelogenous Leukemia Maintaining Major Cytogenetic Response After ImatinibDivision of Hematology/Oncology, Departments of Medicine, Neurosurgery, and Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea A 42-year-old man with Philadelphia chromosome positive chronic myelogenous leukemia (CML) in chronic phase received imatinib 300 mg/d to 400 mg/d. He achieved major cytogenetic response by fluorescent in situ hybridization (FISH) of BCR-ABL at 12 months. The patient’s major cytogenic response (MCR; defined as 1% to 35% Ph-positive cells in metaphase in a bone marrow sample) was documented by BCR/ABL FISH of bone marrow aspirate. Real-time reverse transcriptase polymerase chain reaction demonstrated continuous decreasing level of BCR-ABL patients from 0.0022 at 12 months to 0.00071 at 19 months that was normalized by the level of glucose 6-phosphatase dehydrogenase using LightCycler (Roche Molecular Biochemicals, Lewes, United Kingdom). From that time on, he received an increased dose of imatinib of 600 mg/d to control residual disease. Twenty-five months after receiving imatinib, he had headache and low back pain. Lumbar magnetic resonance imaging (MRI) demonstrated protruded intervertebral disc at L4-5 level of lumbar spine. He underwent surgical discectomy but his symptoms persisted. His physical examination was normal. Hemoglobin level was 11.0 g/dL, white cell count was 9,600/mm3 with normal distribution of differential count without precursor cells, and platelet count 196,000/mm3. Brain MRI demonstrated severe obstructive hydrocephalus with mass-like lesion in right cerebellum that compressed the fourth ventricle (Fig 1; arrows, cerebellar mass). Whole spine and brain MRI showed no definite evidence of leptomeningeal seeding. Lumbar puncture demonstrated abnormally high pressure of 30 cmH20 but CSF and protein, glucose, and lactate hydrogenase levels were all within normal limits. The CSF cell count was 5 RBCs per mm3 and 0 WBC, without leukemic cells on cytospin. We administered 25mg of dexamethasone and mannitol every 6 hours to control increased intracranial pressure; since his headache and vertigo progressed rapidly. He received emergency external ventriculostomy drain placement in the lateral ventricle on hospital day 3, but he soon required surgical decompression of the posterior fossa. At craniotomy, he had massive brain swelling due to a hard mass in both cerebellar hemispheres. Only partial resection was possible. Pathology revealed diffuse infiltration with B lymphoblasts, which were Tdt positive (Fig 2A; level of magnification, x400). BCR-ABL FISH was positive (Fig 2B; arrows, BCR-ABL fusion signals; level of magnification, x1,000). Given the isolated CNS lymphoid blast crisis in cerebella, we administered intrathecal combination chemotherapy with cytarabine, methotrexate, and hydrocortisone given every other day together with imatinib 800 mg/d through the nasogastric tube. Despite these measures plus mechanical hyperventilation, he died 15 days after craniectomy.
The International Randomized Study of Interferon and STI571 (IRIS) trial reported that imatinib was much more active than interferon plus cytarabine in patients with CML in chronic phase.1,2 Thereafter, imatinib has become the treatment of choice for patients with CML in chronic phase who are not candidates for hematopoietic stem cell transplantation.3 The activity of imatinib against CNS lesions has not been yet established. Case reports suggest that imatinib has limited activity against CML in the CNS due to poor blood-brain-barrier penetration,4-6,8 possibly due to the P-glycoprotein-mediated efflux.7 No surveillance strategy for CNS relapse or treatment guidelines for documented CNS relapse in CML patients treated with imatinib has yet been defined. The rarity of CNS relapses suggest that regular CSF examination or prophylactic intrathecal chemotherapy is not indicated. Intrathecal drug levels of imatinib have not been routinely measured. Given long-term CML disease control in the peripheral blood and marrow with imatinib, it is possible that late CNS relapses could become more common over time. Three previously reported cases of isolated CNS blast crisis in patients who maintained major cytogenetic remission, involved meningeal seeding, not mass formation as in our patient.4,9,10 We propose that clinicians be aware of the possibility of CNS relapse in CML patients, even if they have experienced a cytogenetic or hematologic remission on imatinib. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
REFERENCES
1. Hughes TP, Kaeda J, Branford S, et al: Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med 349: 1423-1432, 2003 2. O'Brien SG, Guilhot F, Larson RA, et al: Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 348: 994-1004, 2003 3. Peggs K, Mackinnon S: Imatinib mesylate: The new gold standard for treatment of chronic myeloid leukemia. N Engl J Med 348: 1048-1050, 2003 4. Bornhauser M, Jenke A, Freiberg-Richter J, et al: CNS blast crisis of chronic myelogenous leukemia in a patient with a major cytogenetic response in bone marrow associated with low levels of imatinib mesylate and its N-desmethylated metabolite in cerebral spinal fluid. Ann Hematol 83: 401-402, 2004[CrossRef][Medline] 5. Leis JF, Stepan DE, Curtin PT, et al: Central nervous system failure in patients with chronic myelogenous leukemia lymphoid blast crisis and Philadelphia chromosome positive acute lymphoblastic leukemia treated with imatinib (STI-571). Leuk Lymphoma 45: 695-698, 2004[CrossRef][Medline] 6. Takayama N, Sato N, O'Brien SG, et al: Imatinib mesylate has limited activity against the central nervous system involvement of Philadelphia chromosome-positive acute lymphoblastic leukaemia due to poor penetration into cerebrospinal fluid. Br J Haematol 119: 106-108, 2002[CrossRef][Medline] 7. Dai H, Marbach P, Lemaire M, et al: Distribution of STI-571 to the brain is limited by P-glycoprotein-mediated efflux. J Pharmacol Exp Ther 304: 1085-1092, 2003 8. Wolff NC, Richardson JA, Egorin M, et al: The CNS is a sanctuary for leukemic cells in mice receiving imatinib mesylate for Bcr/Abl-induced leukemia. Blood 101: 5010-5013, 2003 9. Bujassoum S, Rifkind J, Lipton JH: Isolated central nervous system relapse in lymphoid blast crisis chronic myeloid leukemia and acute lymphoblastic leukemia in patients on imatinib therapy. Leuk Lymphoma 45: 401-403, 2004[CrossRef][Medline] 10. Petzer AL, Gunsilius E, Hayes M, et al: Low concentrations of STI571 in the cerebrospinal fluid: A case report. Br J Haematol 117: 623-625, 2002[CrossRef][Medline]
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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