The chronic phase of expanded clonal myelopoiesis lasts several years but commonly evolves slowly into the accel- erated phase and then finally into a blast ...
International Journal of
HEMATOLOGY Case Report
Extramedullary Blast Crisis Derived from 2 Different Clones in the Central Nervous System and Neck during Complete Cytogenetic Remission of Chronic Myelogenous Leukemia Treated with Imatinib Mesylate Mitsuhiro Matsuda, Yasuyoshi Morita, Takahiro Shimada, Junichi Miyatake, Chikara Hirase, Miyako Tanaka, Yoichi Tatsumi, Yasuhiro Maeda, Akihisa Kanamaru Division of Hematology, Nephrology and Rheumatology, Department of Internal Medicine, Kinki University School of Medicine, Osaka, Japan Received November 29, 2004; received in revised form January 20, 2005; accepted February 16, 2005
Abstract We describe a patient with Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML) who developed an extramedullary blast crisis in the central nervous system (CNS) and then a subcutaneous tumor of the neck during treatment with imatinib mesylate. Administered 400 mg of imatinib mesylate after the diagnosis of chronic-phase CML, the patient achieved a complete cytogenetic remission 4 months later. However, he developed a mixed myeloid/B-cell blast crisis with additional karyotype abnormalities only in the CNS during a complete cytogenetic remission in the bone marrow. Several doses of intrathecal chemotherapy and whole-brain irradiation were effective in treating the blast crisis in the CNS. After 7 months of complete cytogenetic remission, the patient experienced a subcutaneous tumor in the right neck. A biopsy of the tumor revealed a mixed myeloid/T-cell blast crisis. The cytogenetic analysis showed that the blast crisis clone in the neck tumor was different from that of the CNS. An increased dose of imatinib mesylate was ineffective in treating the neck tumor. Irradiation to the right neck was therefore undertaken. This case suggests that the development of a clone resistant to imatinib mesylate is not always detected in the bone marrow and that multiple Ph-positive clones have the potential to become transformed into a blast crisis. Int J Hematol. 2005;81:307-309. doi: 10.1532/IJH97.04188 ©2005 The Japanese Society of Hematology Key words: Chronic myelogenous leukemia; Extramedullary blast crisis; Imatinib mesylate
ment of CML. However, the long-term outcomes for and complications of treatment with imatinib mesylate remain unknown. We describe a patient with CML who developed an extramedullary blast crisis derived from different clones in the central nervous system (CNS) and a neck tumor during treatment with imatinib mesylate.
1. Introduction Chronic myelogenous leukemia (CML) is a clonal proliferative disorder of hematopoietic stem cells characterized by the presence of the Philadelphia chromosome (Ph). The chronic phase of expanded clonal myelopoiesis lasts several years but commonly evolves slowly into the accelerated phase and then finally into a blast crisis. Most Ph-positive CML patients are able to achieve cytogenetic remission in response to treatment with imatinib mesylate, a tyrosine kinase inhibitor approved for the treatment of CML. This drug is now used as a first choice for the treat-
2. Case Report A 17-year-old male received a diagnosis of chronic-phase CML in May 2003. He was administered 400 mg of imatinib mesylate, which resulted in complete cytogenetic remission 4 months later. However, the patient was admitted to our department in September 2003 because of headache. A computed tomography scan of his head demonstrated no specific signs of meningeal and cerebral involvement. A lumbar puncture revealed blasts in the cerebrospinal fluid (CSF) (Figure 1). The blasts were found by CD45 blast gating methods to be positive for CD10, CD13, CD19, CD33, CD34, and HLA-DR (Table 1). A cytogenetic analysis of blasts in the
Correspondence and reprint requests: Mitsuhiro Matsuda, MD, PhD, Division of Hematology, Nephrology and Rheumatology, Department of Internal Medicine, Kinki University School of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan; 81-72-366-0221 ext 3128; fax: 81-72-368-3732 (e-mail: matsuda@ int3.med.kindai.ac.jp).
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Figure 1. Morphologic study of the blasts in the central nervous system (CNS) (Wright and Giemsa, original magnification 400). Myeloperoxidase-negative small-sized blasts with prominent nucleoli and narrow cytoplasm can be seen in the CNS.
with cytosine arabinoside, methotrexate, and dexamethasone given once a week, as well as whole-brain irradiation, led to the disappearance of the headache and the blasts in the CSF. After 7 months with complete hematologic and cytogenetic remission with 400 mg of imatinib mesylate, the patient developed a subcutaneous tumor in the right neck (Figure 2). RT-PCR analysis for major bcr/abl genes revealed 740 copies/g RNA in the bone marrow. A biopsy of the neck tumor demonstrated a mixed myeloid/T-cell blast crisis expressing CD2, CD3, CD4, CD5, CD7, CD10, CD13, and HLA-DR detected by CD45 blast gating methods (Table 1). The blasts expressed neither CD33 nor CD34. A cytogenetic analysis of blasts in the neck tumor showed 47,XY,+6,t(9;22) (q34;q11) in 3 (15%) of 20 metaphases, Ph in 8 metaphases (40%), and a normal karyotype in 9 metaphases (45%). Accordingly, the patient had developed a mixed myeloid/ T-cell blast crisis derived from a clone other than that of the CNS crisis. Although the dose of imatinib mesylate was increased to 600 mg, the effect was poor, and the tumor invaded the right ethmoidal sinus. Irradiation of the right neck was undertaken.
3. Discussion CSF showed 48,XY,+8,t(9;22)(q34;q11),+10 in 20 (100%) of 20 metaphase chromosomes examined. However, an examination of a bone marrow aspirate showed normocellular marrow with no increase in the percentage of blasts or dysplasia. A cytogenetic analysis indicating a normal karyotype in all analyzed metaphase chromosomes from the bone marrow was consistent with a complete cytogenetic remission in the marrow. A reverse transcriptase–polymerase chain reaction (RT-PCR) analysis for major bcr/abl genes showed a decrease to 1300 copies/g RNA in the bone marrow. The patient’s diagnosis was a mixed myeloid/B-cell blast crisis only in the CNS. Several doses of intrathecal chemotherapy
We describe a patient with CML who developed an extramedullary blast crisis in the CNS and neck. The cell surface marker and cytogenetic analysis of the blasts indicates that he sequentially developed an extramedullary blast crisis derived from 2 different clones in the CNS and in the neck subcutaneous tumor. Unexpectedly, the marrow of the patient remained in complete cytogenetic remission during the development of the 2 different clonal evolutions. To our knowledge, this case is the first of sequential extramedullary blast crisis derived from 2 different clones developing in a
Table 1. Immunophenotyping Analysis of Blasts in the Cerebrospinal Fluid and the Neck Tumor* Antigen
Central Nervous System, %
Neck Tumor, %
CD2 CD3 CD4 CD5 CD7 CD8 CD10 CD13 CD19 CD20 CD33 CD34 CD56 HLA-DR
0.4 1.1 ND ND 0.8 ND 60 99.8 94.2 ND 99.7 99.9 1.3 99.9
60.2 61.2 41.8 56.5 50.3 11.5 28.4 99.8 5.6 ND 11.4 6.3 21.6 54.5
*The blasts in the cerebrospinal fluid were found by CD45 blast gating methods to be positive for CD10, CD13, CD19, CD33, CD34, and HLA-DR, indicating a mixed myeloid/B-cell blast crisis. In contrast, a biopsy of the neck tumor demonstrated a mixed myeloid/T-cell blast crisis expressing CD2, CD3, CD4, CD5, CD7, CD10, CD13, and HLA-DR. ND indicates not done.
Figure 2. Computed tomography of the neck revealed right-sided lesions and a subcutaneous mass in the right neck.
Extramedullary Blast Crisis in CML
relatively short interval and accompanied by the achievement and maintenance of complete cytogenetic remission in the bone marrow with imatinib mesylate treatment for CML. This case suggests that multiple Ph-positive clones have the potential to transform to a blast crisis in CML. Because the levels of imatinib mesylate and its metabolite are much lower in CSF than in plasma [1-3], the CNS involvement may be resistant to imatinib therapy, as has been reported previously [1-5]. The efficacy of imatinib mesylate treatment in an extramedullary blast crisis, however, remains controversial. Some reports have indicated that imatinib mesylate has a significant effect on an extramedullary blast crisis [6,7]. In one study, imatinib mesylate was found to be effective in lymph nodes infiltrated by blasts [7]. However, another report has indicated that imatinib mesylate was ineffective in treating extramedullary lesions in subcutaneous nodules of the chest wall or in pleural effusion, although a complete hematologic response was obtained in response to imatinib mesylate [8]. These reports lead us to speculate that the efficacy of imatinib mesylate may depend on the acquisition of drug resistance or on a different drug-delivery system in an extramedullary blast crisis. In the present patient, 600 mg of imatinib mesylate had no effect on the extramedullary blast crisis. The present results suggest that the ineffectiveness of imatinib mesylate was probably due to both the acquisition of resistance and poor delivery of the drug to the neck subcutaneous tumor. Determining the cell lineage of the blasts is clinically important for predicting the response to chemotherapy and survival in blast-crisis CML. However, a high frequency of the mixed-lineage phenotype, which seems to reflect the stem cell origin of CML, makes lineage classification difficult [9]. Although immunophenotypic studies play a limited role, the evaluation of the blasts in the neck tumor of the present patient showed a mixed myeloid/T-cell phenotype. Previous reports have indicated that some patients with a mixed myeloid/T-cell or T-cell blast crisis of CML present an extramedullary mass [10-13] or CD10 expressed on blasts [10], which are manifestations similar to those of the present patient. In conclusion, to our knowledge we are the first to report the sequential development of extramedullary blast crisis from 2 different clones within a short interval in a chronicphase CML patient. Because most CML patients can achieve cytogenetic remissions in response to treatment with imatinib mesylate, the clinical manifestation of blast crisis in CML has changed recently. As indicated by the patient described here, the number of patients who extramedullarly develop clones resistant to imatinib mesylate may increase in the future. The detailed mechanisms of the ineffectiveness of imatinib mesylate in extramedullary blast crisis, including the drug-delivery system and point mutations in bcr/abl genes, should be clarified. Extramedullary involvement in the blast crisis of CML is associated with significantly short event-free survival times [14]; therefore, more appropriate treatment, including allogeneic stem cell transplantation, should be
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offered in cases of extramedullary blast crisis in CML treated with imatinib mesylate.
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