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Annals of Clinical & Laboratory Science 38:283-286 (2008)
© 2008 Association of Clinical Scientists

Case Report

Promyelocytic Blast Crisis of Chronic Myeloid Leukemia during Imatinib Treatment

Hee-Jung Chung1, Hyun-Sook Chi1, Young-Uk Cho1, Chan-Jeoung Park1, Eul Ju Seo1, Kyung-Hee Kim1 and Je-Hwan Lee2
1 Departments of Laboratory Medicine and 2 Internal Medicine, University of Ulsan College of Medicine and Asan Medical Center, Seoul, South Korea

Address correspondence to Hyun-Sook Chi, M.D., Department of Laboratory Medicine, University of Ulsan College of Medicine, 388-1 Pungnap-2dong, Songpa-gu, Seoul 138-736, South Korea; tel 82 2 3010 4502; fax 82 2 478 0884; e-mail hschi{at}amc.seoul.kr.


   Abstract
Top
 Abstract
Introduction
 Case Report
 Discussion
 References
 
A 32-yr-old man with the chronic phase of chronic myeloid leukemia (CML-CP) was treated with imatinib mesylate for 6 mo. The real-time quantitative reverse transcription PCR ratio for BCR/ABL in blood mRNA (BCR/ABL RT-QPCR) decreased from an initial value of 0.0159 to a low value of 0.0012 after 3 mo, indicating complete hematologic response. During the next 3 mo, the patient progressed to a promyelocytic blast crisis, displaying leukemic cells containing both BCR/ABL and PML/RAR{alpha} chimeric mRNAs. Complete remission was achieved by therapy with all-trans retinoic acid (ATRA) and high-dose imatinib mesylate. Using retrospective PML/RAR{alpha} RT-QPCR with a bone marrow specimen obtained at the initial diagnosis of CML-CP, we quantified the mRNA ratio as 0.000321, suggesting that the clonal evolution of PML/RAR{alpha} translocation occurred early in the CML-CP.

Keywords: acute promyelocytic leukemia, all-trans retinoic acid, BCR/ABL, PML/RAR{alpha}, imatinib


   Introduction
Top
 Abstract
 Introduction
Case Report
 Discussion
 References
 
Imatinib mesylate selectively binds to the ATP-binding domain in the ABL protein, and is widely used as the drug of choice in chronic myeloid leukemia (CML), producing high response rates, particularly in the chronic phase [1]. Since CML originates from stem cells, it can progress to any cell line of blast crisis [1,2]. Promyelocytic blast crisis of CML is extremely rare, accounting for fewer than 30 cases worldwide [3–14]. To our knowledge, only a single case of promyelocytic blast crisis during imatinib treatment has been documented [15]. Here, we describe the occurrence of promyelocytic blast crisis in a CML patient after 6 mo of treatment with imatinib.


   Case Report
Top
 Abstract
 Introduction
 Case Report
Discussion
 References
 
A 32-yr-old man was referred to the University of Ulsan College of Medicine and Asan Medical Center due to leukocytosis (16.3 x 109/L), anemia, and marked thrombocytosis, with 2% blasts in the blood. Mild splenomegaly was observed on physical examination. A bone marrow (BM) aspirate displayed marked myeloid hyperplasia with 1.0% myeloblasts, 2.0% promyelocytes, 3.8% myelocytes, 16.6% metamyelocytes, 29.2% bands, 27.8% segmented neutrophils, 10.2% eosinophils, and 3.0% basophils. The myeloid/erythroid ratio was markedly increased to 26.8:1. Classical G-banding with BM cells revealed 46,XY,t(9;22)(q34;q11.2) in 20 cells examined at metaphase. The BCR/ABL real-time quantitative reverse transcription PCR ratio (BCR/ABL RT-QPCR) of blood mRNA was 0.0159. The patient was diagnosed as CML chronic phase, and initially was treated with 400 mg of imatinib mesylate daily.

Mutation studies for imatinib mesylate resistance targeting 11 abl kinase domains revealed wild type in bone marrow aspirate samples. After 3 mo of imatinib mesylate treatment, the BCR/ABL RT-QPCR ratio in the blood mRNA decreased to 0.0012, signifying complete hematologic response.

At 6 mo after the initial diagnosis of CML chronic phase, the patient’s anemia and thrombocytopenia were aggravated, requiring several packed RBC transfusions. Peripheral blood analysis revealed a white blood cell count of 4.9 x 109/L (53% abnormal promyelocytes or blastic cells, 2% bands, 18% segmented neutrophils, 2% eosinophils, 0% basophils, 20% lymphocytes, 5% monocytes), hemoglobin (9.5 g/dl), and platelets (15 x 109/L). Prothrombin time was 12.6 sec (normal value, 10.0–13.0) and activated PTT was 25.0 sec (normal value, 25.0–35.0). The plasma concentrations of fibrinogen and fibrin degradation products were 209 mg/dl (normal value, 200–400) and 160 µg/ml (normal value, 0.0–5.0), respectively, while that of the D-dimer was 87.1 µg/ml (normal value <0.4).

Hypercellular marrow (95%) with a marked increase in blasts and abnormal promyelocytes (86.6% of marrow nucleated cells) was observed. The blasts displayed kidney-shaped nuclei and hypergranulated cytoplasm containing bundles of Auer rods ("Faggot cells"). Cytochemical staining for myeloperoxidase showed a granular-positive reaction on leukemic cells. Flow cytometry showed homogeneously positive reactions for CD13, CD33, and CD117, but negative reactions for CD34 and HLA DR on marrow leukemic cells.

Karyotyping showed 46,XY,t(9;22)(q34;q11.2) ,t(15;?;17)(q22;?;q21) in all 20 cells examined (Fig. 1Go). Using fluorescence in situ hybridization (FISH) analysis, we detected major BCR/ABL fusion genes in 96.0% of cells (360/400) with typical two-fusion, one-orange and one-green signals, and no loss of 3'BCR or 5'ABL1, signifying poor prognosis. FISH with PML/RAR{alpha} fusion genes detected 5'PML/3'RARA fusion signals on der(15)t(15;?;17) chromosome, small green signal probing 5'RARA on der(17)t(15;?;17) chromosome, and small orange signal probing 3'PML on another chromosome, but not der(17) in 90.0% of cells (288/300). The patient was diagnosed with promyelocytic blast crisis of CML. BCR/ABL and PML/RAR{alpha} real-time quantitative reverse transcription PCR of bone marrow disclosed values of 2.21 and 0.81, respectively. Mutation studies targeting 11 abl kinase domains were also wild type in BM aspirates of blast crisis. With administration of all-trans retinoic acid (ATRA) and high-dose imatinib mesylate (800 mg/day), the patient achieved complete remission without complications. A chimeric mRNA value of 0.000321 was obtained by retrospective PML/RAR{alpha} real-time quantitative reverse transcription PCR with the BM specimen at the initial diagnosis of CML-CP (Fig. 2Go).


Figure 1
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  		Fig. 1. Laboratory findings at the time of promyelocytic blast crisis. Panel 1A (upper left): Leukemic cell morphology of bone marrow aspiration specimen (1000x magnification, H&E stain). Panel 1B (upper right): Karyotyping with bone marrow aspiration specimen (400x magnification, G-banding). Panel 1C (lower): FISH analysis showing PML/RAR{alpha} and BCR/ABL gene rearrangements (1000x magnification, fluorescent microscope).

 

Figure 2
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  		Fig. 2. Diagram of the clinical course of the patient. ATRA = All-trans retinoic acid; WBC = white blood cell count.

 

   Discussion
Top
 Abstract
 Introduction
 Case Report
 Discussion
References
 
Reports on promyelocytic blast crisis of CML are extremely rare, accounting for less than 30 cases worldwide [3–14]. A single report in 2007 dealt with promyelocytic blast crisis during imatinib mesylate therapy [15]. Most patients with promyelocytic blast crisis have died of disseminated intravascular coagulation within 6 mo. However, our patient had no bleeding complications or evidence of disseminated intravascular coagulation. The duration from chronic phase to promyelocytic blast crisis has varied from 8 mo to 9 yr [1]. Blastic progression was evident within 6 mo in our patient (the shortest duration to date), consistent with the presence of a small proportion of PML/RAR{alpha} chimeric mRNA at the time of diagnosis of CML chronic phase. Evidently, clonal evolution of the PML/RAR{alpha} translocation had arisen in the early chronic phase of CML. Although complete hematologic response was achieved with imatinib mesylate treatment, clonal dominance may have dramatically changed. The BCR/ABL chimeric clone fell into apoptosis upon tyrosine kinase targeted therapy, while the leukemic clone with both chimeric mRNAs expanded and was replaced rapidly. This is supported by mutation studies targeting 11 abl kinase domains, which showed wild type without imatinib mesylate resistance in either chronic or blastic phase samples.

The origin of coexisting clones comprising BCR/ABL and PML/RAR{alpha} chimeric mRNAs is unknown. Imatinib mesylate does not appear to play a role, since the drug does not induce gene damage or secondary cancers, until now. Karyotypic analysis of BM aspirates at blast crisis revealed homogenous clones with 46,XY,t(9;22)(q34;q11.2) ,t(15;?;17)(q22;?;q21) in all 20 cells examined. Additional chromosomal abnormalities reported in the accelerated phase and blast crisis of CML were mainly +der(22),+8, i(17q), +19, +21, -Y, and -7.

This patient contained a crucial 5'PML/3'RARA fusion gene on der(15) as a consequence of variant type of translocation in FISH analysis. Limited candidate genes or chromosomal abnormalities possibly contribute to progression of CML to blast crisis. Candidate genes include SOCS-2 [16] and BRCA-1 [17], with additional abnormal chromosomes, such as +Ph, i(17q), and –Y [13]. However, all previous studies focusing on promyelocytic blast crisis of CML revealed the simultaneous presence of PML/RAR{alpha} and BCR/ABL chimeric genes, implying origin from the CML clone.


   References
Top
 Abstract
 Introduction
 Case Report
 Discussion
 References
 

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