Letter to the Editor

Ann Lab Med 2021; 41(3): 328-332

Published online May 1, 2021

Copyright © Korean Society for Laboratory Medicine.

Promyelocytic Blast Phase of Chronic Myeloid Leukemia, BCR-ABL1-Positive: Points to be Considered at Diagnosis

Bohyun Kim, M.D., Ph.D.1 , Hyun Young Chi, M.D.2 , Young Ahn Yoon, M.D.1 , and Young-Jin Choi, M.D.1

1Department of Laboratory Medicine, Soonchunhyang University Cheonan Hospital, Soonchunhyang University College of Medicine, Cheonan, Korea; 2Samkwang Medical Lab, Seoul, Korea

Correspondence to: Bohyun Kim, M.D., Ph.D.
Department of Laboratory Medicine, Soonchunhyang University Cheonan Hospital, 31 Soonchunhyang 6-gil, Dongnam-gu, Cheonan 31151, Korea
Tel: +82-41-570-3571, Fax: +82-41-572-2316

Received: June 22, 2020; Revised: July 13, 2020; Accepted: November 11, 2020

Dear Editor,

Progression to promyelocytic blast phase (BP) in chronic myeloid leukemia (CML), BCR-ABL1-positive is very rare, and only few cases have been reported since the introduction of Tyrosine Kinase Inhibitor (TKI) therapy [1-3]. However, there are no studies on the important considerations for an accurate diagnosis. We report the case of a patient with promyelocytic BP of CML after short-term TKI therapy and provide a review on the diagnosis. The Institutional Review Board of Soonchunhyang University Cheonan Hospital, Chungcheongnam-do, Korea, approved this study (file No. 2020-10-036) and exempted the need for informed consent as there was no identifying information and no harm caused to the patient.

A 35-year-old male patient with leukocytosis (60.55 × 109/L) was admitted to Soonchunhyang University Cheonan Hospital in March 2017. Bone marrow (BM) study revealed hypercellularity with myeloid and megakaryocytic hyperplasia.Chromosomal analysis revealed 46,XY,t(9;22)(q34;q11.2)[20]. The quantity of major BCR-ABL1 fusion transcript was 30.02% (Table 1). The patient was diagnosed as having CML, chronic phase (CP). However, he refused TKI therapy.

Table 1 . Clinical and laboratory features of patients with promyelocytic BP of CML with both BCR-ABL1 and PML-RARA rearrangements after TKI therapy

Oku, et al. 2007 [1]Chung, et al. 2008 [2]Hoehn, et al. 2013 [3]Current study
At primary diagnosis of CML, CP
WBC count (×109/L)16.2016.3039.8060.55
Hemoglobin (g/L)Not reportedNot reportedNot reported137
Platelet count (×109/L)Not reportedNot reportedNot reported413
Peripheral blood findingNot reported2% blasts1% blastsOccasional blasts, 14% myelocytes, 12% metamyelocytes, 6% band neutrophils, 55% neutrophils
SplenomegalyNot reportedMildNot reportedNone
Bone marrow finding7.20% blasts, M:E ratio 9.55:11.00% blasts, M:E ratio 26.8:1Not reported1.20% blasts, M:E ratio 12.6:1
FISH for major BCR-ABL1 rearrangementPositive (89.3%)Not reportedPositiveNot tested
Quantity of BCR-ABL1 transcriptNot reported0.016Not reported30.02%
TreatmentImatinib 400 dailyImatinib 400 dailyImatinibDasatinib 100 mg daily two yrs after diagnosis
Clinical course after TKI therapyCHR, good CCyR after eight monthsCHR after three monthsCCyR and MMRNot evaluated
At diagnosis of CML, BP
Time to progression to BP16 months after diagnosisSix months after diagnosisNot reported26 months after diagnosis
WBC count (×109/L)0.304.9017.8045.67
Hemoglobin (g/L)96959879
Platelet count (×109/L)491593
Peripheral blood finding91% leukemic promyelocytes53% leukemic promyelocytes90% leukemic promyelocytes97% leukemic promyelocytes
Bleeding symptomGingival bleedingNoneEcchymosisOral bleeding
Prothrombin time47% (reference range 60–130)12.6 sec (reference range 10.0–13.0)19.0 sec (reference range 12.7–15.0)18.6 sec (reference range 9.5–12.3)
Fibrinogen (g/L)0.57 (reference range 2.00–4.00)2.09 (reference range 2.00–4 00)1.56 (reference range 2.02–4 50)0.96 (reference range 1.94–4.32)
D-dimer (mg/L FEU)Not reported87.10 (reference range <0.40)>20.00 (reference range <0.40)6.65 (reference range <0.48)
Presence of DICYesYesYesYes
Bone marrow finding26.8% leukemic promyelocytes86.6% leukemic promyelocytes90.0% leukemic promyelocytes (microgranular variant)96.2% leukemic promyelocytes
ImmunophenotypingPositive: CD13 and CD33
Negative: CD34 and HLA-DR
Positive: CD13, CD33, and CD117
Negative: CD34 and HLA-DR
Positive: CD2, CD13, CD15, CD33, CD34, CD56, CD64, CD117, and MPO
Negative: HLA-DR
Positive: CD13, CD15, CD33, CD64, CD117, and MPO
Negative: CD34 and HLA-DR
Chromosome46,XX,t(9;22)(q34;q11.2),t(15;17)(q24;q21)Not reported46,XX,der(3)t(3;15)(q21;q15)t(15;17)(q24.1;q21.2),t(9;22)(q34;q11.2),der(15)t(3;15),del(17)(q21)[20]46,XY,t(9;22)(q34;q11.2),t(15;17)(q24;q21)
FISH for major BCR-ABL1 rearrangement89.3% fusion signal96.0% fusion signal85.5% fusion signal100% fusion signal
FISH for PML-RARA rearrangement95.0% fusion signal90.0% fusion signal81.5% fusion signal100% fusion signal
Quantity of BCR-ABL1 transcriptNot reported2.2199.73%53.22%
Quantity of PML-RARA transcriptNot reported0.8113.28%Not tested
TreatmentIdarubicin, Ara-C and ATRAATRA + imatinibATRA and arsenic trioxideIdarubicin, ATRA and dasatinib
Clinical courseNormal hematopoiesis recoveredNot presentedExpired after two monthsMarrow cellularity recovered, but did not reach CR

Abbreviations: M, male; F, female; BP, blast phase; CML, chronic myeloid leukemia; WBC, white blood cells; TKI, tyrosine kinase inhibitor; FISH, fluorescence in-situ hybridization; CHR, complete hematologic response; CCyR, complete cytogenetic response; DIC, disseminated intravascular coagulation; Ara-C, cytarabine; ATRA, all-trans-retinoic acid; CR, complete response; MMR, major molecular response; CP, chronic phase; M:E, myeloid:erythroid.

Two years later (in April 2019), his peripheral blood (PB) smear revealed marked leukocytosis (164.42 × 109/L), anemia, and thrombocytosis, with 2% blasts and left-shifted neutrophilic maturation. Newly developed hepatosplenomegaly was detected. BM finding was similar to the previous results, but diffuse myelofibrosis was additionally detected. The result of chromosomal analysis was same as before, but the quantity of BCR-ABL1 fusion transcript increased to 96.17%. The patient was started on dasatinib treatment (100 mg once daily). His leukocyte count normalized during the first month of therapy but gradually increased thereafter.

After two months of dasatinib therapy, the patient complained of oral bleeding. PB smear showed leukocytosis with 97% abnormal promyelocytes, anemia, and thrombocytopenia. The disseminated intravascular coagulation (DIC) score calculated using the International Society on Thrombosis and Haemostasis scoring system was 9 (Table 1) [4]. BM study revealed 96.20% abnormal promyelocytes (Fig. 1A). Immunophenotype of abnormal promyelocytes was consistent with acute promyelocytic leukemia (APL). Chromosomal analysis revealed 46,XY,t(9;22)(q34; q11.2),t(15;17)(q24;q21)[20]. The quantity of BCR-ABL1 fusion transcript was 53.22%. Multiplex reverse transcriptase-PCR and interphase fluorescence in-situ hybridization (FISH) detected both major BCR-ABL1 and PML-RARA fusion transcripts (Fig. 1B-1D). The patient was diagnosed as having promyelocytic BP of CML and received induction and maintenance chemotherapy. However, complete remission of promyelocytic BP was not achieved, and stem cell transplantation was considered.

Figure 1. Results of BM study, RT-qPCR, and FISH assay at the diagnosis of blast phase of CML. (A) Abnormal promyelocytes on a BM aspirate smear (Wright–Giemsa stain, × 1,000). (B) RT-qPCR analysis of BCR-ABL1 translocation (HemaVision-28N, DNA Diagnostic, Risskov, Denmark), showing a 397-bp band in the M6B split-out PCR and a 353-bp band in the M8C split-out PCR, indicating BCR-ABL1 (b3a2) and PML-RARA (bcr1 isoform) fusion transcripts. (C and D) FISH using a break-apart probe for BCR-ABL1 and PML-RARA fusion genes (Cytocell, Cytocell Ltd, Oxford Gene Technology, Cambridge, UK) showed two fusion signals, one green and one red, suggesting both BCRABL1 and PML-RARA rearrangements.
Abbreviations: BM, bone marrow; CML, chronic myeloid leukemia; FISH, fluorescence in-situ hybridization; RT-qPCR, quantitative reverse-transcription PCR.

We found three reported cases of promyelocytic BP of CML with BCR-ABL1 and PML-RARA rearrangements that have been reported after the introduction of TKI therapy (Table 1) [1-3]. All reported patients were primarily diagnosed as having CML, CP and immediately started on TKI therapy for which they showed good response. The time to progression into promyelocytic BP after starting treatment varied from six to 16 months. In contrast, our patient’s condition aggravated to promyelocytic BP just two months after starting treatment; therefore, the time was insufficient to evaluate the response to TKI therapy. Most patients showed increased hypergranular abnormal promyelocytes, and immunophenotypes were typical for APL. The quantities of fusion transcripts of BCR-ABL1 and PML-RARA were variable, but the proportion of fusion signals in FISH were high in all cases.

The following mechanisms have been suggested for disease progression from CML, CP to common BP despite TKI therapy: competitive advantage to Philadelphia-negative cells with genetic instability, chromosomal aberrations, and mutations of tumor suppressor genes and oncogenes [5, 6]. Specific risk factors for disease progression to promyelocytic BP of CML have not been identified so far. Few studies have suggested selective suppression of the Philadelphia-positive clone by TKI and TKIinduced chromosomal aberrations [1, 3]. The longer the delay in starting TKI therapy, the more the cells exposed to genomic instability [5]. This finding suggests that PML-RARA clones may have already existed with the BCR-ABL1 clone before the initiation of TKI therapy and may have multiplied rapidly during TKI therapy, which only killed the BCR-ABL1 clone, although we could not confirm the presence of a PML-RARA clone in the sample used for primary diagnosis.

Among the reported four patients, three showed bleeding symptoms and accompanying DIC. Coagulopathy is frequently observed in APL and is associated with early death [7]. Thus, when CML patients show bleeding symptoms, early detection of disease progression and starting adequate treatment immediately are critical.

Few studies have reported APL with both PML-RARA and BCR-ABL1 rearrangements [8, 9]. If a patient is primarily diagnosed as having APL with both PML-RARA and BCR-ABL1 rearrangements, the possibility of progression of undiagnosed CML to promyelocytic BP, rather than de novo APL with both PML-RARA and BCR-ABL1 rearrangements should be considered [10].

In conclusion, disease progression of CML to promyelocytic BP should be considered when (1) BCR-ABL1 and PML-RARA rearrangements are detected simultaneously and (2) sudden changes in leukocyte counts or bleeding symptoms occur despite TKI therapy, which could be an important clue suggesting disease progression to promyelocytic BP rather than adverse effects of TKI.

Kim B designed the study and wrote the manuscript. Chi HY analyzed and interpreted the molecular tests. Yoon YA and Choi YJ interpreted the results of laboratory tests and participated in discussion. All authors read and approved the final manuscript.

This study was supported by the Soonchunhyang University Research Fund.

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