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Case Report
Two Cases of Chronic Myeloid Leukemia in Lymphoid Blast Phase Presented as Philadelphia-Positive Acute Lymphoblastic Leukemia
Clin Pediatr Hematol Oncol 2023;30:75-9.
Published online October 31, 2023
© 2023 Korean Society of Pediatric Hematology-Oncology

Tae Hoon Lee, Hee Young Ju, Ji Won Lee, Ki Woong Sung and Keon Hee Yoo

Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
Correspondence to: Keon Hee Yoo
Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea
Tel: +82-2-3410-3532
Fax: +82-2-3410-0043
E-mail: hema2170@skku.edu
ORCID ID: orcid.org/0000-0002-5980-7912
Received July 7, 2023; Revised August 18, 2023; Accepted September 8, 2023.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Patients with chronic myeloid leukemia (CML) in lymphoid blast phase can present clinical characteristics resembling Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). It is crucial to distinguish between two diseases since their treatments differ. We present two cases of children who presented with CML lymphoid blast crisis, who were initially difficult to distinguish from Ph+ ALL.
Keywords: Chronic myeloid leukemia, Blast crisis, Philadelphia chromosome, Precursor cell lymphoblastic leukemia-lymphoma
Introduction

When a pediatric patient shows significantly elevated B-lineage blasts in peripheral blood or bone marrow and tests are positive for the Philadelphia chromosome (Ph+), Ph+ acute lymphoblastic leukemia (ALL) is usually the first diagnosis to be considered. However, because chronic myeloid leukemia (CML) in blast phase can also present like ALL, it is necessary to examine physical findings and test results in detail. Patients with CML frequently exhibit distinct splenomegaly on physical examination, and complete blood count (CBC) generally reveals a left-shifted distribution. Additionally, several criteria have been proposed to differentiate CML from ALL [1].

The two diseases have similar presentation, but the prognosis and treatment differ. Patients with CML blast phase are typically advised to receive a brief course of tyrosine kinase inhibitor (TKI) with chemotherapy followed by allogeneic hematopoietic stem cell transplantation (HSCT) [2]. However, patients with Ph+ ALL who respond satisfactorily to chemotherapy and TKI are not typically considered for HSCT [3].

We present two cases of CML diagnosed in blast phase whose initial diagnosis was challenging to distinguish from Ph+ ALL. This case review was approved by the institutional review board of Samsung Medical Center (IRB No. 2022-11-015).

Case Report

1) Case 1

A 7-year-old boy presented with bruises for 4 months and recent gingival bleeding. He was transferred to our tertiary medical center, considering possibility of hematologic malignancy. His physical examination showed gingival hypertrophy with bleeding of lower gum, multiple enlarged cervical lymph nodes; 0.5 to 1 cm sized, round, and firm lymph nodes of both sides of neck; several bruises of anterior chest, back, buttock, and calves. At the right mid-clavicular line, the liver was palpable as three fingerbreadth size, and the spleen was palpable at left mid-clavicular line with 4 fingerbreadth size, showing hepatosplenomegaly.

His blood test revealed anemia, leukocytosis, thrombocytopenia; hemoglobin 7.0 g/dL, white blood cell (WBC) 351.46×109/L and platelet 34×109/L. Proportion of cells among WBCs was as follows; blast 24%, myelocyte 10%, metamyelocyte 10%, segmented neutrophil 36%, lymphocyte 7% and monocyte 6%. Bone marrow examination revealed B-lymphoblastic cells with nTdT+CD10+CD19+ cCD22+cCD79a+CD66c+CD34+ cells accounting 60.63% of total events. Chromosome study detected Phila-delphia chro-mosome; 46,XY,t(9;22)(q35.1q11.2)[7]/46,sl,del(9)(p21)[13]. Fluorescence in situ hybridization (FISH) study indicated 98.5% of cells with BCR/ABL1 fusion signals (197 among 200) and 32.0% of cells with CDKN2A deletion. Reverse transcription-polymerase chain reaction (RT-PCR) study showed major BCR/ABL1 gene rearrangement with b2a2 type. The bone marrow diagnosis of patient was CML, BCR-ABL1 posi-tive in blastic phase versus acute B-lymphoblastic leukemia with t(9;22)(q34.1;q11.2);BCR-ABL1.

The patient was treated with ALL induction chemothe-rapy including vincristine, L-asparaginase, prednisolone, daunorubicin, intrathecal cytosine arabinoside, and intrathecal methotrexate. After confirmation of major BCR/ABL1 gene rearrangement by hemavision multiplex RT-PCR, imatinib (340 mg/m2/day) was added from the second day of induction. Following induction therapy, the bone marrow examination revealed minimal residual disease (MRD) by flow cytometry (<0.001%). However, 24.5% of cells showed BCR/ABL1 rearrangement with FISH study and karyotype was 46,XY,t(9;22)(q34.1;q11.2)[6]/ 46,XY[14]. RT-PCR result showed 18.547% of major BCR-ABL1 fusion transcript by international scale (Table 1A, Fig. 1A). This finding indicated that cells with BCR/ABL1 rearrangement were presented other than blast cells. After considering these inconsistencies, the patient was consequently diagnosed with CML in lymphoid blast phase. The patient’s somatic next-generation sequencing (NGS) study revealed NF1: c.6148-2insT variant with 10.5% of variant allele frequency (VAF).


Figure 1. Serial change of BCR/ABL1 transcript by quantitative RT-PCR and MRD with flow cytometry (A) patient 1, (B) patient 2. EOI, end of induction; EOC, end of consolidation; HSCT, hematopoietic stem cell transplantation.

The patient received three courses of consolidation chemotherapy together with imatinib while searching for a transplantation donor, and underwent unrelated HSCT. Before HSCT, imatinib was stopped, then reintroduced 40 days later and maintained for a year. There is no evidence of a CML relapse until three years and five months following HSCT.

2) Case 2

An 8-year-old girl presented with recent abdominal pain. As laboratory test done at outside hospital showed hyperleukocytosis with WBC 306×109/L, she was transferred to our hospital considering hematologic malignancy. Upon physical examination, she had multiple bruises, a 2 cm sized enlarged cervical lymph node, and anemic conjunctiva. Abdomen was distended, liver was palpable 3 fingerbreadth at right mid-clavicular line, and spleen was palpable 4 fingerbreadth at left mid-clavicular line. Her WBC count was 323.93×109/L, hemoglobin 5.6 g/dL, and platelet 22×109/L. Proportion of cells among WBCs was as follows; blast 86%, metamyelocyte 1%, band neutrophil 2%, segmented neutrophil 4%, eosinophil 1%, lymphocyte 5%, and monocyte 1%. Bone marrow examination revealed packed marrow with 90% of blasts.

A chromosome analysis revealed a 46,XX,t(9;22)(q34.1; q11.2)[18]/46,XX[2] karyotype. RT-PCR showed major BCR/ABL1 gene rearrangement with b3a2 type. The patient was treated with ALL induction chemotherapy including vincristine, L-asparaginase, prednisolone, daunorubicin, intrathecal cytosine arabinoside and metho-trexate. Imatinib was added from the third day of induction, after achieving the chromosome study result. After 2 weeks, MRD was 0.52% by flow cytometry, but FISH study showed BCR/ABL1 gene in 12% of cells. At the end-of-induction bone marrow study, these values became 0.0032% and 24.5%, respectively (Table 1B, Fig. 1B). According to this discrepancy, the patient’s final diagnosis was confirmed to be CML lymphoid blast phase. The patient’s somatic NGS study reported RUNX1: c.319C>T variant with 41.5% of VAF.

After two courses of consolidation therapy, she received HSCT from a haploidentical sibling donor due to lack of matched donor. After HSCT, imatinib was administered for one more year after HSCT. The patient is remaining disease-free for two years and six months following HSCT.

Discussion

CML is a rare hematologic malignancy accounting for less than 3% of pediatric and adolescent leukemia [4]. More than 95% present as CML chronic phase, and the other 5% present as CML accelerated phase or blast phase [5]. However, the proportion of pediatric patients diagnosed with accelerated phase or blast phase is higher than for adult patients [2]. In children and adolescents diagnosed as CML-BP, the predominant presentation is lymphoid-BP (70%) [6]. In contrast, ALL accounts for approximately 80% of pediatric leukemia [7]. Among ALL, the Ph+ ALL is less than 5% in pediatric population [8].

In our second case, a variant of RUNX1 gene was reported from a somatic NGS test. RUNX1 is a frequently addressed driver of hematologic malignancies. It has been reported that RUNX1 mutation can be acquired as an additional driver mutation of CML progression from the chronic phase to the blast phase [9].

In CML, the site of breakpoint in the BCR gene is usually the major breakpoint cluster regions (M-BCR), with the M-BCR-ABL1 transcripts encoding a 210 kD BCR-ABL1 fusion protein named p210. In contrast, in Ph+ ALL, the breakpoint of BCR gene can be either the M-BCR or the minor BCR (m-BCR), and the mBCR-ABL1 fusion transcripts encode a 190kD BCR-ABL1 fusion protein, named p190 [1]. Thus, if a patient with major BCR/ABL1 rearrangement shows discrepant results in flow cytometry and FISH or RT-PCR, the possibility of CML should also be considered [10].

In Ph+ B-ALL, the BCR/ABL1 rearrangement is only in the lymphoblastic cells, but in CML, the rearrangement can be found in both myeloid cells and lymphoblasts [1]. Flow cytometry represents blast counts, but FISH and RT-PCR targets all kinds of cells. As a result, if there is a noticeable difference in the results between tests, it should be taken into account that BCR/ABL1 translocation may occur in cells other than blast. In this case, the possibility of CML rather than Ph+ ALL should be considered.

According to a previous study, the following characteristics have been proposed as findings suggestive of CML rather than Ph+ ALL; 1) a large discrepancy (≥50%) between the blast count and Ph+ clone at initial diagnosis; 2) a large Ph+ clone (≥50%) paired with minimal residual lymphoblast (<5%), or negative MRD by flow cytometry paired with ≥10% Ph+ clone after chemotherapy; and 3) BCR/ABL1 fusion signals detected in segmented nuclei by interphase FISH [1]. In our case 1, FISH assay revealed 24.5% of BCR/ABL1 rearranged cells even though MRD negativity was achieved at the end of induc-tion. In case 2, FISH showed 24.5% of BCR/ABL1 rear-ranged cells but MRD showed 0.032% of clones at the end of induction.

For Ph+ ALL, intensive multi-agent chemotherapy together with TKI is the recommended treatment. However, for CML blast phase, HSCT after a short course of chemotherapy is the treatment of choice [3,11]. In general, all patients with CML-BP, should be considered for allo-SCT [12,13]. Studies have revealed that adult CML-BP patients who receive subsequent allo-SCT had better outcomes [14].

In case of CML-CP or de novo AP, TKI is generally used first [15]. Three TKIs (imatinib, dasatinib, and nilotinib) are FDA-approved for pediatric patients who are initially diagnosed with CML. However, unlike adult CML risk scoring with Sokal, EUTOS, and Hasford scoring, there are no standards to select TKI in children. In South Korea, Imatinib is the only TKI approved currently for the pediatric CML patients with blast phase at initial diagnosis thus our patients were treated with Imatinib from initial diagnosis.

Because of therapeutic difference between CML blast phase and Ph+ ALL, it is important to distinguish these two diseases. If a patient has increased blast with major BCR/ABL1 rearrangement, the probability of CML blast phase should be taken into account. To distinguish between these diseases, it would be useful to take discrepancy between several assays into account.

Conflict of Interest Statement

The authors have no conflict of interest to declare.

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  • Keon Hee Yoo