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Transformation of CML Blast Crisis into ALL: Case Finding in Patient's First Visit
to Healthcare

Article in International Medical Journal (1994) · February 2020

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 ISSN: 13412051
Volume 25, Issue 02, February, 2020

Transformation of CML Blast Crisis into ALL: Case

Finding in Patient’s First Visit to Healthcare
Edward Kurnia Setiawan Limijadi1*, Imam Budiwijono1, Purwanto Adhipireno1, Villa Sekar Cita2, Wivina
Riza Devi3

Department of Clinical Pathology, Medical Faculty, Diponegoro University, Semarang, Indonesia1

Internal Medicine Department of Ajibarang Goverment Hospital, Banyumas District, Central Java,
Indonesia2
Clinical Pathology Department of Ulin Goverment Hospital, Kota Banjarmasin, South Kalimantan,
Indonesia3

Corresponding author: *

ABSTRACT—The case was found first as chronic myelogenous leukemia (CML), based on clinical sign
and peripheral blood morphology, but later showed signs of acute lymphoblastic leukemia (ALL). A 35-
years-old patient came to the hospital emergency room for the first time, complained of abdomen
enlargement since a few months ago. Physical examination showed conjunctival anemia and splenomegaly
equal with Schuffner 6, but no lymphadenopathy was found. Laboratory test showed normocytic
normochromic anemia, severe leukocytosis, thrombocytopenia, and increased of reticulocytes. Bone marrow
puncture (BMP) results were hypercellular, increased granulopoeisis activity, decreased erythropoeisis and
megakaryopoeisis, with lymphoblasts were 24% and myeloblasts were 1%. Sokal score calculation was
obtained 5.83, classified as high risk of CML. A flowcytometry test found positive of CD34, CD19, and CD
79a and lead diagnosis to B cell acute lymphoblastic leukemia (B-ALL). The case showed the condition of
CML transformed into ALL which obscured the initial diagnosis of CML.

Keywords: leukemia, transformation, blast, chronic, acute

1. Introduction

Chronic Myelogenous Leukemia (CML) was first identified in 1845, marked by the presence of
Philadelphia chromosomes that encoded the oncogenic tyrosine kinase of BCR-ABL1[1-3]. Furthermore,
CML developed from hematopoietic stem cells and potentially had a multilineage differentiation. If not
treated efficiently, CML may experience a triphasic clinical course with early indolent chronic phase
(chronic phase; 5-15 years), followed by the intermediate acceleration phase (acceleration phase) and,
finally, crisis phase or blast cell explosion (blast crisis phase), either myeloid, lymphoid or bi-phenotype [1].
In this case, it will be discussed regarding the transformation of chronic myeloid leukemia into acute
lymphoblastic leukemia on the first visit of the patient.

2. Patient and observation

35 years old female came to the emergency unit in a hospital for the first visit with a chief complaint of an
enlarged stomach since a few months ago. Physical examination showed pale conjunctiva, splenomegaly of
Schuffner 6, but no lymphadenopathy. The results of the laboratory examination showed normochromic
normocytic anemia (based on MCV and MCH), leukocytosis, thrombocytopenia, and increased

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reticulocytes. The peripheral blood morphological readings obtained by using Hematology Analyzer (Figure
1). Clinical chemistry laboratory examination showed hypoalbuminemia with a mild increase in uric acid
(hyperuricemia). Other normal clinical chemistry laboratory examination results can be seen in table 1.

Table 1. Laboratory examination results

Parameter Pre-Induction Post-
1st day of treatment 5th day of treatment Induction the
3rd cycle
Hematology
Hb (gr/dL) 8,3 9.8 8.2
Ht (%) 25,7 31.6 26.3
Erythrocytes (million/mm3) 2,86 3.55 3.02
MCH (pg) 29 27.6 27.2
MCV (fL) 89,9 89.0 87.1
MCHC (g/dL) 32,3 31.0 31.2
Leukocytes (thousand/mm3) 273,4 236.9 3.5
thrombocytes (thousand/mm3) 79 101 342
RDW- CV (%) 20 20.3 20.1
Reticulocytes (%) . 2.62 .
Differential Count
Eosinophil (%) 3.1 6 0.6
Basophil (%) 1.2 4 0.9
Neutrophil (%) 62.7 55.4
Stab (%) 8
Segment (%) 18
Lymphocytes (%) 20.5 6 29.4
Monocytes (%) 12.5 0 13.7
Others . Lymphoblast 17%, .
Promyelocyte 2%,
Myelocyte 27%,
Metamyelocyte 12%,
Nucleated Erythrocyte
4/100 leukocyte
Peripheral blood smear
Erythrocytes . Normochromic, .
anisocytosis, polychromatic
(+), nucleated erythrocyte
(+)
Leukocytes . the impression of an .
increasing number,
basophilia, eosinophilia,
shift to the left, lymphoblast
17%
Thrombocytes . the impression of a .
decreasing number,
morphology within normal
limits
Clinical Chemistry

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Random blood glucose (mg/dL) 136 . .

Albumin (g/dL) 3.9 . .
AST (U/L) 35 . 17
ALT (U/L) 45 . 24
Urea (mg/dL) 20 . 15
Creatinine (mg/dL) 0.82 . 0.7
Uric acid (mg/dL) 8.9 . .
Calcium (mg/dL) 8.3 . .
Sodium (mEq/L) 140 . .
Potassium (mEq/L) 3.2 . .
Chloride (mEq/L) 100 . .

In the fifth day of treatment, bone marrow puncture and aspiration (bone marrow puncture/BMP) carried out
with the results of hypercellular bone marrow. There was an increase in the activity of granulopoiesis (ME
ratio 12.1:1), a decrease in erythropoietic activity and megakaryopoiesis, with lymphoblast of 24% and
Myeloblast of 1% (the results of the BMP gave the impression of blast crisis of chronic myelocytic leukemia
(blast crisis CML phase) that transformed into acute lymphoblastic leukemia type L1. Sokal score
calculation obtained 5.83 which was a relatively high risk to suffer from CML. Another advanced test of
flowcytometry obtained positive for CD34, CD19, and CD 79a, leading to the blast type of cell B lymphoid
(Fig 3).

Figure 1. The spread of cells in peripheral blood smear (A and B) is typical of the CML and encountered several
lymphoblasts (blue arrows; fig B).

Figure 2. spread of cells in the bone marrow (A) showed increased granulocytic with lymphoblasts (blue arrows) (B).

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Figure 3. Immunophenotyping showed positive results for CD34, CD 19, dan CD79a.

The patient underwent a series of induction chemotherapy after the diagnosis of the blast crisis of LLA
enforced, with the protocols of doxorubicin, vincristine, cyclophosphamide, and prednisone (first to fourth
day of treatment). Chemotherapy was administered up to 3 cycles and then re-check the laboratory for
monitoring post-induction therapy. In the results of the post-induction hematology analyzer, it was still
normochromic normocytic anemia, leukopenia, and the increased number of platelets became normal (table
1). Therapy continued until the sixth cycle then BMP evaluation was planned.

3. Discussion
Clinical symptoms found from history taking were symptoms associated with hypermetabolism and anemia,
for example, weight loss, fatigue, anorexia, night sweat, enlarged stomach accompanied by discomfort or
pain. On the physical examination found pale conjunctiva due to anemia and organomegaly (splenomegaly
of Schuffner 6) without lymphadenopathy.

In general, CML showed initially mildly decreased erythrocytes then became progressive into
normochromic anemia. Normochromic normocytic anemia (based on MCV and MCH values) could occur in
chronic diseases including patients with malignancy as a result of a hematopoietic suppression on bone
marrow leading to bone marrow failure. The proliferation and differentiation of abnormal hematopoietic
stem cells (malignant transformations) led to the suppression and replacement of normal bone marrow
elements. Hemoglobin level could decrease to less than 10 g/dL. Leukocytes could increase by 20,000 –
50,000/mm3 at the beginning then continued to reach more than 100,000/mm3. This occurred because of the
leukemia cells released from the bone marrow to the peripheral blood, as seen in this patient. In addition to
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anemia and leukocytosis, thrombocytopenia occurred due to the suppression of hematopoiesis in the bone
marrow, the decreased platelets production, followed by splenomegaly due to the infiltration of leukemia
cells into the spleen and platelet sequestration in the spleen.

The peripheral blood smear results were corresponding to the results of the Hematology analyzer, indicating
normochromic normocytic anemia accompanied by polychromatic cells and the presence of immature
erythrocytes indicating the dyserythropoietic of bone marrow. The complete spectrum of Granulocyte series
begins from Myeloblasts to the neutrophil segment according to the appearance of chronic myeloid
malignancy. Some of the literature mentioned that the blasts in the CML were approximately 5%.
Interestingly, in this patient, the lymphoblasts were found as much as 17% without myeloblasts. To confirm
the findings, the patient underwent an advanced examination of bone marrow puncture and aspiration along
with immunophenotyping.

From bone marrow puncture aspiration, we could see a hypercellular bone marrow, decreased activity of
erythropoiesis and megakaryopoiesis, increased granulopoiesis and increased lymphocytic activity with
lymphoblasts of 23.5%. The findings showed the appearance of blast crisis of chronic myelocytic leukemia
(blast crisis CML phase) transforming into acute lymphoblastic leukemia (ALL). Another advanced test of
immunophenotyping showed dominant positive marker on CD34, CD19, and CD 79a corresponding to the
B-cell ALL [4].

Sokal scores calculation in this patient indicating high-risk CML category. Sokal score is a mathematical
model involving 4 components found from the patient, i.e. the percentage of blast cells, the spleen size, the
number of platelets and the age of the patient. The score indicates the patient's prognosis with a life
expectancy of 2 years for patients at a high risk of 65% [5,6]. In addition to assessing patient prognosis,
Sokal scores can also be used by clinicians to consider the treatment of patients with CML [7].

History taking, the physical examination and the initial laboratory examinations of the patient supported the
diagnosis of CML. However, on the fifth day of treatment, the CML transformed into ALL blurring the
initial diagnosis of the CML based on the clinical findings and the peripheral blood cells appearance. The
clinical course of CML disease starts from the chronic phase and develops into an acceleration phase and
blast crisis phase [8]. Around 90% of CML patients seek health care in the chronic phase due to the
complaints of anemia and enlargement of organs. Approximately 50% of the asymptomatic CML patients
were inadvertently diagnosed during complete hematology examinations done for other purposes.
Interestingly, the examination results of this patient showed blast crisis CML phase during the first visit.

The pathophysiology chronic phase of CML in molecular level is due to the presence of protein oncogenes
encoded by the Philadelphia chromosomes (Ph). Around 90-95% of CML's genetic profile showed
reciprocal translocation of C-ABL oncogene 1 (ABL1) on chromosome 9 with breakpoint cluster region
(BCR) gene on chromosome 22 (t (9; 22) (q 34.1; q 11.2) which can be detected in routine cytogenetic
analysis. The remaining 5-10% are other translocation variants that cannot be detected on the routine
cytogenetic analysis, so it is necessary to do advanced tests such as FISH or RT-PCR. The result of the
translocation of both chromosomes produces a BCR-ABL1 fusion oncogene protein that affects ABL1
kinase activity. Furthermore, the breakpoint location on chromosome 22 is thought to be related to the type
of BCR-ABL fusion protein expression affecting the phenotype of leukemia [2.8].

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The untreated chronic phase of CML will continue to the acceleration phase and the blast crisis phase.
However, there can also be cases of CML that are diagnosed early during the acceleration phase or the blast
crisis phase. In general, blast cell types were myeloblasts but do not cover the possibility of lymphoblasts to
be found. Some researchers suggested that the findings of lymphoblasts in the peripheral blood and or bone
marrow in the chronic or acceleration phase may increase the risk of lymphoblastic crisis. It should be wary
because the lymphoblastic crisis phase was reported to sometimes have a sudden onset, without the previous
acceleration phase [8].

In general blast transformation of precursor myeloid, there is a probability that 25% of patients can
experience a blast transformation on a precursor of pre-B lymphoblast. As previously described, the
breakpoint location on chromosome 22 was thought to be related to the type of BCR-ABL fusion protein
expression affecting the phenotype of leukemia. There are three main types of the BCR region breakpoint,
i.e. M-BCR region on exon 12-16, M-BCR region on exon e2' and e2, as well as U-BCR region on exon 19.
Generally, a breakpoint occurs in the Exon 2 (a2) which causes the e13a2 or the E14A2 mRNA expression
resulting from rearrangement of the major breakpoint cluster region. The e13a2 or e14a2 mRNA expression
produces p210BCR-ABL fusion protein. Another typical type is a breakpoint on the exon 1 (e1) and exon
19 (e19) which results in the rearrangement of e1a2 or e19a2 resulting in a p190BCR-ABL or p230BCR-
ABL fusion protein. This type of p190BCR-ABL fusion protein is associated with acute lymphoblastic
leukemia incidence [2].
The blast crisis in CML and its transformation into ALL is rare and still limited to existing case reports.
There was a similar case reported by Xu et al. on 43 years old female CML patient with the blast crisis
phase of ALL during her first visit, and Karyotype 46, XX, t (9; 22) (q34; q 11.2)/del (7) (p15). The FISH
analysis showed positive results for the BCR-ABL1, and RT-PCR analysis showed the BCR-ABL1 fusion
gene with major breakpoint coding p210 protein with BCR-ABL1/BCR ratio of 0.15. Similar to our case,
peripheral blood smear showed normochromic normocytic anemia, severe leukocytosis and
thrombocytopenia. The differential count analysis showed basophilia, eosinophilia and increased
granulocytic activity. However, the Immunophenotyping showed the dominance of T cell marker, different
from our case showing more dominance of B cells. Other cases reported by Serra et al. on 80 years old male
patients with the CML of karyotype 46, XY, t (9; 22) (q 3411.2), BCR-ABL of 50% obtained from FISH
analysis and RT-PCR analysis showed e1a3BCR-ABL. Different from our case, the patient came during the
chronic phase, then received Imatinib therapy. He had a remission, but 5 months later, he experienced blast
transformation into ALL with supporting immunophenotyping results of a dominant B cell marker. The
presence of e1a3BCR-ABL was believed to be a risk factor of lymphoid blast crisis in CML.

The case of CML transformation into ALL of other B cell was also reported by Al-Khallaf et al. on 27 years
old male patients. This patient experienced a blast crisis phase after receiving 3 years of therapy during the
chronic phase. In addition to the Philadelphia chromosomal translocation, other chromosomal abnormalities
found in i (9) (q10) and the reciprocal translocation found between the Philadelphia chromosome and
chromosome 22. The addition of chromosome abnormalities believed to contribute to the therapeutic
resistance and the transformation of blast crisis of the B cell ALL. The three cases mentioned above had
different chromosomal abnormalities underlying the clinical course of CML and different transformations
[9,10].

The patient underwent a series of induction chemotherapy with the protocols of doxorubicin, vincristine,
cyclophosphamide, and prednisone (day one to fourth) up to 3 cycles then re-check the laboratory
examination for the monitoring of post-induction therapy. In the results of the post-induction Hematology
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Volume 25, Issue 02, February, 2020

analyzer, it still showed normochromic normocytic anemia, decreased leukocytes (leukopenia), and the
increased platelets became normal. Therapy continued until the sixth cycle then BMP evaluation planned to
see the treatment response in this patient.

4. Conclusion
Based on the history taking, the physical examination and laboratory examination results concluded that the
patient experienced the transformation from CML into ALL that could obscure the initial diagnosis of CML
based on clinical findings and peripheral blood cells. Therefore, the clinical interpretation of leukemia needs
to be done thoroughly. Early cell screening, bone marrow puncture and aspiration, confirmed by
Flowcytometry must be done. Other tests that can be performed are genetic tests such as cytogenetic
examination, FISH and RT-PCR to determine the underlying genetic disorder of the blast transformation.

5. Competing interests The authors declare no competing interest.

6. References
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[2] Martinez- Serra J, Campo R, Gutierrez A, Antich JL, Ginard M, Duran MA, et al. Chronic myeloid
leukemia with an e1a3 BCR-ABL fusion protein: transformation to lymphoid blast crisis. Biomarker Res.
2014; 2:14.

[3] Al-Khallaf H, Alali H, Alkhatti A. Precursor B cell lymphoid blast crisis of chronic myeloid leukemia
with novel chromosomal abnormalities; a case report. Oncology Letters. 2018; 16: 6691-6.

[4] Kosasih AS, Setiawan L, Hartini S, Kresno SN, Indarini. Immunophenotyping in the diagnosis and
classification of acute leukemia: “Dharmasi” Cancer Hospital Experience. Indonesian Journal of Cancer.
2011 Mar; 5(1): 3-8.

[5] Sokal JE, Cox EB, Baccarani M, Tura S, Gomez GA, Robertson JE, et al. Prognostic discrimination in
“good-risk” chronic granulocytic leukemia. Blood. 1984 Apr; 63(4): 789-99.

[6] Jiang BG, Kim DW, Shih LY, Chuah C, Then H, Kuo MC. Sokal rick score is superior to Hasford and
EUTOS in determing survival outcomes for newly diagnosed chronic phase chronic myeloid leukemia
patients. Blood. 2015; 126(23): 4044.

[7] Corrigan A. Chronic Myeloid Leukemia. NCCN Guidelines for patients [Internet]. NCCN. 2018 [cited
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[8] Vardiman JW, Melo JV, Baccarani M, Radich JP, Kvasnicka HM. Chronic myeloid leukemia, BCR-
ABL1-positive. In: Swerdlow SH, Campo E, Harris NE, Jaffe ES, Pileri SA, Stein H, et al editors. WHO
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[9] Perrotti D, Jamieson C, Goldman J, Skorski T. Chronic myeloid leukemia: mechanisms of blastic
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[10] Reckel S, Hamelin R, Georgeon S, Armand F, Jolliet Q, Chiappe D. Differential signaling networks of
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