
==== Front
Cureus
Cureus
2168-8184
Cureus
2168-8184
Cureus Palo Alto (CA)

10.7759/cureus.67412
Pathology
Internal Medicine
Hematology
Chronic Myeloid Leukemia Unveils Its Dark Side: A Rare Case of Megakaryocytic Blast Crisis
Muacevic Alexander
Adler John R
Khalid Mehreen 1
Suhail Maymoona 2
Faisal Alizah 3
Poombal FNU 4
Muhammad Asad Khan Fatima 5
1 Hematopathology, Armed Forces Institute of Pathology, Rawalpindi, PAK
2 Hematology, Armed Forces Institute of Pathology, Rawalpindi, PAK
3 Hematology, Rawalpindi Medical University, Rawalpindi, PAK
4 Pathology, Nishtar Medical University, Multan, PAK
5 Medicine, Dow University of Health Sciences, Karachi, PAK
Alizah Faisal alizahfaisal1@gmail.com
21 8 2024
8 2024
16 8 e6741215 8 2024
Copyright © 2024, Khalid et al.
2024
Khalid et al.
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
This article is available from https://www.cureus.com/articles/277962-chronic-myeloid-leukemia-unveils-its-dark-side-a-rare-case-of-megakaryocytic-blast-crisis
Chronic myeloid leukemia (CML) can progress from a chronic phase (CP) to an accelerated phase (AP) or an acute leukemia-like blastic phase (BP). However, transformation into a megakaryoblastic phase is very rare, and such a progression is clinically significant due to its poor prognosis and resistance to standard tyrosine kinase inhibitors (TKIs). This report discusses a case of CML that progressed to a megakaryoblastic phase and the patient’s death within a month despite receiving one cycle of daunorubicin, cytarabine, and TKI chemotherapy.

A 39-year-old female with CML (CP) initially achieved hematological remission with nilotinib but later presented with B symptoms and cytopenias indicative of disease progression. A complete diagnostic workup was performed, including blood counts, bone marrow examination, flow cytometry, fluorescence in-situ hybridization (FISH), and cytogenetic testing. Peripheral blood and bone marrow evaluation confirmed blast crisis with 84% medium to large-sized blasts with basophilic cytoplasm and cytoplasmic blebs. The blasts were positive for CD41 and CD61 by immunohistochemistry (IHC). The blasts also expressed CD45 (dim), CD34, CD33, CD117, CD41, and CD61 by flow cytometry. While BCR-ABL1 positivity is typically associated with CML (90-95%), the additional findings point towards a transformation to acute megakaryoblastic leukemia (AMKL or AML-M7). The rare instance of CML's transformation to AMKL highlights the need for megakaryocytic markers in diagnostic panels to ensure accurate diagnosis and timely, tailored therapies for improved outcomes.

translocation 9 22
tyrosine kinase inhibitors
acute myeloid leukemia (aml)
megakaryoblastic crisis
chronic myeloid leukemia (cml)
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pmcIntroduction

Chronic myeloid leukemia (CML) is a slow-growing blood and bone marrow disorder that typically affects individuals over their middle age, with rare cases reported in children [1]. In most CML cases, normal bone marrow cells are replaced by abnormal cells with the Philadelphia chromosome, which is characterized by the 9;22 translocations and occurs in 90-95% of patients [2]. The BCR-ABL oncogene creates a protein (tyrosine kinase) that fuels CML cell growth [3]. CML can progress through a biphasic or triphasic pattern, starting from an initial chronic phase (CP), advancing through an intermediate accelerated phase (AP), and culminating in an acute leukemia-like blastic phase (BP) [4]. Megakaryocytic blast crisis (MKBC) is marked by >20% bone marrow or peripheral blood blasts expressing megakaryocytic markers (e.g., CD41, CD61) associated with platelet function of adhesion and aggregation. MKBC is a rare entity, accounting for <3% of CML in transformation [5].

CML in blast crisis confers a dismal prognosis with a shorter survival rate compared to earlier phases [6]. This phase presents a significant therapeutic hurdle due to its aggressiveness and refractoriness to standard tyrosine kinase inhibitors (TKIs). Its management often requires a multi-pronged approach, potentially combining chemotherapy, TKIs, and allogeneic stem cell transplantation, tailored to individual response and health status [7]. We present a rare case involving the transformation of CML to a megakaryocytic blast phase. We discuss the patient's clinical course, diagnostic workup, and treatment response.

Case presentation

History of presentation

A 39-year-old female with a documented BCR-ABL1-positive CML diagnosed in February 2021 presented with a one-month history of progressive fatigue and loss of appetite. She received nilotinib 600mg/day initially, achieving hematologic remission. However, nine months later, she experienced cytopenias and B symptoms (constitutional symptoms) prompting readmission.

Physical examination

Physical examination revealed pallor with unremarkable systemic findings.

Laboratory findings

Peripheral blood smear analysis revealed normocytic normochromic anemia with many teardrop-shaped red blood cells. Laboratory findings are presented in Table 1. Morphologically, the blasts exhibited round nuclei with open chromatin, prominent nucleoli, and deep basophilic cytoplasm whereas the platelets were giant and showed anisocytosis, as shown in Figure 1.

Table 1 Laboratory findings

Lab tests	Patients values	Reference values	
Complete blood count	 	 	
Haemoglobin (g/dl)	11.4	12-15	
Platelet count (x109/L)	50	150-450	
Total leukocyte count (x109/L)	25.19	4-10	
Differential count	 	 	
Neutrophils (%)	0	40-80	
Lymphocytes (%)	20	20-40	
Monocytes (%)	2	2-10	
Eosinophils (%)	0	1-6	
Myelocytes (%)	3	0	
Blast cells (%)	75	0	

Figure 1 Peripheral smear at 40X showing blasts

Bone marrow evaluation

Aspiration from the posterior iliac crest revealed hypercellular fragments and trails with depressed erythropoiesis and myelopoiesis. Megakaryocytes were increased in number and there were 84% blast cells. The population of the blast cells was heterogeneous, consisting of medium to large-sized blast cells with a low nuclear-to-cytoplasmic ratio, dispersed chromatin, conspicuous nucleoli, and abundant cytoplasm. The majority of the blast cells had cytoplasmic blebbing (Figure 2). Trephine biopsy showed infiltration with sheets of blast cells (Figures 3-4) and extensive fibrosis (Figure 5).

Figure 2 Bone marrow aspirate at 40X showing blasts with blebs/projections (megakaryoblasts) and occasional myeloblasts (blue arrow: myeloblast, red arrow: megakaryoblast)

Figure 3 H&E-stained trephine biopsy at 10X showing hypercellular marrow with effaced architecture and diffuse infiltration by blast cells

Figure 4 H&E-stained trephine biopsy at 40X showing diffuse infiltration by blast cells

Figure 5 Increased reticulin at 10X indicating extensive fibrosis (MF grade 2)

Flow cytometry and immunohistochemistry confirmed a population of blasts expressing CD45 (dim), CD34, CD33, CD117, CD41 (Figure 6), and CD61 (Figure 7). Additionally, HLA-DR was also expressed. Quantitative PCR (polymerase chain reaction) for BCR-ABL1 confirmed a positive result (41.39% IS). Cytogenetic analysis revealed the presence of the characteristic t(9;22) translocation and a complex karyotype.

Figure 6 Immunohistochemistry (IHC): CD41 at 40X showing positive staining of megakaryoblasts

Figure 7 Immunohistochemistry (IHC): CD61 at 40X showing positive staining of megakaryoblasts

Diagnosis

Based on the clinical presentation, laboratory findings, bone marrow evaluation, and molecular analysis, the diagnosis of chronic myeloid leukemia in megakaryocytic blast crisis was established.

Treatment

Unfortunately, the patient passed away four months after receiving one cycle of chemotherapy. While we do not currently have details on the specific type of chemotherapy administered, we have requested the patient's family for this information.

Discussion

The abnormal fusion of two genes, BCR (on chromosome 22) and ABL1 (on chromosome 9) through reciprocal translocation, t(9;22)(q34;q11), results in the BCR-ABL1 fusion protein [8]. The presence of the BCR-ABL1 fusion gene in hematopoietic stem cells is adequate to trigger CML. The shortened chromosome 22, termed the Philadelphia chromosome, contains the BCR-ABL1 oncogene, a significant player in the leukemogenesis of CML due to its deregulated tyrosine kinase activity [9]. BCR-ABL1 is also present in other leukemia types, including acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) [10].

As discussed previously, CML is classified into three phases: CP, AP, and BP [11]. Annually, about 1-1.5% of CML patients treated with a TKI progress to an advanced phase or blast crisis [12]. Two-thirds of CML blast phase cases exhibit a myeloid phenotype; the remaining cases present a lymphoid phenotype, though blast transformation into a megakaryocytic phenotype is rare. Immunophenotypic analysis helps classify the blast nature. Extramedullary blast crisis may affect various sites and manifest as either lymphoid or myeloid [13].

The blast phase of CML is a poor prognostic factor. Other prognostic factors include age (60 years and older), platelet count, increased basophil counts, blasts in the blood, and spleen size. These factors are integrated into prognostic scoring systems such as Sokal, European Treatment and Outcome Study for CML (EUTOS) long-term survival (ELTS), and Hasford, which determine the risk profile of CP-CML patients at diagnosis [14]. Despite significant advancements in managing the CP phase of CML, the blast crisis continues to present significant therapeutic challenges, underlining the need for novel therapies to induce a second CP, thereby facilitating the transition to allogeneic stem cell transplantation [15].

CML megakaryocytic blast crisis typically has a poor prognosis [16]. Detecting the specific type is crucial as management protocols differ. In our case, the patient's bone marrow aspiration showed diluted marrow, likely associated with myelofibrosis, a common occurrence in both de novo acute megakaryocytic leukemia (AMKL or AML-M7) and megakaryocytic blast crisis [17]. Diagnosing unusual blast forms presents challenges but is essential for appropriate management. Patients with megakaryocytic blast phase CML have a poor prognosis, with a median survival rate of less than 12 months [16].

Conclusions

AML-M7 blastic crisis in CML is a very rare manifestation, and the detection of this condition is crucial as the management protocols differ. The case report highlights the significance of distinguishing the CML blast crisis from other similar differentials. This case also emphasizes the importance of extensive diagnostic evaluations to accurately identify rare subtypes of blast crisis. Including one megakaryocytic marker in the initial flow cytometry panel is crucial to prevent underdiagnosis as AML alone and ensure appropriate treatment decisions. Recognizing the rare AML-M7 type in a blast crisis can lead to more effective therapeutic involvement and improve patient outcomes.

Disclosures

Author Contributions

Human subjects: Consent was obtained or waived by all participants in this study.

Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following:

Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work.

Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work.

Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.

Concept and design:  Alizah Faisal, Mehreen Khalid, Maymoona Suhail, FNU Poombal, Fatima Muhammad Asad Khan

Acquisition, analysis, or interpretation of data:  Alizah Faisal, Mehreen Khalid, Maymoona Suhail, FNU Poombal

Drafting of the manuscript:  Alizah Faisal, Mehreen Khalid, Maymoona Suhail, FNU Poombal, Fatima Muhammad Asad Khan

Critical review of the manuscript for important intellectual content:  Alizah Faisal, Mehreen Khalid, Maymoona Suhail, Fatima Muhammad Asad Khan

Supervision:  Alizah Faisal, Mehreen Khalid, Maymoona Suhail
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References

1 Chronic myelogenous leukemia treatment 5 2024 Chronic Myelogenous Leukemia Treatment 2024 https://www.cancer.gov/types/leukemia/patient/cml-treatment-pdq
2 Chronic myeloid leukemia with variation of translocation at (Ph) [ins (22;9) (q11;q21q34)]: a case report Int J Clin Exp Pathol Wang Z Zen W Meng F 13707 13710 8 2015 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4680543/ 26722598
3 BCR-ABL1 tyrosine kinase complex signaling transduction: challenges to overcome resistance in chronic myeloid leukemia Pharmaceutics Amarante-Mendes GP Rana A Datoguia TS Hamerschlak N Brumatti G 42 44 14 2022
4 Accelerated and blastic phases of chronic myelogenous leukemia Hematol Oncol Clin North Am Giles FJ Cortes JE Kantarjian HM O'Brien SM 753 774 18 2004 15271404
5 Megakaryocytic blast crisis in chronic myeloid leukiemia: an uncommon presentation in a common neoplasm Hematol Transfus Cell Ther Agrawal S Kumar K Singh M Chandra H 264 268 44 2022 32962960
6 A case of chronic myeloid leukaemia presenting as megakaryocytic blast crisis (AML M7) Ecancermedicalscience Karkuzhali P Shanthi V Usha T 375 7 2013 24282446
7 Diagnosis and treatment of chronic myeloid leukemia in 2015 Mayo Clin Proc Thompson PA Kantarjian HM Cortes JE 1440 1454 90 2015 26434969
8 CML with megakaryocytic blast crisis: report of 3 cases Pathol Oncol Res Khemka R Gupta M Jena NK 1253 1258 25 2019 30357754
9 Molecular biology of bcr-abl1-positive chronic myeloid leukemia Blood Quintás-Cardama A Cortes J 1619 1630 113 2009 18827185
10 The Philadelphia chromosome in leukemogenesis Chin J Cancer Kang ZJ Liu YF Xu LZ 48 35 2016 27233483
11 Chronic myeloid leukemia: 2020 update on diagnosis, therapy and monitoring Am J Hematol Jabbour E Kantarjian H 691 709 95 2020 32239758
12 Blast crisis J Educ Teach Emerg Med Kirwin M Yee J 0 77 5 2020
13 Chronic myeloid leukemia Hematology (Seventh Edition) 1055 1070 Amsterdam, Netherlands Elsevier Health Sciences 7 2018 https://books.google.com.pk/books/about/Hematology.html?id=a1estSuaQ6kC&redir_esc=y
14 Prognostic factors for overall survival in chronic myeloid leukemia patients: a multicentric cohort study by the Italian CML GIMEMA Network Front Oncol Specchia G Pregno P Breccia M 739171 11 2021 34513714
15 Current management of chronic myeloid leukemia myeloid blast phase Clin Med Insights Oncol Yohanan B George B 11795549221139357 16 2022 36507316
16 Prognostic factors and survival outcomes in patients with chronic myeloid leukemia in blast phase in the tyrosine kinase inhibitor era: cohort study of 477 patients Cancer Jain P Kantarjian HM Ghorab A 4391 4402 123 2017 28743165
17 Clinical diagnosis of adult patients with acute megakaryocytic leukemia Oncol Lett Zhao G Wu W Wang X Gu J 6988 6997 16 2018 30546432
