Myelomastocytic transformation in chronic myeloid leukemia: A diagnostic puzzle in two patients following treatment interruption

INTRODUCTION

Blast crisis (BC) in chronic myeloid leukemia (CML) is most commonly of myeloid origin but may rarely involve other lineages such as lymphoid, megakaryoblastic, basophilic, or erythroid types.^[1,2] Exceptionally, CML may evolve into rare entities such as mixed phenotype acute leukemia (MPAL) or myelomastocytic leukemia (MML).^[3]

MML, first described by Valent et al., is a rare and aggressive hematological neoplasm characterized by proliferation of >10% immature mast cells (iMCs) with bright CD117 and tryptase positivity, usually arising in patients with myelodysplastic syndrome or CML-BC.^[4] Similar cases with <10% iMC have been described as a potential pre-MML condition.^[3]

We report two CML patients who defaulted on tyrosine kinase inhibitor (TKI) therapy and presented in BC with numerous blasts containing metachromatic granules. Flowcytometric immunophenotyping (FCI), immunohistochemistry (IHC), and molecular studies were pivotal in identifying iMCs and excluding the other differentials.

CASE REPORT

Case 1

A 22-year-old male, diagnosed with CML 1 year prior, presented after multiple treatment defaults with hyperleukocytosis (total leukocyte count [TLC] 2,06,090/μL). Peripheral smear revealed ~20% blasts, 2–3 times the size of lymphocytes, with fine chromatin and basophilic agranular cytoplasm. In addition, ~66% immature cells with numerous metachromatic granules were seen [Figure 1]. Morphological differentials included basophilic BC, myeloid BC with mast cell (MC) differentiation/MML, MCL, and systemic mastocytosis with associated hematologic neoplasm (SM-AHN).

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Figure 1:

(a) Peripheral smear shows blasts with many showing prominent granules on MayGrünwald Giemsa (MGG) stain (x1000 magnification) , inset shows blasts with metachromatic granules on Toulidine blue stain (x1000 magnification), (b) Immunohistochemical stain for CD117 shows bright and moderate positivity with no dense/compact clusters (200x magnification), (c) Immunohistochemical stain for Tryptase shows >10% positivity (x400 magnification), inset showing blasts with membranous positivity for Tryptase (x1000 magnification).

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FCI identified two abnormal populations in bone marrow (BM) [Figure 2]. The major population (~70%) displayed an iMC phenotype seen as bright CD117, moderate-heterogeneous CD34 and human leukocyte antigen – DR isotype (HLA-DR), moderate CD13/CD33/CD203c, dim CD123/CD38/CD25, and negative CD2/CD15/CD64/cytoMPO. The minor population (~13%) showed myeloblast phenotype with bright CD34 and HLA-DR, moderate CD117, CD13, CD33, CD123, CD203c, dim CD38/CD25, and negative CD14/CD15/CD64/cytoMPO. Mature basophils (~0.2%) were also present.

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Figure 2:

(A) Case 1- Dot plot (a) shows an abnormal population with dim CD45 labelled as Blasts on CD45 vs Side scatter. Dot plot (b) On CD117 vs CD34 scatter plot, two types of blast population identified – P1 (Myeloblast) in red with moderate CD117 & CD34 and P2 (Immature mast cells) in green with bright CD117 & moderate CD34. Dot plots (c),(d),(e),(f) show antigen expression patterns of various markers in immature mast cells differentiating from the myeloblasts. Dot plot (g) shows the absence of CD2 and dot plot (h) shows dim CD25 expression in immature mast cells. (B) (a-h): Case 2- Dot-plots with expression patterns of the above-mentioned markers in immature mast cells and Myeloblasts.

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BM biopsy was hypercellular and packed with immature cells. IHC with CD117 showed increased blasts with many precursor MC with brightest CD117 expression but without forming compact clusters [Figure 1]; Tryptase was positive in ~20% cells [Figure 1]. Next-generation sequencing (NGS) revealed breakpoint cluster region– abelson murine leukaemia viral oncogene homolog 1 (BCR-:ABL1). rearrangement and was negative for any tyrosine-protein kinase (KIT) mutations. A final diagnosis of CML in myeloid BC with MC differentiation (MML) was established.

DISCUSSION

The advent of TKIs has transformed CML into a largely controllable disease.^[5] However, treatment interruption remains the major cause of disease progression to BC due to persistent BCR: ABL1 activity promoting genomic instability, clonal evolution, and acquisition of secondary mutations, occasionally driving transformation into rare phenotypes such as basophilic BC, MPAL, or MML.^[6] Both our cases underscore the clinical consequences of TKI non-adherence in CML progression.

The presence of metachromatic granules in immature cells poses significant diagnostic difficulty, necessitating distinction among SM-AHN, MCL, basophilic BC, and myeloid BC with MC differentiation/MML.^[7] In both cases, the absence of systemic symptoms or organ infiltration excluded mastocytosis.

On FCI, the blasts exhibited iMC phenotype with bright CD117, CD203c positivity, moderate heterogeneous CD34 and HLA-DR, and absence of CD2 but dim CD25 expression, thereby not fulfilling SM/MCL criteria. Lack of dense MC clusters on the BM biopsy excluded the major World Health Organization (WHO) criterion for SMAHN. Furthermore, both cases were negative for the KITD816V mutation, definitively excluding clonal MC disease.

Interestingly, in Case 2, both myeloblasts and iMCs expressed CD7, suggesting a shared leukemic progenitor, consistent with earlier reports.^[3,8] These findings highlight the continuum of MC differentiation within leukemic transformation.

In the first case, iMCs accounted for >10% of nucleated cells, meeting criteria for MML; in the second, 3% iMCs suggested a pre-MML phase. However, due to a lack of formal recognition of MML or pre-MML in the current WHO classification, both our cases were best described as CML in myeloid BC with MC differentiation.

Therapeutically, the first patient was treated at our center with induction chemotherapy (7+3 regimen: cytarabine for 7 days and idarubicin for 3 days) along with dasatinib. He was subsequently lost to follow-up and later sought further treatment, including BM transplantation, at a government facility. The second case was an international patient who went back to his home country after diagnosis without receiving any treatment at our center.

According to the limited case reports, treatment of MML requires an aggressive approach, including TKIs and combination chemotherapy followed by allogeneic stem cell transplantation, with several patients achieving complete remission. These observations indicate that intensive treatment strategies, particularly those incorporating allogeneic transplantation, may offer superior outcomes, although the optimal therapeutic approach and the role of novel targeted or immunotherapeutic agents remain to be defined.^[9]

CONCLUSION

These two cases emphasize the importance of integrated diagnostic evaluation in CML BC presenting with MC differentiation. Careful morphologic assessment for metachromatic granules, IHC with CD117 and tryptase, and FCI with extended markers (CD25, CD2, CD203c) are essential to identify iMCs and distinguish MML from mimickers. Molecular testing, particularly for KIT D816V, is indispensable to rule out SMAHN or MCL.

Moreover, these cases reinforce that interruption of TKI therapy can result not only in relapse but also in evolution toward rare, diagnostically challenging blast phenotypes.

This report highlights the urgent need for updated classification criteria recognizing MML and related entities within future WHO revisions. Formal inclusion will enhance diagnostic precision, prognostic assessment, and therapeutic decision-making. Further molecular profiling studies are warranted to clarify the pathobiological continuum between myeloid blasts and immature MCs in CML transformation, potentially paving the way for targeted therapeutic strategies.