Introduction

Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the presence of the Philadelphia chromosome, resulting in BCR::ABL1 fusion gene, which drives the uncontrolled proliferation of myeloid cells. CML typically progresses through three phases: chronic, accelerated, and blast crisis. The blast crisis marks the most aggressive form of the disease, in which CML transforms into acute leukemia, usually involving the bone marrow and peripheral blood [1].

Central nervous system (CNS) involvement in CML is exceedingly rare, particularly in the context of a blast crisis, and isolated CNS relapse is even less common [2]. The blood-brain barrier presents a significant obstacle for systemic therapies such as tyrosine kinase inhibitors (TKIs), which are the cornerstone of CML treatment. As a result, CNS relapse is a challenging and potentially life-threatening complication that often requires a multimodal approach, including intrathecal chemotherapy.

This report presents a rare case of isolated CNS relapse in a patient with CML in blast crisis. This case emphasizes the importance of being vigilant and promptly recognizing neurological symptoms in patients with CML in blast crisis, and the need for tailored treatment approaches to overcome the limitations due to the blood-brain barrier.

Case

Ethics statement: This study was approved by the National Medical Research Register of Malaysia (NMRR ID-24-03581-UMA). Written informed consent was obtained from the patient to participate in the study.

A 46-year-old woman with CML in chronic phase was referred to our hematology team in 2019 after an incomplete abortion. Upon further investigation, we found that she had been diagnosed with CML in chronic phase in 2003 at another center and had been treated with multiple lines of TKIs until discontinuation of her medication in 2017 due to financial constraints. Upon review, her full blood count was within normal limits (hemoglobin, 12.2 g/dL; white blood cells, 6.1×10⁹/L; platelets, 347×10⁹/L), and she was asymptomatic.

The patient was started on ponatinib, and subsequent BCR::ABL kinase domain mutation analysis showed no detectable mutations, with polymerase chain reaction (PCR) BCR::ABL1 quantitation of 0.14% (international scale). She continued to undergo regular follow-ups until November 2021, when she reported dizziness, bruising, and loss of appetite. Further evaluation with a full blood picture, bone marrow aspiration/trephine biopsy, and immunophenotyping confirmed transformation to lymphoid blast crisis. She was treated using the MASPORE protocol (consisting of CNS prophylaxis, which includes high-dose methotrexate and intrathecal therapy), and ponatinib was continued. The CNS prophylaxis included weekly intrathecal methotrexate administration during the induction phase and fortnightly intravenous methotrexate administration for four cycles during the consolidation phase. Cytogenetic analysis revealed t(9;22) translocation with additional chromosomal abnormalities, including monosomy 7 and isochromosome 9q, and BCR::ABL1 kinase domain mutation analysis showed E255K mutation. The patient responded well to chemotherapy, and a subsequent bone marrow biopsy revealed morphological remission, with PCR BCR::ABL1 quantitation showing a major molecular response (MR3). Cerebrospinal fluid (CSF) cytology revealed no CNS involvement. The absence of a suitable donor delayed hematopoietic stem cell transplantation.

Unfortunately, in July 2024, the patient complained of blurry vision in her left eye and left-sided headache. Computed tomography of the brain revealed a bulky and enhanced left optic nerve, raising the suspicion of CNS infiltration due to the underlying malignancy. CSF cytology and immunophenotyping confirmed lymphoblast infiltration (Figs. 1, 2). Unfortunately, there are no modalities to diagnose or monitor BCR::ABL1 mutations using CSF in our country. A bone marrow aspiration/trephine biopsy repeated shortly thereafter showed no increase in blasts (Fig. 3), and no new mutations were detected in the BCR::ABL1 kinase domain. The patient was started on fludarabine and cytarabine along with biweekly intrathecal chemotherapy, and ponatinib was switched to dasatinib because of the latter’s enhanced ability to cross the blood-brain barrier.

One month later, CSF immunophenotyping was performed for disease reassessment, which revealed no significant abnormal cell populations, indicating a positive response to treatment. The patient is scheduled to undergo haploidentical stem cell transplantation with her daughter in the near future.

Discussion

Our patient had a disease relapse purely in the CNS with no involvement of the bone marrow or blood, which signifies that this was a case of an isolated CNS relapse of lymphoid blast crisis. CML is a hematological malignancy characterized by the presence of the Philadelphia chromosome, resulting in BCR::ABL1 fusion gene [1]. This gene alteration leads to the uncontrolled proliferation of myeloid cells. With the advent of TKIs, such as imatinib, dasatinib, and nilotinib, the prognosis of patients with CML has significantly improved, with many achieving long-term remission. Despite these advancements, some patients progress to blast crisis, requiring more intensive treatment, including chemotherapy and stem cell transplantation. Isolated CNS relapse remains a rare but challenging complication in this subset of patients [2].

Isolated CNS relapse of CML refers to recurrence of the disease, specifically within the CNS, including the brain and spinal cord, while the rest of the body remains in remission, as in our case [3]. This phenomenon is particularly unusual, given the general efficacy of TKIs in controlling CML. However, the blood-brain barrier which has selective permeability, often prevents an adequate concentration of TKIs from reaching the CNS, which may contribute to CNS-specific relapses, especially with first-generation TKIs.

The pathophysiology underlying isolated CNS relapses in patients with CML is not completely understood. One hypothesis is that leukemic cells enter the CNS early in the disease course, remaining dormant and undetected until the condition allows for their proliferation [4]. Alternatively, the inadequate penetration of TKIs across the blood-brain barrier could allow cells to evade treatment [5]. Mutations in the BCR::ABL1 gene, which confers resistance to TKIs, may also play a role in facilitating CNS relapse.

Patients with an isolated CNS relapse of CML blast crisis may present with a variety of neurological symptoms depending on the location and extent of CNS involvement. Common symptoms include headaches, visual disturbances, seizures, cognitive impairment, and motor deficits [2]. Given the rarity of this complication, these symptoms may initially be misattributed to other neurological conditions.

CSF cytology is an important tool for assessing cell morphology. The presence of atypical lymphocytes can be caused by infections, autoimmune conditions, or malignancies [6] and distinguishing these cells from blasts may be challenging. Atypical lymphocytes exhibit distinct characteristics. They are larger in size and have abundant blue cytoplasm, enlarged nuclei, and less dense chromatin. This may lead to confusion with acute leukemia resulting in misdiagnosis. However, distinguishing features may help differentiate the two conditions, such as the tendency of atypical lymphocytes to display dark blue cytoplasmic edges and the likelihood of their cytoplasm forming pseudopods [7]. Accurate diagnosis requires the correlation of CSF findings with clinical history, imaging, and laboratory tests. In our case, the presence of atypical cells/blasts, coupled with significant immunophenotyping findings, were suggestive of a relapse of the underlying condition.

Among the TKIs, imatinib is particularly notable for its inability to cross the blood-brain barrier, leading to a higher incidence of CNS relapse. This may be due to the P-glycoprotein pump, which reduces imatinib concentrations in the CNS [8]. In contrast, dasatinib demonstrates greater efficacy in penetrating the CNS. The data for ponatinib are mixed, with some patients responding well [9] while others do not [10]. In our patient, ponatinib did not prevent CNS relapse. Thus, the decision to switch to dasatinib aims to achieve a more effective response.

The prognosis of patients with isolated CNS relapse in CML varies and largely depends on the timeline and effectiveness of the intervention. Early detection and prompt treatment can lead to favorable outcomes; however, delayed diagnosis may result in more significant morbidity and poorer prognosis. CNS involvement is typically accompanied by systemic involvement. However, isolated CNS blast crises are rare and limited to a few cases [11]. To the best of our knowledge, this is the first such case reported in Malaysia. The rarity of this condition makes it challenging to establish standardized protocols necessitating individual patient management.

Through this case, we aim to emphasize the importance of remaining vigilant about the possibility of CNS relapse, even in patients who have achieved hematological and cytogenetic remission. Therefore, a high index of suspicion and prompt CSF studies are important to assist in the management of the patient and aggressive management is critical. Advances in the understanding of the pathophysiology of CNS involvement and the development of more effective therapies with better CNS penetration are essential for improving the outcomes of these patients. Continued research and clinical awareness are vital for addressing this unique and challenging aspect of CML.

Article information

Conflicts of interest

No potential conflict of interest relevant to this article was reported.

Acknowledgments

We would like to thank the Director General of Health Malaysia for his permission to publish this article.

Funding

None.

Author contributions

Conceptualization: all authors; Data curation: HPR, BYL; Formal analysis, Supervision: CHSL, WSY, BYL, EJ, IS; Funding acquisition, Validation: WSY, BYL, EJ, IS; Investigation: CHSL; Writing-original draft: HPR; Writing-review & editing: CHSL, WSY, BYL, EJ, IS.

Fig. 1.

Immunophenotyping of the cerebrospinal fluid shows presence of 23% blasts (red), which are CD45 dim with low side scatter area, CD34 dim to negative, CD19 positive, cyCD79a positive, cyCD3 negative, sCD3 negative, CD20 heterogeneous, CD10 (bright), and cynTdT (bright). Lymphocytes are represented by the blue population.

Fig. 2.

(A, B) Cerebrospinal fluid cytology shows the presence of many background lymphocytes and some blasts (arrows) (May-Grünwald stain, ×400).

Fig. 3.

(A) Bone marrow aspirate and (B) trephine biopsy performed after the central nervous system relapse show heterogeneous population of cells with no increase in blasts (May-Grünwald stain, x400 [A]; hematoxylin-esoin stain, x400 [B]).

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References

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