A Peculiar Manifestation of Chronic Myelogenous Leukemia in Lymphoid Blast Crisis

Chronic myelogenous leukemia (CML) is a malignant neoplasm of the hematopoietic cells with the hallmark feature of a t(9;22) chromosomal translocation with the formation of the BCR/ABL fusion oncogene (1). This myeloproliferative disease usually progresses from chronic to accelerated to blast phase; the blast phase is defined as more than 20% blasts in the peripheral blood or bone marrow (2). Leukocytosis on routine examination is the most common manifestation (3).

The blast phase may comprise lymphoid or myeloid blasts. The presence of lymphoid blasts with Philadelphia chromosome positivity (Ph+) may point toward the diagnosis of B-cell acute lymphoblastic leukemia; the correct diagnosis can be established with advanced cytogenetic analyses.

We describe a case of CML in lymphoid blast crisis in which the patient presented with slight leukocytosis, memory impairment, and behavioral changes.

The primary care physician of a 61-year-old man with depression, hypothyroidism, uncontrolled type 2 diabetes mellitus, heterozygous factor V Leiden mutation, and 4 transient ischemic attacks sent him to the emergency department. He presented to the office but could not state the reason for the visit or find the way back to his car. Sometimes he would drive to the grocery store and forget why he was there or the way back home. His factor V Leiden mutation had been discovered after an episode of abdominal venous thromboembolism. He received anticoagulation with enoxaparin for a year. His transient ischemic attacks were not believed to be due to the factor V Leiden mutation. There had not been any recent changes to his medications.

At presentation, he was hypertensive to 160/100 mm Hg and oriented to place and person. Physical examination was significant for decreased sensation to touch and pinprick on the bilateral upper and lower extremities as well as the face. Laboratory test results (Table 1) showed an elevated random glucose level of 21.53 mmol/L (388 mg/dL; reference range, 3.61–6.11 mmol/L [65–110 mg/dL]), a slightly increased leukocyte count of 11.5 × 10⁹/L (reference range, 4.0–10.8 × 10⁹/L) with a slight basophilia of 2.7% (reference range, 0.0–2.0%), and a thyroid-stimulating hormone level of 2.340 μU/mL (reference range, 0.45–4.5 μU/mL). Urinalysis results showed glucosuria without bacteriuria. Urine toxicology results were negative. Computed tomography of the head performed in the emergency department did not reveal any acute intracranial pathology.

An extensive neurologic work-up was pursued. Results from magnetic resonance imaging of the brain and the cervical, thoracic, and lumbar spine were unremarkable. Lumbar puncture revealed an elevated cerebrospinal fluid (CSF) glucose level of 8.77 mmol/L (158 mg/dL; reference range, 2.22–3.89 mmol/L [40–70 mg/dL]) without leukocytosis. The CSF protein level was 370 mg/L (reference range, 150–450 mg/L). IgG index was normal, and oligoclonal bands were absent. Results from flow cytometry of the CSF were negative for malignant cells. Results from an extensive neuro-immunologic work-up, including the Mayo Clinic paraneoplastic panel, returned negative as did the infectious disease work-up. His vitamin B₁₂ and B₁ levels were normal. Behavioral health evaluation was not consistent with conversion disorder.

Because the patient continued to have slight leukocytosis with persistent basophilia, occult malignancy as a cause for his symptoms was pursued. Computed tomography of the chest, abdomen, and pelvis was unremarkable. Tumor markers, including prostate-specific antigen, were normal. However, results from flow cytometry of peripheral blood showed a small population of atypical B lymphoblasts suggestive of B lymphoblastic leukemia/lymphoma. Bone marrow biopsy was performed.

Bone marrow examination revealed a hypercellular marrow packed with immature cells, consistent with blasts (Figure 1). Immunostaining was positive for CD34 (Figure 2), CD10 (Figure 3), and CD19 but negative for CD20 and CD33. Bone marrow flow cytometry results showed 60% blasts and intermediate to bright CD10 and CD19 positivity. Chromosomal evaluation revealed 2 related cell lines, with the Ph translocation between chromosomes 9 and 22. The final cytogenetic analysis revealed the karyotype: 46, XY, t (9;22) (q34; q11.2), typical of Ph chromosome. Next-generation sequencing mutation panel results were negative. The heme malignancy fusion panel revealed p210 as the major oncoprotein from the BCR/ABL1 translocation. The patient was finally diagnosed with CML with lymphoid blast crisis. His cognitive function notably improved after receiving induction therapy with prednisone and dasatinib. He received prophylactic intrathecal chemotherapy and was evaluated for bone marrow transplant versus blinatumomab therapy.

We present a case of CML in lymphoid blast crisis in which the patient presented with slight leukocytosis and unique symptoms: memory loss and emotional lability. These features are atypical for CML—a disease that is usually diagnosed, in up to 50% of patients, incidentally during routine laboratory investigations that reveal increased leukocyte counts (3). The most common clinical manifestations include fatigue, weight loss, splenomegaly (abdominal fullness), purpura, and bleeding. In almost 85% of cases, the disease is diagnosed in its chronic phase (3). Our case is unique because the patient presented without significant leukocytosis or any of the common presenting clinical features. His altered mental status was most likely due to acute toxic metabolic encephalopathy.

The patient's persistent basophilia prompted us to pursue flow cytometry that was pivotal in establishing the diagnosis. There is an increased production of basophil-committed colony-forming units and basophils in CML (4). Hyperbasophilia (>1 × 10⁹/L) and massive basophilia (>20% basophils) are common in CML (5). However, our patient's absolute basophil count at presentation was 0.31 × 10⁹/L despite being in the lymphoid blast phase—another uncommon presentation, thus leading to more diagnostic dilemma. Persistent basophilia should be confirmed with the examination of a peripheral blood smear; flow cytometry should be pursued if the cause of basophilia remains unclear or the suspicion for a hematologic malignancy is high (6).

Another interesting finding is the presence of lymphoid blasts in the bone marrow of our patient. B-lineage lymphoid blast crisis accounts for 30% of CML in blast crisis (7). Based on the phenotypic characteristics, the patient was initially diagnosed as having Ph+ B-cell acute lymphoblastic leukemia (B-ALL). However, a later hematologic malignancy fusion panel showed a BCL/ABL1 fusion gene, which translated into the p210 oncoprotein. p210 and p190 are the 2 major isoforms expressed after the Ph translocation (8). The molecular hallmark of CML is the expression of the p210 oncoprotein, whereas almost three-fourths of the cases of Ph+ B-ALL express p190 BCR/ABL. p210 oncoprotein strongly upregulates Stat5, a transcription factor that is essential in the initiation and disease maintenance of CML (9). Chronic myelogenous leukemia in lymphoid blast crisis is also associated with the loss of chromosome 9p (10).

In most cases, lymphoid blast crisis occurs in patients previously exposed to or currently receiving tyrosine kinase inhibitors (TKIs). In the rare cases of no previous exposure to TKIs, like our patient, the treatment is the same as for de novo Ph+ ALL; induction can be done with a TKI and chemotherapy or TKI and glucocorticoids (11). Although CML in lymphoid blast crisis is treated the same as de novo Ph+ ALL in adults, it is important to differentiate the disease in pediatric patients, because pediatric patients with B-ALL are usually not offered stem cell transplant after the first remission (12). A large retrospective study found patients presenting with de novo lymphoid blast crisis had improved overall survival compared with patients with a prior history of CML in the chronic or accelerated phase (13). Chronic myelogenous leukemia in lymphoid blast crisis is also associated with a better prognosis compared with myeloid blast crisis, with longer overall survival and better response to therapy (14).