Cerebral localization of chronic myelomonocytic leukemia and improvement with high-dose cytarabine: A case report

Abstract

Chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative neoplasm characterized by the infiltration of blood and bone marrow by immature monocytes, in which extra-hematopoietic localization is uncommon. We report the case of a 69-year-old-man with highly likely ectopic brain CMML involvement by MRI. Without the possibility of cerebral biopsy and with a negative infectious disease assessment, high-dose cytarabine-based chemotherapy was successfully administered. The favorable evolution in this case highlights the potential benefit of such treatment, even without a cerebral biopsy to confirm the disease. This case can aid clinical decision-making in the future.

Abbreviations
• AML
• acute myeloid leukemia
• ANA
• antinuclear antibodies
• CMML
• chronic myelomonocytic leukemia
• CMV
• cytomegalovirus
• CT-Scan
• computed tomography scan
• EBV
• Epstein-Barr virus
• HBV
• hepatitis B virus
• HCV
• hepatitis C virus
• HIV
• human immunodeficiency viruses
• MRI
• magnetic resonance imaging
• PET-CT
• positron emission tomography with computerized tomography
• PS
• performance status
• R-IPSS
• revised international prognostic scoring system
• WBC
• white blood cells

INTRODUCTION

Chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative neoplasm characterized by the infiltration of blood and bone marrow by immature monocytes. The diagnosis of CMML is made according to the WHO classification.[1] Prognostic evaluation is based on the age, the white blood cell count, cytopenia and the percentage of blasts in the blood and bone marrow, cytogenetics, and mutational analysis[2] to evaluate the risk of transformation to AML and survival. Cerebral involvement is uncommon in CMML.

Here, we report the case of a 69-year-old man with CMML, with evolution to AML and suspected brain involvement by MRI, who was successfully treated with chemotherapy.

CASE PRESENTATION

A Caucasian 69-year-old man with a history of arterial hypertension and sleep apnea syndrome was diagnosed in 2016 with a probable autoimmune peripheral thrombocytopenia without any other cytopenia and the absence for a central cause. There was no family medical history. The etiological workup came back negative and the platelet count was approximately 100 × 10⁹/L, with hemoglobin at 148 g/L and the absence of circulating blasts and a monocyte count of 0.53 × 10⁹/L (12.0%). Bone marrow aspiration did not provide any arguments for a central cause of the thrombocytopenia. Neither cytogenetics nor molecular analysis was performed at that time. A watch-and-wait approach was chosen.

In November 2019, the platelet count had decreased to 30 × 10⁹/L and the diagnosis was upgraded to CMML-1, with intermediate-1 CPSS-Mol. Bone marrow aspiration showed 7% blasts without promonocytes and 5% monocytes, cytogenetics showed the addition of genetic material in 2q, and next generation sequencing showed mutations of IDH2 c.419G > A (VAF 41.98%), DNMT3A c.2362_2363delinsCT (VAF 41.94%), and SRSF2 c.284C > T (VAF 40.17%) on a panel of 54 genes (Figure 1A,B). Treatment with corticosteroids (1 mg/kg) for one month and then Danazol from March 2020 to June 2020 was administered without success. The patient subsequently refused the introduction of another treatment, and the platelet count remained stable at approximately 20 × 10⁹/L without bleeding symptoms or splenomegaly. In January 2021, worsening cytopenia led to a new bone marrow aspiration, showing CMML-2, with 17% blasts leading to the diagnosis of an accelerated phase (Figure 1A). Cytogenetic analysis showed the addition of genetic material to 2q without any other anomalies, in particular, no Philadelphia chromosome. Treatment with azacytidine was given, with the first cycle administrated from February 18 to 25, 2021.

FIGURE 1. Overview of the cerebral localization of chronic myelomonocytic leukemia and improvement with high-dose cytarabine. (A) Peripheral blood (PB) and bone marrow (BM) smear of samples from 2019 and 2021 showing dysgranulopoiesis with hypogranulation and dyserythropoiesis in 2021. Blasts cells are shown with an arrow. (B) New-generation sequencing (NGS) analysis and gene mutations identified at diagnosis. (C) T1 signal of axial magnetic resonance imaging (MRI) and computerized tomography (CT) scan showing in the cortex and the cerebellum in 2021 before treatment. (D) CT scans one month and eight months after the beginning of aracytine and enasidenib showing a significant reduction in lesions and the MRI at 24 months. Bar chart showing assessment of gene mutations variant allelic frequency (VAF) by NGS.

On March 1st, 2021, one week after the first cycle of azacytidine, the patient was admitted to the emergency department with a cough, fever, and proximal myalgia and the body temperature was 38.9°C. Blood gases with 2 L/min of oxygen showed a pH of 7.42, PCO₂ of 33 mmHg, PO₂ of 88 mmHg, and lactates at 2.5 mmol/L. Laboratory tests showed a leukocyte count of 6.22 × 10⁹/L, hemoglobin at 68 g/L, platelets at 3 × 10⁹/L, and circulating blasts at 2%. Acute renal failure, with creatinine at 137 μmol/L, natremia at 127 mmol/L, and urea at 14.5 mmol/L, was also found.

Blood cultures on March 1st and March 2nd were positive for methicillin-sensitive Staphylococcus aureus. Antibiotic therapy with cloxacillin was started.

Upon the onset of back pain with a motor deficit of the lower limbs, a CT-scan was performed to search for spondylodiscitis. The exam did not reveal any spondylodiscitis but showed numerous cerebral lesions with a hemorrhagic aspect above and below the tentorial. The lesions were detected in the T1 hyper signal sequences (Figure 1C).

On March 5, the neurological condition worsened, with increased drowsiness and a Glasgow score of 11. After discussion with neurosurgeons, a biopsy of the lesion was considered not possible due to an unfavorable benefit-risk balance, with a high risk of bleeding. On March 6, MRI was performed and showed diffuse infiltration of the spinal bone marrow and numerous hemorrhagic nodular lesions in the brain above and below the tentorial, without arguments for septic emboli encephalitis or vasculitis (Figure 1C). A PET-computed tomography (CT) showed diffuse osteomedullary hypermetabolism. Laboratory tests showed a leukocyte count of 4.33 × 10⁹/L, with a WBC of 1.98 × 10⁹/L with 2% of peripheral blasts, hemoglobin at 88 g/L, and platelets at 79 × 10⁹/L spontaneously. Autoimmune assessment, including C3, C4, CH50, and ANA was negative. Infectious assessment was negative, as was serology for HIV, HBV, HBC, CMV, and EBV. Mycological assessment was also negative.

Cerebrospinal fluid analysis was not performed because of the poor general condition of the patient and the risk of cerebral herniation.

In such a situation of increased intracerebral lesions, which may be related to thrombocytopenia and/or secondary lesions of CMML in the absence of histological evidence, the risk of death related to these lesions, and the previous experience of similar cases in the center, treatment with aracytine (1.5 g DT) and dexamethasone was administered on March 10. Platelet transfusions were provided daily. From March 11, the neurological state of the patient showed improvement, with improved vigilance and a Glasgow score of 15. The treatment was therefore repeated on D15 (March 24).

On April 13, treatment targeted against IDH2, enasidenib, was introduced. Control CT performed on April 14 showed regression of all lesions, with only images of sequalae (Figure 1D). The neurological state of the patient was normal, and he was discharged from the hospital. Several CT-scans were performed to monitor recovery and MRI on December 29, 2021, showed a favorable evolution, with the regression of all lesions and the persistence of sequalae (Figure 1D). Furthermore, under the IDH2 inhibitor, there was a complete hematological response, without significant changes in molecular analyzes except appearance of a CSF3R c.1853C > T mutated subclone at 14 months of treatment (Figure 1D). At 24 months, the patient is in perfect general condition: PS = 0, without any neurological symptoms (Figure 1D).

DISCUSSION AND CONCLUSION

We describe the case of a 69-year-old man followed up for two years for CMML who presented with an uncommon presentation of CMML with very probable cerebral involvement and spectacular improvement with chemotherapy. Aracytine was chosen due to its efficacy against myeloid neoplasm with an accelerated phase and its capacity to cross the blood brain barrier.

A fatal case of CMML with such cerebral involvement was described in a previous case report [3], but the patient did not receive any treatment and the disease was not considered to be in an accelerated phase. The cerebral involvement of CMML was found upon autopsy. As in the present case, the cerebral lesions were very similar by imaging and all infectious disease assessment was also negative. The patient did not receive any treatment for the CMML, and his condition quickly deteriorated.

Other cases have been described but can be explained by systemic inflammatory and/or autoimmune manifestations, such as those that occur in systemic vasculitis, which can be associated with myeloid malignancies.[4, 5] Meningeal infiltration was described by Rogulj et al.[6] In this case, MRI showed signs of leukoencephalopathy and cortical atrophy, the bone marrow showed CMML in an accelerated phase, and the patient was treated with aracytine and methotrexate.

There have been no reports of such brain lesions with such a favorable evolution after treatment in the context of CMML.

The favorable evolution highlights the potential benefit of such treatment, even without a cerebral biopsy to confirm the disease. This case can aid clinical decision-making in the future.

AUTHOR CONTRIBUTIONS

CH, AM, LDLR, NV, LJ, and EG analyzed and interpreted the patient data concerning the hematological disease and neurological condition. OH and NR analyzed and interpreted the patient data concerning hematological biological aspects. JPC interpreted and reflected on the diagnosis of the lesions found on MRI. All authors read and approved the final manuscript.

CONFLICT OF INTEREST STATEMENT

The authors have no competing interest to declare.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available on request from the corresponding author, CH.

ETHICS STATEMENT

Written informed consent was obtained from the patient‘s next of kin for publication of this case report.