J Hematol

Journal of Hematology, ISSN 1927-1212 print, 1927-1220 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Hematol and Elmer Press Inc

Journal website https://www.thejh.org

Case Report

Volume 12, Number 4, August 2023, pages 187-196

Leukostasis With Isolated Central Nervous System Involvement in Chronic Phase of Chronic Myelogenous Leukemia

Figure 1. CT of head without contrast. Multiple lesions, prominently left frontal and right frontal lobe leukemic infiltrates with surrounding vasogenic edema and mass effect, concerning for a CNS manifestation of leukostasis. CT: computed tomography; CNS: central nervous system.

Figure 2. Autopsy images of hemorrhagic intracranial masses and pathology of mass lesions. (a) High power histology of the CML mass lesion in the brain. The black arrow represents an early myeloid cell (immature eosinophil), the blue arrow shows a neutrophil/band and the white arrow (with black outline) shows the monocytes. (b) Medium power histology of the CML mass with background of necrotic brain parenchyma. (c) High power histology of the tumor cells showing myeloid lineage including neutrophils and monocytes with myeloid precursors of various degrees of maturation. (d) Coronal sections of the patient’s brain which demonstrates several hemorrhagic masses. CML: chronic myelogenous leukemia.

Figure 3. IHC staining of leukemic infiltrates in the frontal and brain stem lesions. IHC staining of the central nervous system lesions which was positive for MPO and CD68, consistent with known CML, and negative for CD20, confirming that the lesions do not originate from B-cell neoplasm. (a) IHC staining negative for CD20. (b) IHC staining negative for CD34. (c) IHC staining positive for MPO. (d) IHC staining positive for CD68. CML: chronic myelogenous leukemia; IHC: immunohistochemistry; MPO: myeloperoxidase.

**Table 1.** A Review of the Cases of CNS Involvement in CML in Current Literature
Authors	Age/gender	Diagnosis	Imaging/CSF/pathology	Treatment	Response/outcome
The review of both pediatric and adult cases of CML in current literature including the case report of this study along with histopathologic and imaging characteristics of each case and outcomes based on varying treatment modalities. BM: bone marrow; BMT: bone marrow transplant; CML: chronic myelogenous leukemia; CNS: central nervous system; CR: complete remission; CT: computed tomography; DLI: donor lymphocyte infusion; HAD: homoharringtonine, cytarabine, daunorubicin; HSCT: hematopoietic stem cell transplant; hyperCVAD: cyclophosphamide, vincristine, doxorubicin, and dexamethasone; LP: lumbar puncture; MPO: myeloperoxidase; MRA: magnetic resonance angiography; MRI: magnetic resonance imaging; SCT: stem cell transplant; TKI: tyrosine kinase inhibitor.
Current case	25/M	Known CML	CT of head showing multiple parenchymal leukemic infiltrates with mass effect; lesions with positive staining for MPO, CD43, and CD68	Started on imatinib but changed to dasatinib due to concern for resistance; did not tolerate leukapheresis	Death
Jin et al [7]	5/M	Newly diagnosed CML	Extramedullary blast crisis in CNS. BM aspirate revealed active hyperplasia of BM. + BCR/ABL1	Methotrexate, dexamethasone, and cytarabine intrathecal injection therapy; HAD for three cycles, followed by second generation TKIs	CR
Radhika et al [8]	15/F	CML on imatinib	MRI of brain showed thrombosis of posterior part of superior sagittal sinus. CSF showed large atypical looking cells comprising 48%, with hyperchromatic nuclei; CSF cytospin showed > 90% blasts	BMT not possible, as the patient did not have an HLA matched sibling donor. Imatinib dose increased and underwent six cycles of triple intrathecal chemotherapy and cranial radiotherapy	Lost to follow-up
Radhika et al [8]	37/M	CML on imatinib	MRI of brain revealed bilateral multiple small infarcts with features of meningitis. CSF showed increased numbers of immature cells (30%); CSF cytospin showed 60% blasts.	BMT was not possible, as the patient did not have an HLA matched sibling donor. The dose of Imatinib was increased to 600 mg once daily, and six cycles of triple intrathecal chemotherapy and cranial radiotherapy were also given.	Death 3 months after CNS blast crisis due to CNS disease.
Abuelgasim et al [9]	29/M	Newly diagnosed CML	CT of head showed new 4 cm left frontoparietal subdural collection, 1.5 cm left frontotemporal lobe collection, and right frontoparietal subdural collection. CSF showed 95% blasts. Flow cytometry of CSF showed blast cells + for CD34, CD33, CD11b, CD71 and CD13/CD117. BM showed chronic phase CML.	Whole brain radiation therapy and dasatinib therapy with AML induction with cytarabine and idarubicin + intrathecal methotrexate/cytarabine/hydrocortisone (allo-HSCT not recommended due to multiple infections/pancytopenia)	CR
Jain et al [10]	35/M	Noncompliance in known CML	MRI of brain with heterogenous enhancement of falx cerebri and tentorium (pachymeningitis) and bilateral optic nerves. CSF flow cytometry showed myeloid blasts + CD13, CD33 (negative for CD10 and CD19). No mutation for TKI resistance. BM with 2% myeloblasts.	Imatinib and intrathecal methotrexate and dexamethasone	Death after two doses of intrathecal therapy
Healey et al [11]	23/F	Newly diagnosed CML	MRI of brain after imatinib showed enhancement of left posterior frontal lobe including subarachnoid space. BM with 14% blasts (accelerated phase of CML), CSF with 51% blasts	Imatinib initially then started on dasatinib due to relapse. Underwent unmatched donor HSCT	CR
Chiba et al [12]	30/M	Newly diagnosed CML	MRI of brain showed hypertrophic dura without obvious tumor. BM with increased myeloid cells (no specific number), CSF flow cytometry positive for CD10, CD19, HLADR, CD34	Hydroxyurea, dasatinib, and hyperCVAD/MA therapy with dasatinib along with intrathecal methotrexate, cytarabine, and dexamethasone. Underwent allo-HSCT after whole brain radiation and total body radiation (with cyclophosphamide)	CR
Atilla et al [3]	72/M	Progression of known chronic phase CML to blast crisis	MRI of brain showed enhancement of clivus and occipital condyles. BM with 42% blasts; CSF flow cytometry normal	Bosutinib with methotrexate, dexamethasone involvement. Radiotherapy and intrathecal methotrexate with cytarabine	CR
Gomez et al [13]	33/M	Known CML, CNS involvement on imatinib	Normal head CT. Normal brain MRI. Unavailable CSF and serum flow cytometry	Intrathecal methotrexate, cytosine arabinoside, dexamethasone; then started on dasatinib.	CR but with persistent severe visual impairment
Neumann et al [14]	25/F	CML with previous HSCT and relapses treated with DLIs and imatinib	Leptomeningeal relapse confirmed by CSF cytology and flow cytometry	Intrathecal methotrexate, cytarabine, and dexamethasone followed by high dose cytarabine for persistent neurological symptoms. DLI in increasing doses with addition of nilotinib	CR for 15 months followed by relapse and death
Park et al [15]	54/M	Known CML	Diffusion MRI of brain with MRA revealed abnormal leptomeningeal enhancement of both paramedian gyri. CSF confirmed CNS involvement	Dasatinib, intrathecal methotrexate, and cranial irradiation therapy	CR
Kim et al [16]	42/M	CML on imatinib	Craniotomy for increased intracranial pressure from mass of bilateral cerebellar hemispheres. Underwent partial resection with biopsy confirming isolated CNS lymphoid blast crisis	Cytarabine, methotrexate, and hydrocortisone with imatinib	Death 15 days after craniectomy
Beyazit et al [17]	46/F	CML treated with hydroxyurea and interferon-alpha/cytarabine followed by imatinib at remission	Lumbar MRI suggested malignant infiltration of the spinal cord. LP showed blastic cellular infiltration	Intrathecal methotrexate and craniospinal radiotherapy	Death from pulmonary aspergillosis
Gaur et al [18]	30/M	CML on ponatinib	MRI of brain showed diffuse supratentorial and infratentorial leptomeningeal enhancement. CSF showed myeloblasts	Intrathecal cytarabine and craniospinal irradiation	CR; pending allogeneic SCT
Rajappa et al [19]	39/M	CML on Imatinib	MRI of brain showed meningeal enhancement and CSF positive for blasts	Cranial radiotherapy and triple intrathecal chemotherapy	CR
Bornhauser et al [20]	56/F	CML on imatinib	MRI of brain revealed minimal dural enhancement. LP revealed lymphoid blast crisis in CSF	Intrathecal cytosine arabinoside, methotrexate, and dexamethasone and irradiation of the total neuraxis	Death 22 days after HSCT
Bujassoum et al [21]	42/F	Known CML	MRI of brain showed increased signal intensity in the periventricular area with LP showing CML blast crisis. Flow cytometry showed an increase in myeloid blasts CD34⁺, CD117⁺. BM showed BCR/ABL1 fusion	Intrathecal methotrexate and cytarabine	CR
Johnson et al [22]	50/M	Known CML	CSF showed CD19⁺, CD10⁺, CD34⁺	Intrathecal chemotherapy and HSCT	Death
Matsuda et al [23]	17/M	CML on imatinib	CT of head demonstrated no specific signs of meningeal and cerebral involvement. LP revealed blasts in the CSF	Intrathecal chemotherapy with cytosine arabinoside, methotrexate, and dexamethasone and whole-brain radiation	CR
Aichberger et al [24]	52/M	CML on imatinib	CT of head and MRI of brain normal. LP showed myeloblasts. CD34⁺, HLADR⁺, CD117⁺	Intrathecal liposomal cytarabine and intracranial radiation	CR
Aichberger et al [24]	73/F	CML on imatinib	CT of head showed leukoencephalopathy and microangiopathy without meningeal involvement. CD117⁺, CD13⁺, CD33⁺, CD34⁺	Intrathecal liposomal cytarabine	CR
Barlow et al [25]	68/M	CML on imatinib	CSF showed increased white blood cell count	Intrathecal methotrexate and dexamethasone; switched to dasatinib. Underwent cranial irradiation	Clinical improvement
Altintas et al [26]	39/M	CML on hydroxyurea and imatinib	MRI of brain showed meningeal enhancement at the frontoparietal region and tentorium. CSF showed lymphoblasts.	Radiation, intrathecal chemotherapy, and imatinib	CR
Lee et al [27]	39/M	CML on imatinib	MRI of brain with abnormal high signal intensity in the petrous region bilaterally	Intrathecal cytarabine and methotrexate and increased imatinib dose	CR
Isobe et al [28]	61/M	Known CML	CT of head showed swelling of cerebellar cortex and fourth ventricle dilatation. CSF showed lymphoblasts and flow cytometry showed blasts positive for CD10, CD19, and CD20.	Intrathecal methotrexate and dexamethasone, and allogeneic HSCT with thiotepa, etoposide and cyclophosphamide; also underwent optic nerve irradiation	CR
Thomas et al [29]	33/M	CML treated with hydroxyurea, cytosine arabinoside, dasatinib, and SCT	MRI of brain and spine unremarkable. CSF showed blast-like cells positive for MPO and BCR-ABL fusion signal in 91% of cells and flow cytometry showed myeloid associated antigens.	Intrathecal methotrexate and craniospinal irradiation. Started on nilotinib.	CR
Fuchs et al [30]	64/F	CML treated with imatinib followed by cytosine arabinoside and mitoxantrone and hydroxyurea	MRI of brain revealed leukemic infiltration of lateral ventricles walls and hydrocephalus. CSF with about 50% immature blasts with highly elevated BCR-ABL/ABL ratio	Intrathecal cytarabine, methotrexate, and dexamethasone followed by dasatinib	CR
Nishimoto et al [31]	22/M	CML on imatinib	CML blast crisis in CNS after 29 months of therapy	Allogeneic HSCT following combination therapy with dasatinib, intrathecal chemotherapy and cranial irradiation. Followed by dasatinib maintenance therapy	CR

Table 1. A Review of the Cases of CNS Involvement in CML in Current Literature

Authors

Age/gender

Diagnosis

Imaging/CSF/pathology

Treatment

Response/outcome

The review of both pediatric and adult cases of CML in current literature including the case report of this study along with histopathologic and imaging characteristics of each case and outcomes based on varying treatment modalities. BM: bone marrow; BMT: bone marrow transplant; CML: chronic myelogenous leukemia; CNS: central nervous system; CR: complete remission; CT: computed tomography; DLI: donor lymphocyte infusion; HAD: homoharringtonine, cytarabine, daunorubicin; HSCT: hematopoietic stem cell transplant; hyperCVAD: cyclophosphamide, vincristine, doxorubicin, and dexamethasone; LP: lumbar puncture; MPO: myeloperoxidase; MRA: magnetic resonance angiography; MRI: magnetic resonance imaging; SCT: stem cell transplant; TKI: tyrosine kinase inhibitor.

Current case

25/M

Known CML

CT of head showing multiple parenchymal leukemic infiltrates with mass effect; lesions with positive staining for MPO, CD43, and CD68

Started on imatinib but changed to dasatinib due to concern for resistance; did not tolerate leukapheresis

Death

Jin et al [7]

5/M

Newly diagnosed CML

Extramedullary blast crisis in CNS. BM aspirate revealed active hyperplasia of BM. + BCR/ABL1

Methotrexate, dexamethasone, and cytarabine intrathecal injection therapy; HAD for three cycles, followed by second generation TKIs

Radhika et al [8]

15/F

CML on imatinib

MRI of brain showed thrombosis of posterior part of superior sagittal sinus. CSF showed large atypical looking cells comprising 48%, with hyperchromatic nuclei; CSF cytospin showed > 90% blasts

BMT not possible, as the patient did not have an HLA matched sibling donor. Imatinib dose increased and underwent six cycles of triple intrathecal chemotherapy and cranial radiotherapy

Lost to follow-up

Radhika et al [8]

37/M

CML on imatinib

MRI of brain revealed bilateral multiple small infarcts with features of meningitis. CSF showed increased numbers of immature cells (30%); CSF cytospin showed 60% blasts.

BMT was not possible, as the patient did not have an HLA matched sibling donor. The dose of Imatinib was increased to 600 mg once daily, and six cycles of triple intrathecal chemotherapy and cranial radiotherapy were also given.

Death 3 months after CNS blast crisis due to CNS disease.

Abuelgasim et al [9]

29/M

Newly diagnosed CML

CT of head showed new 4 cm left frontoparietal subdural collection, 1.5 cm left frontotemporal lobe collection, and right frontoparietal subdural collection. CSF showed 95% blasts. Flow cytometry of CSF showed blast cells + for CD34, CD33, CD11b, CD71 and CD13/CD117. BM showed chronic phase CML.

Whole brain radiation therapy and dasatinib therapy with AML induction with cytarabine and idarubicin + intrathecal methotrexate/cytarabine/hydrocortisone (allo-HSCT not recommended due to multiple infections/pancytopenia)

Jain et al [10]

35/M

Noncompliance in known CML

MRI of brain with heterogenous enhancement of falx cerebri and tentorium (pachymeningitis) and bilateral optic nerves. CSF flow cytometry showed myeloid blasts + CD13, CD33 (negative for CD10 and CD19). No mutation for TKI resistance. BM with 2% myeloblasts.

Imatinib and intrathecal methotrexate and dexamethasone

Death after two doses of intrathecal therapy

Healey et al [11]

23/F

Newly diagnosed CML

MRI of brain after imatinib showed enhancement of left posterior frontal lobe including subarachnoid space. BM with 14% blasts (accelerated phase of CML), CSF with 51% blasts

Imatinib initially then started on dasatinib due to relapse. Underwent unmatched donor HSCT

Chiba et al [12]

30/M

Newly diagnosed CML

MRI of brain showed hypertrophic dura without obvious tumor. BM with increased myeloid cells (no specific number), CSF flow cytometry positive for CD10, CD19, HLADR, CD34

Hydroxyurea, dasatinib, and hyperCVAD/MA therapy with dasatinib along with intrathecal methotrexate, cytarabine, and dexamethasone. Underwent allo-HSCT after whole brain radiation and total body radiation (with cyclophosphamide)

Atilla et al [3]

72/M

Progression of known chronic phase CML to blast crisis

MRI of brain showed enhancement of clivus and occipital condyles. BM with 42% blasts; CSF flow cytometry normal

Bosutinib with methotrexate, dexamethasone involvement. Radiotherapy and intrathecal methotrexate with cytarabine

Gomez et al [13]

33/M

Known CML, CNS involvement on imatinib

Normal head CT. Normal brain MRI. Unavailable CSF and serum flow cytometry

Intrathecal methotrexate, cytosine arabinoside, dexamethasone; then started on dasatinib.

CR but with persistent severe visual impairment

Neumann et al [14]

25/F

CML with previous HSCT and relapses treated with DLIs and imatinib

Leptomeningeal relapse confirmed by CSF cytology and flow cytometry

Intrathecal methotrexate, cytarabine, and dexamethasone followed by high dose cytarabine for persistent neurological symptoms. DLI in increasing doses with addition of nilotinib

CR for 15 months followed by relapse and death

Park et al [15]

54/M

Known CML

Diffusion MRI of brain with MRA revealed abnormal leptomeningeal enhancement of both paramedian gyri. CSF confirmed CNS involvement

Dasatinib, intrathecal methotrexate, and cranial irradiation therapy

Kim et al [16]

42/M

CML on imatinib

Craniotomy for increased intracranial pressure from mass of bilateral cerebellar hemispheres. Underwent partial resection with biopsy confirming isolated CNS lymphoid blast crisis

Cytarabine, methotrexate, and hydrocortisone with imatinib

Death 15 days after craniectomy

Beyazit et al [17]

46/F

CML treated with hydroxyurea and interferon-alpha/cytarabine followed by imatinib at remission

Lumbar MRI suggested malignant infiltration of the spinal cord. LP showed blastic cellular infiltration

Intrathecal methotrexate and craniospinal radiotherapy

Death from pulmonary aspergillosis

Gaur et al [18]

30/M

CML on ponatinib

MRI of brain showed diffuse supratentorial and infratentorial leptomeningeal enhancement. CSF showed myeloblasts

Intrathecal cytarabine and craniospinal irradiation

CR; pending allogeneic SCT

Rajappa et al [19]

39/M

CML on Imatinib

MRI of brain showed meningeal enhancement and CSF positive for blasts

Cranial radiotherapy and triple intrathecal chemotherapy

Bornhauser et al [20]

56/F

CML on imatinib

MRI of brain revealed minimal dural enhancement. LP revealed lymphoid blast crisis in CSF

Intrathecal cytosine arabinoside, methotrexate, and dexamethasone and irradiation of the total neuraxis

Death 22 days after HSCT

Bujassoum et al [21]

42/F

Known CML

MRI of brain showed increased signal intensity in the periventricular area with LP showing CML blast crisis. Flow cytometry showed an increase in myeloid blasts CD34⁺, CD117⁺. BM showed BCR/ABL1 fusion

Intrathecal methotrexate and cytarabine

Johnson et al [22]

50/M

Known CML

CSF showed CD19⁺, CD10⁺, CD34⁺

Intrathecal chemotherapy and HSCT

Death

Matsuda et al [23]

17/M

CML on imatinib

CT of head demonstrated no specific signs of meningeal and cerebral involvement. LP revealed blasts in the CSF

Intrathecal chemotherapy with cytosine arabinoside, methotrexate, and dexamethasone and whole-brain radiation

Aichberger et al [24]

52/M

CML on imatinib

CT of head and MRI of brain normal. LP showed myeloblasts. CD34⁺, HLADR⁺, CD117⁺

Intrathecal liposomal cytarabine and intracranial radiation

Aichberger et al [24]

73/F

CML on imatinib

CT of head showed leukoencephalopathy and microangiopathy without meningeal involvement. CD117⁺, CD13⁺, CD33⁺, CD34⁺

Intrathecal liposomal cytarabine

Barlow et al [25]

68/M

CML on imatinib

CSF showed increased white blood cell count

Intrathecal methotrexate and dexamethasone; switched to dasatinib. Underwent cranial irradiation

Clinical improvement

Altintas et al [26]

39/M

CML on hydroxyurea and imatinib

MRI of brain showed meningeal enhancement at the frontoparietal region and tentorium. CSF showed lymphoblasts.

Radiation, intrathecal chemotherapy, and imatinib

Lee et al [27]

39/M

CML on imatinib

MRI of brain with abnormal high signal intensity in the petrous region bilaterally

Intrathecal cytarabine and methotrexate and increased imatinib dose

Isobe et al [28]

61/M

Known CML

CT of head showed swelling of cerebellar cortex and fourth ventricle dilatation. CSF showed lymphoblasts and flow cytometry showed blasts positive for CD10, CD19, and CD20.

Intrathecal methotrexate and dexamethasone, and allogeneic HSCT with thiotepa, etoposide and cyclophosphamide; also underwent optic nerve irradiation

Thomas et al [29]

33/M

CML treated with hydroxyurea, cytosine arabinoside, dasatinib, and SCT

MRI of brain and spine unremarkable. CSF showed blast-like cells positive for MPO and BCR-ABL fusion signal in 91% of cells and flow cytometry showed myeloid associated antigens.

Intrathecal methotrexate and craniospinal irradiation. Started on nilotinib.

Fuchs et al [30]

64/F

CML treated with imatinib followed by cytosine arabinoside and mitoxantrone and hydroxyurea

MRI of brain revealed leukemic infiltration of lateral ventricles walls and hydrocephalus. CSF with about 50% immature blasts with highly elevated BCR-ABL/ABL ratio

Intrathecal cytarabine, methotrexate, and dexamethasone followed by dasatinib

Nishimoto et al [31]

22/M

CML on imatinib

CML blast crisis in CNS after 29 months of therapy

Allogeneic HSCT following combination therapy with dasatinib, intrathecal chemotherapy and cranial irradiation. Followed by dasatinib maintenance therapy