Involvement of the central nervous system (CNS) with acute myeloid leukemia (AML)

INTRODUCTION — Involvement of the central nervous system (CNS) in a patient with acute myeloid leukemia (AML) diagnosis is uncommon at initial diagnosis, but it occurs more often with relapsed AML. CNS involvement is investigated for patients with AML who have new or progressive neurologic signs or symptoms, but routine evaluation is not performed for asymptomatic patients (ie, those with no neurologic findings), except for infants <1 year with AML or patients with remission after relapse of acute promyelocytic leukemia (APL). CNS involvement by AML is a dire prognostic finding. Management of CNS involvement by AML is guided by the nature of CNS disease, symptoms, systemic disease status, and patient fitness and values.

This topic discusses the clinical presentation, diagnosis, and treatment of CNS involvement in patients with AML.

Clinical features, diagnosis, classification, treatment, and overall prognosis of AML are discussed separately.

●(See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia".)

●(See "Acute myeloid leukemia: Induction therapy in medically fit adults".)

●(See "Acute myeloid leukemia: Management of medically unfit adults".)

●(See "Acute myeloid leukemia in children and adolescents".)

EPIDEMIOLOGY

Incidence — The incidence of CNS involvement with AML is not well-defined and reports vary widely. Estimates differ because detection methods vary among studies, diagnostic lumbar puncture (LP) is not routinely performed in patients with AML due to the low incidence, and contemporary AML management may have reduced the frequency of leukemic involvement of the CNS.

●Adults – In one study, CNS involvement was detected by cytology and/or flow cytometry in one-third of 103 consecutive adult patients with newly diagnosed AML who underwent routine diagnostic LP (regardless of neurologic findings) [1]. In another study, CNS involvement was identified in 19 percent of 42 patients with AML who underwent routine LP, regardless of clinical findings [2]. However, the same group detected CNS involvement in only 3 percent of 1370 consecutive patients with AML when an LP was performed only for findings suggestive of CNS disease [2]. Another study reported CNS involvement in <1 percent of 3261 adults with newly diagnosed AML and CNS symptoms who were enrolled in a series of clinical trials; the rate was 3 percent in patients with relapsed AML [3].

●Children – Among 1344 children with AML, 395 (29 percent) had evidence of CNS involvement at presentation; 217 had ≤5 white blood cells (WBC)/microL with blasts (ie, CNS2 involvement), and 178 had >5 WBC/microL with blasts or CNS symptoms (CNS3 involvement) [4].

The incidence of CNS leukemia appears to have decreased since the incorporation of high dose cytarabine (HiDAC; which can penetrate into the CNS) into initial induction and/or post-remission therapy. Prior to the use of HiDAC, meningeal disease developed in up to 20 percent of children and 16 percent of adults with AML [5].

Risk factors — CNS involvement is more common in patients with AML with the following features [1-7]:

●Clinical features:

•Hyperleukocytosis (>100,000/microL)

•Age <2 years

•Elevated lactate dehydrogenase (LDH)

●Leukemic factors:

•Prominent monocytic component (eg, acute monoblastic/monocytic leukemia or acute myelomonocytic leukemia)

•Acute promyelocytic leukemia (APL) with PML::RARA in relapse

•Molecular/cytogenetic findings, such as FLT3-internal tandem duplication, AML with inv(16) or chromosome 11 abnormalities, complex karyotype

•Expression of CD56 (adhesion molecule) on leukemia blast cells

PATHOGENESIS — The pathogenesis of leukemic meningitis is not well understood. Mechanisms by which AML can seed the CNS include [8]:

●Extension from the bone marrow of the skull through bridging veins into the subarachnoid space

●Contamination of the cerebrospinal fluid (CSF) via the choroid plexus

●Invasion of the brain parenchyma via brain capillaries

●Direct infiltration of the leptomeninges through bony lesions of the skull

●Extension along nerve roots through the neural foramina and into the extradural space

●Hemorrhage into the CNS with blood containing blasts

●Iatrogenic introduction of blasts into the CSF at the time of lumbar puncture

CLINICAL PRESENTATION — Patients with CNS involvement by AML may be asymptomatic, but most patients present with neurologic signs or symptoms [9].

CNS involvement may manifest as:

●Increased intracranial pressure – Symptoms of increased intracranial pressure (eg, constant headache, lethargy, other mental changes) may occur in patients with leptomeningeal involvement by AML.

●Cranial nerve palsy – The cranial nerves (CN) that are most often affected are CN III, V, VI, or VII. There are few, if any, other causes of palsies that affect CN III, V, or VI in patients with AML. However, it can be difficult to clinically distinguish leukemic involvement of CN VII from "Bell's palsy" (facial nerve palsy), which occurs frequently in the normal population; magnetic resonance imaging (MRI) focused on the path of CN VII may be helpful in this circumstance.

●Other neurologic findings – An intracranial collection of blasts and/or bleeding (eg, from thrombocytopenia or a coagulopathy) can cause altered mental status, headache, visual changes, weakness, and other neurological findings. The cause of such findings may resemble those of a spontaneous intracranial hemorrhage or tumor.

●Spinal cord compression – Back pain, weakness or paresthesias of extremities, and/or bladder dysfunction may indicate spinal cord compression by an extramedullary collection of blasts (chloroma).

EVALUATION — Patients with suspected CNS involvement by AML should undergo imaging, as guided by neurologic findings, and a lumbar puncture (LP).

Rarely, retina exam by an ophthalmologist or other experienced clinician may demonstrate leukemic infiltrates, but this is more likely to detect ischemia or hemorrhage.

Imaging — Imaging can identify leptomeningeal involvement by AML and detect a mass lesion of the brain or spine. The choice of imaging is guided by findings from the history and neurologic examination.

●Magnetic resonance imaging (MRI)

•Brain – Brain MRI is useful for excluding acute or subacute stroke, multifocal inflammatory lesions, or when posterior fossa or vascular lesions are suspected. In patients with cranial nerve palsies, careful examination with thin sections of the course of the nerve roots is often helpful, since the spinal fluid can be unrevealing ("negative") in patients with isolated nerve involvement by AML.

Mass lesions are uncommon in patients with CNS involvement by AML, although they have been reported in patients with inv(16) [6].

•Spine – MRI of the spine is indicated if there are concerns of spinal cord compression. (See "Clinical features and diagnosis of neoplastic epidural spinal cord compression".)

●Computed tomography (CT) – Brain CT may be used to evaluate a potential stroke, tumor, hemorrhage, or infection.

Patients with symptoms suggestive of increased intracranial pressure (eg, headache, lethargy, other mental changes) generally undergo head CT scan prior to LP. (See 'Lumbar puncture (LP)' below.)

Lumbar puncture (LP) — LP is performed to diagnose leptomeningeal involvement. LP may also reveal abnormalities in patients with other types of CNS involvement by AML, but it is less reliable in those settings.

Indications — LP should be performed for patients with symptoms or signs that suggest CNS or ocular involvement. (See 'Clinical presentation' above.)

A diagnostic LP is not routinely performed for adults or children with AML who do not have neurologic abnormalities; however, an LP should be performed routinely for infants (≤1 year) and patients who achieve remission after relapsed acute promyelocytic leukemia (APL).

LP technique — It is critically important to avoid cerebral herniation (eg, caused by a mass effect in the brain) and to reduce the risk of bleeding or a traumatic LP. (See "Lumbar puncture: Technique, contraindications, and complications in adults".)

●Imaging prior to LP – Prior to performing an LP, patients with altered mentation, focal neurologic signs, papilledema, or a seizure within the previous week should undergo MRI or CT imaging to identify a possible mass lesion and other causes of increased intracranial pressure.

●Avoidance of bleeding/traumatic LP – Complete blood count (CBC) with platelet count and coagulation studies should be obtained, and deficits corrected before performing the LP.

To reduce the risk of bleeding or a traumatic LP, the LP should be performed by the most experienced available clinician; some centers routinely refer patients to a radiologist to have the procedure performed with the aid of fluoroscopy.

•Bleeding – Thrombocytopenia and/or coagulopathy should be corrected prior to performing the LP.

We generally do not perform an LP in patients who are actively bleeding, have severe thrombocytopenia (eg, ≤10,000 to 20,000/microL in many centers), or with an international normalized ratio (INR) >1.4, without first correcting the abnormalities.

There is controversy and relatively few data about the minimal platelet count at which an LP can be performed safely.

-Children – A study in children demonstrated the safety of LPs at platelet counts >10,000/microL [10]. However, a larger study by the same group indicated that the risk for a traumatic or blood LP was higher in children with platelets <100,000/microL, compared with ≥100,000/microL (odds ratio [OR] 1.5 [95% CI 1.2-1.8]) [11].

-Adults – It is difficult to extrapolate the findings from children to adults because of differences in size and because most children were sedated for the procedure. Compared with children, a longer length of tissue must be traversed to access the lumbar space in adults; this general concern is magnified in adults with obesity because of difficulties identifying the lumbar space.

One review stated that 40,000/microL is a "safe" count for LP, but they acknowledged that lower platelet counts may also be safe [12]. Platelet count >20,000/microL was considered desirable, according to a study of 195 LPs in 66 patients with acute leukemia [13].

For patients with APL, an LP should be deferred until correction of the coagulopathy and, in the absence of symptoms, can usually be done after a second complete response is achieved. (See "Treatment of relapsed or refractory acute promyelocytic leukemia in adults".)

•Traumatic LP – Every effort should be taken to avoid a traumatic LP in patients with leukemia, since this can seed leukemic blasts into the cerebrospinal fluid (CSF). Because of concern about introducing circulating leukemic blasts into the CSF, many centers routinely administer a dose of intrathecal chemotherapy when LPs are performed at diagnosis or in relapse. (See 'Intrathecal chemotherapy' below.)

●Complications – The most serious complication of LP is cerebral herniation. Other complications include bleeding (which can cause impingement of the spinal cord), infection, seeding of CSF with blasts, and post-LP headache. (See "Lumbar puncture: Technique, contraindications, and complications in adults", section on 'Complications'.)

CSF analysis — A total of 8 to 15 mL of CSF is typically removed during an LP, but up to 40 mL of fluid can safely be removed, if needed. (See "Lumbar puncture: Technique, contraindications, and complications in adults" and "Lumbar puncture in children".)

CSF should be evaluated for cell count and differential count, protein and glucose concentrations, gram stain and culture (if infection is suspected), cytology of stained cytospin slides (with flow cytometry or immunohistochemistry, if needed to identify blasts that cannot be characterized with certainty by morphology). These studies should be repeated each time the CSF is accessed for treatment to assess response to therapy. (See 'Delivery' below and 'Response evaluation' below.)

DIAGNOSIS — CNS involvement by AML should be suspected in patients with new or progressive neurologic signs or symptoms.

CNS leukemia is diagnosed by identifying leukemic blasts in cerebrospinal fluid (CSF) by microscopy of a cytocentrifuge specimen, with or without confirmation by flow cytometry and/or molecular studies [14]. In some cases, CSF studies are inconclusive, but the diagnosis is based on evidence of leptomeningeal involvement (with or without parenchymal disease) by MRI or CT or biopsy/aspirate of a CNS mass.

In addition to cytologic evidence of CNS involvement by AML, most patients have moderately elevated CSF protein and a modest decrease in glucose. Interpretation of CSF studies is discussed separately. (See "Cerebrospinal fluid: Physiology and utility of an examination in disease states", section on 'Composition of the CSF'.)

Blast counts can range from 5 white blood cells (WBC)/microL to >1000 WBC/microL; however, some patients with clinical signs of cranial nerve involvement or a mass with imaging can have a relatively bland CSF without detectable blasts.

Because patients with AML may have neutropenia or other causes for immunosuppression, bacterial and other causes of meningitis should be excluded, as discussed separately. (See "Clinical features and diagnosis of acute bacterial meningitis in adults".)

MANAGEMENT — Management of CNS involvement by AML varies according to the nature of CNS involvement and associated neurologic findings, medical fitness, institutional/clinician practice, and patient goals. The extent of disease should be evaluated with imaging (eg, MRI or CT of brain or spine), if this was not previously performed. (See 'Imaging' above.)

Management decisions should be made promptly to prevent or limit further neurologic deficits and complications. Treatment should not be delayed if CNS involvement is suspected, but findings for the diagnostic lumbar puncture are ambiguous.

No prospective studies have directly compared intrathecal (IT) chemotherapy, radiation therapy (RT), and/or systemic chemotherapy for management of CNS involvement by AML. Because few studies are available, treatment suggestions are based on clinician experience and extrapolation from treatment of carcinomatous meningitis.

Asymptomatic leptomeningeal involvement — For patients with leptomeningeal involvement, but no signs of neurologic deficit (eg, no cranial nerve impairment or other neurologic findings), we suggest treatment with IT chemotherapy alone, rather than systemic chemotherapy or cranial RT, based on the efficacy and rapid action of IT therapy and little toxicity, compared with the other management techniques.

Treatment with IT chemotherapy is discussed below. (See 'Intrathecal chemotherapy' below.)

Leptomeningeal involvement with neurologic findings — For patients with cranial nerve abnormalities or other neurologic impairment associated with leptomeningeal involvement, we suggest treatment with IT chemotherapy plus RT and/or systemic chemotherapy that penetrates the CNS. (See 'Intrathecal chemotherapy' below.)

RT is quickest and most reliable way to salvage a cranial nerve, which is typically compressed in the neural foramen. Addition of RT and/or systemic chemotherapy are discussed below. (See 'Radiation therapy' below and 'Systemic chemotherapy' below.)

Mass lesion — A mass lesion of the brain, spine, or a paraspinous mass that threatens the spinal cord generally requires RT and/or surgical debulking to reduce or prevent neurologic symptoms. The choice of approach by the location and size of the mass, nature of neurologic symptoms, and institutional practice. Prompt consultation with both a surgeon and radiation oncologist is useful when a tumor mass impinges on the spinal cord or other critical structure.

Treatment with a glucocorticoid (eg, dexamethasone, prednisone) should be considered for all patients who have vasogenic edema or symptoms related to peritumoral edema. (See "Management of vasogenic edema in patients with primary and metastatic brain tumors", section on 'Initiation of glucocorticoids'.)

Initial management with surgery or RT can be supplemented with IT chemotherapy, RT, and/or systemic chemotherapy, as needed. (See 'Intrathecal chemotherapy' below and 'Systemic chemotherapy' below.)

Isolated CNS relapse — Patients with an apparent isolated CNS relapse should be re-evaluated for systemic disease with examination of bone marrow or blood by microscopy, flow cytometry, and/or molecular studies. Systemic relapse is inevitable for patients with an apparent isolated CNS relapse of AML.

Systemic management of relapsed AML is discussed separately. (See "Treatment of relapsed or refractory acute myeloid leukemia".)

TREATMENTS

Intrathecal chemotherapy — Intrathecal (IT) therapy involves injection of chemotherapy into the cerebrospinal fluid (CSF). IT therapy can be injected into the lumbar thecal sac by lumbar puncture (LP) or directly into the lateral ventricle through a subcutaneous reservoir and ventricular catheter (eg, Ommaya reservoir) (figure 1).

Delivery — IT chemotherapy is injected into CSF via LP or using an Ommaya reservoir. An equivalent volume of CSF (eg, 7 to 10 mL) should be removed prior to instilling IT chemotherapy; many patients have rapid relief of symptoms related to increased intracranial pressure as fluid is removed. Treatment should be administered slowly (over several minutes) to reduce the risk of vomiting.

Cell counts, chemistries, cytology, and other studies (as clinically indicated) should be repeated each time the CSF is accessed for treatment; if possible, CSF pressures should be measured in patients receiving IT therapy via LP. After IT therapy has been administered, cytocentrifuge preparations may demonstrate reactive ependymal cells that can be difficult to distinguish from leukemic blasts, particularly if the CSF leukocyte count is low.

An Ommaya reservoir may be placed because of difficulties or discomfort with repeated LPs or because of concern that, for some individuals, CSF flow will not adequately deliver sufficient drug from the lumbar space to the entire CNS. Typically, CSF flows from the choroid plexus in the lateral ventricles down through the aqueduct to the base of the spine and then back up along the spinal cord until it is reabsorbed over the surface of the brain. (See "Treatment of leptomeningeal disease from solid tumors", section on 'Technique of administration'.)

We generally leave an Ommaya reservoir in place after completing IT therapy, in case it is needed for management of a subsequent relapse. Accessing an Ommaya reservoir (figure 1) is described separately. (See "Treatment of leptomeningeal disease from solid tumors", section on 'Intrathecal therapy'.)

Agents and doses — Initial IT therapy uses either methotrexate or cytarabine. No prospective studies have directly compared these agents in this setting and the preferred treatment varies among practitioners.

CSF cytology should be performed with each treatment to assess response. (See 'Response evaluation' below.)

●Adults – We consider either methotrexate or cytarabine acceptable for initial IT therapy; cross-over to the other agent is useful for patients with an inadequate response or for relapse after prior IT therapy. We generally switch agents if the CSF blast count has not dropped after three injections.

For adults, we generally treat as follows; note that doses differ according to administration via LP versus Ommaya reservoir:

•Methotrexate – Treat with 15 mg/dose when administered via an LP, or 12 mg when administered via an Ommaya reservoir.

To reduce the local chemical arachnoiditis, we usually add 50 mg of hydrocortisone to preservative-free methotrexate and administer treatment slowly. Nevertheless, injecting into an Ommaya often results in projectile vomiting (perhaps due a pressure effect on the chemoreceptor area on the medial wall of the lateral ventricle).

Adverse effects of IT methotrexate include chemical (aseptic) meningitis, delayed leukoencephalopathy, acute encephalopathy, and transverse myelopathy, as discussed separately. (See "Overview of neurologic complications of conventional non-platinum cancer chemotherapy", section on 'Methotrexate'.)

•Cytarabine – Treat with 50 mg/dose via LP or 40 mg via Ommaya.

IT cytarabine may be associated with chemical (aseptic) meningitis and, less often, with encephalopathy, seizures, and myelopathy as discussed separately. (See "Overview of neurologic complications of conventional non-platinum cancer chemotherapy", section on 'Cytarabine'.)

A liposomal formulation of cytarabine was removed from the market because of excessive toxicity.

So-called "triple therapy" (ie, IT therapy using methotrexate plus cytarabine plus hydrocortisone) has been used for treatment of some children with acute lymphoblastic leukemia/lymphoblastic lymphoma (ALL/LBL), but it has not been broadly applied for treatment of adults with AML. (See "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents", section on 'CNS management'.)

●Children – Young children should have the dose calculated according to body weight.

Note that management of a child with myeloid leukemia associated with Down syndrome (ML-DS) requires distinctive treatment, as described separately. (See "Myeloid leukemia associated with Down syndrome (ML-DS)".)

Thio-TEPA has been used less often for treatment of leukemic involvement. This alkylating agent is more often used to treat carcinomatous meningitis, but it may also have benefit against CNS leukemia.

Schedule — To limit adverse effects, we generally try to avoid temporal overlap of IT therapy with radiation therapy (RT) or systemic high-dose chemotherapy. Nevertheless, individual circumstances (eg, simultaneous leptomeningeal and cranial nerve involvement) may require concurrent treatments, while prolonged IT therapy after clearing of blasts (below) often overlap with these other treatments. (See 'Radiation therapy' below.)

●Initial treatments – IT treatment is given two to three times per week until the CSF has been cleared of the leukemic cells, which generally occurs after a few treatments.

●After clearing blasts from CSF – Subsequent treatment is given at weekly intervals for two more doses, followed by monthly administration, for a total of one year. (See "Treatment of leptomeningeal disease from solid tumors", section on 'Intrathecal therapy'.)

Radiation therapy — We generally reserve RT for patients who have neurologic abnormalities (eg, cranial nerve involvement or other motor, sensory, or visual deficits); a tumor mass in the brain, spinal cord, or one that impinges on important structures (eg, spinal cord); and patients who fail to respond adequately to IT chemotherapy. (See 'Management' above.)

●Treatment field – To avoid excess myelosuppression, we favor cranial RT rather than craniospinal RT. The treatment field should include the base of the brain (typically down to C2) to adequately cover the foramina for the cranial nerves. Patients with lower extremity weakness, or bladder or bowel dysfunction, may receive lumbosacral spine RT in addition to cranial RT, particularly if an MRI demonstrates nerve involvement at this level.

●Dose and timing – We initiate RT (eg, 18 to 25 gray [Gy] for the brain) as soon as CNS involvement is suspected, because the effect of IT therapy can be unpredictable and the chance of nerve recovery from ischemic injury decreases substantially the longer the deficit has been present.

Concurrent therapy:

•IT therapy – We routinely administer IT therapy two or three times per week while the patient is receiving cranial RT for a cranial neuropathy.

•Systemic therapy – We avoid concurrent high-dose systemic chemotherapy (ie, with methotrexate or cytarabine) for two weeks before or after cranial RT; concurrent therapy may be acceptable for RT at other sites (eg, a lumbar or sacral mass).

Concurrent administration of an anthracycline with RT usually results in increased skin toxicity.

●Adverse effects (AEs) – RT is associated with acute and long-term toxicities [15-18].

•Acute – Myelosuppression, mucositis, and esophagitis vary with the RT dose and treatment field.

•Long term – Late toxicity of RT includes second cancers, endocrine disorders, neurocognitive dysfunction, neurotoxic effects, and growth retardation in children, as discussed separately. (See "Delayed complications of cranial irradiation".)

●Efficacy – A retrospective single-center study reported outcomes of 163 adults with CNS leukemia (66 with AML) treated between 1996 and 2012 [19]. The most common CNS-related symptoms were headache (49 percent), cranial nerve (CN) VII deficit (28 percent), and CN II deficit (27 percent). Patients were treated with either whole brain, craniospinal, or base-of-skull ports; some patients with AML received concurrent IT chemotherapy, but doses of RT and chemotherapy were not reported. Following RT, symptoms were resolved in 16 percent, improved in 54 percent, and stable in 15 percent. Median survival after radiation was 3.8 months.

Systemic chemotherapy — Systemic chemotherapy that penetrates the CNS can serve as an adjunct to IT treatment.

High-dose methotrexate or cytarabine (used more commonly for AML) can reduce the CNS tumor load [16,20]. Unfortunately, the relapse rate, even after initially rapidly successful therapy, is high, either in association with bone marrow relapse or independently [15].

We generally avoid high-dose systemic chemotherapy for two weeks before, concurrently, and for two weeks after cranial RT. (See 'Radiation therapy' above.)

Systemic therapy with high-dose methotrexate for CNS leukemia is discussed separately. (See "Therapeutic use and toxicity of high-dose methotrexate".)

RESPONSE EVALUATION — Response to CNS-directed therapy is evaluated by periodic examination of cerebrospinal fluid (CSF) from a lumbar puncture (LP), even if treatment has been administered via an Ommaya reservoir. We do not routinely repeat imaging after completion of planned treatment, but re-evaluation is appropriate for patients who do not improve or whose clinical findings progress.

An LP should be performed periodically to monitor response, whether intrathecal (IT) therapy is administered via LP or via Ommaya reservoir:

●Treatment via LP – CSF should be evaluated with each IT treatment.

●Treatment via Ommaya reservoir – An LP should be performed periodically to evaluate CSF.

CSF obtained from an Ommaya reservoir is typically negative from the beginning of therapy; leukemic cells are rarely detected in the lateral ventricles (where the Ommaya catheter is inserted), even when there are abundant leukemic cells in CSF from the base of the spine (ie, via LP).

Treatment failure should be suspected if the CSF does not clear after four or five IT treatments or if there are increasing numbers of blasts, with or without worsening symptoms.

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SUMMARY AND RECOMMENDATIONS

●Description – Involvement of the central nervous system (CNS) by acute myeloid leukemia (AML) is uncommon at initial diagnosis for adults and children, but the incidence is higher with relapsed AML. (See 'Epidemiology' above.)

●Presentation – Patients can be asymptomatic but more often have symptoms of increased intracranial pressure (eg, headache, lethargy, altered mental status), cranial nerve palsy, weakness or paresthesias of extremities. (See 'Clinical presentation' above.)

●Evaluation – Evaluation is by imaging (according to the neurologic findings) and diagnostic lumbar puncture (LP).

•Imaging – MRI or CT of the brain or spine is guided by clinical findings. (See 'Imaging' above.)

•Lumbar puncture – Diagnostic LP (with cytology, flow cytometry, and/or molecular studies) is performed for patients with neurologic findings that suggest CNS or ocular involvement. (See 'Lumbar puncture (LP)' above.)

For asymptomatic patients with AML, we do not perform routine diagnostic LP, with the following exceptions:

-Infants ≤1 year

-Second remission in a patient with relapse of acute promyelocytic leukemia (APL)

●Diagnosis – CNS involvement should be suspected in patients with AML with new or progressive neurologic findings. (See 'Diagnosis' above.)

Diagnosis is based on identification of leukemic blasts by microscopy of a cytocentrifuged cerebrospinal fluid (CSF) specimen, with or without flow cytometry and/or molecular studies.

For inconclusive CSF findings, diagnosis can be made with leptomeningeal involvement by MRI/CT, or biopsy of a mass.

●Management – Treatment varies with the nature of CNS involvement, neurologic findings, medical fitness, institutional/clinician practice, and patient goals.

•Asymptomatic leptomeningeal involvement – For patients with asymptomatic leptomeningeal involvement (ie, no cranial nerve impairment or other neurologic deficit), we suggest intrathecal (IT) chemotherapy alone, rather than radiation therapy (RT) or systemic chemotherapy (Grade 2C). (See 'Asymptomatic leptomeningeal involvement' above.)

•Leptomeningeal involvement with neurologic deficit – For cranial nerve abnormalities or other neurologic impairment, we suggest IT chemotherapy plus RT and/or systemic chemotherapy that penetrates the CNS (Grade 2C). (See 'Leptomeningeal involvement with neurologic findings' above.)

•Mass lesion – A mass in brain, spine, or paraspinous mass that threatens the spinal cord generally requires RT and/or surgical debulking; is guided by location, nature of neurologic symptoms, and institutional practice. Glucocorticoid treatment can reduce vasogenic edema symptoms. (See 'Mass lesion' above.)

•Isolated CNS relapse – Patients with an apparent isolated CNS relapse should be evaluated for systemic disease (eg, bone marrow or blood examination) and managed accordingly, as systemic relapse is inevitable.

●Intrathecal chemotherapy – IT treatment can be delivered by LP or via Ommaya reservoir (figure 1).

Either IT methotrexate or cytarabine is acceptable, but doses vary with route of administration. Initial treatment is three times per week, with increasing intervals between treatments as CSF blasts clear. (See 'Intrathecal chemotherapy' above.)

●Radiation therapy – RT is generally restricted to patients with neurologic findings; a brain, spine, or threatening paraspinous mass; and patients who respond inadequately to IT chemotherapy. (See 'Radiation therapy' above.)

●Systemic therapy – Systemic chemotherapy that penetrates the CNS (eg, high-dose methotrexate or cytarabine) can be an adjunct to IT treatment. (See 'Systemic chemotherapy' above.)