Acute myeloid leukemia: Involvement of the central nervous system

INTRODUCTION — 

Involvement of the central nervous system (CNS) by acute myeloid leukemia (AML) is an adverse finding that can lead to potentially devastating complications. CNS involvement can manifest as a mass lesion or as leptomeningeal disease.

CNS involvement is uncommon at initial diagnosis of AML, but it occurs more often with relapsed or refractory AML. It is usually accompanied by other sites of disease, but isolated CNS disease (ie, no evidence of AML in bone marrow, blood, or other extranodal sites) can occur at relapse.

Patients with AML who have new or progressive neurologic abnormalities - whether at diagnosis, in apparent remission, or at systemic relapse - must be evaluated for involvement of the CNS. Investigation of the CNS is not routine for most neurologically asymptomatic patients with AML, except for very specific clinical settings. Evaluation and treatment of AML in the CNS must be initiated promptly to prevent persistent or progressive neurologic abnormalities.

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 "Acute myeloid leukemia: Clinical manifestations, pathologic features, and diagnosis".)

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

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

●(See "Acute myeloid leukemia: Children and adolescents".)

EPIDEMIOLOGY

Incidence — CNS involvement by AML is uncommon at diagnosis, but it can occur at any stage of disease, including at the time of systemic relapse or while in apparent systemic remission after induction therapy.

●Adults – Reports of the incidence of CNS involvement by AML in adults vary widely, but most studies suggest an incidence of 1 to 3 percent at diagnosis.

•CNS involvement was reported in 1.1 percent of 3240 patients in an analysis of 11 consecutive cooperative group clinical trials for AML [1]. There was no difference in the incidence of CNS involvement between the five trials in which a lumbar puncture (LP) was mandatory for all enrolled patients and the other trials (in which an LP was performed at the discretion of the investigator). Importantly, patients with CNS involvement had similar rates of overall survival (OS) and complete remission (CR) compared with patients who had no extramedullary disease.

•A study of 3261 adults with newly diagnosed AML with CNS symptoms enrolled in clinical trials reported <1 percent incidence of CNS involvement; the incidence was 3 percent in patients with relapsed AML [2].

•The incidence of CNS involvement was 3 percent in 1370 consecutive patients with AML in a study in which an LP was performed only for findings suggestive of CNS disease [3].

•Several small studies reported a higher incidence of CNS involvement. A retrospective single-institution study of 548 patients with AML reported CNS involvement in 4.6 percent, including 2.4 percent at initial diagnosis [4]. 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) [5], while another study reported CNS involvement in 19 percent of 42 patients with AML [3].

●Children – Among 1344 children with AML, 395 (29 percent) had evidence of CNS involvement at presentation; 217 had ≤5 white blood cells (WBCs)/microL with blasts (ie, CNS2 involvement), and 178 had >5 WBCs/microL with blasts or CNS symptoms (CNS3 involvement) [6].

The wide range of estimated incidence of CNS involvement may be related, in part, to various definitions of CNS involvement, different diagnostic techniques (ie, cytology versus flow cytometry), inconsistent expertise in evaluating cytospin preparations, and variable numbers of "bloody taps" (ie, a mixture of cerebrospinal fluid with peripheral blood containing blasts). The discordance between the incidence of CNS involvement in asymptomatic patients at diagnosis and neurologic manifestations after achieving remission may relate to the efficacy of chemotherapy (eg, cytarabine) in eradicating low levels of disease in the CNS.

Risk factors — The incidence of CNS involvement at diagnosis is associated with certain clinical and pathologic features at diagnosis.

CNS involvement is more common in patients with AML with the following features [2,3,5-10]:

●Clinical features

•Hyperleukocytosis (>100,000/microL)

•Age <2 years

•Elevated lactate dehydrogenase

●Leukemic factors

•Prominent monocytic, myelomonocytic, or monoblastic features

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

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

PATHOGENESIS — 

The pathogenesis of leukemic meningitis is not well understood.

Mechanisms by which AML can seed the CNS include [11]:

●Extension from bone marrow of the skull (eg, through bridging veins into the subarachnoid space, direct infiltration of the leptomeninges, extension along nerve roots through the neural foramina into the extradural space, invasion of brain parenchyma via brain capillaries).

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

●Hemorrhage into the CNS with blood containing blasts.

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

CLINICAL PRESENTATION — 

Most patients with CNS involvement by AML present with neurologic signs or symptoms; a small number are asymptomatic [12]. Most patients with CNS involvement also have systemic AML (ie, at initial diagnosis or with relapsed or refractory disease). For patients with isolated CNS involvement, systemic relapse is inevitable unless the patient is treated systemically.

CNS involvement by AML 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 (CNs) that are most often affected are CNs III, V, VI, or VII.

Aside from leukemic involvement, there are very few other causes of palsies of CNs 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 neurologic 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 AML who have new or progressive neurologic abnormalities require evaluation for CNS involvement. (See 'Indications' below.)

Evaluation generally includes imaging and a lumbar puncture (LP). Rarely, a retina exam by an ophthalmologist or another experienced clinician may demonstrate leukemic infiltrates, but this is more likely to detect ischemia or hemorrhage.

Most patients with CNS involvement by AML also have systemic disease. Patients who initially appear to have isolated CNS leukemia must be carefully evaluated for systemic disease, including the examination of bone marrow, blood, and/or extranodal sites by microscopy, flow cytometry, and/or molecular studies, as discussed separately. (See "Acute myeloid leukemia: Clinical manifestations, pathologic features, and diagnosis".)

Imaging — Imaging can identify a mass lesion (chloroma) in the brain or spine, leptomeningeal involvement, and CNS bleeding. The choice of imaging is guided by findings from the history and neurologic examination.

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

Head CT should be performed prior to performing an LP in patients with symptoms suggestive of increased intracranial pressure (eg, headache, lethargy, other mental changes). (See 'Lumbar puncture' below.)

●Magnetic resonance imaging

•Brain – Brain MRI with gadolinium enhancement 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, examination using specific imaging protocols is often helpful because the spinal fluid can be unrevealing in patients with isolated cranial nerve involvement by AML.

Mass lesions are uncommon in patients with CNS involvement by AML.

•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".)

Lumbar puncture — 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 — An LP should be performed in any patient with newly diagnosed, relapsed, or refractory AML who has new neurologic abnormalities.

We do not perform diagnostic LPs in adults who have no neurologic abnormalities; the incidence of asymptomatic CNS involvement in adults is low, and there is no evidence that CNS involvement is associated with inferior outcomes [1], as described above. (See 'Incidence' above.)

Some treatment protocols for AML in children may specify an LP in asymptomatic children with higher risk (eg, age <2 years).

Lumbar puncture 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.

LP is relatively contraindicated in patients with a mass lesion or hemorrhage. (See "Lumbar puncture: Technique, contraindications, and complications in adults".)

●Imaging prior to lumbar puncture – 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 lumbar puncture – Complete blood count (CBC) with platelet count and coagulation studies should be obtained and deficits corrected, if needed, 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/microL or 20,000/microL), or have 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 [13]. However, a larger study by the same group indicated that the risk for a traumatic or bloody 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]) [14].

-Adults – It is difficult to extrapolate the findings from children to adults because of differences in size and because most children are 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).

A retrospective review of LPs performed for the administration of intrathecal (IT) chemotherapy reported no difference in bleeding complications in 218 patients with <50,000 platelets/microL compared with 682 who had ≥50,000 platelets/microL (6.5 versus 6.8 percent, respectively), although the rate of traumatic taps (red blood cells >200) was higher in patients with lower platelet counts [15]. A review of the literature stated that ≥40,000 platelets/microL is a "safe" count for LP but acknowledged that lower platelet counts may also be safe [16].

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

•Traumatic lumbar puncture – Every effort should be taken to avoid a traumatic LP in patients with leukemia. Traumatic LPs can provide false positive results and can seed leukemic blasts into the cerebrospinal fluid (CSF).

Because of the concern about introducing circulating leukemic blasts into the CSF, many centers routinely administer a dose of IT chemotherapy when LPs are performed at diagnosis or in relapse. (See 'Intrathecal chemotherapy' below.)

●Complications – The most serious complication of an LP is cerebral herniation. Imaging should be performed to exclude a mass effect, mid-line shift, and/or herniation caused by a tumor mass or hemorrhage.

Other complications of an LP include bleeding (which can cause impingement on 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'.)

Cerebrospinal fluid 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, and cytology of stained cytospin slides (with flow cytometry or immunohistochemistry 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. Cytocentrifuge preparations may demonstrate reactive ependymal cells that can be difficult to distinguish from leukemic blasts, particularly if the CSF leukocyte count is low.

DIAGNOSIS — 

CNS involvement should be suspected in patients with newly diagnosed AML, relapsed AML, or refractory AML who have 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 [17]. In some cases, CSF studies are inconclusive, but the diagnosis is based on evidence of leptomeningeal involvement (with or without parenchymal disease) by MRI, 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, composition, and findings in disease states", section on 'Composition of the CSF'.)

Blast counts in CSF can range from 5 to >1000 white blood cells/microL. Some patients with clinical signs of cranial nerve involvement or a mass on 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".)

PROPHYLAXIS — 

We do not provide CNS prophylaxis for adults with AML who have no neurologic abnormalities or other evidence of CNS involvement because there is no proven benefit, and it avoids potential adverse effects of prophylaxis.

CNS prophylaxis for infants and children should be guided by the chosen treatment protocol and institutional practice. (See "Acute myeloid leukemia: Children and adolescents", section on 'Central nervous system management'.)

Note that CNS prophylaxis is routinely administered for patients with blastic plasmacytoid dendritic cell neoplasm, an acute leukemia that is distinct from AML, as discussed separately. (See "Blastic plasmacytoid dendritic cell neoplasm".)

MANAGEMENT OF CNS DISEASE — 

Management of AML involving the CNS should be initiated promptly to prevent or limit further neurologic deficits and complications. CNS management must be integrated with systemic treatment, which should not be delayed by CNS involvement.

Leptomeningeal involvement — Leptomeningeal involvement by AML is diagnosed by findings from a diagnostic lumbar puncture (LP) or by imaging, as discussed above. (See 'Diagnosis' above.)

No prospective studies have directly compared intrathecal (IT) chemotherapy, radiation therapy (RT), and CNS-penetrating systemic chemotherapy for management of CNS involvement by AML. Treatment suggestions are primarily based on clinical experience and extrapolation from treatment of carcinomatous meningitis.

Asymptomatic — For patients with leptomeningeal involvement but no cranial nerve impairment or other neurologic findings, we suggest IT methotrexate, IT cytarabine, or "triple therapy" (IT methotrexate plus IT cytarabine plus IT hydrocortisone) rather than cranial RT or systemic chemotherapy alone. This approach is based on the low toxicity, efficacy, and rapid action of IT therapy compared with the other treatments.

Preferred IT agents vary among practitioners, and no prospective studies have directly compared them in this setting. Management of CNS disease must be integrated with treatment for systemic AML.

Administration and toxicity of IT chemotherapy are discussed below. (See 'Intrathecal chemotherapy' below.)

Patients with neurologic findings — For patients who have cranial nerve abnormalities or other neurologic impairment in association with leptomeningeal disease, we suggest RT with or without IT chemotherapy and/or systemic chemotherapy.

No studies have compared outcomes with these approaches, but RT is the quickest and most reliable way to salvage a cranial nerve, which is typically compressed in the neural foramen. Treatment with RT is discussed below. (See 'Radiation therapy' below.)

Some experts favor triple IT therapy (rather than IT methotrexate or IT cytarabine alone) when giving IT chemotherapy to patients with symptomatic leptomeningeal disease, but no studies have directly compared IT regimens in this setting. Administration and toxicity of IT chemotherapy are discussed below. (See 'Intrathecal chemotherapy' below.)

CNS-penetrating systemic chemotherapy is discussed below. (See 'Systemic chemotherapy' below.)

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

We initiate dexamethasone in patients who have symptoms related to peritumoral edema or evidence of vasogenic edema with imaging. Dexamethasone is the preferred agent due to its high potency, limited mineralocorticoid activity (which reduces the potential for fluid retention), and availability of both intravenous and oral formulations (with a 1:1 conversion ratio). Dexamethasone dose, schedule, and response assessment are discussed separately. (See "Management of vasogenic edema in patients with primary and metastatic brain tumors", section on 'Initiation of glucocorticoids'.)

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

TREATMENTS

Intrathecal chemotherapy — Intrathecal (IT) therapy involves an injection of chemotherapy directly into the cerebrospinal fluid (CSF). Various IT chemotherapy regimens are effective, and the preferred approach varies among practitioners.

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). (See 'Delivery' below.)

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

Agents and doses — IT treatment for CNS involvement with AML usually uses IT methotrexate, IT cytarabine, or "triple therapy" (IT methotrexate plus IT cytarabine plus IT hydrocortisone).

No prospective studies have directly compared IT agents in this setting, and the preferred approach varies among practitioners.

IT thiotepa, which is more often used to treat carcinomatous meningitis, may also have efficacy against AML blasts in the CNS. (See "Treatment of leptomeningeal disease from solid tumors", section on 'Thiotepa'.)

Intrathecal methotrexate

●Administration – The dose of IT methotrexate varies according to the method of delivery. We usually add 50 mg of hydrocortisone to preservative-free methotrexate and administer the treatment slowly (eg, over several minutes) to reduce local chemical arachnoiditis.

•Adults – For adults, we generally treat as follows:

-Lumbar puncture – Treat with 12 to 15 mg/dose twice or thrice weekly

-Ommaya reservoir – Treat with 12 mg twice or thrice weekly

•Children – Young children should have the dose calculated according to body weight and guided by the chosen treatment protocol.

●Toxicity – Adverse effects (AEs) 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'.)

●Duration of therapy – Continue treatment until the CSF is clear, then weekly for four to six weeks.

Blasts are typically cleared from CSF within several weeks of IT therapy.

If blasts persist after two to three weeks of IT methotrexate, we generally change to an alternate IT regimen (eg, IT cytarabine, triple therapy) and/or treat with CNS-penetrating systemic therapy, as discussed below. (See 'Systemic chemotherapy' below.)

Intrathecal cytarabine

●Administration – The dose varies according to the method of delivery. We usually add 50 mg of hydrocortisone and administer the treatment slowly (eg, over several minutes) to reduce local chemical arachnoiditis.

•Adults – For adults, we generally treat as follows:

-Lumbar puncture – Treat with 50 to 100 mg/dose twice or thrice weekly

-Ommaya reservoir – Treat with 40 mg twice or thrice weekly

•Children – Young children should have the dose calculated according to body weight and guided by the chosen treatment protocol.

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

●Toxicity – 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'.)

●Duration of therapy – Continue treatment until the CSF is clear, then weekly for four to six weeks.

Blasts are typically cleared from CSF within several weeks of IT therapy.

If blasts persist after two to three weeks of IT cytarabine, we generally change to an alternate IT regimen (eg, IT methotrexate, triple therapy) and/or treat with CNS-penetrating systemic therapy, as discussed below. (See 'Systemic chemotherapy' below.)

Delivery — IT chemotherapy should be delivered slowly via LP or using an Ommaya reservoir. Slow administration (ie, over several minutes) reduces the risk of vomiting.

An Ommaya reservoir (figure 1) 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.

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

Whether using an LP or 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 decreased intracranial pressure as fluid is removed.

Cell counts, chemistries, cytology, and other studies (as clinically indicated) should be repeated each time the CSF is accessed for treatment. CSF pressure should be measured in patients receiving IT therapy via LP, when possible.

Radiation therapy — We generally reserve radiation therapy (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 'Patients with neurologic findings' above and 'Mass lesion' 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 cranial nerve foramina. Patients with lower extremity weakness or bladder or bowel dysfunction may receive lumbosacral spine RT in addition to cranial RT, particularly if 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 chance of nerve recovery from ischemic injury decreases substantially the longer the deficit has been present.

Concurrent therapy:

•Intrathecal 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.

●Toxicity – RT is associated with acute and long-term AEs [18-21].

•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) who were treated with RT between 1996 and 2012 [22]. 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. The median survival after radiation was 3.8 months.

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

Either high-dose cytarabine (HiDAC; which is most commonly used for AML) or high-dose methotrexate can reduce the CNS tumor load [19,23]. However, even after initially successful therapy, the rate of relapse is high, either in association with bone marrow relapse or independently [18].

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

HiDAC and high-dose methotrexate are discussed separately. (See "Acute myeloid leukemia in younger adults: Post-remission therapy", section on 'Dose of cytarabine' and "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 completing 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 lumbar puncture – 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).

Patients with persistent or increasing blasts in CSF, with or without worsening symptoms, after two to three weeks of IT therapy should be managed as discussed above. (See 'Intrathecal chemotherapy' above.)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Acute myeloid leukemia (AML) treatment in adults (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

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

●Presentation – Patients usually have symptoms of increased intracranial pressure (eg, headache, lethargy, altered mental status), cranial nerve palsy, and weakness or paresthesias of extremities. Some patients are asymptomatic. (See 'Clinical presentation' above.)

●Evaluation – Patients with AML who have new or progressive neurologic abnormalities require evaluation for both CNS involvement and for systemic disease. Evaluation is not performed in asymptomatic adults, but it may be specified in some pediatric treatment protocols. (See 'Evaluation' above.)

Evaluation of CNS involvement includes:

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

•Lumbar puncture – Diagnostic lumbar puncture (LP), including cytology, flow cytometry, and/or molecular studies. (See 'Lumbar puncture' above.)

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

Diagnosis is based on the 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 by detecting leptomeningeal involvement with MRI/CT or a biopsy of a mass.

●Prophylaxis – We do not provide CNS prophylaxis for patients with AML who have no neurologic abnormalities. (See 'Prophylaxis' above.)

●Management of CNS disease – Treatment of CNS disease must be integrated with systemic therapy.

•Asymptomatic leptomeningeal involvement – For asymptomatic leptomeningeal involvement, we suggest intrathecal (IT) methotrexate, IT cytarabine, or "triple therapy" (IT methotrexate plus IT cytarabine plus IT hydrocortisone) rather than cranial radiation therapy (RT) or systemic chemotherapy (Grade 2C). (See 'Asymptomatic' above.)

•Leptomeningeal disease with neurologic deficit – For leptomeningeal involvement associated with cranial nerve abnormalities or other neurologic impairment, we suggest RT, with or without IT chemotherapy and/or systemic chemotherapy (Grade 2C). (See 'Patients with neurologic findings' above.)

•Mass lesion – A mass in the brain or spine or a paraspinous mass that threatens the spinal cord generally requires RT and/or surgical debulking. The approach is guided by location, nature of neurologic symptoms, and institutional resources. (See 'Mass lesion' above.)

Dexamethasone (or other glucocorticoid) is typically given to reduce vasogenic edema symptoms.

●Intrathecal chemotherapy (see 'Intrathecal chemotherapy' above)

•Agents – Administration and toxicity of IT methotrexate, IT cytarabine, or "triple therapy" are discussed above. (See 'Agents and doses' above.)

•Delivery – IT therapy can be delivered by LP or via Ommaya reservoir (figure 1). (See 'Intrathecal chemotherapy' above.)

●Radiation therapy – RT is generally restricted to patients with neurologic abnormalities; cranial nerve involvement, 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 cytarabine or high-dose methotrexate) is discussed. (See 'Systemic chemotherapy' above.)