Presentation

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Dr. Tanjina Afrin

FCPS (Part-II) Trainee

Department of Haematology

BSMMU

Managing CNS disease in adults with acute�lymphoblastic leukemia

Richard A. Larson

23 May 2017

Department of Medicine, Section of Hematology/Oncology, and Comprehensive Cancer Center,

The University of Chicago, Chicago, IL, USA

The central nervous system (CNS) is an important site of involvement by acute lymphoblastic leukemia (ALL).

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Malignant cells of both B-cell and T-cell origin have a predilection for infiltrating into the cerebrospinal fluid (CSF) and the meningeal membranes surrounding the brain and the spinal cord.

Introduction

The meninges may harbor residual leukemia cells, and the blood–brain barrier may shelter them from systemic chemotherapy.

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Because oral and intravenous (IV) chemotherapy drugs, with some exceptions, penetrate poorly from the blood into the CNS, this space is considered a sanctuary site where ALL cells can escape the full cytotoxic effects of systemic chemotherapy.

Introduction

Although isolated CNS relapses do occur, recurrence of ALL within the CNS usually coincides with or predicts for systemic relapse soon afterwards in the marrow and blood.

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Recurrence of leukemia in the CNS is more easily prevented than treated.

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Risks of CNS leukemia vary by ALL phenotype and genotype.

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Introduction

Objective

Objective

Less than 10% of adults with ALL have CNS involvement at diagnosis.

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However, this incidence is probably underestimated. CNS involvement has been identified around 60% of patients at autopsy who were at presentation considered as having bone marrow disease only.

Incidence of CNS leukemia in adults

Factors associated with CNS disease at presentation include:

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• A higher white blood cell (WBC) count and a high proliferative index.

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• T-cell immunophenotype.

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• The presence of a mediastinal mass.

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• Mature B-cell ALL.

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Risk factors of CNS leukemia in adults

• High LDH level

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• The presence of the Philadelphia chromosome.

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• Serum high levels of B2-microglobulin.

Risk factors of CNS leukemia in adults

A lumbar puncture (LP) should be routinely performed in all newly diagnosed patients.

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However, there is always concern about obtaining a false positive result if the CSF sample is contaminated with peripheral blood containing ALL blasts. A formula is sometimes used to distinguish between contamination from the blood and a truly positive CSF

Diagnosis of CNS ALL

If the patient has leukemia cells in the peripheral blood and the lumbar puncture is traumatic and contains 5 WBC/lL with blasts, the following algorithm should be used to define CNS disease:

Steinherz/Bleyer method of evaluating initial traumatic lumbar punctures

Contamination of the CSF by leukemia cells as a result of a traumatic LP at diagnosis is associated with an inferior treatment outcome in children with ALL.

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Thus, opinions differ regarding when the first LP should be performed. It has been argued that the first LP should wait until there are no circulating blasts in the blood in order to reduce the likelihood of a false positive result.

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Diagnosis of CNS ALL

However, many protocols now require the procedure at diagnosis and also instill the first dose of chemotherapy intrathecally (IT) at that time.

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Traditionally, CNS leukemia has been defined by the presence of at least 5 leukocytes per microliter of CSF (with leukemic blast cells apparent in a cytocentrifuged sample) or by the presence of cranial nerve palsies

Diagnosis of CNS ALL

Classification of CNS status.

Diagnosis of CNS ALL

Platelet transfusion to raise the platelet count to >50,000/lL provides an appropriate margin of safety.

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Active disseminated intravascular coagulation or an elevated prothrombin time or partial thromboplastin time is a relative contraindication to the procedure.

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Diagnosis of CNS ALL

The LP should be delayed until these coagulopathies are adequately corrected. However, this may delay the initial LP until well into the remission induction course and perhaps yield a false-negative result.

A careful retinal eye exam should be done. Retinal hemorrhages and ‘cotton wool’ spots indicate bleeding, edema, or cellular infiltrates in the retinal nerve layer which is part of the CNS.

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Diagnosis of CNS ALL

Computed tomography (CT) scans of the brain or magnetic resonance imaging (MRI) are not routinely done in asymptomatic patients.

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However, if a cranial neuropathy were detected on physical examination, then MRI is the best way to evaluate impingement of cranial nerves by leukemia or infiltration of the meninges along the base of the brain by ALL cells. Intracerebral mass lesions are rare.

Diagnosis of CNS ALL

A cell count should be performed promptly and a cytospin slide of the CSF examined after staining with Wright–Giemsa.

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Increasingly, flow cytometry is also being performed on CSF samples to identify ALL blast cells by their distinctive immunophenotype.

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Protein levels in the CSF are often elevated when ALL is present.

Diagnosis of CNS ALL

• A 35-year-old woman presented with precursor B-cell ALL.
• She has no neurological symptoms or signs on exam.
• Her white blood cell (WBC) count is 56,000/lL with 87% blasts.
• The immunophenotype is positive for CD10, CD19, CD20, and CD34.
• The karyotype is normal, and molecular analysis for BCR/ABL1 is negative.

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First Case: CNS prophylaxis

• A lumbar puncture is performed and the CSF is clear and colorless. Intrathecal chemotherapy is injected.
• The cell count shows 3 RBC and 2 WBC per microliter.
• A cytospin slide shows no lymphoblasts.
• Flow cytometry does not detect any cells with her ALL immunophenotype in the CSF.

First Case: CNS prophylaxis

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What will be the management of this patient?

This patient has no detectable CNS disease at diagnosis despite her high WBC count. Routine CNS prophylaxis is recommended in conjunction with her planned systemic chemotherapy.

Management: CNS prophylaxis

Central Nervous System prophylaxis regiments in Adult Acute Lymphoblastic Leukemia Protocols

Central Nervous System prophylaxis regiments in Adult Acute Lymphoblastic Leukemia Protocols

Chemotherapy agents used to prophylaxis or treat the CNS in adults with acute lymphoblastic leukemia.

• The choice of systemic chemotherapy agents also impacts on the success of CNS prophylaxis. In an early randomized trial by the CALGB, patients who received oral dexamethasone had significantly fewer CNS relapses than those who received oral prednisone.

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• It is clear that the use of systemic asparaginase lowers asparagine levels in the CNS, but it is uncertain whether this provides any additional benefit for CNS prophylaxis.

Management: CNS prophylaxis

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• This patient is identical to the first case.
• The initial CSF contains 120 lymphoblasts/lL.
• The CSF protein is elevated.

Second Case: Overt CNS leukemia at diagnosis

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What will be the management of this patient?

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This patient has overt CNS leukemia despite the lack of symptoms and merits more intensive CNS-directed treatment as part of remission induction.

Management: Overt CNS leukemia at diagnosis

Management: Overt CNS leukemia at diagnosis

• Individual protocols provide guidance regarding reducing the frequency of injections after the CSF clears of lymphoblasts.

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• If repeated lumbar punctures are difficult for a patient, an Ommaya reservoir can be placed for greater comfort.

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• Flow cytometry can be used on CSF to detect minimal residual disease, but as yet, there are no prospective data on how best to use this technique to adjust therapy.

Management: Overt CNS leukemia at diagnosis

In an independent study from the city of Hope reveals

However, there was no difference in outcome among those patients presenting with CNS involvement at diagnosis, those with an early isolated CNS relapse, and those with combined marrow and CNS relapse before transplantation.

Management: Overt CNS leukemia at diagnosis

• This patient presents identically to the first case but the initial LP was difficult because of spinal stenosis.

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• The CSF had 550 RBC/lL and 9 WBC/lL.

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• Flow cytometry showed blasts were present with the same immunophenotype as the lymphoblasts circulating in the blood.

Third Case: Equivocal CNS involvement at diagnosis

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What will be the management of this patient?

• This patient has had a traumatic spinal tap with an equivocal result.

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• It is possible that the CNS was not previously infiltrated by ALL and that the findings are all due to contamination by blood.

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• Nevertheless, we would treat this patient with a more intensive IT therapy in the same manner as Case 2.

Management: Equivocal CNS involvement at diagnosis

• A 35-year-old man completed 3 years of intensive multi-agent chemotherapy, CNS prophylaxis, and prolonged maintenance treatment for T-cell ALL.

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• Three months later, he presented with headache and blurred vision. He is noted to have a third cranial nerve palsy.

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Forth Case: Recurrence in the CNS

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• MRI shows an infiltrative process along the base of the brain. His blood counts are unremarkable and his bone marrow biopsy shows no recurrence.

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• An LP shows 60 lymphoblasts/lL.

Forth Case: Recurrence in the CNS

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What will be the management of this patient?

• The appearance of neurological signs or symptoms at any time during or after treatment of ALL is ominous and must be promptly investigated.

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• Although the differential diagnosis includes many benign or common disorders such as migraine headache, Bell’s palsy, herpes zoster or other infection, orbital myositis, Guillain–Barre or Horner’s syndrome, a Relapse of ALL in the CNS must be the first suspicion.

Management: Recurrence in the CNS

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• This patient has had an isolated CNS relapse. However, therapy directed at the CNS alone is likely not sufficient to prevent a systemic relapse. Thus, CNS-directed treatment followed by combined systemic therapy is warranted.

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Management: Recurrence in the CNS

Treatment of CNS Relapse

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• Immediate improvement in neurological symptoms and signs can often be achieved with IV or oral dexamethasone, usually given at 4mg every 6 h or 10mg every 12 h. IT therapy should be started promptly.

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• Although high doses of systemic chemotherapy plus IT chemotherapy given through the lumbar space are sufficient for prophylaxis, they are inadequate to treat gross recurrent disease.

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Management: Recurrence in the CNS

• Cranial irradiation has obvious advantages in this circumstance.

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• Chemotherapy resistant ALL cells remain quite sensitive to radiation therapy.

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(2) The cytotoxic effect of radiation is rapid, quickly relieving pressure on sensitive cranial nerves and thus preserving neurological function.

Management: Recurrence in the CNS

(3) Radiation fields can be quickly designed and treatment started the same day.

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(4) Adults tolerate whole cranium radiation treatments of 24–30 Gy with little local toxicity and few long-term side-effects.

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(5) Cranial irradiation can be employed even while patients are cytopenic from myelosuppressive chemotherapy.

Management: Recurrence in the CNS

• IT chemotherapy penetrates only 1–2mm into tissue and thus is not adequate for a thick layer of leukemia cells infiltrating along the base of the brain.

• Because of the normal pattern of circulation of CSF, very little of the chemotherapy administered by LP at the base of the spine reaches the base of the brain.

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Management: Recurrence in the CNS

• Thus, an Ommaya reservoir is the preferred method for delivering chemotherapy into the CNS to treat overt disease. Advantages include ease of administration, assurance that the drug reaches the spinal fluid, and safety, since these injections can be done even in a thrombocytopenic patient.
• The Ommaya reservoir is placed surgically under local or general anesthesia. The surgeon raises a skin flap over the temporal bone. A burr hole is drilled through the calvarium and a thin plastic tube is advanced through the frontal lobe into the lateral ventricle. The subcutaneous reservoir is attached and held in place by the skin flap which is sutured back into place. Treatment can usually begin immediately.

Management: Recurrence in the CNS

• When properly placed, an Ommaya ventricular reservoir provides a great advantage for both patient and physician. Premedication with anti-emetics is recommended. With the patient sitting upright, the Ommaya is accessed through the scalp with a 25 gauge scalp vein (butterfly) needle. One can usually feel a slight pop as the needle penetrates the plastic dome of the reservoir. A perpendicular approach is recommended, and care must be taken not to displace the dome off of the metal base (3.4 cm in diameter). When CSF is observed to back up through the tubing, a syringe is attached and chemotherapy is slowly injected over about one minute. If the solution is injected too quickly or if the tip of the Ommaya catheter is too close to the chemoreceptor locus that lies medial to the ventricle, the patient is likely to experience sudden projectile vomiting.

• There is no advantage to withdrawing CSF first before the injection, as ALL blasts are almost never found in the ventricular CSF, even when CSF obtained from the lumbar space is heavily involved. When methotrexate (6–12 mg) or cytarabine (30–50 mg), or both together, are injected into a lateral ventricle via an Ommaya, the chemotherapy- containing CSF flows through the third ventricle and down the center of the spinal cord and then upward again over the surface of the cord, eventually reaching the top surface of the brain. Typically, intraventricular injections are given twice per week for 6 doses to patients with active CNS leukemia. This treatment can continue between radiation treatments as the chemotherapy-containing CSF quickly drains out of the cranium and diffuses down the spinal canal.

• To monitor the effectiveness of the treatment, it is important to return to the lumbar space where the blasts were originally measured for another CSF examination.
• The ventricular CSF typically remains negative even when the lumbar CSF is positive, and thus is not useful for response assessments.

Management: Recurrence in the CNS

• If the CSF blast count is decreasing, then the CSF injections are changed to weekly for 1 month, and after clearance of lymphoblasts, to every 2 weeks, and eventually monthly for 1 year.

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• However, patients with isolated CNS relapses have a high risk of systemic recurrence, often within a few months, so induction and post-remission treatment should be started again from the beginning.

Management: Recurrence in the CNS

Methotrexate

Dose:

• For adults with CNS ALL, 6–15mg of preservative-free methotrexate are given into the lumbar IT space or ventricle once or twice weekly.
• It is often given IV in high doses (1–5 g/m2) concurrently with IT methotrexate, thereby thoroughly exposing the CNS tissues to this drug.
• When using high doses, the drug penetrates the blood-brain barrier via mass action. Oral or IV leucovorin is required, typically starting 24–42 h after the methotrexate infusion began and continuing for at least 72 h.
• Importantly, leucovorin readily diffuses into the CNS, markedly increasing reduced folate levels, and thus interfering with subsequent IT therapy for at least a week.

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Intrathecal and intraventricular chemotherapy�agents

• Mechanism of action: It is a classical folate antagonist that targets dihydrofolate reductase.

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• Toxicity:
• Arachnoiditis: Due to solutions containing preservatives such as benzyl alcohol
• Mucositis and myelosuppression
• Leukoencephalopathy (transient white matter changes on MRI or a characteristic clinical course with waxing and waning symptoms usually leading to complete, but sometimes only partial, resolution within a week).
• Febrile neutropenia

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Intrathecal and intraventricular chemotherapy�agents

• Renal toxicity (associated with older age, male sex, decreased baseline creatinine clearance, and the use of proton pump inhibitors)

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• acute neurotoxicity (symptoms of dizziness, malaise, blurred vision, headache, nausea, or seizures may appear within 1 d and for up to 2 weeks).

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• Methotrexaterelated stroke-like syndrome is uncommon (occurs within 21 d of IV or IT methotrexate with new onset of paresis or paralysis, aphasia or dysarthria, altered mental status, and/or seizures).

Intrathecal and intraventricular chemotherapy�agents

• The high-dose regimen was associated with more mucositis and febrile neutropenia.

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• Several cycles of high-dose methotrexate at 1000–3000 mg/m2 with leucovorin rescue are commonly used for CNS prophylaxis for adults with high-risk lymphomas. In one report, renal toxicity occurred in 9.1% of cycles among 151 patients and was associated with older age, male sex, decreased baseline creatinine clearance, and the use of proton pump inhibitors

Intrathecal and intraventricular chemotherapy�agents

Cytarabine

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• Dose: For adults, 30–70mg of preservative-free cytarabine in saline is injected into the CSF once or twice weekly.

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• Mechanism of Action: is an antimetabolite whose intracellular metabolite ara-CTP is incorporated into DNA.

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• Side effects: are minimal. High-dose cytarabine (1–3 gm/m2) given by IV infusion is used together with high-dose methotrexate in alternate courses of the HyperCVAD regimen; this combination is myelosuppressive.

Intrathecal and intraventricular chemotherapy�agents

• Toxicity:
• Cytarabine has also been encapsulated within liposomes. The usual liposomal cytarabine regimen is 50mg IT every 2 weeks. The frequency decreases in responding patients. The drug is provided in a single-use vial and does not contain any preservative; dilution is not needed.

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• Serious and unexpected neurotoxicity was observed when it was combined with high-doses of intravenous methotrexate and cytarabine.

Intrathecal and intraventricular chemotherapy�agents

• ThioTEPA

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• Dose: 10mg in 5–10 ml of normal saline are given once or twice weekly into the lumbar IT space or ventricular reservoir.

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• Mechanism of action: is a lipid soluble alkylating agent similar to nitrogen mustard. However, it is not a vesicant. It is not cell cycle specific. For CNS treatment,

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Intrathecal and intraventricular chemotherapy�agents

• Side effect: The dose-limiting side effect is myelosuppression. There appears to be no advantage for thioTEPA over methotrexate for patients who can tolerate the latter drug.

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• It has been reported that patients with Philadelphia-chromosome positive (Ph+) ALL and CNS involvement have achieved remissions with oral dasatinib.

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• Imatinib on the other hand is known not to cross the blood–brain barrier.

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Intrathecal and intraventricular chemotherapy�agents

The treatment of ALL requires multiple agents, often given on the same day.

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Catastrophe results if vincristine is ever placed into a syringe and injected IT; the patient almost always dies.

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An educational campaign advocates always preparing vincristine in a 50ml mini-IV-drip bag and never in a syringe, making this very preventable error unlikely to happen again.

Intrathecal and intraventricular chemotherapy�agents

• A 50-year-old man has been receiving monthly cycles of maintenance therapy with vincristine, dexamethasone, mercaptopurine, and methotrexate for 18 months for B-cell ALL in first CR.

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• When seen in the clinic, he is asymptomatic.

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• However, his blood smear shows 15% blasts.

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• A bone marrow exam shows recurrent ALL, and his LP shows 28 lymphoblasts/lL in the CSF.

Fifth Case: Combined CNS and systemic relapse

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What will be the management of this patient?

• This patient has had a combined systemic and CNS relapse. Reinduction therapy together with CNS-directed treatment is recommended.

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• The outcome for adults with ALL after a CNS relapse is poor.

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• Survival is usually less than 1 year, even if there is clearance of ALL blasts from the CSF.

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• Systemic relapse is often present or will occur soon after ALL reappears in the CSF.

Management: Combined CNS and systemic relapse

• Systemic relapse is often present or will occur soon after ALL reappears in the CSF.

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• Submicroscopic disease can often be detected in the marrow at this time by sensitive flow cytometric or molecular techniques.

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• The outcome may be slightly better for those who have an isolated CNS relapse.

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• Patients with CNS recurrence receive cranial irradiation and intra- Ommaya chemotherapy, and restart a multi-agent remission induction regimen again from the beginning, followed by consolidation therapy and maintenance.

Management: Combined CNS and systemic relapse

• Patients who are candidates for allogeneic hematopoietic cell transplantation may still be cured with this modality, particularly after achieving a second CR and undetectable minimal residual disease state. There is no clear benefit of any specific CNS-directed therapy.

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• Whether newer immunotherapeutic approaches using agents such as blinatumomab or chimeric antigen receptor (CAR) engineered T-cells will improve these outcomes remains to be determined. Blinatumomab is not recommended for patients with active CNS disease because of concern about local inflammatory responses, but it has been given to those with previous CNS involvement

Management: Combined CNS and systemic relapse

• Rituximab has been given IT and intraventricularly to children with CD20+ lymphoblasts in their CSF along with other CNS-directed therapy, and remissions have been reported

Management: Combined CNS and systemic relapse

• In summary, the CNS is an important site of involvement by ALL in adults. The prevalence is sufficiently high that prophylactic treatment is routinely given to this sanctuary site in order to eradicate occult disease that might otherwise lead to a relapse. Standardized treatment protocols direct the management of CNS prophylaxis, although the optimal schedule for IT chemotherapy has not been established. Recurrences within the CNS usually coincide with or predict for systemic relapse soon afterwards. CNS leukemia is more easily prevented than treated after it occurs; once overt CNS leukemia has developed after prior hematologic remission, there is a high likelihood of subsequent CNS relapse and poor survival despite additional treatment.

Conclusion