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Acute Lymphoblastic Leukemia

 

 

 

CNS Disease

Clinical Features of CNS involvement in ALL:

Incidence

In less than 5% of ALL patients at diagnosis
Clinical features
  • Raised ICP with headache & vomiting
  • Cranial nerve palsies
  • Loss of vision
  • Parenchymal involvement with chloromas leading to problems such as seizures and hemiparesis
  • Diabetes insipidus
  • Hypothalamic syndrome - polyphagia and excessive weight gain
  • Chloromas of the spinal cord
  • CNS Hemorrhage

 

Definition of CNS Disease Criteria
CNS 1
  • No blasts seen on cytocentrifuge (CNS negative)
CNS 2
  • Total Nucleated Cell Count <5 x 106/L, but blasts seen on cytocentrifuge
CNS 3
  • Total Nucleated Cell Count ≥ 5 x 106/L with blasts on cytocentrifuge and/or signs of CNS leukemia (e.g. cranial nerve palsy)

 

CNS Disease at diagnosis:

  • Occurs in 3 - 5% of children with ALL
  • Most current protocols include cranial RT after intensification therapy for CNS 3 disease
  • Recommended dose RT is 18 Gy in 150 - 180 cGy fractions whole brain RT (same volume as prophylactic cranial RT)

 

CNS Disease at relapse:

Therapy

Intensive re-induction chemotherapy, IT chemotherapy (MTX alone or in combination with cytosine arabinoside and hydrocortisone) to clear the CSF and then cranial radiation therapy (RT).

Effective anti-leukemic agents used systemically that penetrate the blood brain barrier and blood testes barrier include:

  • Dexamethasone
  • PEG asparaginase
  • High-dose Ara-C
  • High dose methotrexate (MTX)

Generally RT is delayed by 6 months to allow the delivery of intensive systemic chemotherapy - unless there is a problem such as visual loss or cranial nerve palsies where urgent intervention with RT may have some hope of reversing neurological damage.

The previous research COG pilot study for late (more than or equal to 18 months after complete remission for initial leukemia), isolated extramedullary relapse in CNS was AALL02P2. This study is now closed because analyses showed that the outcome for patients with isolated central nervous system relapse treated on AALL02P2 was inferior to that of similar patients treated on the previous POG P9412 trial.  This study's aim was to use intensified systemic chemotherapy and reduced dose RT (to a total of 12 Gy) and is now closed to accrual.

The rational for reducing the dose of cranial RT:

  • POG 9412 used 12 months of intensive chemotherapy and reduced the treatment volume and dose from 24 Gy (craniospinal RT) to 18 Gy (cranial RT only) for isolated CNS relapse and there was no significant change in event free survival.
  • Cranial RT is associated with significant late effects which include:
    • Neurocognitive delay (treatment with MTX and cranial RT increases the risk of this)
    • Hypothyroidism and thyroid cancer
    • RT induced meningiomas
    • Second malignancy - less risk with lower RT dose

However at the present time, there is no evidence that it is safe to reduce the dose of cranial RT for CNS relapse.

 

Current recommendations:

The current standard RT for ALL cranial relapse:

EARLY RELAPSE: For early CNS relapse occurring less than 18 months after complete remission for initial leukemia, the recommendation would be 24 Gy to the whole brain and a lower dose to the spine (600 cGy to 1500 cGy).

LATE RELAPSE: CNS relapse occuring more than 18 months after complete remission for initial leukemia would be 18 Gy (given in 150 cGy fractions) cranial RT alone.

For CNS relapse which is not isolated (in setting of bone marrow relapse for example) a cranial boost is often used prior to TBI (low dose whole body RT) given in the setting of bone marrow transplant.

 

Prognosis

For isolated CNS relapse patients, the most significant factor influencing survival is
the length of the first complete remission. The later the relapse is, the better the prognosis.

 

 

 

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