Clinical features

• Commonly presents insidiously in three ways, separately or combined.

• Signs of marrow failure—often anaemia predominates, with extreme pallor and listlessness (60%); also bruising/petechiae (40%).

• Hepatosplenomegaly and lymphadenopathy ('lymphomatous' features) 10-20%.

• Bone pain mimicking irritable hip(s) or juvenile rheumatoid 10-20%.

Laboratory features

• Usually pancytopenia with circulating blast cells indicates diagnosis.

• Confirmed by bone marrow examination and classified by immunophe-notyping and cytogenetic/molecular genetic analysis.

• In sick children with very high blast cell counts classification studies can be carried out on peripheral blood, but marrow always preferred.

• Peripheral blood count may show cytopenias without obvious blasts (aleukaemic picture) when differential diagnosis is aplastic anaemia.

• Kidney/liver function usually normal, but ALLs with high blast counts and rapid cell turnover may have tumour-lysis organ dysfunction before therapy (urate nephropathy with 4 urea, creatinine and 5 urine output).

Treatment of newly diagnosed disease

• All modern protocols have common elements of remission induction (RI), consolidation/intensification (C/I), CNS directed treatment and continuing (maintenance) therapy with or without delayed intensification (DI).

• RI drugs include dexamethasone, vincristine and asparaginase.

• C/I and DI drugs include anthracyclines, cytarabine, cyclophosphamide asparaginase and thioguanine.

• CNS therapy is intrathecal cytarabine and methotrexate (radiotherapy now reserved for those with active CNS infiltration only).

• Maintenance therapy is a 2-3 year schedule of daily thiopurine (6-mer- 475 captopurine) and weekly oral methotrexate.

• ALL is the only human malignancy that requires such a drawn-out chemotherapy module, immunosuppressive rather than antineoplastic.

• B-ALL is an exception; it does not respond to conventional ALL therapy, does not need maintenance and is treated on a 6 month intensive lymphoma schedule (ffl p478).

• Treatment is usually risk-directed based on biological features of the disease with more intensive schedules reserved for those with adverse prognostic factors (see below).

• BMT rarely used as first-line therapy.

Outlook

98% overall will remit on modern therapy, 75-80% overall will become long term disease-free survivors—figures vary according to prognostic factors (see below). >90% long term survivors in low risk disease.

Treatment of relapse

• Some 20-25% of children will relapse; either on treatment or after its completion.

• Outlook depends on length of first remission; very bleak if relapse on treatment.

• Salvage therapy more successful if relapse >2 years off therapy.

• Relapsed T-ALL more difficult to treat successfully than other types.

• Treatment includes intensive chemotherapy with the addition of podophyllins, anthracycline analogues and fludarabine.

• BMT reserved for those who show slow-to-clear residual disease by PCR amplification of unique disease-specific Ig or TCR gene rearrangements, those who relapse on treatment and those with relapsed T-ALL.

Prognostic factors

• Several features of ALL predict response to current standard therapies and are used to stratify treatment. Infants <1 year have a poor outlook, and older children >10 years do less well than those 1-10 years.

• High presenting WBC (>100 x 109/L) in boys marks high risk, as do some genetic features (MLL gene rearrangements, BCR-ABL fusion genes, hypodiploidy).

• All children with T-ALL , and all with slow disease clearance during the first few days of therapy, are excluded from being classified as low risk.

• Low risk B-precursor ALL is that which shows none of these features.

Late effects of therapy

With 4 long survivors, late effects of therapy are becoming more important. Most morbidity seen after TBI given for BMT.

Problems include

• Growth failure due to CNS damage from radiation.

• Intellectual deficit due to CNS damage from radiation.

• Precocious puberty (girls > boys) after cranial radiation.

• Infertility (boys > girls) not dependent on radiation.

• Obesity (girls > boys) not dependent on radiation.

• 7-10 fold 4 risk of brain tumours not dependent on radiation.

0 0

Post a comment