ALL § 2-6 years § 80% B cells, 20% T cells § 90% survival
Clinical Features § Marrow failure § Hepatosplenomegaly and lymphadenopathy § Bone pain
Diagnosis § Pancytopenia with circulating blasts § PB may show pancytopenia without blasts (aleukaemic) § DD is AA § Confirm with marrow immuno and cytogenetics
Treatment – current trail UKALL 2003 § Front line therapy based on NCI risk § Age 1 - 10 and wcc < 50 = Standard § Age <1 or >10 or WC > = Poor
1. Remission induction § 98% expected to achieve CR § Dexamethasone, vincrisitine, asparaginase, 6 mercaptopurine § Anthracycline added if high risk
§ MRD performed on day 28 (strongest prognostic marker) and this dictates which regimen is used for condolidation and maintainance.
§ MRD on marrow doesn’t predict for CNS relapse
2. Consolidation/ intensification § Children with <5% blasts can still have up to 1010 tumour cells § Aim of consolidation is to rapidly reduce tumour burden before drug resistence develops § Anthracyclines, cytarabine, cyclophos, asparaginase, methotrexate, 6-mercaptopurine
3. CNS directed treatment § Cytarabine, MTX and hydrocortisone more effective than MTX alone
4. Maintenance with or without delayed intensification § Maintainance continues for 2-3 years § Oral 6-mercaptopurine daily, weekly MTX and pulsed dexamethasone and vincristine § Doxorubicin added if high risk
§ Tranplantation § Treatment of choice for children with Ph+ve ALL in 1st CR § Can be used for patients with late relapse § Increasing use of cord and unrelated donor transplants
§ B-ALL is an exception and treated on an intensive lymphoma schedule
§ Outlook § 2% induction death rate, usually due to infection § 98% remit § 75-80% long term survival § Other side effects § Thrombosis and pancreatitis secondary to asparaginase § AVN (10-15years)
§ Treatment of relapse § 25% relapse § Relapse on treatment = poor prognosis § Salvage therapy more successful if after 2 years § BMT reserved for those who are slow to clear residual disease, relapse on treatment or have relapsed T-ALL
§ Prognostic factors § Poor § <1 year, >10 years § Wcc > 50 § boys § MLL (infants with organomegaly often t(4:11) § Bcr-Abl § Hypodiploidy § Internal amplification 21 § T-ALL § Slow to clear disease § MRD positive in 1st CR
§ Long-term sequalae § Growth failure § Intellectual deficit § Precocious puberty § Infertility § Obesity § Increased risk of brain tumours NHL § Disseminated high grade
B-cell 60% Abdominal/ nasopharyngeal masses § Burkitt 42% § Pathologically indistinguishable from B-ALL § 8;14 with dysregulation of MYC § DLBCL 3% § Abdominal > mediastinal § Pre- BALL 5% § Pathologically indistinguishable from common ALL § Commonly present as a solitary subcutaneous swelling on scalp T-cell 40% § Large cell anaplastic 15% § Nodes/ skin § KI-1, CD30+ § T(2;5) § Pre- TALL 20% § Mediastinal masses § Pathologically indistuigishable form T-ALL § 66% have mediastinal involvement
§ Staging = St Judes (I-IV)
Treatment Burkitts and DLBCL § LMB type protocol – different regimens depending on stage § Usually involves COPADM (high dose methotrextae and high dose ARA-C) and intrathecals § Risk of infertility § Very few relapses Pre-B ALL and Pre-T ALL § With large mediastinal masses, may be too compromised for a GA to allow tissue diagnosis, therefore steroids may be started first § Treated with Euro LB – similar to ALL protocol § 2 years maintenance rather than 3 years Anaplastic § Treated with modified B cell regimens § 90% EFS
AML § Therapy similar to adults § Anthracycline and cytaribine induction – 2 courses § Followed by 2-3 further courses of intensive chemotherapy § Transplantation reduces survival in both good and poor risk and is therefore rarely performed
§ MRD monitoring if possible – about 40% have a marker to follow
§ Causes of death § Infection § Use combination antifungals (ambisone and caspofungin) § Haemorrhage § Greatest in high white counts, which is usually M5 (>50) – need to give anthracycline ASAP – often given D 1, 2, 3 rather than 1, 3, 5 § Cardiac § free radicals generated form anthracycline are toxic to myocytes resulting in fatty replacement and cardiomyopathy = irreversible § Very young and girls are at greatest risk § Almost one third get cardiac event § At times of stress (eg. Pubertal growth spurt, pregnancy), may develop cardiac failure – 6% overall
APML (AML-M3) § Treatment is similar to Spanish protocol, but with less anthracycline § Molecular monitoring § Still prone to retinoic acid syndrome – 15% - risk increased with WC >10
Downs (AML-DS) 1. 20x more likely to develop leukaemia § Infants (1-4years) – M7 § Often prodromal dysplastic phase (RAEB) § GATA-1 mutations which lead to transient abnormal myelopoiesis – 2nd hit then leads to AML § Highly curable with reduced dose chemo (OS around 60%) § Marrow difficult to aspirate due to fibrosis § Older children – ALL 2. Transient abnormal myelopoiesis § Mimics leukaemia § Self-limiting within days-weeks (neonates) § Not associated with marrow failure § No genetic abnormality other than trisomy 21 § Mediated by a GATA 1 mutation § Rarely arises in non-down children in whom trisomy 21 can be found only in the bone marrow § Common cytogenetic abnormalities in childhood AML
Juvenile Myelomonocytic Leukaemia § Clonal with all cell lines involved, but mainly granulocytic and monocytic § 1.3 per million children up to 14 years § 75% in children <3 years § 10% occur in children with NF1 § Association with Noonan’s § Blood and bone marrow show myelomonocytic proliferation § Liver and spleen viturally always involved § Diagnostic criteria 1. PB monocytes >1 2. Blasts incl promonocytes <20% of wbcs in blood and of nucleated marrow cells 3. No Ph 4. 2 or more of the following § HbF increased for age § Immature granulocytes in blood § Wcc >10 § Clonal chromosomal abnormality § Monosomy 7 § GM-CSF hypersensitivity of myeloid progenitors in vitro
Comparison with CML
§ Clinical features 1. Maculopapular rash in 40-50% 2. Dysplasia is often minimal § Prognosis 1. Poor 2. Better if <1 year 3. Relatively few evolve to acute leukaemia 4. Most die from organ failure, such as respiratory failure due to leukaemic infiltration 5. BMT only therapy which clearly improves survival - 60% cured 6. Chemotherapy/ splenectomy for symptom control only
CML § 1 in 100,000 children § Median age 12-13years § 95% Ph +ve, 5% Ph –ve but Bcr-Abl mRNA +ve
§ No published data to suggest any difference in the natural history compared with adult disease, but anecdotally more children present in accelerated phase and have rapid unpredicted transformation to blast crisis.
§ Leucostasis appears to be more common, but may be because presents later due to the fact that most are teenagers at diagnosis.
Management § HLA type siblings § Cryopreserve patient stem cells (in case of graft failure)
Chronic phase § Sibling SCT or imatinib § Equivalent 5 year survival of 90% § Preferance of parents is often to go for curative procedure § If have suboptimal response – by Bacharani criteria (ie no MmolR at 18 months) need SCT § VUD 70% 5 year survival, therefore not recommended up front § HU used for initial disease control only § IFN – if TKI resistant/ SCT not planned § Dasatinib as part of clinical trial if poor response to imatinib
Accelerated phase § SCT – if no match, consider haplo Blast crisis § Myeloid – imatinib and SCT § Lymphoid – ALL type induction
Risk of relapse during pregnancy due to altered immunity
If increasing BCR-ABL transcripts post transplant, DLI is preferred to imatinib as it has curative potential |
Haemato-oncology >