• TdT+ (all other lymphomas are TdT-), CD19+, cyt CD79a
• Precursor B-ALL (CD10-)
• Common ALL (CD10+)
• Pre-B-ALL (cyt-mu+)

Precursor T lymphoblastic leukaemia (T-ALL) / lymphoblastic lymphoma (T-LBL)

• TdT, CD1a, CD2, CD3, CD4, CD5, CD7, CD8

Precursor B-ALL

• Use of B-ALL / B-LBL is arbitrary since they are biologically similar.
• Lymphoma diagnosed, when < 25% lymphoblasts in marrow.
• Primarily a disease of children (75% age<6)
• Precursor B-LBL is uncommon accounting for 10% of lymphoblastic lymphoma

Clinical features

B-ALL

• Bone marrow failure
• Leukocyte count can be decreased, normal or elevated
• Bone pain
• Extramedullary involvement common in B-ALL – particularly
• CNS
• Lymph nodes
• Liver and spleen
• Gonads

B-LBL

• Most frequent sites of involvement:
• Skin (cutaneous nodules)
• Bone
• Lymph nodes  (mediastinal masses are rare)

Morphology

• Variable from small blasts with scant cytoplasm, indistinct nucleoli and condensed chromatin to larger cells with moderate amounts of light blue to blue-grey cytoplasm, occasionally vacuolated, dispersed chromatin and prominent nucleoli.
• Coarse azurophilic granules (associated with t(9:22)(q34;q11.2) – BCR/ABL)
• Less mitotic figures than T-ALL

Immunophenotype

• TdT+, HLA-DR, CD19+, +/- cyt CD79a, +/- CD22

• Pro B-ALL (Pre-Pre-B-ALL)  TdT+, HLA-DR, CD19+,  CD10-
• Common ALL   TdT+, HLA-DR, CD19+,  CD10+
• Pre-B-ALL    TdT+, HLA-DR, CD19+,  CD10+/-, cyIgM+
• B-ALL    TdT+, HLA-DR, CD19+,  CD10+/-, sIgM+

• Can express myeloid markers CD13 and CD33

Cytogenetics

• Abnormalities in 85%

Prognosis

• Complete remission 95% children 60-85% adults
• Disease free survival 70% in children

Good prognositic factors in children

• Age 4-10
• Hyperdiploid chromosomes especially 54-62 with trisomy 4 +/- 10 +/- 17
• t(12;21)
• Low / normal WC at diagnosis

Poor prognosis

• Age < 1
• BCR/ABL
• MLL
• PBX/E2A

Precursor T-ALL / T-LBL

• Lymphoma if <25% blasts and a mass
• 15% of childhood ALL
• 90% of childhood lymphoblastic lymphoma

Clinical features

• Often presents with a large mediastinal mass (50%)
• Relative sparing of bone marrow function
• Other extramedullary sites include
• Lymph nodes, spleen, Waldeyer’s ring. CNS and gonads

Immunophenotype

• TdT, CD1a, CD2, CD3, CD4, CD5, CD7, CD8
• CD3 / 7 most common
• May demonstrate TCR gene rearrangement but this is not lineage specific
• Order of expression cytoCD2, CD3, CD7

Cytogenetics

30% involve the TCR loci

• Alpha and delta at 14q11
• Beta at 7q35
• Gamma at 7p14-15  with a variety of partner genes including
• MYC (8q24.1)
• TAL1 (1p32)
• RBTN1 (11p15)
• RBTN2 (11p13)
• HOX11 (10q24)
• LCK (1p34.3-35)

• 25% involve micro deletions in TAL1
• 30% involve the del 9p resulting in the loss of tumour suppressor gene CDKN2A

Prognosis

• Treated as high risk in children
• In adults treated the same as normal ALL

Haematogones

• May be increased in young children and in the marrows of older patients with iron deficiency, neuroblastoma, ITP and following chemo
• Cells have a very high n-c ratio but usually don’t have nucleoli
• Not usually found in the peripheral blood
• Distributed uniformly in the interstitium of trephine
• Can be difficult to distinguish from leukaemic T lymphoblasts (TdT+ and express CD10)
• But they lack aberrant antigen expression and there is a continuum of expression of these markers indication maturation and tend to be CD20+ and SIg+ in contrast to B-ALL in which these tend to be negative.

Treatment of adults (see page on childhood malignancies for treatment in children)

Investigations

1. FBC / film
2. Marrow
3. UE LFT Coag CRP
4. CXR
5. CT chest abdo pelvis abdominal / pelvic lymphadenopathy
6. Lumbar puncture to detect occult CNS disease

Supportive treatment

• Counselling re diagnosis
• Resuscitate if septic shock
• Transfusion support
• Neutropenic prophylaxis
• Allopurinol (tumour lysis special problem in ALL)
• Hickman line

Prognosis

• Adults
• 80% CR
• 30% overall survival
• >50% if good risk
• <20% if poor risk

Induction therapy

• 80% expected in to go into CR in adults / 98% in children
• Dexamethasone, vincristine, aspariginase and daunarubicin
• Failure of induction
• Very poor prognosis
• Can go straight to transplantation

Consolidation therapy

• Intensification regimes include the use of Dexamethasone, vincristine, Ara-C, etopiside, Daunarubicin, cyclophosphamide and HDMTX
• Allograft / autografting now the major approach for high risk disease in first CR
• Ph positive
• Undifferentiated phenotype
• High white counts
• Longer time to achieve CR

Continuation

• 1-3 years – optimal duration not known
• Methotrexate with methyl pred in UKALL XII can also use 6MP
• Also pulses of vincristine and prednisolone

Relapsed disease

Poor prognosis with standard salvage chemotherapy

30-70& response rates with a median survival of 6 months

With allografting in 2^nd CR approximately 40% will be alive at 4 years

UKALL XII

1. Remission induction

Phase I

• Daunorubicin 60mg/m2 on days 1, 8, 15, 22
• Vincristine 1.4 mg/m2 on days 1, 8, 15, 22
• Prednisolone 60mg/m2 on days 1-28
• Aspariginase 5,000U/m2 on days 17, 19, 21, 23, 25, 27, 29

Bone marrow performed on day 28 (or when counts recover)

• Remission defined as <5% blasts

Phase II – begins on day 29 or when WC>3.0

• Cyclophosphamide 650mg/m2 on days 1, 15, 29
• Cytosine arabinoside 75mg/m2 on days 1-4, 8-11, 15-18 and 22-15

Prevention of infection

• PCP prophylaxis – cotrimoxazole 960mg bd MWF or pentamidine 300mg every 4 weeks
• Consider antifungal prophylaxis (NB vincristine interacts with itraconazole and voriconazole)

2. CNS prophylaxis

• Phase I - Methotrexate 12.5mg on day 24 with CSF examination (unless CNS disease at presentation in which case IT Methotrexate is given weekly until blasts no longer in CSF).
• Phase II - Methotrexate on days -1, 7, 14, 21 with no folinic acid rescue (CSF examined with each IT)

3. Consolidation

High risk (BCR/ABL+)

Allogenic / autologous transplantation

• Fractionated TBI (two fractions / day) days -7 to -4
• Etoposide 60mg/kg day -3
• Cyclosporin day -1
• Cells day 0 (must be at least 48h after etoposide)

Chemotherapy

• CNS irradiation
• IT Ara-C

Further

Consolidation 1

• Dexamethasone 10mg/m2 days 1-28
• Vincristine 1.4mg/m2 d1, 8, 15, 22
• Ara-C 75mg/m2 d1-5
• Etoposide (VP16) 100mg/m2 d1-5

Consolidation 2

• Ara-C 75mg/m2 d1-5
• Etoposide 100mg/m2 d1-5

Consolidation 3

• Daunarubicin d1, 8, 15, 22
• Cyclophosphamide d29
• Ara-C 75mg/m2 d31-34, 38-41
• Thioguanine (po) 60mg/m2 d29-42

Consolidation 4

• Ara-C 75mg/m2 d1-5
• Etoposide 100mg/m2 d1-5

4. Maintainance

• Methyl pred 75mg/m2 (po) daily
• Methotrexate 20mg/m2 (po) weekly

Every 3 months

• Prednisolone 60mg/m2 d1-5
• Vincristine 1.4mg/m2 d1

And

• IT AraC 50mg every 3 months (2 weeks after vincristine)

Minimal residual disease monitoring

• Flow cytometry for clonal immunophenotypes
• FISH or RT-PCR for fusion proteins or clonal Ig rearrangements

Late complications of therapy

• Biological cure – chance of relapse approaches zero
• Functional cure – patient is free of the sequelae of the tumour and its treatment
• Emotional cure – patient is able to function in society

• Late complications
• Brian tumours (cerebral irradiation)
• AML from topoisomerase inhibitors and alkylating agents
• Cardiomyopathy (anthrcyclines)
• Osteoporosis (corticosteroids)
• Growth disturbances
• Thyroid dysfunction (cranial irradiation)
• Obesity (uncertain aetiology)
• Neuropsychiatric disturbances and seizures (IT MTX and cranial irradiation)
• Emotional problems
• Discrimination with insurance, job applications and military service
• No evidence children of survivors of childhood ALL have increased rates of cancer or birth defects

Lymphoblastic lymphoma

• 2% of adult NHL
• 40% of childhood NHL
• Distinguished from ALL on the basis of bone marrow infiltration (<25%) and the presence of circulating blasts.
• Peak incidence in teens and 40s
• M>F
• Bone marrow and CNS involvement common at diagnosis
• >80% T lineage
• Immunophenotype
• TdT +
• B cell CD10, CD19, CD22
• T cell CD3, CD7 and TCR
• Cytogenetics
• Common in T lineage LBL
• Involve TCR genes fused to a variety of partner genes
• Treatment
• Similar regimes to ALL
• CR children 95% and adults 55-95% - similar to normal ALL
• Long term survival 80-90% in children and 40-80% in adults
• Poor response to relapsed disease