Acute Lymphoblastic Leukaemia

(ESMO 2016, UKALL14, training day 2016, BCSH 2018)

B-ALL: TdT+, CD19+, CD10+/-, CD20+/-, cIg+/-, sIg +/-

T-ALL: TdT+/-, CD7+, CD2+, cCD3+, CD5+/-, sCD3+/-

Intro

Rare disease in adults.

1 per 100,000 per year in Europe

Risk Stratifications

High/Poor Risk

-       Age >40/55/65

-       WBC >30 (B-ALL) or >100 (T-ALL)

-       >4 weeks to reach CR

-       t(9;22) MLL-AFA4

-       t(1;19) PBX-E2A

-       t(4;11)

-       Hypodiploidy (e.g. del(6q), del(7p), del(17p), -7, +8)

-       NOTCH1 unmutated

-       Complex Karyotype (³5 clonal abnormalities)

Standard Risk

-       Not high risk

-       More favourable, but rare in adults, are t(12;21) TEL-AML1 and hyperdiploidy

Prognosis

UKALL 2012 5 year survival (patients recruited between 1996-2006)

-       Ph+ 22%

-       Ph- 43%

WHO 2016 Classification

who 2016 ALL.png

Work-Up

Initial work up should be completed within 1-2 days to confirm diagnosis and prevent delay in Rx

CSF

- For assessment of CNS involvement

BM Aspirate Morphology

-       >20% blasts, differentiates from lymphoblastic lymphoma with marrow involvement

Flow Cytometry

-       MPO negative, differentiates from AML

-       B-lineage

o   Pro-B: CD19+, CD79a+, cCD22+

o   Common: CD10+, cIg –

o   Pre-B: cIg+, sIg-

o   Mature: sIg+

-       T-Lineage

o   Pro: cCD3+, CD7+

o   Pre: CD2+, CD5+

o   Cortical: CD1a+

o   Mature: CD3+, CD1a -

Cytogenetics / FISH / RT-PCR for adverse features:

-       Rapid detection kit for t(9;22)

-       t(4;11)

-       t(1;19)

Next Generation Sequencing for adverse features:

-       Ph-like ALL

-       ETP ALL

-       NOTCH1/FBW7-unmutated/RAS/PTEN-altered

-       IKZF1, CLRF2, MLL, TP53, CREBBP

Identification of a MRD marker

-       Flow or PCR

HLA Tissue Typing

-       Including parents and siblings

Cell banking

-       Future research

Treatment Principle (ESMO 2016)

Pre-Phase

- Prednisolone 20-60mg/day or Dexamethasone 6-16mg/day

- Hydration + Allopurinol

+/- Rasburicase

+/- Vincristine

Provides safe tumour reduction, usually avoiding TLS

Allows time for results of cytogenetics for risk stratification

 

Induction & Consolidation

Two broad approaches

-       BFM (Berlin-Frankfurt-Munster) protocols, e.g. UKALL14

-       Alternating two chemo regimens for 8 cycles, e.g. hyper-CVAD

 

UKALL14 Protocol

ukall.png

Treatment Rationale

Immunosuppressive > Myelosuppressive but harder to tolerate

15-17 yo treated by paediatric regimens do significant better than those on the adult regimens        --> Why?

- Paediatric regimens are more immunosuppressive  - prednisolone,  asparaginase, vincristine

- Adult regimens ate more myelosuppressive – daunorubicin, cytarabine, cyclophosphamide

Dexamethasone > Prednisolone, Why?

- Better in vitro anti-leukaemic effect

- Greater CNS penetration

- Reduced CNS relapse rate (RR 0.5)

- Reduced risk of death / relapse / 2o malignancy

At the cost of: 7x increase in myopathy, more neuro SE’s, more mid-treatment deaths

 

Vincristine

- Inhibits microtubule formation

- Neuropathic side effects worse in presence of CEP72 gene mutations

- Consider TPMT status

 

Asparaginase

- Derived from E.coli, Pegylated-E.coli or Erwinia

- Unlike normal cells, leukaemic cells unable to produce asparagine à Asparaginase depletes asparagine and starves leukaemic cells of amino acid essential for replication.

 

Adverse Effects

-       Thrombosis – depletes AT, Prot C and Prot S. Evidence of AT replacement is marginal

-       Immunogenicity – some patient develop antibodies against drug à rendered ineffective

-       Pancreatitis

-       Hepatic toxicity

 

Anthracyclines

- Daunorubicin vs Doxorubicin – not much difference

- Mitoxantrone > Idarubicin in treatment of relapse

 

CNS Prophylaxis

- Combination of intrathecal / high dose intravenous methotrexate, steroids and cytarabine

- Reduces CNS relapse rates from 10% to <5%

- Historical use of craniospinal radiotherapy caused increased rates of 2o malignancy

 

Role of Stem Cell Transplant

Adults > Children, as cure rates so good in children

Adult relapse --> survival <10% with salvage chemotherapy

Limited evidence for Graft vs Leukaemia effect in ALL transplants

 

UKALL 2012

-       Biological randomization to transplant – i.e. all patients with a matched sibling got HSCT

-       53% patients had a matched, sibling HSCT

o   Increased treatment-related mortality upfront

o   Long term reduced relapse rate

-       No benefit from Autograft

 

Currently who to offer HSCT in 1st CR:

-       Improves OS and EFS for high risk, MRD+, Ph+ or MLL-rearranged patients

 

Complications

Osteonecrosis

Not just steroid effect. Seen pre-treatment in acute leukaemia patients

Risk Factors

-       Age

-       Female

-       BMI >26

Other drug causes:

-       Asparaginase

-       MTX

-       Cyclophosphamide

 

Long-term

Endocrine (thyroid/gonad), Skin & mucosal disorders, Catarct, CVS disease, Infection, GVHD

Second malignancy (<3% of patients)

 

Future Therapies

Rituximab

-       CD20 present on 30-50% of pre-B ALL cells

-       Pre-treatment with steroids increases the expression of CD20

-       Better EFS and reduced relapse seen in GRAALL-R 2005

Inotuzumab Ozogamin

-       Anti-CD22 monoclonal antibody bound to calichemicin

-       Promising role in elderly patients in combo with mini-hyper-CVAD

Blinatumumab

-       Bispecific antibody, CD19 + CD3 - Brings T-cells into contact with tumour target

-       Use in primary refractory and relapsed ALL

Chimeric Antigen Receptor (CAR) T-Cells

-       NEJM 2014 – CTL019-transduced autologous T cells can induce sustained remissions

-       SE: Severe cytokine release syndrome requiring ITU support

 

Children

 

Outcomes

Cure rates now approx. 90%

Therefore risk stratification ever more important to reduce Rx-related morbidity

 

Risk Stratification

1966 Sidney Fisher 

-       ‘not possible to predict outcome’

1990’s Clinical Risk

-       ³10 y.o. & WBC >50 poor risk in B-ALL

Currently

1.     Clinical features at diagnosis

a.     Age <1 or >10 (Age correlates with cytogenetic findings)

b.     WBC >50

c.      CNS disease

d.     Down Syndrome

e.     Male

f.      Black/Hispanic

2.     Disease Characteristics

a.     T-ALL

b.     Hyperdiploidy

c.      TP53 mutation

d.     Ph+

e.     MLL, RUNX1, Ph-like ALL, IKZF1

3.     Response to initial therapy

a.     BM at day 8 (Regimen B) or day 15 (Regimen A)

                        i.     <25% = rapid early response

                       ii.     >25% = slow early response

b.     Minimal Residual Disease at day 29 (UKALL11)

                        i.     Flow vs PCR

                       ii.     83% of relapses in UKALL 2003 were in MRD+ patients

 

Treatment (UKALL 2011)

Pre-B ALL with NCI standard risk (Age <10, WBC <50)

-       Regimen A (3 drugs)

Pre-B ALL with NCI high risk or T-ALL or Lymphoblastic Lymphoma

-       Regimen B (4 drugs)

 

Split into:

-       Induction

-       BFM consolidation

-       Interim maintenance

-       Delayed Intensification

-       Maintenance

Different nomenclature to the adult UKALL14 but an essentially similar strategy

 

BCSH 2018: Management of thrombotic and haemostatic issues in paediatric malignancy

 

VTE

Incidence

Reports vary widely

Asymptomatic thromboses identified by radiological screening in up to 40% of patients

More common in ALL, Sarcoma and Lymphoma.

 

Risk Factors

Patient-related

-       Age >10

-       Inherited thrombophilia

-       Personal or family history of VTE

-       Obesity

-       Immobilisation

-       Concurrent infection

Disease-related

-       Pulmonary/intrathoracic/pelvic disease

-       Sarcomas

-       APML

-       ALL

-       Lymphoma

Treatment-Related

-       Major surgery

-       Central lines

-       Induction chemotherapy for ALL

 

Congenital Thrombophilia

Conflicting data. Routine thrombophilia screening is not recommended outside of a trial setting

 

Reducing risk of VTE

Simple

-       Early mobilization

-       Good hydration

-       Prompt removal of central lines at completion of treatment

-       Adolescents: Consider compression stockings

-       Discontinue COCP at diagnosis and use alternative

Lines

-       Internal port preferred to tunneled line for children at high risk of VTE

-       Tunneled line preferred to PICC for children with cancer

-       Avoid femoral access

-       No evidence for waiting until end of ALL induction chemo before line insertion

Replacement

-       FFP is not recommended for asparaginase

-       Insufficient evidence to support AT concentrate for asparaginase

o   Therefore, do not check AT levels

Routine thromboprophylaxis

-       Not recommended in children. Consider in adolescents at high risk.

 

Management of VTE

ALL AC.jpeg

Central line-related VTE

-       Removal of line is not necessary if it still required, in a good position and functioning well

-       Symptomatic clot should be treated with 3 month’s anticoagulation

-       Insufficient evidence to recommend subsequent prophylactic doses if line remains in

 

Cerebral Venous Thrombosis (CVT)

-       Standard anticoagulation recommended, minimum of 3 months

-       AC is not contraindicated in presence of ICH unless risk of further bleeding > benefit.

 

VTE at other sites

-       Initial 3 months treatment

-       Consider treatment beyond three months if ongoing active cancer or other risks

 

Incidental VTE finding

-       Treat as for symptomatic VTE

-       If solely line-related, consider monitoring initially to see if AC required.

 

Choice of anticoagulant

-       LMWH treatment of choice

-       Routinely measurement of Anti-Xa levels (0.5-1.0) recommended for children

-       Trials of DOACs underway.

 

AT Replacement

-       Routine AT replacement is not recommended during LMWH/UFH treatment

 

AC around time of invasive procedures

-       Stopping of LMWH / warfarin same as for adults

 

AC and thrombocytopenia

-       Continue whilst plt count >50

-       Use platelet transfusion to support >50 if life-threatening VTE within last 1-3 months.

-       Consider 50% dose when plt count 25-50

 

Re-exposure to asparaginase following VTE

-       Further doses may be given but should be covered by prophylactic or Rx-dose LMWH

-       This AC should be continued for 3 weeks following a dose of peg-asparaginase

 

Thrombocytopenia and coagulopathies

 

Plt thresholds prior to LP

-       Follow other BCSH guidelines

 

Monitoring for coagulopathies

-       FBC, Film, PT, APTT, FGN should be performed on all children with new malignancy

-       FVIII and VWF should be performed on all children with suspected Wilms tumour

-       Evidence of DIC should be sought in acute leukaemia

-       Repeat testing after starting treatment only indicated in presence of abnormal bleeding

-       In absence of the above, no need to recheck clotting prior to surgery or LP in ALL patients

 

Fibrinogen supplementation

-       Replace if <1g/l and due surgery or at high risk of bleeding

 

Choice of menstrual suppression

-       Progestogens should be considered first – medroxyprogesterone or norethisterone

-       Sufficiency evidence to recommend routine use of gonadotropin-releasing hormone analogues over progesterone for purely fertility preservation purposes.