Acute Lymphoblastic Leukaemia

(ESMO 2016, UKALL14, 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) BCR-ABL1 (Philidelphia chromosome, “Ph+”)

  • t(1;19) PBX-E2A

  • t(4;11) MLL-AFA4

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

  • NOTCH1 unmutated

  • Complex Karyotype (5 or more clonal abnormalities)

Standard Risk

  • Not high risk

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

Prognosis

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

  • Ph+ 22%

  • Ph- 43%

WHO 2016 Classification

who 2016 ALL.png

investigation

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

    • Pro-B: CD19+, CD79a+, cCD22+

    • Common: CD10+, cIg –

    • Pre-B: cIg+, sIg-

    • Mature: sIg+

  • T-Lineage

    • Pro: cCD3+, CD7+

    • Pre: CD2+, CD5+

    • Cortical: CD1a+

    • 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 (NGS) 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

Consist of:

  • 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 are more myelosuppressive – daunorubicin, cytarabine, cyclophosphamide

Dexamethasone > Prednisolone, Why? (Leukaemia 2011)

  • 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 —> 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 & Transplant

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

  • 53% patients had a matched, sibling HSCT

    • Increased treatment-related mortality upfront

    • 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

For Ph+ Patients post-allograft 

  • Continue TKI maintenance

  • 3 monthly IT/LP in patients who received reduced intensity conditioning (RIC)

Treatment Complications

Osteonecrosis

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

  • Risk Factors

    • Age

    • Female

    • BMI >26

  • Drug causes:

    • Steroids, Aspraginase, MTX, Cyclophosphamide

Long-term

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

  • Second malignancy (<3% of patients)

 

Other 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

Blinatumumab

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

  • Use in primary refractory and relapsed ALL

  • Pros: Good for low level disease (eg MRD+)

  • Cons: 28 day infusional treatment. Neurotoxicity. Theoretical concern re: losing CD19 as a target for subsequent CAR-T

Inotuzumab Ozogamin

  • Anti-CD22 monoclonal antibody bound to calichemicin

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

  • Pros: Avoids CD19 target, thinking of subsequent CAR-T use

  • Cons: Up to 20-30% increased risk of VOD in any subsequent allograft

Chimeric Antigen Receptor (CAR) T-Cells

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

  • At present, allograft still probably comes first, CAR-T for further down the line. This may change.

  • SE: Severe cytokine release syndrome requiring ITU support

 

Relapse/Refractory disease

The following notes on R/R disease are based on local practice/teaching - treatment needs to be individualised and will be debateable

Frank refractory disease after Phase 1 induction

  • Alternative intensive induction, e.g. FLAG-Ida

  • If Ph+, check the BCR-ABL1 mutation, e.g. is a different TKI indicated?

Low level BCR-ABL1 MRD positivity after Phase 1 induction in Ph+

  • Consider proceeding straight to transplant (ie not chasing MRD negativity)

MRD positivity after Phase 2 induction in Ph neg B-ALL

  • Blinatunumab > Inotuzumab (see above in Other Therapies)

Relapse <12 months post allograft

  • Clinical trial

  • Inotuzumab re-induction prior to CAR-T

Relapse >12 months post allograft

  • Clinical trial

  • Inotuzumab —> CAR-T —> Consider 2nd Allograft

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

  • 10 or more years old & WBC >50 poor risk in B-ALL

Currently

  1. Clinical features at diagnosis

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

    • WBC >50

    • CNS disease

    • Down Syndrome

    • Male

    • Black/Hispanic

  2. Disease Characteristics

    • T-ALL

    • Hyperdiploidy

    • TP53 mutation

    • Ph+

    • MLL, RUNX1, Ph-like ALL, IKZF1

  3. Response to initial therapy

    • BM at day 8 (Regimen B) or day 15 (Regimen A)

      • <25% = rapid early response

      • >25% = slow early response

    • Minimal Residual Disease at day 29 (UKALL11)

      • Flow vs PCR

      • 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)

If meeting certain criteria for poor risk features as treatment progresses

  • Switch from Regimen A/B to Regimen C

Treatment split into:

  • Induction

  • BFM consolidation

  • Interim maintenance

  • Delayed Intensification

  • Maintenance

Total 2 years for girls, 3 years for boys (due to testicles as sanctuary site risk)

Different nomenclature to the adult UKALL14 but an essentially similar strategy

 

BSH 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

Antithrombin Replacement

  • FFP is not recommended for asparaginase

  • Insufficient evidence to support AT concentrate for asparaginase

  • 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

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

  • Trials of DOACs underway.

 

Antithrombin 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

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