Acute Lymphoblastic Leukaemia
(BCSH 2018, ELN2024(1), ELN2024(2))
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
B-aLL Risk Stratification
EWALL-PI new risk stratification score in 2024 (Blood advances 2024)
Based on: WBC, genetics and end-of-induction MRD status
Strongly correlates with relapsed and death
Will be used in UK trials from 2025 onwards
High/Poor Risk Features
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 Features
Not high risk
More favourable, but rare in adults, are t(12;21) TEL-AML1 and hyperdiploidy
Prognosis
UKALL 2012 five-year survival for B-ALL (patients recruited between 1996-2006)
Ph+ 22%
Ph- 43%
WHO Haem-5 Classification
Precursor B-cell neoplasms
B-cell lymphoblastic leukaemias/lymphomas
Defined by individual genetics, ie long list of ‘B-lymphoblastic leukaemia/lymphoms with …”
Precursor T-cell neoplasms
T-lymphoblastic leukaemia/lymphoma
T-lymphoblastic leukaemia/lymphoma, NOS
Early T-precursor lymphoblastic leukaemia/lymphoma
investigation
Initial work up should be completed within 1-2 days to confirm diagnosis and prevent delay in Rx
Lumbar Puncture / CSF
For assessment of CNS involvement
Timing may be deferred in presence of circulating PB blasts to avoid contaminating CSF
Intrathecal chemotherapy typically adminstered at same time
BM Aspirate Morphology
>25% blasts, differentiates from lymphoblastic lymphoma with marrow involvement
Flow Cytometry
MPO negative, differentiates from AML
B-lineage
Pro-B: CD19+, CD79a+, cCD22+, CD10-
Common: CD10+, cIgM–
Pre-B: cIgM+, 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) / BCR::ABL1
t(4;11) / KMT2A re-arrangement
t(1;19) / TCF::PBX1
Moelcular genetics for other adverse features:
Ph-like ALL
ETP ALL
NOTCH1/FBW7-unmutated/RAS/PTEN-altered
IKZF1, CLRF2, MLL, TP53, CREBBP
Table 2 of ELN 2024 guideline contains details of molecular subgroups w/ frequency and prognosis
Identification of a MRD marker
Flow or PCR - Sensitivity ranges from 0.1% (10-3) to 0.01% (10-4)
Molecular monitoring of fusion genes - sensitivity of 0.01%
HLA Tissue Typing
Including parents and siblings
Cell banking
DNA, RNA, viables cells +/- germline material. All for future research / targeted therapies.
management
broad Treatment Principles (ELN 2024)
Goals of Treatment
Intensive chemotherapy aimed at a CR as early, deeply and safely as possible
90% CR rate in adults <55/65yo with Ph-neg ALL, with a 5% early TRM
Paediatric-based approach now standard of care, largely replaced regimens such as Hyper-CVAD
OS 60% in adults <45/55yo, and up to 70% in MRD-neg standard risk ALL
Pre-Phase
Consist of:
Prednisolone 20-60mg/day or Dexamethasone 6-16mg/day for 5-7 days
Hydration + Allopurinol
+/- Rasburicase
+/- Vincristine +/- Cyclophosphamide +/- Intrathecal Chemotherapy
Provides safe tumour reduction, usually avoiding TLS
Allows time for results of cytogenetics for risk stratification
Induction (approx. 4-8 weeks)
First induction, adapted to age/fitness, is based around:
Steroids
Vincristine
Anthracyclines
Peg-Asparaginase
Second induction based around
Cyclophosphamide + Cytarabine + Mercaptopurine
Or HD-Methotrexate + Cytarabine
Consolidation (approx. 6 months)
For patients in CR after induction, consolidation follows with rotating cycles based around:
HD-Methotrexate
HD-Cytarabine
Peg-Asparaginase
+/- other drugs
Maintenance (approx 1.5 to 2 years)
Maintenance has not been formally test in randomised trials but high relapse rates seen when omitted
Based around:
Mercaptopurine + Methotrexate
Intermittent intrathecal prophylaxis
+/- Vincristine +/- steroids (being used less frequently)
CNS Prophylaxis
Present throughout the above treatment regimens, with a combination of intrathecal chemotherapy + high dose systemic drugs that cross CNS. Various combinations of steroids, methotrexate and cytarabine.
CNS infiltration present in 5-10% patients at diagnosis, highest risk with T-ALL, high WBC, high risk cytogenetics
Example of a paediatric-based regimen for Adults, UKALL14 Protocol:
N.B. Addition of Blinatumumab now standard of care in 1st line regimens. See below
modifications/additions for disease characteristics
Ph-Negative B-ALL
Rituximab (8+ doses) at induction
Blinatumumab in consolidation, now available in UK for both MRD- and MRD+ patients
In MRD+ patients, the blina should be followed by allograft if patient fit
Ph-Positive B-ALL
TKI’s achieve CR in 90-95% of patients with low toxicity - start as early in treatment as possible
TKI’s may allow for reduced intensity chemotherapy
TKI + Blinatumumab is highly effective (but not yet NICE approved as of 2025)
BCR-ABL/ABL monitoring and a rising ratio should prompt testing for Kinase domain mutations
Typically proceed to allograft if fit. This may change depending on data for 3rd gen TKI’s
Ph-like B-ALLL
Describes the 30% of B-ALL patients with a gene expression profile similar to Ph-positive cases
However, not currently standard of care to routinely identify Ph-like profiles as there is genetic heterogeneity and no specific change to treatment algorithms in place yet.
T-ALL
25% of adult ALL cases
Treatment follows B-ALL protocols. Debatable benefit of adding nelarabine.
Consider allograft in first CR if patient fit.
Lymphoblastic Lymphoma (LBL)
1-3% of NHL.
80-90% are T-cell (T-LBL)
T-LBL vs T-ALL = 25% bone marrow blasts is the arbitary divider.
Treated as per ALL regimens
MRD positive
Best time point for MRD assessment debatable, on balance preferred after 2-3 months from diagnosis - ie after exposure to all standard chemotherapy drugs administered in induction.
Definition of MRD? A threshold of 0.01% achievable with most assays now
Treatment of MRD+ patients should include allograft when fit enough
modifications/additions for patient characteristics
Adolescents/TYA
Outcomes for TYA patients historically worse than for children, complex multifactorial reasons
Importance of psychosocial support
Older Patients (>55/65 yo)
Up to 35% mortality whilst in complete remission when intensive treatments used for older adults
T-ALL and Ph-positive ALL more common, and performance status poorer
Pre-phase essential to optimise performance status
5-yr OS rates of 30-40% have been achieved when striking the right balance
Modifications often include
Oral idarubicin as anthracycline of choice
Omission of asparaginase
Tolerability of anitbody therapies (Ritux, Blina) often similar to younger adults
ALL in Pregnancy
Acute leukaemia affects 2 in 100,000 pregnancies
Limited evidence suggests pregnancy does not necessarily affect the outcome of ALL
Management depends on gestation, disease biology and patient’s clinical status
Many chemotherapy drugs can be given in 2nd trimester onwwards
Rationale for drugs/regimens described above
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
Blinatumomab
Bispecific Antibody - anti-CD19 + anti-CD3
28 day infusional cycles. Neurotoxicity. Theoretical concern re: losing CD19 as a target for future CAR-T
NICE approved across a range of indications.
NEJM 2024 - Blina as consolidation for MRD- adults. Phase 3. Blina+chemo vs chemo alone. 3yr OS 85% vs 68%, 3yr RFS 80% vs 64%
Blood 2018 - Blina for MRD+ B-ALL. Single arm. 78% acheived MRD-neg and had good outcomes
NEJM 2017 - Blina for R/R B-ALL. Phase 3. Blina vs SOC. Improved event free survival.
Watch this space: GIMEMA 2024 - Blina+Ponatinib for 1st line Ph+ ALL. Single arm. 12mo OS 94%!
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
Tyrosine Kinase Inhibitors (TKIs) - Imatinib etc
Addition of TKIs to induction in Ph+ B-ALL —> CR rates of 90-95%
Start as early as possible, start time correlates with efficacy
Should continue as long-term maintenance post-treatment
Rituximab
CD20 present on 30-50% of pre-B ALL cells
Pre-treatment with steroids increases the expression of CD20
GRAALL-R 2005 - Phase 3. Ritux+SOC vs SOC alone. Est. 2-yr EFS 65% vs 52%
Inotuzumab Ozogamin
Anti-CD22 monoclonal antibody bound to calichemicin
Approved for CD22+ R/R B-ALL. Ph+ patients must have received at least 1 TKI. NICE 2018
Pros: Avoids CD19 target, thinking of subsequent CAR-T use
Cons: Up to 20-30% increased risk of VOD in any subsequent allograft
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)
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.
Limitations: Further relapse/progression during time taken for cell manufacture
SE: Severe cytokine release syndrome requiring ITU support, Neurotoxicity
Relapsed/Refractory disease
5-10% primary refractory + 30-60% relapse (historical numbers and affected by protocol/subtype)
R/R ALL responds poorly to salvage chemotherapy —> 20-40% CR but limited duration even w/ allograft
Treatment needs to be individualised
Extramedullary Relapse
CNS most common site of EM relapse
Requires 2x/wk intrathecals + systemic re-induction +/- immunotherapies (inotuzumab/blina)
Consider allograft if CR achieved
Little data to guide treatment of other sites of EM relapse
Considerations re: sequencing of drugs at relapse?
Changing field, more data need, as of 2024 ELN guideline:
?Blina for patients with low disease burden and preserved T cell function
?Ino for to reduce high disease burden
?CAR-T for more advanced disease, although currently still allograft first
Emerging therapies
Drugs targeting BCL2, TP53, RAS, mTOR/PI3K, NOTCH under investigation
Late Effects
Systems affected
Sex hormone deficiency
Thyroid disorders
Premature menopause
Infertility
Osteonecrosis/osteoporosis
Cardiotoxicity (cardiomyopathy, pericarditis, heart failure)
Neuropsychological disorders
Fatigue
Secondary malignancy
(Specific to allograft: Chronic GVHD, Sicca Syn, Pulmonary disease, Cataracts)
GMALL review of 538 long term survivors
66% no co-morbidities, 27% neurological symptoms, 18% skin symptoms, 17-24% endocrine symptoms, 12% infections, 13% fatigue, 15% GVHD
Children
Largely beyond scope of Haembase but a few principles below
Outcomes
Cure rates now approx. 90%
Therefore risk stratification ever more important to reduce Rx-related morbidity
Risk Stratification in children
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
Clinical features at diagnosis
Age <1 or >10 (Age correlates with cytogenetic findings)
WBC >50
CNS disease
Down Syndrome
Male
Black/Hispanic
Disease Characteristics
T-ALL
Hyperdiploidy
TP53 mutation
Ph+
MLL, RUNX1, Ph-like ALL, IKZF1
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
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
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.