Cytogenetic and molecular studies - BCR-ABL t(9;22)

The Philadelphia chromosome

t(9;22)(q34;q11) = the Philadelphia chromosome
- ABL1 (chromosome 9) fused to BCR (chromosome 22)
- -> a constitutively active tyrosine kinase (ABL1 loses its autoinhibitory cap)
- The first molecularly targeted cancer therapy and still the template for all of them

Breakpoint	Protein	Disease
M-bcr (b3a2/b2a2, e13a2/e14a2)	p210	CML (>95%); ~1/3 of Ph+ ALL
m-bcr (e1a2)	p190	Ph+ ALL (~2/3); rare CML with monocytosis
mu-bcr (e19a2)	p230	Neutrophilic CML (rare)

Always specify the transcript at diagnosis - the monitoring assay must match it, and atypical transcripts cannot be tracked on the international scale

CML: ~1-2 per 100,000/yr; ~350 new cases/yr in Australia; median age ~55-60; M>F slightly
- Ph is present in essentially 100% of CML (a Ph-negative "CML" is an atypical CML or another MPN/MDN)
Ph+ ALL: ~25-30% of adult ALL, rising to >50% over age 60; only 3-5% of paediatric ALL
- The commonest recurrent genetic lesion in adult ALL
Only established risk factor: ionising radiation
Ph-like (BCR-ABL1-like) ALL - ~10-15% of adult ALL; a similar kinase-activated transcriptional signature without the t(9;22)

Reciprocal translocation in a haematopoietic stem cell
BCR provides an oligomerisation domain -> forced dimerisation -> autophosphorylation, constitutive kinase activity
Downstream: RAS/MAPK, PI3K/AKT, STAT5, SRC
- inc proliferation, dec apoptosis, dec stromal adhesion -> premature release of immature cells into blood
- Genomic instability -> clonal evolution
p190 is more kinase-active than p210 -> more aggressive lymphoid phenotype
Resistance mechanisms
- Kinase domain point mutations (~50% of resistance)
  - T315I - the "gatekeeper": resistant to imatinib, nilotinib, dasatinib and bosutinib
  - Sensitive only to ponatinib and asciminib
- BCR-ABL1 amplification, drug efflux, clonal evolution, quiescent leukaemic stem cells (TKI-insensitive - why most patients need indefinite therapy)

Test	Use
Karyotype	Diagnosis + detects additional chromosomal abnormalities (ACAs) signalling progression
FISH	Rapid; detects cryptic/variant translocations and deletions of the derivative 9q
RT-qPCR (BCR-ABL1 IS%)	Baseline transcript type + all subsequent monitoring

CML film: left shift with a myelocyte bulge and basophilia, low LAP/NAP score
Basophilia >2% is the near-constant clue

BCR-ABL1 transcripts / control gene, normalised so that the standardised baseline = 100%
MMR = MR3.0 = 0.1% IS (a 3-log reduction)
Deep response: MR4.0 = 0.01%, MR4.5 = 0.0032%
Only reportable for typical p210 transcripts; use the same laboratory throughout

Time	Optimal	Warning	Failure
3 months	<=10%	>10%	>10% if confirmed
6 months	<=1%	>1-10%	>10%
12 months	<=0.1% (MMR)	>0.1-1%	>1%
Any time after	<=0.1%	>0.1-1%	>1%, resistance mutation, or new ACA

Failure -> test for kinase domain mutations and switch TKI
A rising transcript level is most often non-adherence - ask before changing drug

Blast phase: >=30% blasts in blood/marrow or extramedullary disease (WHO uses >=20%)
Accelerated phase: 15-29% blasts, blasts+promyelocytes >=30%, basophils >=20%, persistent thrombocytopenia, new ACA

A TKI, indefinitely, with molecular monitoring - the treatment is the monitoring
Choice by risk score (ELTS), comorbidity and toxicity profile

TKI	Watch for
Imatinib	Oedema, cramps, GI - cheapest, most long-term data
Nilotinib	Vascular occlusive events, QT prolongation, hyperglycaemia, pancreatitis
Dasatinib	Pleural effusion, pulmonary arterial hypertension, cytopenias, bleeding
Bosutinib	Diarrhoea, transaminitis
Ponatinib	Arterial thrombosis - reserved for T315I or multi-TKI failure; dose-reduce on response
Asciminib	STAMP inhibitor - allosteric, binds the myristoyl pocket, not the ATP site; pancreatitis, hypertension

Asciminib is now a first-line option - ASC4FIRST showed superior major molecular response at 96 weeks (74% vs 52%) with better tolerability than investigator-selected TKIs
- Australian availability via the ALLG ASCEND study and PBS listing for later lines - confirm current PBS criteria before prescribing first-line
Second-generation TKIs achieve deep responses faster but have not shown an overall survival advantage over imatinib

Attempt only if all of:
- Chronic phase, no prior accelerated/blast phase
- TKI for >=3-5 years
- Sustained MR4.0 or deeper for >=2 years
- Typical transcript, access to a reliable monitoring laboratory
Monthly PCR for the first 6-12 months; restart TKI immediately on loss of MMR
~40-50% maintain TFR; nearly all who relapse regain response on restarting
~30% get a transient TKI withdrawal syndrome - musculoskeletal pain

TKI + chemotherapy, or TKI + blinatumomab (chemotherapy-free)
- Ponatinib or dasatinib + blinatumomab gives very high MRD-negative rates
CNS prophylaxis (p190 disease has a high CNS relapse rate)
Allogeneic HSCT in first remission for MRD-positive or high-risk disease - its role is receding as MRD-negativity rates rise
Monitor BCR-ABL1 as the MRD marker

TKI (choose by mutation) + chemotherapy induction -> allogeneic HSCT - the only durable option
Hydroxyurea for cytoreduction at presentation; leucapheresis if hyperleucocytosis with symptoms

Chronic myeloid leukaemia; Ph+ B-ALL; rare Ph+ AML and mixed-phenotype acute leukaemia
Ph-like ALL - CRLF2, ABL-class and JAK-STAT fusions; some respond to TKIs (test for it in high-risk ALL)
Ionising radiation exposure
T315I mutation -> ponatinib or asciminib
Chronic eosinophilic leukaemia and other ABL-class fusion neoplasms (ETV6-ABL1) - also TKI-responsive
Low-level BCR-ABL1 transcripts are detectable in healthy people by ultrasensitive PCR - the fusion alone is not sufficient for leukaemia

10-year survival ~85-90%; life expectancy now approaches that of the age-matched population
Most deaths are from unrelated causes
Progression to blast phase now ~1-1.5% per year, mostly in the first 2-3 years
- Pre-TKI, median survival was 3-5 years with inevitable blast transformation
Blast phase: median survival 6-12 months even with TKIs; lymphoid blast phase does better than myeloid
Achieving <=10% IS at 3 months is the strongest early predictor of long-term outcome

Ph+ ALL

Pre-TKI, the worst adult ALL subtype
TKI + chemotherapy now gives ~50-70% long-term survival; chemotherapy-free TKI + blinatumomab regimens are improving on that further

Indefinite TKI: cardiovascular and metabolic toxicity, fatigue, cost, adherence
TKIs are teratogenic - contraception is mandatory; pregnancy planning needs a TFR attempt or interferon
Second malignancy surveillance
Adherence <90% markedly reduces the chance of a deep molecular response - the commonest reason for "resistance"

15 more sections, plus exam facts

Premium unlocks every note across every specialty, and the full exam fact library behind it.