Teaching pack: Acute lymphoblastic leukaemia

Acute lymphoblastic leukaemia is the commonest childhood cancer and a rarer, harder disease in adults. B-cell precursor ALL (85%) is classified by genetics into favourable (ETV6::RUNX1, high hyperdiploidy), intermediate, and adverse groups (KMT2A rearrangement, hypodiploidy, Ph-like/CRLF2, iAMP21, TCF3::HLF); Ph-positive (BCR::ABL1) disease accounts for a quarter of adult cases. T-ALL (15%) has its own genetics and, since 2023, its own targeted options (nelarabine, BCL-2 inhibition in trials). Measurable residual disease after induction is the strongest predictor of relapse in every subgroup.

Children are cured in over 90% with risk-adapted multi-agent chemotherapy over two to three years, and since 2024 with blinatumomab woven into consolidation (AALL1731: 3-year DFS 96% vs 88%). Adults do worse with chemotherapy alone, but three immunotherapies changed the picture: blinatumomab (E1910: 3-year OS 85% vs 68% when added frontline; standard in MRD-positive and relapsed disease), the CD22 ADC inotuzumab ozogamicin (INO-VATE: 81% remission in relapse), and CD19 CAR-T (tisagenlecleucel for patients up to 25; obe-cel for adults, 2024). Ph-positive ALL is treated with a BCR::ABL1 inhibitor (ponatinib preferred since PhALLCON, 2024) and increasingly with TKI plus blinatumomab and no chemotherapy at all (D-ALBA), while KMT2A-rearranged disease now has menin inhibitors.

• Immunotherapy in frontline paediatric therapy.
• Blinatumomab in frontline consolidation improves survival in adults (E1910) and children (AALL1731) regardless of MRD; approved June 2024.
• Ph-positive ALL: ponatinib is the preferred TKI (PhALLCON) and chemotherapy-free TKI + blinatumomab regimens achieve 18-month survival near 95%.
• Two CD19 CAR-T products for ALL (tisagenlecleucel, obe-cel) with obe-cel showing markedly lower severe CRS and neurotoxicity; REMS removed for CAR-T in 2025.
• Inotuzumab ozogamicin gives ~80% remission in relapse and is moving into frontline lower-intensity regimens for older adults and children.
• MRD at 10^-5 to 10^-6 (clonoSEQ, PCR) is the organising principle for transplant, blinatumomab, and de-escalation decisions.

1. 1948Farber: aminopterin remissions, birth of chemotherapy
2. 1948Farber induces the first leukaemia remissions
3. 1962Combination chemotherapy and CNS prophylaxis
4. 1990Risk-adapted therapy standardised
5. 2000Imatinib transforms Ph-positive leukaemia
6. 2009MRD becomes the key risk factor
7. 2012First CAR-T cures: Emily Whitehead
8. 2014Blinatumomab: first BiTE
9. 2014Blinatumomab: first bispecific T-cell engager approved
10. 2016INO-VATE: CD22 ADC beats chemotherapy in relapse

• Revumenib (product)
• Obecabtagene autoleucel (product)
• Ponatinib (product)
• Asciminib (product)
• BCR::ABL1 TKI + blinatumomab (chemotherapy-free Ph+ ALL) (pairing)
• Transplant-free Ph-positive ALL for MRD-negative adults (idea)
• Menin inhibitors for infant KMT2A-rearranged ALL (idea)
• Ziftomenib (product)
• Inotuzumab ozogamicin (product)
• NGS-based MRD (clonoSEQ and molecular MRD) (technology)
• Blinatumomab added to frontline chemotherapy (pairing)
• Allogeneic stem cell transplantation (technology)

• ECOG-ACRIN E1910 (phase 3, n=488): Overall survival at 3 years (MRD-negative cohort): 85% vs 68%, HR 0.41
• TOWER (phase 3, n=405): Overall survival (median): 7.7 months vs 4 months, HR 0.71
• COG AALL1731 (phase 3, n=1,440): Disease-free survival at 3 years: 96% vs 87.9%, HR 0.39
• INO-VATE ALL (phase 3, n=326): Complete remission / CRi: 80.7% vs 29.4%
• Interfant-06 (phase 3, n=651): Event-free survival at 6 years: 46.1%
• PhALLCON (phase 3, n=245): MRD-negative complete remission at end of induction: 34.4% vs 16.7%

• Adult ALL outcomes.
• CD19-negative relapse.
• CD19-negative relapse after blinatumomab or CAR-T; CD22 and dual-antigen CARs are early.
• T-cell ALL has no approved immunotherapy; CD7 CAR-T (fratricide) and venetoclax combinations are experimental.
• Ph-like ALL (CRLF2, JAK) has poor outcomes and only trial access to JAK/ABL-class inhibitors.
• Infant KMT2A-rearranged ALL still has EFS under 50% on chemotherapy alone.

1. What is CAR-T and which cancers is it approved for?
   Answer

   A patient's T cells are engineered with a synthetic receptor, multiplied, and returned. Approved CD19 products treat B-cell lymphomas and leukaemias; BCMA products treat multiple myeloma; the first solid-tumour approval (Claudin 18.2, gastric) is in China.
2. What is the first menin inhibitor and who is it for?
   Answer

   Revumenib (Revuforj, Syndax), approved 2024 for relapsed KMT2A-rearranged acute leukaemia and 2025 for NPM1-mutant AML.
3. Why does venetoclax work in leukaemia?
   Answer

   It blocks BCL-2, the protein that stops leukaemia cells from self-destructing, so the built-in death programme (apoptosis) can run; used in CLL (fixed duration with obinutuzumab) and AML (with azacitidine).
4. What is in vivo CAR-T and why is it exciting?
   Answer

   Targeted lipid nanoparticles or viral vectors deliver CAR-encoding mRNA or DNA to T cells inside the patient, avoiding manufacturing, lymphodepletion, and wait time and allowing redosing; first-in-human data in 2025-26 show B-cell depletion. AbbVie bought Capstan for up to $2.1B.

• NCCN ALL guidelines: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1410
• Wikipedia: https://en.wikipedia.org/wiki/Acute_lymphoblastic_leukemia
• Guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1410