How to treat relapsed acute lymphoblastic leukaemia

Summary

The presentation reviews the biology, diagnosis, risk assessment, and treatment of childhood relapsed acute lymphoblastic leukaemia (ALL), focusing on European and international trials and emerging therapies.

Why relapse prevention and risk balance matter

• Relapse occurs in roughly 15% of children treated for ALL. Preventing relapse is important, but intensifying treatment for every child would expose many to unnecessary toxicity.
• The goal is to balance effective treatment against short- and long-term harms, while developing drugs that may be more targeted and less toxic.
• The speaker emphasizes the value of clinicians working with pharmaceutical companies. Without clinical input, drug-development plans may be impractical for children or incompatible with real-world treatment strategies.

How relapse develops

• Some ALL may begin with genetic changes that arise before birth, creating a pre-leukaemic clone. Additional changes after birth can drive progression to overt leukaemia.
• ALL is genetically diverse. Common subtypes include hyperdiploid disease and ETV6–RUNX1 leukaemia, which are generally associated with more favourable outcomes. Other subtypes, including some infant leukaemias, have poorer outcomes.
• Leukaemia cells descend from a common clone but continue to acquire different genetic changes. This clonal heterogeneity helps explain why the dominant cell population can change between diagnosis and relapse.
• Mutations in signalling pathways, including RAS/MAPK and JAK/STAT, and alterations such as TP53 changes can promote cell growth and affect treatment response. Some may provide targets for new drugs.
• The presentation highlights TP53 alterations as a particularly adverse feature, associated with poor outcomes even in otherwise more favourable-risk groups. Some cases may reflect an inherited predisposition, such as Li-Fraumeni syndrome.

Diagnosis and risk assessment

Relapse diagnosis uses many of the same tools as initial diagnosis:

• Cytology is an important early test and can guide initial decisions while further results are pending.
• Additional testing includes immunophenotyping, cytogenetics, molecular genetics, and gene-expression profiling.

Risk assessment relies on several factors:

• Timing of relapse: very early, early, or late relapse.
• Site of relapse: bone marrow, isolated extramedullary disease, or combined relapse.
• Genetic features: high-risk findings such as TP53 alterations and certain other genetic subtypes.
• Minimal residual disease (MRD): response to treatment, especially after induction and before transplant.

The speaker describes standard-risk patients as having substantially better outcomes than high-risk patients. For some very high-risk genetic groups, conventional chemotherapy and transplantation alone remain inadequate.

Treatment approach

The treatment pathway is adapted to relapse risk and treatment response.

Standard-risk relapse

• Use combination chemotherapy.
• Patients with a good MRD response may be treated with chemotherapy without a transplant.
• Patients with a poor MRD response are considered for allogeneic stem-cell transplantation.

High-risk relapse

• Use intensive chemotherapy and, increasingly, the immunotherapy blinatumomab as a bridge to transplant.
• Allogeneic stem-cell transplantation is generally part of the plan.

Very high-risk or refractory relapse

• Consider experimental or individualized approaches, including inotuzumab ozogamicin, personalized consolidation, CAR T-cell therapy, and/or transplantation.
• Provide local treatment when indicated, such as CNS-directed treatment or treatment for testicular relapse.

A central lesson is that MRD after induction helps identify which patients need transplant. The presentation describes evidence that patients with a good MRD response can do well with chemotherapy alone, while those with a poor response have a stronger indication for transplantation. Achieving a good remission before transplant is also important.

Transplantation and conditioning

• The speaker reports that about two-thirds of relapsed patients may have an indication for allogeneic transplantation, including high-risk patients and some standard-risk patients with a poor MRD response.
• In the international FORUM study, total-body irradiation (TBI) conditioning produced better survival than chemotherapy-only conditioning in the population discussed. The trial was stopped early after this difference emerged.
• TBI has significant potential late effects, including effects on growth and hormones and a risk of secondary malignancies. Despite these concerns, the presenter describes it as the standard conditioning approach for the relevant patients because of its survival advantage.
• Haploidentical donors are accepted, although a well-matched sibling or unrelated donor is generally preferred when available. Outcomes may also depend on the transplant centre’s experience.

Chemotherapy and international trials

• European treatment protocols have used different chemotherapy schedules, including continuous and short-course approaches.
• The IntReALL SR 2010 trial compared established European regimens. The presenter reports similar overall outcomes between the two arms, while noting subgroup findings: one regimen appeared more favourable for isolated CNS relapse, while the other appeared better at preventing subsequent bone-marrow relapse.
• The trial also tested an additional monoclonal antibody. Recruitment to that component stopped after the company ceased supplying the drug; the speaker reports no clear benefit from adding it.
• International collaboration is essential because relapsed ALL is uncommon. Pooling patients across countries makes adequately sized trials possible within a reasonable time.

Immunotherapy

Blinatumomab

• Blinatumomab is a CD19-directed immunotherapy for B-cell precursor ALL.
• In a high-risk setting, replacing a chemotherapy cycle with blinatumomab improved outcomes as a bridge to transplant, including overall survival, and was less toxic than the chemotherapy comparator.
• Other trial results discussed support using blinatumomab in patients with a transplant indication. The speaker also describes a study in which blinatumomab replaced or supplemented chemotherapy in other risk groups; toxicity was generally lower.
• Its role in isolated extramedullary relapse is less certain. The presenter notes that available evidence is not definitive, but does not show clear harm; further comparisons are needed.

Inotuzumab ozogamicin

• Inotuzumab is a CD22-directed antibody linked to a toxin. It can produce high remission rates, including MRD-negative remissions, in difficult-to-treat patients.
• It may be useful for remission induction, but its effects may not persist without further treatment.
• A major concern is veno-occlusive disease (VOD) after transplantation, which can be life-threatening. The timing of transplant and close monitoring are therefore important.

CAR T-cell therapy

• The presentation cites encouraging results for tisagenlecleucel in relapsed or refractory B-cell precursor ALL, with long-term survival around 50% in the population discussed.
• The speaker considers CAR T cells an important option to integrate into strategies for very high-risk disease, while noting that access and licensing vary.

Personalized and targeted treatment

• Molecular profiling and expert tumour-board review can identify potentially actionable targets, particularly for patients with refractory disease or limited standard options.
• The INFORM programme is described as a platform that combines molecular testing with multidisciplinary recommendations. A target was identified for most patients in the group discussed, though identifying a target does not guarantee that it can be treated effectively or quickly enough.
• Potential targeted approaches include inhibitors of signalling pathways and other small-molecule drugs. Trials are especially important for T-ALL, where B-cell-directed immunotherapies such as blinatumomab are not applicable.
• Because these patients are rare, some targeted-treatment studies require international or transatlantic collaboration.

Future directions

Proposed next steps include:

• Testing inotuzumab as an induction option in selected risk groups.
• Expanding the use of blinatumomab, including as a way to reduce exposure to conventional chemotherapy.
• Developing CAR T-cell strategies for very high-risk disease.
• Continuing research into transplant conditioning and ways to reduce treatment-related and late toxicity.
• Establishing personalized-treatment platforms and targeted trials, especially for T-ALL.
• Securing access and licensing for promising therapies in children.

Speakers and sources featured

Speakers

• Main presenter: An unnamed clinician/researcher discussing childhood relapsed ALL and international trial strategies.
• Audience members: Several unnamed attendees asked questions about post-transplant relapse and mortality, transplant donor types, standard-risk treatment, trial timing, and blinatumomab for extramedullary/CNS relapse.

Studies, programmes, and evidence cited

• AIEOP-BFM and other frontline ALL trial results.
• IntReALL SR 2010 and the related high-risk trial programme.
• FORUM transplant-conditioning trial.
• COG studies of blinatumomab.
• ITCC-059 inotuzumab study and the 215 blinatumomab study mentioned in the talk.
• ELIANA trial of tisagenlecleucel (CAR T-cell therapy).
• INFORM molecular-profiling programme and related expert-board approaches.