2023 ELN recommendations Part 2: Clinical management of adult ALL

The European Working Group of the European Leukemia Net (ELN) identified the clinical management of adults with acute lymphoblastic leukemia (ALL) as an unmet need.¹

The ALL Hub is pleased to present a summary of the second and final part of the 2023 European LeukemiaNet (ELN) recommendations, published by Gokbuget et al.¹ in Blood. Part one was focused on the diagnosis, prognosis, and assessment of adult ALL. This final update is focused on the clinical management of ALL, including new immunotherapies, application of minimal residual disease (MRD), management of specific subgroups, late effects, and supportive care. ¹

Application of MRD in treatment decisions¹

• Key factors guiding MRD-based treatment decisions include time-point, level, and method of MRD detection and presence of other prognostic factors.
  • Earlier time points could help to identify patients for de-escalation therapy
  • The current threshold for clinical decisions is a sensitivity level of 0.01% or 10^-4
  • Quantitative polymerase chain reaction warrants a 4–6 week set-up for appropriate assay, whereas multi-flow cytometry can deliver faster but more uncertain results
  • In patients with persistent or recurrent MRD, a change in therapy is recommended.
  • Patients with MRD >0.01% after three blocks of standard therapy can be given stem cell transplantation (SCT) or targeted therapies.

Treatment recommendations for specific subgroups¹

Adolescent and young adults (15–20 years) and older patients (>55–65 years)

• For adolescents and young adults, pediatric-based protocols are used until ages 55-65 years.
• For older patients, age-adapted protocols can achieve complete remission (CR) rates of 43–90% and overall survival <30–40%; pre-phase therapy is critical for management.

Philadelphia chromosome-negative ALL

• Immunotherapies such as rituximab, blinatumomab, and inotuzumab ozogamicin (InO) have demonstrated promising efficacy and have been incorporated in frontline trials (Figure 1).
  • Rituximab for at least eight doses is recommended for the treatment of CD20⁺ ALL.
  • Participation in InO and blinatumomab trials is encouraged for newly diagnosed patients with CD22⁺ and CD19⁺ B-ALL, respectively.
• For older patients, SCT is not recommended for MRD-negativity outside of clinical trials.

Philadelphia chromosome-positive ALL

• Tyrosine kinase inhibitors (TKIs) achieve high CRs, low toxicity, and allow a higher proportion of patients to undergo SCT (Figure 1); therefore, it should be given as early as possible.
  • Choice of first-line TKI depends on treatment regimen and comorbidities
  • A high initial dose of imatinib (800 mg/day for 6–8 weeks) is linked to better outcomes.
  • Reducing ponatinib dose (45–30 mg/day) when CR is reached lowers the risk of arterial occlusive events without affecting efficacy.
• Combining TKIs with immunotherapy could further improve clinical efficacy
• SCT remains the standard of care, but its role in the era of third-generation TKIs could be limited

ALL, acute lymphoblastic leukemia; Allo-SCT, allogeneic stem cell transplantation; BID, twice a day; CR, complete remission; EFS, event-free survival; EWALL, European Working Group for Adult Acute Lymphoblastic; GRAALL, Group for Research on Adult Acute Lymphoblastic Leukemia; Hyper-CVAD, hyperfractionated-cyclophosphamide, vincristine, doxorubicin, and dexamethasone; MDACC, MD Anderson Cancer Center; MR, molecular response; OS, overall survival; Ph+, Philadelphia chromosome-positive; Ph- Philadelphia chromosome-negative; QD, once daily; R, rituximab; RFS, relapse-free survival; SOC, standard of care.
*Data from Gokbuget, et al.¹ 

Philadelphia chromosome-like ALL

• Treatment of Philadelphia (Ph)-like ALL remains a challenge, but novel therapies such as blinatumomab and InO have demonstrated encouraging efficacy.
• Due to poor MRD response, most groups rely on an MRD-based approach and will be offered SCT and/or targeted therapy.

T-cell ALL

• Participation in nelarabine trials is recommended until concrete data is available
• ETP ALL has a poor prognosis, while chemotherapy and unfavourable oncogenetics should also lead to consideration of SCT
• Older patients with high-risk T-ALL could benefit from reduced-intensity conditioning if they have a well-matched donor

Relapsed/refractory ALL

• All patients with relapsed/refractory (R/R) ALL should be referred to experienced centers and considered for SCT
• The choice of regimen will depend on several factors, including age, comorbidities, disease characteristics, type of prior therapy, and duration of prior remission
  • Patients with extramedullary relapse should be given CNS-directed treatments
  • Patients with isolated or combined CNS relapse should be directed to SCT
• Clinically approved immunotherapies such as blinatumomab, InO, and chimeric antigen receptor T-cell have demonstrated efficacy in R/R ALL (Figure 2)
• The indication for chimeric antigen receptor-T in relapse after SCT is generally accepted, even in the setting of MRD relapse

B-ALL, B-cell acute lymphoblastic leukemia; Allo-SCT, allogeneic stem cell transplantation; CRS, cytokine release syndrome; FHCRC: Fred Hutchinson Cancer Research Center; HCR, hematologic complete remission; HR, high risk; IR, intermediate risk; MRD, minimal residual disease; MSKCC: Memorial Sloan Kettering Cancer Center; MR, molecular response; NA, not available; NR, not recorded; ORR, overall response rate; OS, overall survival; Ph, Philadelphia chromosome
*Data from Gokbuget, et al.¹ 

ALL in pregnancy

• ALL in pregnancy should be managed in experienced centers
• Treatment options will be based on gestational age, disease biology, and clinical status
  • Termination of pregnancy is strongly considered in the first trimester.
  • Systemic antifolates should not be used at any time during pregnancy.

Down syndrome ALL

• Reduction of anthracyclines is recommended for down syndrome ALL
• Prophylactic management of infections is strongly recommended

Late effects¹

• Late effects in ALL can include thyroid disorders, infertility, osteonecrosis, cardiotoxicities, neuropsychological disorders, fatigue, and secondary malignancies.
  • Avascular osteonecrosis is most commonly observed in adolescents/young adults
  • Cardiovascular check-ups should be performed in the aftercare of patients
  • Risk factors linked to secondary malignancies include alkylating agents, central nervous irradiation, total body irradiation before SCT, and different gene mutations

Supportive care¹

• Organ damage due to very high white blood cell counts can be treated with leukapheresis
• Patients at high risk of developing tumor lysis syndrome should be given hydration
• Antibacterial, antifungal, and antiviral prophylaxis for infection management is essential
• Sperm and ovarian tissue cryopreservation is encouraged in men and women to preserve fertility.

Key learnings

Immunotherapies, such as monoclonal antibodies, are the standard of care for R/R ALL and are increasingly being used in the frontline setting, although the sequencing of these therapies remains a challenge. Important research questions in Ph+ ALL include the optimal selection of TKIs, the efficacy of chemotherapy-free treatments, and the role of immunotherapies. Although the overall prognosis of T-ALL has improved, new treatments are urgently needed for poor prognostic subgroups. There is a need for the collaboration of pediatric and adult study groups to understand the biology, improve surveillance, and define treatment modifications for late effects.