What is the initial treatment approach for acute lymphoblastic leukemia (ALL)?

Initial Treatment Approach for Acute Lymphoblastic Leukemia

Begin intensive multiagent induction chemotherapy immediately with a 4-drug backbone consisting of vincristine, anthracycline (daunorubicin or doxorubicin), corticosteroid (dexamethasone or prednisone), and L-asparaginase for adults under 65 years with newly diagnosed ALL. 1, 2

Treatment Framework by Patient Age and Fitness

Adults Under 65 Years

For fit adults under 65 years, initiate high-intensity regimens such as CALGB 9111, ECOG 1910, or dose-adjusted Hyper-CVAD, which alternate between intensive chemotherapy cycles. 1 The Hyper-CVAD regimen specifically alternates between "A" cycles (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) and "B" cycles (high-dose methotrexate and cytarabine). 3

Moderate-intensity alternatives include modified DFCI 91-01, GMALL, GRAALL, or EWALL regimens for patients who may not tolerate the most intensive approaches. 1 For CD20-positive disease, add rituximab to the GMALL regimen. 1

Adults 65 Years and Older

For older adults or those with substantial comorbidities, use low-intensity options such as vincristine with prednisone, or moderate-intensity regimens like ALLOLD07, EWALL, GMALL, or GRAALL protocols. 4 These patients should be treated in clinical trials when possible. 3

The combination of tyrosine kinase inhibitors (TKIs) with corticosteroids alone has shown excellent outcomes in older patients with Ph-positive ALL, with the EWALL-PH-01 study demonstrating a 96% complete remission rate using dasatinib combined with vincristine and dexamethasone. 3 This low-intensity approach significantly reduces severe adverse events compared to intensive chemotherapy (39% vs 90%; P=0.005). 3

Pediatric Patients

For standard-risk pediatric patients, use 3-drug induction without anthracyclines (vincristine, corticosteroid, L-asparaginase), while high-risk patients require 4-drug induction including anthracyclines. 4, 2

Essential Treatment Components from Day One

CNS Prophylaxis

Initiate intrathecal chemotherapy immediately at diagnosis, with triple intrathecal therapy (methotrexate, cytarabine, corticosteroids) preferred over methotrexate alone. 1, 3 CNS prophylaxis must continue throughout all treatment phases—induction, consolidation, and maintenance. 3

Prophylactic cranial irradiation is not recommended for B-ALL when effective systemic and intrathecal therapy are used. 1 However, cranial irradiation should be considered for patients with CNS leukemia present at diagnosis. 3

Corticosteroid Selection

Use dexamethasone over prednisone for superior CNS penetration and reduced CNS relapse risk, but monitor closely for increased toxicity. 1, 2 Dexamethasone significantly reduces CNS relapse and improves event-free survival, but carries higher risks of induction mortality, neuropsychiatric events, and myopathy. 1, 2 No conclusive overall survival advantage has been demonstrated. 2

Critical MRD-Guided Treatment Decisions

Perform MRD assessment immediately after completing induction therapy to guide all subsequent treatment decisions. 1, 3 This is mandatory and non-negotiable. 1

MRD-Negative Patients

Proceed with standard consolidation using high-dose methotrexate, cytarabine, and other agents, followed by maintenance therapy. 1, 4

MRD-Positive Patients

Add blinatumomab or inotuzumab ozogamicin before consolidation therapy for patients with persistent MRD. 1 Blinatumomab achieves 88% complete MRD response in patients with MRD ≥10⁻³. 1 The FDA approved blinatumomab specifically for adult and pediatric patients with B-cell precursor ALL in first or second complete remission with MRD ≥0.1%. 3

For MRD-positive patients in second complete remission, administer 1-2 additional courses of therapy to achieve MRD negativity prior to allogeneic hematopoietic cell transplantation. 3

High-Risk Features Requiring Treatment Intensification

Identify high-risk features at diagnosis that mandate consideration for allogeneic HCT in first complete remission: age ≥35 years, WBC >30 × 10⁹/L (B-cell) or >100 × 10⁹/L (T-cell), time to complete remission >4 weeks, poor-risk cytogenetics (hypodiploidy, MLL/KMT2A rearrangements), and persistent MRD. 1, 2

For Ph-positive ALL, the combination of TKIs with chemotherapy has dramatically improved outcomes, with 5-year survival rates exceeding 80%. 5 The EWALL-PH-02 study using nilotinib with multiagent chemotherapy achieved 94.4% complete remission rates and 4-year overall survival of 47% in older patients. 3

Consolidation and Maintenance Structure

Following induction, administer consolidation therapy with high-dose methotrexate and cytarabine to eliminate residual leukemic cells, followed by maintenance therapy with daily mercaptopurine, weekly methotrexate, monthly vincristine, and pulse dexamethasone for 30 months total. 4, 6, 7 The mercaptopurine starting dose is 1.5 to 2.5 mg/kg orally once daily, adjusted to maintain adequate neutrophil counts. 6

Philadelphia Chromosome-Positive ALL Specific Approach

For Ph-positive ALL, combine a TKI (imatinib, dasatinib, or nilotinib) with corticosteroids and/or chemotherapy from the start of induction. 3 Post-consolidation maintenance TKI therapy is mandatory. 3

The GRAAPH 2005 trial demonstrated that high-dose imatinib combined with vincristine and dexamethasone achieved superior overall response rates compared to Hyper-CVAD, largely due to reduced treatment-related toxicities. 3

Critical Pitfalls to Avoid

• Never delay MRD assessment after induction—this is the single most important prognostic factor guiding subsequent therapy. 1
• Never omit CNS prophylaxis from day one—CNS relapse remains a significant cause of treatment failure. 1
• Never use chronologic age alone to determine treatment intensity—functional status and comorbidities matter more than age. 2
• Never proceed to allogeneic HCT with detectable MRD without attempting additional therapy first—blinatumomab can effectively bridge patients to transplant. 3

Treatment Setting

Treat all patients with ALL at specialized cancer centers with expertise in managing this complex disease, given the intensive nature of therapy and need for sophisticated supportive care. 3