What is the treatment approach for lymphoblastic leukemia (LL), including acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukemia (CLL)?

Treatment of Lymphoblastic Leukemia

Critical Distinction: ALL vs CLL

Lymphoblastic leukemia encompasses two fundamentally different diseases requiring completely different treatment approaches: Acute Lymphoblastic Leukemia (ALL) and Chronic Lymphocytic Leukemia (CLL). These are not variations of the same disease but distinct malignancies with separate treatment paradigms.

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Acute Lymphoblastic Leukemia (ALL)

Treatment Framework

For adults <65 years with B-cell ALL, initiate intensive multiagent chemotherapy with a 4-drug backbone consisting of vincristine, anthracycline, corticosteroid, and L-asparaginase, combined with intrathecal chemotherapy from day one. 1, 2, 3

Induction Phase (Adults <65 years)

• High-intensity regimens include CALGB 9111, ECOG 1910, or dose-adjusted Hyper-CVAD 3
• Moderate-intensity alternatives include modified DFCI 91-01, GMALL, GRAALL, or EWALL regimens 3
• For CD20-positive disease, add rituximab to GMALL 3
• Triple intrathecal therapy is preferred over methotrexate alone for CNS prophylaxis 3
• Prophylactic cranial irradiation is not recommended for B-ALL when effective systemic and intrathecal therapy is used 3

Corticosteroid Selection

• Dexamethasone provides superior CNS penetration and reduces CNS relapse risk compared to prednisone 3, 4
• However, dexamethasone carries higher risks of induction mortality, neuropsychiatric events, and myopathy 3, 4
• No conclusive overall survival advantage has been demonstrated between dexamethasone and prednisone 4

Treatment Modifications for Older Adults (≥65 years)

• Low-intensity options: vincristine and prednisone or POMP regimens 2
• Moderate-intensity options: ALLOLD07, EWALL, GMALL, or GRAALL regimens 2
• Chronologic age alone is a poor surrogate for determining fitness—assess comorbidities and functional status 4

Minimal Residual Disease (MRD) Monitoring

MRD assessment after induction is mandatory and guides all subsequent treatment decisions. 3

• MRD-negative patients proceed with standard consolidation and maintenance 3
• MRD-positive or rising patients require addition of blinatumomab or inotuzumab ozogamicin before consolidation 3
• Blinatumomab achieves 88% complete MRD response in patients with MRD ≥10⁻³ 3
• MRD negativity (<0.01% blast cells) after induction/consolidation is achieved in ~70% of standard-risk patients with 5-year OS of 70% 1

Consolidation Therapy

• Typically includes high-dose methotrexate and cytarabine 2
• CNS prophylaxis with intrathecal chemotherapy continues throughout consolidation 2
• MRD assessment guides therapy intensification and consideration for stem cell transplantation 2

Maintenance Therapy

Standard maintenance includes daily mercaptopurine, weekly methotrexate, monthly vincristine, and pulse dexamethasone. 2

High-Risk Features Requiring Intensification

Consider allogeneic hematopoietic cell transplantation in first complete remission for patients with: 3

• Age ≥35 years 3
• WBC >30 × 10⁹/L 3
• Time to complete remission >4 weeks 3
• Poor-risk cytogenetics (hypodiploidy, MLL/KMT2A rearrangements) 2, 4
• Persistent MRD positivity 3

Philadelphia Chromosome-Positive (Ph+) ALL

• Combine BCR::ABL1 tyrosine kinase inhibitors with multiagent chemotherapy or blinatumomab 5
• Achieving complete molecular remission by next-generation sequencing may identify patients who can avoid allogeneic SCT 5
• 5-year survival rates now exceed 80% with TKI-based regimens 5

T-cell ALL

• Use combination chemotherapy regimens incorporating pegylated asparaginase and nelarabine 5
• Early T-cell precursor (ETP) ALL is high-risk—consider allogeneic SCT 5
• Venetoclax may be beneficial for ETP-ALL and is under investigation 5

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Chronic Lymphocytic Leukemia (CLL)

Treatment Indications

Treat only patients with active, symptomatic disease—watch and wait for early, stable disease (Binet A/B without symptoms, Rai 0-II without symptoms). 1

Active disease is defined by: 1

• Significant B-symptoms
• Cytopenias not caused by autoimmune phenomena
• Symptoms from lymphadenopathy, splenomegaly, or hepatomegaly
• Lymphocyte doubling time <6 months (only if >30,000 lymphocytes/μL)
• Autoimmune anemia/thrombocytopenia poorly responsive to conventional therapy

First-Line Therapy for Active Disease

Patients WITHOUT TP53 mutation or del(17p)

For physically fit patients with normal renal function, BTK inhibitors (ibrutinib or acalabrutinib) are first-line therapy. 1, 6

• Ibrutinib 420 mg orally once daily until disease progression or unacceptable toxicity 6
• Can be administered as single agent or in combination with rituximab or obinutuzumab 6
• Alternative: Venetoclax plus obinutuzumab as time-limited therapy 1

For patients with relevant comorbidities:

• Chlorambucil is standard 1
• Alternatives include dose-reduced purine analog-based therapies (FC, PCR) or bendamustine 1

Patients WITH TP53 mutation or del(17p) (5-10% of patients)

BTK inhibitors (ibrutinib or acalabrutinib) are mandatory first-line therapy—chemoimmunotherapy is not an option. 1

• If BTK inhibitors are contraindicated (arrhythmias, cardiovascular comorbidity, anticoagulation, CYP3A4 inhibitor interactions), use venetoclax as continuous monotherapy or venetoclax plus obinutuzumab 1
• Venetoclax plus obinutuzumab shows less efficacy in TP53 mutation/del(17p) compared to other CLL subtypes, though still superior to chemoimmunotherapy 1
• For physically fit young patients, consider effective initial regimen followed by allogeneic stem cell transplantation within clinical trials 1

Relapsed/Refractory Disease

Treat relapse only when symptomatic—stopping continuous BCR inhibitor or venetoclax does not require immediate alternative treatment if CLL is in remission. 1

For symptomatic relapse <3 years after fixed-duration therapy or non-response:

Change the therapeutic regimen using one of these options: 1

• Venetoclax plus rituximab for 24 months 1
• Ibrutinib, acalabrutinib, or other BTK inhibitors as continuous therapy 1

Alternative options: 1

• Idelalisib plus rituximab 1
• Chemoimmunotherapy (unless TP53 mutation/del(17p) present); response to prior bendamustine-rituximab should have lasted ≥3 years to justify re-administration 1
• Do not repeat FCR due to increased toxicity and risk of secondary myeloid neoplasm 1

For relapse >3 years after therapy:

• May repeat first-line treatment 1

Critical Pitfalls to Avoid

• Never treat asymptomatic early-stage CLL—early treatment with alkylating agents does not improve survival 1
• Never use chemoimmunotherapy in TP53 mutation/del(17p) patients—poor prognosis regardless of IGHV status 1
• Never delay MRD assessment in ALL—it is mandatory for treatment decisions 3
• Never omit CNS prophylaxis in ALL—intrathecal therapy must start from day one 3