What is the treatment approach for a patient with a KMT2A (lysine methyltransferase 2A) mutation?

Treatment Approach for KMT2A-Rearranged Leukemia

The treatment strategy for KMT2A-rearranged leukemia depends critically on three factors: whether it is ALL versus AML, the specific fusion partner involved, and the patient's age, with emerging menin inhibitors now offering targeted therapy for relapsed/refractory disease. 1

Initial Risk Stratification

Identify the Leukemia Subtype and Fusion Partner

For KMT2A-rearranged ALL:

• In childhood (non-infant) ALL, KMT2A rearrangements account for approximately 2% of cases with a 5-year event-free survival (EFS) of 59.3-69.1%, significantly worse than the 87.3% in patients without KMT2A rearrangements 1
• The t(4;11) translocation carries the worst prognosis with only 64.8% 5-year EFS and highest relapse risk 1
• Other common translocations include t(11;19) (20%), t(9;11) (14.3%), t(6;11) (3.8%), and t(10;11) (2.6%) 1

For KMT2A-rearranged AML:

• Detected in 15-25% of pediatric AML patients with 5-year EFS around 45% and overall survival around 60% 1
• High-risk fusion partners include KMT2A::AFDN, KMT2A::AFF1, KMT2A::MLLT10, KMT2A::ABI1, and KMT2A::MLLT1, which have 30.3% EFS versus 54.0% for non-high-risk partners 1
• The high-risk cohort shows 59.7% cumulative incidence of relapse versus 35.2% for non-high-risk 1

Front-Line Treatment Strategy

For Infant ALL (Age <12 months)

Use Interfant-based chemotherapy protocols:

• Risk-stratify based on KMT2A status, age, white blood cell count, and prednisone response at day 8 1
• Low-risk: KMT2A germline patients 1
• High-risk: KMT2A-rearranged with age <6 months and WBC ≥300,000/μL or poor prednisone response 1
• Medium-risk: all other KMT2A-rearranged cases 1

After induction, assess minimal residual disease (MRD):

• MRD-negative patients continue risk-stratified chemotherapy 1
• MRD-positive patients require intensified consolidation 1
• High-risk patients (age <3 months with any WBC, age <6 months with WBC ≥300,000, or persistently MRD-positive) should be considered for allogeneic hematopoietic stem cell transplant (HSCT) after at least 6 months of age using non-total body irradiation-based preparative regimens 1

For Childhood (Non-Infant) ALL

Enroll in clinical trials when available, otherwise:

• Use intensive ALL chemotherapy protocols with risk stratification based on fusion partner and MRD response 1
• The t(4;11) translocation requires the most aggressive approach given highest MRD rates and relapse risk 1
• Consider HSCT in first complete remission for high-risk features 1

For KMT2A-Rearranged AML

Add gemtuzumab ozogamicin to conventional chemotherapy:

• The Children's Oncology Group AAML0531 trial demonstrated improved 5-year EFS to 48% with addition of gemtuzumab ozogamicin (anti-CD33 antibody-drug conjugate) to standard chemotherapy 1
• This represents the first specific agent showing efficacy in KMT2A-rearranged AML 1

Risk-stratify based on fusion partner:

• High-risk fusion partners warrant consideration for HSCT in first complete remission 1
• Non-high-risk fusion partners may be managed with chemotherapy alone if good MRD response 1

Relapsed/Refractory Disease

Menin Inhibitor Therapy (Revumenib)

For relapsed/refractory KMT2A-rearranged leukemia, use revumenib (menin inhibitor):

• The AUGMENT-101 trial demonstrated a combined complete response (CR) + complete response with partial hematologic recovery (CRh) rate of 31.2% and overall response rate of 64.9% in relapsed/refractory KMT2A-rearranged acute leukemia 1
• In the pediatric subgroup (n=15), 10 patients responded (1 CR, 2 CRh, 2 CR with incomplete platelet recovery, 5 morphologic leukemia-free state), with 4 proceeding to HSCT 1
• Phase 2 data showed CR+CRh rate of 22.8% with 70% achieving negative measurable residual disease 1

Dosing and administration:

• Recommended phase 2 dose: 276 mg every 12 hours (or 160 mg/m² if body weight <40 kg) without strong CYP3A4 inhibitor 1
• Administer continuously in 28-day cycles 1

Monitor for treatment-related adverse events:

• Most common: nausea (27.7%), differentiation syndrome (26.6%), and QTc prolongation (23.4%) 1
• Grade 3 or higher events occur in 25% of patients 1
• Only 6% discontinue due to adverse events 1

Bridge to transplant:

• 38% of responders in the overall population proceeded to HSCT 1
• Use menin inhibitor therapy as a bridge to definitive HSCT in responding patients 1

Critical Pitfalls to Avoid

Do not assume all KMT2A rearrangements have identical prognosis:

• The specific fusion partner dramatically impacts outcomes, with high-risk partners having 30.3% EFS versus 54.0% for non-high-risk 1
• The t(4;11) translocation in ALL has particularly poor outcomes requiring most aggressive therapy 1

Do not delay HSCT evaluation in high-risk patients:

• Patients with high-risk fusion partners, persistent MRD positivity, or infant ALL with poor prognostic features benefit from early HSCT consideration 1
• For infants, wait until at least 6 months of age and use non-total body irradiation preparative regimens 1

Do not overlook lineage plasticity:

• KMT2A-rearranged ALL frequently co-expresses myeloid markers (CD15, CD65) and can switch lineages during therapy 1
• Monitor for lineage switches that may require treatment modification 1

Do not miss therapy-related KMT2A-rearranged leukemia:

• Up to 70% of therapy-related myeloid neoplasms result from topoisomerase II inhibitors with 11q23 translocations 1
• These have particularly poor prognosis with 5-year overall survival of only 28%, requiring allogeneic HSCT for curative intent 1