What are the implications of an inversion of chromosome 16 on a karyotype?

Acute Myeloid Leukemia with Inversion 16

The finding of inv(16)(p13.3q22) in 99% of cells is diagnostic of AML with favorable-risk cytogenetics, which mandates immediate confirmation with molecular testing for CBFB-MYH11 fusion, followed by standard intensive induction chemotherapy with cytarabine plus an anthracycline. 1

Diagnostic Significance

• Inv(16) alone is sufficient for AML diagnosis regardless of blast percentage, as this genetic abnormality defines a specific WHO disease entity: AML with recurrent genetic abnormalities 1
• This chromosomal abnormality creates the CBFB-MYH11 fusion gene, which is the critical molecular product driving leukemogenesis 2
• The inversion is characteristically associated with acute myelomonocytic leukemia (M4 subtype) with abnormal bone marrow eosinophils, though it can occasionally present as M1 subtype 3, 4

Risk Stratification

Inv(16) is classified as favorable-risk (better-risk) cytogenetics in both the NCCN and European LeukemiaNet risk stratification systems 5, 1:

• NCCN guidelines explicitly list inv(16) or t(16;16) as better-risk cytogenetics 5
• The 2017 ELN recommendations classify inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 as favorable risk 5
• Other cytogenetic abnormalities in addition to inv(16) do not alter the favorable-risk status 5

Important Caveat on c-KIT Mutations

• Emerging data indicate that c-KIT mutations in patients with inv(16) confer a higher risk of relapse, though to a lesser extent than in t(8;21) patients 5
• Patients with inv(16) and c-KIT mutations should be considered for clinical trials when available 5

Required Confirmatory and Additional Testing

Immediate Confirmatory Testing

• FISH or molecular analysis (RT-PCR) must confirm the CBFB-MYH11 fusion gene 1
• FISH with CBFB rearrangement or fusion probes is recommended because inv(16) can be subtle if chromosome morphology is suboptimal 5

Comprehensive Molecular Profiling

Complete the following molecular workup to refine prognosis and guide therapy 1:

• NPM1 mutation status
• FLT3-ITD and FLT3-TKD mutations
• CEBPA mutations (biallelic vs monoallelic)
• RUNX1 mutations
• ASXL1 mutations
• DNMT3A mutations
• TP53 mutations

Bone Marrow Evaluation

• Bone marrow aspiration and biopsy for morphology, immunophenotyping by flow cytometry, and cytogenetic/molecular studies 1
• Look specifically for abnormal eosinophils with distinct morphology, which are characteristic of inv(16) AML 4

Treatment Algorithm

For Patients <60 Years with Inv(16)

Standard intensive induction chemotherapy 1:

• Cytarabine combined with either idarubicin or daunorubicin
• This is the recommended first-line approach for favorable-risk cytogenetics

For Patients ≥60 Years

• If fit for intensive therapy: Standard-dose cytarabine with idarubicin, daunorubicin, or mitoxantrone 6
• If not candidates for intensive therapy: Hypomethylating agents (azacitidine or decitabine) 6

Consolidation Therapy

• After achieving complete remission, consolidation therapy is required 5
• Allogeneic hematopoietic stem cell transplant (HSCT) in first remission is generally NOT recommended for favorable-risk inv(16) AML unless additional high-risk features are present (such as c-KIT mutations or failure to achieve deep molecular remission) 5

Response Assessment

• Complete remission (CR) is defined as: bone marrow blasts <5%, absence of blasts with Auer rods, absence of extramedullary disease, absolute neutrophil count ≥1.0 × 10⁹/L, platelet count ≥100 × 10⁹/L, and independence from red cell transfusions 5
• Bone marrow evaluation should be performed 14-21 days after initiation of induction to assess response 6

Molecular Monitoring

• RT-PCR for CBFB-MYH11 fusion transcript should be used for minimal residual disease (MRD) monitoring 5
• The CBFB-MYH11 fusion transcript can be detected with sensitivity up to 1 in 10³-10⁴ 5
• MRD status is a better predictor of relapse risk than cooperating mutations in core binding factor AML 5
• Sequential MRD monitoring helps identify patients at risk for relapse who may benefit from preemptive intervention 5

Critical Monitoring Caveat

• In rare cases of AML M1 with inv(16), the CBFB-MYH11 fusion transcript may not be detected at relapse despite being present at diagnosis 3
• RT-PCR analysis should be correlated with cytogenetics when available and interpreted cautiously in cases with atypical morphology 3

Prognosis

• Patients with inv(16) have a favorable prognosis with good response to intensive induction therapy 4
• Historical data show that 13 of 17 treated patients (76%) entered complete remission, with the majority remaining in first remission 4
• The favorable prognosis is maintained even with additional cytogenetic abnormalities, as long as inv(16) is present 5

Special Considerations for CNS Involvement

• Screening lumbar puncture at first remission should be considered for patients with M4 or M5 morphology or WBC >100,000/mcL at diagnosis 5
• If CNS involvement is detected, intrathecal chemotherapy 2×/week until clear, then weekly for 4-6 weeks is recommended 5