Core binding Factor AML

Core binding factors are heterodimeric transcription factors necessary in different stages of hematopoiesis.

Core binding factor alpha and beta subunits form heterodimers to bind to DNA and regulate hematopoetic differentiation, cell cycles, and ribosome biogenesis.

Core binding factor alpha has three subunits-RUNX1, 2, and 3, whereas core binding factor beta has one subunit.

Translocation events creating fusion proteins alter DNA binding of the transcription factors. 

The transcription program changes toward down regulation of differentiation genes and maintenance of stem ess genes.

The normal function of the core binding factors to promote differentiation, seeing that an orderly maturation in the process of hematopoesis  occurs.

When the normal function of core binding factors are disrupted, the cells are  arrested in an early state, which sets the stage for development of leukemia.

Core binding factor acute myelogenous leukemia (CBF-AML), characterized by the presence of either t(8;21) (q22;q22) or inv(16) (p13q22)/t(16;16).

It is considered good-risk AML.

The incorporation of gemtuzumab ozogamicin into frontline therapy should be standard. for core binding factor acute myelogenous leukemia (CBF-AML), 

Cytarabine based induction/consolidation regimen may be combined with anthracycline (3 + 7 standard) or antimetabolite, fludarabine. 

Core-binding factor (CBF) acute myeloid leukemia (AML), comprising up to 12–15% of all AML cases.

Core-binding factor (CBF) acute myeloid leukemia (AML)is characterized by the presence of either t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16), which leads to the formation of RUNX1/RUNX1T1 (AML1/ETO) and CBFB/MYH11 fusion genes respectively. 

Core-binding factor (CBF) cytogenetic aberrations are associated with favorable response and increased sensitivity to cytarabine. 

Core binding factors are hematopoietic transcription factors characterized: by a DNA binding unit, and a CBFA and non-DNA binding unit, CBFB

CBFA comprises of three subunits; RUNX1, RUNX2, and RUNX3.

CBFB  is the non-DNA binding unit of the heterodimer. 

Core binding factors are necessary in normal hematopoiesis: Translocation events alter the normal DNA binding of the heterodimer create alternate binding, leading to disruption of the normal transcription program and resulting in maturation arrest.

Both t(8;21) and inv16 AML involve CBF translocations and are considered good-risk AML, outcomes of t(8;21) and inv16 are quite different. 

Relapses are more frequent in the t(8;21)AML and long-term outcome is worse.

The mutational profiles are also different: t(8;21) AML is associated more often with epigenetic/chromatin modulator/cohesion mutations.

Inv16 AML is associated more often with kinase mutations, particularly MAPK pathway mutations. 

Multiple mutations in the same signaling pathway are frequent in CBF AML.

Remission rates are usually high in CBF AML. 

Remission induction with cytarabine/anthracycline-based chemotherapy combinations and consolidation with high-dose cytarabine (HDAC)-based regimens is considered as the standard of care for AML. 

Early reduction in the CBF related fusion transcript translates into better relapse-free survival (RFS).

Fludarabine, cytarabine and based regimens can be effective alternative to the traditional “3 + 7” based approach.

The addition of Gemtuzumab Ozogamicin (GO) to remission induction therapy improved survival in CBF AML, 

with an absolute survival benefit of 20.7%, even though remission rates were not higher with GO containing regimens. 

The incorporation of GO into the remission induction should be considered standard for CBF AML.

Optimizing the post-remission therapy in CBF AML with consolidation therapy consisting of 3 or 4 cycles of HDAC is associated with a lower relapse rate and a better OS compared with one course of HDAC.

Quantitative monitoring of measurable residual disease in CBF AML and MRD-based decision making is useful in disease management and outcome prediction.

The presence of KIT mutations (exon 17) in CBF AML  is associated with a higher relapse rate, as are ASXL2

epigenetic mutations, kinase mutations (JAK2), and cohesion/spliceosome mutations.

Adding potent KIT inhibitors into frontline therapy may improve outcome of CBF AML. 

Allogeneic stem cell transplant in CBF AML is for relapsed disease.

Patients older than 60 years comprise about 5-15% of adult CBF AM?

Older patients have a worse overall survival.

A French AML Intergroup study evaluated the outcome of CBF AML among patients 60 years or older with Cytarabine and anthracycline-based induction chemotherapy resulted in a CR of 80% with the first course, and 88% after a second course. 

Post-remission therapy included either maintenance chemotherapy of low-dose cytarabine, methotrexate, and mercaptopurine; or intensive consolidation therapy [IDAC/HDAC-based regimen for at least 2 days, or high-dose melphalan followed by auto-SCT.

After a median follow-up of 48 months, the 5-year probabilities of overall survival (OS) and leukemia-free survival (LFS) were 31% and 27%, respectively. 

The 5-year DFS rate was significantly longer with intensive consolidation compared with low intensity maintenance chemotherapy: most of the benefit was observed in patients with t(8;21) but not in patients with inv(16)/t(16;16).

Older patients with CBF AML should be offered intensive post-remission chemotherapy if considered fit.

Treatment of relapsed CBF AML

salvage intensive chemotherapy has a median survival for patients with inv(16) of  15.6 months and for patients with t(8;21) 9 months .

t(8;21) is associated with a higher hazard of death after adjusting for age and stem cell transplant.

In the French group, a first remission duration of over 1 year and treatment with regimens incorporating Gemtuzumab Ozogamicin (GO) were associated with better DFS and OS. 

CBF AML can rarely emerge as part of therapy-related AML: the outcome of secondary or therapy-related CBF AML (tCBF-AML) is significantly worse than de novo CBF AML 

A JAK2 mutation, a poor risk mutation in newly diagnosed CBF AML, is more common in therapy-related CBF AML. 

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