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Survival outcomes and treatment response in patients with CBF-AML

Feb 15, 2023
Learning objective: After reading this article, learners will be able to discuss factors affecting treatment outcomes in patients with core-binding factor AML.

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Core-binding factor acute myeloid leukemia (CBF-AML) is associated with either the t(8;21)(q22q22)RUNX1-RUNX1T1 fusion gene, or inv(16)p13.1q22)/t(16;16)(p13.1;q22) resulting in the CBFB-MYH11 fusion gene.1,2 While the 2022 European LeukemiaNet (ELN) guidelines classify CBF-AML as favorable risk, a large proportion of patients with CBF-AML experience relapse.1,2 Furthermore, the prognostic significance of somatic mutations in patients with CBF-AML remains unclear.3

Cytarabine is often used for consolidation treatment in patients with CBF-AML following complete remission (CR); however, more information is needed on the optimal dose intensity.1 Novel agents, such as sorafenib, a type-II multitargeted tyrosine kinase receptor inhibitor, are being investigated in combination with chemotherapy.2

Below, we summarize a presentation and an abstract from the 64th American Society of Hematology (ASH) Annual Meeting and Exposition by Hyak1 investigating the treatment of patients with CFB-AML with high-dose cytarabine (HDAC) and Shi et al.2 on a phase II trial assessing sorafenib in patients with CBF-AML. We also summarize a poster presentation from the Society of Hematologic Oncology (SOHO) 2022 Annual Meeting by Ball3 looking at the impact of somatic mutations in patients with CBF-AML.

Cytarabine consolidation1

Study design and patient characteristics

This study included 304 patients with CBF-AML who were aged 18–59 years and enrolled on Cancer and Leukemia Group B/Alliance protocols between 1986 and 2016. Of these patients, 186 had CBFB-MYH11 and 118 had RUNX1-­RUNX1T1 fusion genes. All patients achieved CR following cytarabine/anthracycline-based induction therapy and received HDAC consolidation therapy.

Key findings

Overall, survival outcomes were favorable (Table 1).

Table 1. Survival outcomes in patients with CBF-AML*

Outcome, % (unless otherwise stated)

Patients with CBF-AML
(N = 304)

Death in CR


Relapse rate




               Median DFS, years


               5-year DFS




               Median OS, years


               5-year OS


CBF-AML, core-binding factor acute myeloid leukemia; CR, complete remission; DFS, disease-free survival; NR, not reached; OS, overall survival.
*Adapted from Hyak.1

Subgroup analysis revealed the following:

  • Receiving ≥3 cycles of HDAC was associated with better disease-free survival (DFS; p < 0.001) and overall survival (OS; p < 0.001) than <3 cycles of HDAC.
  • Both DFS and OS were similar between patients with CBFB-MYH11 and RUNX1-­RUNX1T1.
  • Among patients with CBFB-MYH11, DFS and OS were numerically but not significantly longer in patients with t(16;16) compared with inv(16).
  • None of the frequently observed secondary abnormalities impacted OS in patients with CBFB-MYH11, including trisomy 22, trisomy 8, and complex karyotype.
  • Similarly, secondary cytogenetics had no impact on OS in patients with RUNX1-­RUNX1T1, including loss of Y chromosome, loss of X chromosome, trisomy 8, and complex karyotype.

Notable co-occurring gene mutations included FLT3-TKD, KIT, KRAS, and NRAS, which occurred at the following frequencies:

  • In patients with CBFB-MYH11, co-mutations in FLT3-TKD, KIT, KRAS, and NRAS were observed in 8%, 17%, 7%, and 28% of patients respectively.
  • In patients with RUNX1-­RUNX1T1, co-mutations in FLT3-TKD, KIT, KRAS, and NRAS were detected in 3%, 24%, 1%, and 15% of patients respectively.

In these co-mutational subgroups, analysis of survival outcomes found the following:

  • The presence of KIT mutations with variant allele frequency (VAF) ≥10% was associated with worse DFS compared with KIT wild-type (KITwt) in patients with CBFB-MYH11 (p < 0.001) and RUNX1-­RUNX1T1 (p = 0.03), and worse OS in patients with CBFB-MYH11 (p = 0.04).
    • Patients with KIT mutations with a VAF of ≥2 but <10 had comparable DFS and OS with patients with KITwt.
  • FLT3-TKD, KRAS, and NRAS mutations had no impact on DFS and OS in patients with CBFB-MYH11.
  • NRAS mutations had no impact on DFS and OS in patients with RUNX1-­RUNX1T1.

Sorafenib in combination with chemotherapy2

Study design and patient characteristics

This multicenter phase II study included 64 patients with newly diagnosed CBF-AML enrolled between January 2020 and March 2022. Patients were randomized 1:1 to either chemotherapy alone (control) or sorafenib combined with chemotherapy. The control group received one cycle of induction therapy with idarubicin plus cytarabine followed by one cycle of idarubicin plus cytarabine, and two cycles of HDAC consolidation therapy. In the sorafenib group, patients received treatment with chemotherapy plus sorafenib 400 mg twice daily on Days 8–21 for the induction cycle, on Days 1–21 for each consolidation cycle, and as maintenance for 12 months. Following four cycles of therapy, patients proceeded to allogeneic or autologous hematopoietic stem cell transplantation directed by measurable residual disease (MRD) status and donor availability.

Key findings

  • Hematologic CR rates were comparable between patients treated with sorafenib and those in the control group (Table 2).
  • Following three and four cycles of therapy, major molecular response and complete molecular remission rates were higher in the sorafenib group compared with the control group (Table 2).

Table 2. Response rates in the sorafenib and control groups*

Response, %

Sorafenib group
(n = 32)

Control group
 = 32)

p value

Hematologic CR




Following three cycles of therapy




               Major molecular response




               Complete molecular remission




Following four cycles of therapy




               Major molecular response




               Complete molecular remission




CR, complete remission.
*Data from Shi, et al.2
Defined as transcript ratio <0.1%.
Defined as transcript ratio <0.001%.

No significant differences in Grades 3–4 adverse events were observed between the two treatment groups.

The impact of somatic mutations3

Study design and patient characteristics

This single-center retrospective study analyzed 51 patients with CBF-AML treated at the Moffit Cancer Center, including 21 with RUNX1-­RUNX1T1 and 38 with CBFB-MYH11 fusion genes. The median age at diagnosis was 48 years.

Key findings

  • Cytarabine and anthracycline (7+3) was the most common induction regimen (48%) followed by 7+3 plus gemtuzumab ozogamicin (37%); gemtuzumab ozogamicin was the most common consolidation therapy (36%).
  • In total, 39% of patients received allogeneic hematopoietic stem cell transplantation.
  • The most common mutations at baseline included KIT (31%), NRAS (26%), KRAS (15%), FLT3-TKD (11%), and FLT3-ITD (9%).
    • Among patients with CBFB-MYH11, NRAS was the most frequent mutation (32%), while in patients with RUNX1-­RUNX1T1, KIT mutations occurred most commonly (45%)
  • The rate of CBF-MRD negativity was 15% post-induction and 70% post-consolidation, with no significant impact from kinase mutational status.
  • In patients with RUNX1-­RUNX1T1, the CBF-MRD negativity rate was numerically lower in patients with KIT mutations than in patients with KITwt (38% vs 75%).
  • The presence of kinase mutations at baseline was associated with worse relapse-free survival (RFS) compared with patients who were wild-type (median RFS, 7.7 months vs 12.9 months; p = 0.01) but had no impact on median OS (94.1 months vs not-reached; p = 0.44).


These studies confirmed the generally favorable survival outcomes of patients with CBF-AML, although varying long-term survival was noted. Treatment with more cycles of HDAC seemed to have a positive effect on survival1 and the addition of sorafenib to induction, consolidation, and maintenance chemotherapy increased molecular response without any additional adverse events.2

Regarding somatic mutations, Hyak1 reported no significant impact of secondary cytogenetics on survival outcomes, with only the presence of KIT co-mutations with a VAF ≥10% negatively affecting RFS in patients with either RUNX1-­RUNX1T1 or CBFB-MYH11 and OS in patients with CBFB-MYH11. However, in the study by Ball3, kinase mutations had a negative impact on RFS; therefore, the impact of somatic mutations in CBF-AML warrants further investigation, and based on the study by Hyak1, the VAF cut-off should also be explored.

  1. Hyak J. Characterization of survival outcomes and clinical and molecular modulators in adult patients with core-binding factor acute myeloid leukemia (CBF-AML) treated with Hidac consolidation: an Alliance Legacy study. Oral abstract #536. 64th American Society of Hematology Annual Meeting and Exposition; Dec 11, 2022; New Orleans, US.
  2. Shi P, Jia X, Liao N, et al. Prospective evaluation of sorafenib combined with chemotherapy in newly diagnosed adult core-binding factor acute myeloid leukemia: an open-label, randomized controlled, multicenter phase II trial. Abstract #830. 64th American Society of Hematology Annual Meeting and Exposition; Dec 12, 2022; New Orleans, US.
  3. Ball S. Impact of somatic mutations on treatment response and outcomes in patients with core binding factor acute myeloid leukemia. Poster #488. Society of Hematologic Oncology 2022 Annual Meeting; Sep 28–Oct 1, 2022, Houston, US.


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