Can Dasatinib Overcome the Negative Effects of KIT Mutations in Core Binding Factor AML?

A chemotherapy regimen of cytarabine and daunorubicin plus dasatinib was well tolerated in patients with previously untreated core binding factor acute myeloid leukemia (CBF-AML) and was associated with a relatively high short-term survival rate, according to an analysis of the CALGB 10801 study published in Blood Advances. The results were similar between patients with and without KIT-mutated disease, suggesting that adding the multi-kinase inhibitor dasatinib to conventional cytarabine/daunorubicin chemotherapy could overcome the negative effects of these mutations.

The study authors, led by Guido Marcucci, MD, from City of Hope in California, screened 779 patients with previously untreated AML for RUNX1/RUNX1T1 or CBFB/MYH11 fusion transcripts. In addition, the investigators performed analyses for KIT mutations and expression; KIT mutations are present in 15 to 45% of cases of CBF-AML and in most studies have been associated with poorer outcomes.

Treatment in the CALGB 10801 trial consisted of the following:

  • days 1-7: induction chemotherapy with continuous intravenous infusion of cytarabine 200 mg/m2/day
  • days 1-3: intravenous daunorubicin 60 mg/m2/day
  • days 8-21: oral dasatinib 100 mg/day

Consolidation therapy, consisting of high-dose cytarabine (at either 3,000 mg/m2 for patients <60 years or 1,000 mg/m2 for those ≥60 years) on days 1, 3, and 5, plus dasatinib 100 mg/day on days 6 to 26, was administered to patients who achieved complete remission (CR) after 1 or 2 cycles of induction therapy. If patients remained in CR following consolidation, they received maintenance therapy with dasatinib 100 mg daily for 12 months.

The study’s primary endpoint was safety, assessed by the 30-day post-induction survival rate, while the CR rate, overall survival (OS), and disease-free survival (DFS) served as secondary efficacy endpoints.

A total of 61 of the 779 (7.8%) patients who were screened at study entry were found to be positive for RUNX1/RUNX1T1 or CBFB/MYH11 fusion transcripts. Most patients were younger than 60 years (n=46; 75%). Among these patients, 20 harbored t(8;21)(q22;q22) and 40 harbored inv(16)(p13q22)/t(16;16)(p13;q22) . In addition, 11 of the molecularly evaluable patients (19%) had a KIT mutation.

During a median follow-up of 45 months (range = 1.4-60 months), 54 patients (89%) experienced CR and completed most or all the planned induction therapy, while 42 (76%) and 19 (31%) completed consolidation and maintenance therapy, respectively.

Overall, 4 of the patients died while receiving therapy, including 3 during induction therapy and 1 while in CR during consolidation therapy. The cause of death in these patients was sepsis with respiratory or multiorgan failure.

The investigators also reported that 10 patients experienced an adverse event (AE) that led to discontinuation of treatment. Most of these AEs occurred during consolidation and were as expected and similar to those previously reported with this chemotherapy regimen and/or dasatinib and included pleural effusions and abnormal liver function tests that were considered possibly associated with dasatinib.

In the efficacy analysis, the overall 30-day survival rate was 97%. A slightly higher 30-day survival rate was observed in patients <60 years of age versus patients ≥60 years of age (98% vs. 93%, respectively), although p value was not reported. Rates of CR also appeared to be higher in the younger patients (93% vs. 80%, respectively).

During follow-up, 10 patients relapsed: 4 with RUNX1/RUNX1T1 and 6 with CBFB/MYH11, and 6 younger and 4 older patients. The rate of 3-year DFS was 75% and the rate of 3-year OS was 77% in the overall cohort. Survival rates for the younger and older patient populations were:

  • 3-year DFS: 79% and 60%, respectively
  • 3-year OS: 85% and 51%, respectively

When the researchers looked at survival outcomes according to mutation status, they observed that older patients with RUNX1/RUNX1T1 mutations had 3-year DFS and OS rates of 71% and 68%, while those with CBFB/MYH11 mutations had 3-year DFS and OS rates of 76% and 81%.

Results from a post hoc analysis demonstrated that survival rates were similar for patients with KIT mutation versus KIT wild-type (KITwt), as well as patients with lower or higher levels of KITwt expression (TABLE).

“Overall, our findings support further evaluation of KIT inhibitors in combination with chemotherapy in CBF-AML through future larger prospective randomized trials,” the authors concluded. “However, despite our encouraging results, it is evident that even when dasatinib was added to chemotherapy, not all [patients] achieved long-term leukemia-free status. Thus, the treatment approach for CBF-AML patients should be further refined with the rational addition of other molecularly targeted agents.”

Limitations of the study include the small number of participants, the single-arm design, the small number of patients who completed the dasatinib maintenance post-chemotherapy regimen (n=19), and the lack of assessment of measurable residual disease during and after treatment.

The study authors report no relevant conflicts of interest.

Reference

Marcucci G, Geyer S, Laumann K, et al. Combination of dasatinib with chemotherapy in previously untreated core binding factor AML: CALGB 10801. Blood Adv. 2020;4:696-705.

CBF-AML is commonly referred to as a “favorable” subtype of AML, with many frontline AML clinical trials excluding these patients because their expected outcomes with traditional therapy were considered too good to justify trial enrollment. However, some patients with CBF-AML do have poor outcomes. One such subset includes those with KIT mutations. There is controversy regarding the magnitude of the negative impact of KIT mutations and whether allogeneic hematopoietic cell transplantation (alloHCT) in first CR is justified in patients with such mutations.

In this study, Marcucci et al. enrolled 61 patients with CBF-AML who received standard induction and consolidation combined with dasatinib, followed by a year of dasatinib maintenance. The authors observed expected toxicities, a 90% CR rate, and 3-year survival rates that did not differ significantly based on KIT mutation status, suggesting that dasatinib might overcome the negative effect of KIT mutations.

These results are intriguing and raise questions regarding implications for clinical practice. While the results compare favorably with historical data and are supported by a similar German trial (AMLSG 11-08), there are no randomized data to support routine use of dasatinib. Furthermore, addition of gemtuzumab ozogamicin (GO) to standard chemotherapy has significantly improved clinical benefits for the CBF-AML patient population and has become a standard treatment option for CBF-AML.
Until randomized data favor one approach over the other, the addition of GO or dasatinib (or midostaurin in FLT3-positive patients), are all reasonable options for CBF-AML – especially those with KIT mutations. Questions regarding use of other agents for combinations with chemotherapy (e.g., other tyrosine kinase inhibitors or venetoclax), as well as the role of measurable residual disease and alloHCT in the management of CBF-AML with KIT mutations will need to be evaluated in future clinical trials.

Amer Zeidan, MBBS
Yale University
New Haven, CT