Exploration of veneclax combined with geeritinib in patients with FLT3-mutated relapsed/refractory acute myeloid leukemia

Despite recent advances in first-line treatment of acute myeloid leukemia (AML), most patients develop relapsed/refractory (R/R) disease

About 30% of newly diagnosed AML patients have activating mutations in FMS-associated tyrosine kinase 3 (FLT3) (including internal tandem repeat mutations [FLT3-ITD] and tyrosine kinase domain mutations [FLT3-TKD])

Research methods

^{This Phase Ib, open-label, dose-escalation/dose-expansion study enrolled patients with FLT3 wild-type (FLT3 WT} ) and FLT3 ^mut (dose escalation) or FLT3 ^mut (dose-expansion) R/R AML from 11 U.

Research result

1.

From October 29, 2018, to December 30, 2020, a total of 61 patients were enrolled

Table 1

2.

400mg veneclax once daily and 120mg giritinib once daily for RP2D

3.

59/61 (97%) patients experienced grade 3/4 AEs regardless of attribution (Table 2)
.

No cases of reversible posterior encephalopathy syndrome or differentiation syndrome occurred
.

Forty-six (75%) patients experienced serious AEs, with febrile neutropenia (27/61, 44%) and pneumonia (8/61, 13%) being the most common (≥10%)
.

The most common (≥25%) grade 3/4 AEs associated with veneclax and gieritinib were decreased white blood cell count (36%; 33%), decreased platelet count (25%; 20%), and anemia (25%), respectively.
%; 20%)
.

AEs led to discontinuation of veneclax and gieritinib in 31 (51%) and 29 (48%) patients, respectively
.

Veneclax was discontinued due to AEs in 9 (15%) patients and giritinib was discontinued due to AEs in 8 patients (13%)
.

Table 2

The 30-day and 60-day mortality rates for all patients were 0 and 13% (8/61), respectively
.

Of the 42 deaths in the study, 29 died from disease progression and 10 patients died from AEs
.

4.
Curative effect

^{Among FLT3 mut} patients (n=56) treated at any dose , the mCRc rate (CR+CRi+CRp+MLFS) was 75% (42/56; CR, 18%; CRi, 4%; CRp, 18%; MLFS, 36%), with a median follow-up of 17.
5 (range, 0.
8-27.
5) months, with a median DOR of 4.
9 months (95% CI, 3.
4-6.
6; Figure 1)
.

The median time to first mCRc was 0.
9 (range, 0.
7-3.
5) months
.

The CRc rate (CR+CRi+CRp) was 39% (22/56 cases), and the median DOR was 4.
9 months (95% CI, 2.
6 to not reached [NR])
.

The median time to first CRc was 2.
1 (range, 0.
7-4.
6) months
.

figure 1

The median OS for all FLT3 ^mut patients was 10.
0 months (95% CI, 6.
3-12.
3) (Figure 2A)
.
^{Among FLT3 mut}
patients treated at any dose , the mCRc rate was 67% in 21 patients not previously exposed to FLT3 TKIs (14/21, CR, 29%; CRi, 5%; CRp, 14%; MLFS, 19 %), the mCRc rate of 35 patients previously exposed to FLT3 TKIs was 80% (28/35; CR, 11%; CRi, 3%; CRp, 20%; MLFS, 46%) (Figure 1) .
Median OS was 10.
6 months (95% CI, 3.
1-20.
9) and 9.
6 months (95% CI, 4.
2-11.
6) in patients with previously unexposed and previously exposed FLT3 TKIs, respectively (Figure 2B) .
^{Among FLT3 mut} patients previously exposed to veneclax (n=10), the mCRc rate was 60% and the median OS was 6.
7 months (95% CI, 1.
7-10.
6) .

figure 2

Analysis conclusion

VenGilt induced high mCRc rates and molecular response rates in R/R FLT3 ^mut AML patients, including those who had failed prior multi-line therapy and those who had been exposed to ≥1 prior FLT3 TKI, with the majority of responding patients achieving molecular response, The response occurred rapidly, indicating that this combined regimen could induce a deep FLT3 clonal response
.

Although the results of this phase Ib study are limited by the small sample size, it provides a piece of evidence supporting the combination of veneclax with a FLT3 inhibitor in FLT3 ^mut AML
.

Although this all-oral regimen is designed for outpatient administration, the potential for myelosuppression and serious infection should be noted
.

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