Prof. Jiajun Liu: Interpretation of the research progress of geratinib in the treatment of FLT3-mutated R/R AML patients

Gilteritinib is an oral, highly specific second-generation type I FMS-like tyrosine kinase 3 (FLT3) inhibitor capable of simultaneously inhibiting FLT3-ITD and FLT3-TKD mutations, and the phase III ADMIRAL trial (NCT02421939) demonstrated that giratinib alone versus salvage chemotherapy (SC) significantly prolongs FLT3-mutated relapsed refractory acute myeloid leukemia (R/R).
AML) patients with overall survival (OS; The median OS in the geratinib group and SC group was 9.
3 months and 5.
6 months, respectively, bilateral P=0.
0013), improving the survival of
AML patients.
This year, several journals have published the latest data
on the treatment of R/R AML with geratinib.

summary

Next-generation sequencing (NGS) technology enables in-depth evaluation of AML molecular signatures, with Catherine Smith and colleagues reporting in the journal Blood Advances NGS-based baseline co-mutation and pre- and post-treatment mutation profile analysis of patients from the ADMIRAL trial to assess the relationship between mutation profiles and clinical outcomes; The effects of FLT3-ITD allele ratio and length on treatment response and OS are also observed below
.

Research methods

In this post-hoc analysis of the ADMIRAL study, allele ratios and gene lengths were measured in 335 evaluable patients, with a median FLT3-ITD length of 51 base pairs (bp), and the patient results
were evaluated when FLT3-ITD lengths were > 51 bp and ≤ 51 bp.

Research results

In addition to TP53-aneuploidy, the CR/CRh rate before HSCT was higher in the geratinib group than in the SC group (Figure 1A).

In the DNMT3A and NPM1/DNMT3A co-mutation subgroups, the pre-transplant CR/CRh rate was much higher in patients treated with giratinib than in patients treated with high-intensity SC (Figure 1B).

Figure 1

In six gene subgroups with co-mutations in NPM1, DNA methylation/hydroxymethylation, transcription factors, DNMT3A, WT1, and DNMT3A/NPM1, the OS in the geratinib group was higher than in the SC group (Figure 2A).

。 Among the five gene subgroups of DNMT3A, NPM1, WT1, IDH1/IDH2 and NMT3A/NPM1, the OS in the higher-intensity SC group in the geratinib group was longer.
Patients with DNMT3A/NPM1 co-mutations had a more significant OS benefit with higher-intensity chemotherapy with geratinib (15.
1 versus 5.
2 months) (Figure 2B).

Figure 2

Regardless of FLT3-ITD length, there was a trend towards longer median OS in the giratinib group compared to the SC group: among patients with FLT3-ITD length > 51 bp, the median OS in the giratinib group was 10.
4 months and the median OS in the SC group was 6.
0 months (HR = 0.
480; 95% CI: 0.
311-0.
74); at FLT3-ITD length ≤ 51 bp, the median OS was 8.
9 months in the geratinib group and 6.
1 months in the SC group (HR = 0.
807; 95% CI: 0.
520 to 1.
250) (Figure 3A).

。 Patients in the geretinib group with FLT3-ITD length > 51 bp had the longest median OS; The presence of multiple mutations in FLT3-ITD did not appear to have a negative effect on OS compared to the short or long ITD subgroups; The ratio of FLT3-ITD alleles in the geratinib group was not associated with OS (Figure 3B).

Figure 3

Conclusion of the study

(1) AML patients treated with FLT3 inhibitors may have their mutation profile change over time, which may affect their long-term outcomes and risk of
recurrence.

(2) In other gene subgroups except TP53-aneuploiloidy, geratinib has a tendency to
have a higher pre-transplant response rate and longer OS compared with SC.

(3) Patients with DNMT3A/NPM1 co-mutations treated with gemitinib had a better
prognosis.

(4) The survival outcome of the geratinib group was not affected by
the FLT3-ITD allele ratio, FLT3-ITD length or the number of FLT3-ITD mutations.

In summary, for patients with FLT3 mutation R/R AML, the evolution of molecular map mutations during treatment is significantly related
to the therapeutic benefit of gemitinib.

summary

The key phase III clinical trial of jirelatinib (ADMIRAL), which included 371 patients with R/R AML who received jiratinib (120 mg) or SC, respectively, showed that compared with SC, geratinib significantly prolonged OS (9.
3 vs.
5.
6 months) and event-free survival (2.
8 vs 0.
7 months), and reduced the risk of death by 36% (HR 0.
64).

In terms of safety, the rate of grade 3 or higher adverse events and serious adverse events in the geratinib group was lower than that in the SC group
.
A multicenter retrospective study published in the journal Am J Hematol further evaluated the clinical efficacy and safety of geratinib in patients with FLT3 mutational R/R AML and is presented below
.

Research methods

According to the selection criteria, 410 patients with R/R AML diagnosed with FLT3 mutations at 11 medical centers in the United States were screened between January 2020 and June 2021, all of whom had previously received FLT3 inhibitor therapy and then continued to receive geratinib monotherapy or gemicitinib combination therapy, and finally a total of 113 patients were eligible for inclusion in the study analysis
.
The study evaluation criteria were the same as for the ADMIRAL trial, which used a modified version
of the International Working Group definition.

Research results

Fig.
4a showed that there was no significant difference in OS between patients who received HSCT before starting jiretinib and those who did not receive HSCT, 7.
4 months and 7.
1 months, respectively, but patients who received HSCT after starting jiretinib had a statistically significant difference in median OS compared with patients who did not receive HSCT, 12 months and 5.
2 months, respectively, and patients who received HSCT after starting jiretinib had better clinical outcomes
.

Figure 4b shows that in the CR group, patients who achieved MRD-negative detection by MFC (n=11) or PCR (n=16) had an improvement in median OS compared to their respective MRD-positive patients (Figure 1b).

Patients with cMRD (n=11) who were both negative for MFC and PCR had a 100% chance
of survival.

Figure 4c showed that ASXL-1, TP53, and RUNX1 mutations persisted at diagnosis and recurrence, and these mutations did not affect the median OS (5.
7 versus 7.
1 months) compared to the wild type of each mutation, with no statistically significant difference
.

Figure 4d showed that mutations activating the MAPK kinase pathway had been identified prior to geratinib treatment and were associated with giratinib resistance, such as NRAS and PTPN11 (N=19), and that the presence of these mutations did not significantly differ in CRc rate (59 versus 37.
5 percent) and median OS (4.
9 versus 7.
8 months) (p=0.
0057).

In addition, patients in the study took geratinib for an average of 5.
7 months, and the probability of achieving CRc was 48.
7%, slightly lower than the 54% reported in the ADIMIRAL trial, but this study is a real-world study and the research data may be biased; It is also worth noting that in patients with AML with midotoline induction therapy with or without consolidation therapy, the CRc rate of geratinib was 58%, and the median OS remained up to 7.
8 months
.

Conclusion of the study

The study analyzed the effects of subsequent transplantation therapy, FLT3 mutation clearance, MRD negative and other factors on the clinical benefits of geratinib treatment, which provided more clinical basis
for the future application of geratinib.

The study once again showed that geratinib still achieves efficacy benefits
in patients with R/R AML who have previously failed treatment with FLT3 inhibitors.

summary

This study is a follow-up analysis based on the phase III ADMIRAL clinical trial of girutinib to clarify the long-term efficacy and safety of giratinib in FLT3-mutated R/R AML patients.

Research methods

In this review, the data from the ADMIRAL trial were analyzed post-hoc and, based on the results of the preliminary analysis of ADMIRAL, the long-term efficacy of jirelatinib was analyzed to determine the characteristics of patients in the geratinib group who survived for ≥ 2 years without recurrence, and to evaluate the incidence of late-onset adverse events associated with continued use of
jiretinib for more than 1 year.

Research results

A flowchart of the treatment regimen for patients with relapsed refractory FLT3 mutations during the study period is shown in Figure 5
.
By the end of 2 years of follow-up, there were 203 deaths (82%) in the geratinib group and 97 deaths (78%) in the SC group; In the giratinib group, 49 patients survived ≥ 2 years, 26 of the 49 patients survived ≥ 2 years without recurrence, and 16 patients continued to receive jiratinib
.
A total of 40 (62.
5%) patients in the giratinib group and 19 patients in the SC group received HSCT, a total of 40 (62.
5%) patients resumed jiratinib treatment after HSCT, 24 patients did not resume jiratinib treatment after HSCT, 24 of them received other drugs as follow-up therapy, and 9 patients received HSCT as follow-up therapy
。 Among the patients in the giratinib group who received hiratinib maintenance therapy after HSCT, 4 patients achieved CR before HSCT and 9 patients achieved CR/CRh, and the cumulative recurrence rate at 24 months was 0%; The cumulative recurrence rate of 20 patients who achieved CRc was 18.
6%.

Figure 5

The median OS in the girulatinib group and the SC group were 9.
3 months and 5.
6 months, respectively (HR, 0.
665; 95% CI, 0.
518, 0.
853; bilateral P=0.
0013), and the estimated survival rates of 1-year, 2-year, and 3-year survival in the jiratinib group were 36.
6%, 20.
6%, and 15.
8%, respectively, which were higher than those in the SC group
.
See Figure 6
for details.

Figure 6

The median duration of CR was 23.
0 months in the geratinib group, and the median duration of CRc and CR/CRh was 4.
6 months and 10.
0 months
, respectively.
The 2-year CIR of patients achieving CR or CRc was 52.
6% and 75.
7%, respectively (Figure 7).

Figure 7

The statistics of adverse events in patients with positive AML R/R FLT3 mutation within 1 year or 1 year after treatment with girutinib are shown in the figure, and the most common adverse events are increased ALT (alanine aminotransferase) and AST (aspartate aminotransferase), and the severity is mostly 1
/2.
The incidence decreased in the second year compared with the first year of geratinib treatment; During treatment, no new significant safety signals
associated with geratinib treatment appeared.
It is important to note that 14 (5.
7%) of the 246 patients in the geratinib group were reduced by AE, and major adverse events included elevated ALT, QT interval prolongation, elevated creatine kinase, elevated AST, elevated blood bilirubin, and heart failure
.

Figure 8

Conclusion of the study

AML patients with R/R FLT3 mutations in the ADMIRAL trial benefit from long-term treatment with gemicitinib and can sustainably improve patient survival
.
Sustained remission
was achieved with both continued jiretinib and maintenance therapy with HSCT.

The safety profile of geratinib can remain stable for 2 years without new clinically significant safety signals
.

Professor Liu Jiajun

• Director of the Department of Hematology, The Third Affiliated Hospital of Sun Yat-sen University

• Professor, chief physician, doctoral supervisor

• New Century Outstanding Talents of the Ministry of Education

• Member of China Immunology AssociationChairman of Hematology Branch of Guangdong Medical Industry Association

• Vice Chairman of Guangdong Health Management Society

• Vice Chairman of Guangdong Medical Safety Association Member of the Standing Committee of Hematology and Oncology Professional Committee of Guangdong Anti-Cancer Association

• Member of the Standing Committee of Hematology Branch of Guangdong Medical Association

• Member of the Standing Committee of the Hematology Branch of Guangdong Medical Association, Guangzhou Anti-Cancer Association

• He has been engaged in clinical and basic work of hematology for more than 30 years
  .
  He has presided over 3 projects of the National Natural Science Foundation of China, 8 provincial and ministerial projects, and published more than 150 papers at home and abroad, including more than 40 SCI papers
  .
  At present, he serves as the executive editorial board member of SCI Journal Anti-Cancer Drugs, the editorial board member of Ann hematol.
  , and the invited reviewer of "China Science and Technology Paper Online" of the Ministry of Education
  .
  In 2012, he won the third prize of Guangdong Province Science and Technology Progress Award
  .
  

Reference sources:

1.
Catherine C Smith, Mark J Levis, Alexander E Perl, et al.
Molecular profile of FLT3-mutated relapsed/refractory patients with AML in the phase 3 ADMIRAL study of gilteritinib.
Blood Adv.
2022 Apr 12; 6（7）:2144-2155.
doi: 10.
1182/bloodadvances.
2021006489.