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Sorafenib is the first-generation type II multikinase inhibitor.
Because the drug has good efficacy data in preclinical and non-randomized clinical studies in acute myeloid leukemia (AML), the Leukemia Research Alliance (SAL) has launched a A randomized trial to evaluate the efficacy and tolerability of sorafenib combined with standard induction therapy as the main treatment for adults with AML less than 60 years old
.
The results of the first study analysis after 36 months of follow-up showed that the addition of sorafenib treatment can significantly prolong the event-free survival (EFS) and recurrence-free survival (RFS) of adult AML patients, and have overall survival The trend of prolonged period (OS)
.
Based on this, the researchers further analyzed this study to explore the type and efficacy of second-line treatment for patients with relapse in the study, including the proportion and method of allogeneic stem cell transplantation (Allo-SCT), and the effect after the second complete remission (CR) Cumulative recurrence rate (CIR) and OS after the first recurrence
.
Research method SORAML is a randomized placebo-controlled double-blind trial conducted in Germany
.
Newly diagnosed AML patients aged 18-60 years (without regard to FLT3 mutation status, ECOG score ≤ 2 points, and sufficient heart, kidney, and liver functions) are eligible for inclusion in the trial
.
After enrollment, the patients were randomly divided into groups at a ratio of 1:1 through randomization of the central group, and the allocation of placebo or sorafenib treatment was hidden
.
Study Results Baseline Distribution of Patients and Treatment Response The study included 276 patients from 25 German research centers from March 27, 2009 to November 28, 2011
.
Nine patients did not receive the study drug, and a total of 267 patients constituted the full analysis set of the intention-to-treat analysis, including 134 in the sorafenib group and 133 in the placebo group
.
A total of 46/267 (17%) AML patients had FLT3 internal tandem duplication (ITD) positive, and 86/267 (33%) AML patients had NPM1 mutations (Table 1)
.
The CR rates of sorafenib and placebo control patients were 60% and 59%, respectively
.
The proportions of patients in the sorafenib and placebo groups who received Allo-SCT at CR1 were 31% and 26%, respectively
.
The median duration of treatment in the sorafenib group was 37.
5 days and that in the placebo group was 41 days (p=0.
13)
.
The induction treatment mortality rates for sorafenib and placebo groups were 3% and 1.
5%, respectively
.
Table 1: Patients with baseline characteristics.
After a median follow-up of 78 months, the 5-year EFS rates of sorafenib and placebo groups were 41% (95% CI 34%-51%) and 27% (95%).
CI 21%-36%), the unadjusted hazard ratio (HR) was 0.
68 (95% CI 0.
51-0.
91; p=0.
011 (Figure 1)
.
In the multivariate Cox model, the established prognostic parameters age, cell Genetic risk, NPM1 and FLT3-ITD mutation status, lactate dehydrogenase (LDH), white blood cell (WBC) and secondary AML.
Sorafenib treatment still has a significant effect on EFS.
The adjusted HR is 0.
61 (95% CI 0.
44-0.
87; p=0.
006)
.
Favorable cytogenetics and NPM1 mutations are associated with patients with better EFS, while patients with poor cytogenetic abnormalities have a poor prognosis (Table 2)
.
Subgroup analysis showed that patients with FLT3-ITD benefited more from sorafenib treatment than patients without FLT3-ITD, and the corresponding HR was 0.
55 (95% CI 0.
28–1.
08) vs 0.
71 (95% CI 0.
51–0.
99 )
.
If patients with FLT3-ITD mutations are excluded from the study population, sorafenib still has significant EFS and RFS advantages over the placebo treatment group
.
Figure 1: EFS status of patients since randomization Table 2: EFS, RFS and OS risk ratio of patients according to multivariate Cox regression model RFS, recurrence after CR, and OS status Among 159 patients who achieved CR, sorafenib The 5-year RFS rates of patients in the placebo group and the placebo group were 53% and 36%, respectively, and the unadjusted HR was 0.
64 (95% CI 0.
42–0.
97; p=0.
035) (Figure 2)
.
Multivariate analysis showed that after adjusting for other prognostic variables such as age, cytogenetic risk, NPM1 and FLT3-ITD mutation status, LDH, WBC, and secondary AML, the HR was 0.
57 (95% CI 0.
35–0.
92, p=0.
021)
.
In patients who did not receive Allo-SCT as post-remission consolidation therapy at CR1, the obvious benefit of RFS did not translate into OS benefit; in patients who received Allo-SCT at CR1, OS benefit was obvious
.
Figure 2: Patients with RFS from CR1 have a higher rate of recurrence after CR than those in the sorafenib-treated group
.
The CIR of patients in the sorafenib and placebo groups after 5 years was 36% (95% CI 25-47) and 50% (95% CI 39-61) (p=0.
087), respectively
.
In the recurrence rate and non-recurrence mortality (NRM) analysis of salvage transplantation, it was observed that the difference in the frequency of the second transplantation and haploidentical SCT did not affect the NRM
.
88% of relapsed patients underwent Allo-HSCT.
The 4-year CIR of sorafenib and placebo patients were 54% and 35%, respectively, and the 4-year OS rate after transplantation was 32% and 50%, respectively; The 5-year OS rates of patients from randomization were 61% and 53% (HR 0.
82; P=0.
282) (Figure 3)
.
Compared with patients in the placebo group, patients who relapsed after sorafenib treatment had a lower 2-year OS rate of 35% and 54% (p=0.
103)
.
Figure 3: The results of the study of the OS status of patients since randomization.
The results of the study showed that the long-term follow-up results of the treatment of young newly diagnosed AML patients with sorafenib on the basis of standard intensive treatment showed that the patients' EFS and RFS were significantly prolonged
.
References: Christoph Röllig, Hubert Serve, Richard Noppeney,et al.
Sorafenib or placebo in patients with newly diagnosed acute myeloid leukaemia: long-term follow-up of the randomized controlled SORAML trial.
Leukemia.
2021 Sep;35(9): 2517-2525.
Stamp "read the original text", we will make progress together
Because the drug has good efficacy data in preclinical and non-randomized clinical studies in acute myeloid leukemia (AML), the Leukemia Research Alliance (SAL) has launched a A randomized trial to evaluate the efficacy and tolerability of sorafenib combined with standard induction therapy as the main treatment for adults with AML less than 60 years old
.
The results of the first study analysis after 36 months of follow-up showed that the addition of sorafenib treatment can significantly prolong the event-free survival (EFS) and recurrence-free survival (RFS) of adult AML patients, and have overall survival The trend of prolonged period (OS)
.
Based on this, the researchers further analyzed this study to explore the type and efficacy of second-line treatment for patients with relapse in the study, including the proportion and method of allogeneic stem cell transplantation (Allo-SCT), and the effect after the second complete remission (CR) Cumulative recurrence rate (CIR) and OS after the first recurrence
.
Research method SORAML is a randomized placebo-controlled double-blind trial conducted in Germany
.
Newly diagnosed AML patients aged 18-60 years (without regard to FLT3 mutation status, ECOG score ≤ 2 points, and sufficient heart, kidney, and liver functions) are eligible for inclusion in the trial
.
After enrollment, the patients were randomly divided into groups at a ratio of 1:1 through randomization of the central group, and the allocation of placebo or sorafenib treatment was hidden
.
Study Results Baseline Distribution of Patients and Treatment Response The study included 276 patients from 25 German research centers from March 27, 2009 to November 28, 2011
.
Nine patients did not receive the study drug, and a total of 267 patients constituted the full analysis set of the intention-to-treat analysis, including 134 in the sorafenib group and 133 in the placebo group
.
A total of 46/267 (17%) AML patients had FLT3 internal tandem duplication (ITD) positive, and 86/267 (33%) AML patients had NPM1 mutations (Table 1)
.
The CR rates of sorafenib and placebo control patients were 60% and 59%, respectively
.
The proportions of patients in the sorafenib and placebo groups who received Allo-SCT at CR1 were 31% and 26%, respectively
.
The median duration of treatment in the sorafenib group was 37.
5 days and that in the placebo group was 41 days (p=0.
13)
.
The induction treatment mortality rates for sorafenib and placebo groups were 3% and 1.
5%, respectively
.
Table 1: Patients with baseline characteristics.
After a median follow-up of 78 months, the 5-year EFS rates of sorafenib and placebo groups were 41% (95% CI 34%-51%) and 27% (95%).
CI 21%-36%), the unadjusted hazard ratio (HR) was 0.
68 (95% CI 0.
51-0.
91; p=0.
011 (Figure 1)
.
In the multivariate Cox model, the established prognostic parameters age, cell Genetic risk, NPM1 and FLT3-ITD mutation status, lactate dehydrogenase (LDH), white blood cell (WBC) and secondary AML.
Sorafenib treatment still has a significant effect on EFS.
The adjusted HR is 0.
61 (95% CI 0.
44-0.
87; p=0.
006)
.
Favorable cytogenetics and NPM1 mutations are associated with patients with better EFS, while patients with poor cytogenetic abnormalities have a poor prognosis (Table 2)
.
Subgroup analysis showed that patients with FLT3-ITD benefited more from sorafenib treatment than patients without FLT3-ITD, and the corresponding HR was 0.
55 (95% CI 0.
28–1.
08) vs 0.
71 (95% CI 0.
51–0.
99 )
.
If patients with FLT3-ITD mutations are excluded from the study population, sorafenib still has significant EFS and RFS advantages over the placebo treatment group
.
Figure 1: EFS status of patients since randomization Table 2: EFS, RFS and OS risk ratio of patients according to multivariate Cox regression model RFS, recurrence after CR, and OS status Among 159 patients who achieved CR, sorafenib The 5-year RFS rates of patients in the placebo group and the placebo group were 53% and 36%, respectively, and the unadjusted HR was 0.
64 (95% CI 0.
42–0.
97; p=0.
035) (Figure 2)
.
Multivariate analysis showed that after adjusting for other prognostic variables such as age, cytogenetic risk, NPM1 and FLT3-ITD mutation status, LDH, WBC, and secondary AML, the HR was 0.
57 (95% CI 0.
35–0.
92, p=0.
021)
.
In patients who did not receive Allo-SCT as post-remission consolidation therapy at CR1, the obvious benefit of RFS did not translate into OS benefit; in patients who received Allo-SCT at CR1, OS benefit was obvious
.
Figure 2: Patients with RFS from CR1 have a higher rate of recurrence after CR than those in the sorafenib-treated group
.
The CIR of patients in the sorafenib and placebo groups after 5 years was 36% (95% CI 25-47) and 50% (95% CI 39-61) (p=0.
087), respectively
.
In the recurrence rate and non-recurrence mortality (NRM) analysis of salvage transplantation, it was observed that the difference in the frequency of the second transplantation and haploidentical SCT did not affect the NRM
.
88% of relapsed patients underwent Allo-HSCT.
The 4-year CIR of sorafenib and placebo patients were 54% and 35%, respectively, and the 4-year OS rate after transplantation was 32% and 50%, respectively; The 5-year OS rates of patients from randomization were 61% and 53% (HR 0.
82; P=0.
282) (Figure 3)
.
Compared with patients in the placebo group, patients who relapsed after sorafenib treatment had a lower 2-year OS rate of 35% and 54% (p=0.
103)
.
Figure 3: The results of the study of the OS status of patients since randomization.
The results of the study showed that the long-term follow-up results of the treatment of young newly diagnosed AML patients with sorafenib on the basis of standard intensive treatment showed that the patients' EFS and RFS were significantly prolonged
.
References: Christoph Röllig, Hubert Serve, Richard Noppeney,et al.
Sorafenib or placebo in patients with newly diagnosed acute myeloid leukaemia: long-term follow-up of the randomized controlled SORAML trial.
Leukemia.
2021 Sep;35(9): 2517-2525.
Stamp "read the original text", we will make progress together
