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In Amsterdam, NL, during the 24th meeting of the European Hematology Association (EHA), the phase II results of the SAIL study were presented by Professor Walter Fielder, University Medical Center Hamburg-Eppendorf, Hamburg, DE. This study is a multi-center, open-label, non-randomized trial investigating the combination of cytarabine (Ara-C), idarubicin and selinexor (KPT-330) in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML).1
Primary endpoint of the study was overall remission rate (ORR; measured by CR, CRi and morphological leukemia-free state [MLFS]). Secondary endpoints included rate of partial remissions (PRs), percentage transplanted post-induction, early death rate, overall survival (OS), event-free survival (EFS) and relapse-free survival (RFS). The investigators also analyzed the safety and tolerability of selinexor.
Table 1: Patient characteristics at baseline in cohort 1 and 2
|
Cohort 1 |
Cohort 2 |
Total |
---|---|---|---|
N |
27 |
15 |
42 |
Dose |
40mg/m2 |
60mg flat dose |
- |
Median age (years) |
58 (22–78) |
60 (29–77) |
59.5 (22–78) |
ECOG of 2 at screening |
3.7% |
13.3% |
7.1% |
Prior SCT |
37.0% |
46.7% |
40.5% |
Secondary AML |
22.2% |
20.0% |
21.4% |
Unfavorable cytogenetics |
33.3% |
40.0% |
35.7% |
Late relapse (over 12 months) |
40.7% |
46.7% |
42.9% |
Prof. Fielder noted that this patient population had many unfavorable characteristics, including 40.5% who had relapsed after SCT, 21.4% with secondary AML and 35.7% who had unfavorable cytogenetic profiles.
In the intention-to-treat (ITT) population, the best responses are shown below (Table 2), with subgroup analysis in Table 3. Two of the secondary endpoints, RFS and EFS are shown in Table 4.
Table 2: Best responses to therapy in ITT population
* Four patients were not evaluable for response due to death (influenza pneumonia [n = 2], asystole [n = 1] and suspected hemophagocytic lymphohistiocytosis [n = 1]). These were unexpected and potentially unrelated to the investigatory drug. |
|||
|
Cohort 1 |
Cohort 2 |
Total |
---|---|---|---|
CR |
22% |
20% |
21% |
CRi |
33% |
13% |
26% |
MLFS |
- |
7% |
2% |
ORR |
56% |
40% |
50% |
Stable disease (SD) |
37% |
27% |
33% |
Progressive disease (PD) or resistant |
7% |
7% |
7% |
Inevaluable* |
- |
27% |
10% |
Non-responder |
44% |
60% |
50% |
Table 3: Subgroup analysis of response to treatment
|
Total (n = 42) |
---|---|
Primary vs secondary AML |
51.6% vs 45.5% |
No prior SCT vs prior SCT |
52.0% vs 47.1% |
Remission <12 vs >12 months |
38.5% vs 72.2% |
Favorable/intermediate vs unfavorable cytogenetics |
65.0% vs 26.7% |
FLT3-ITD vs FLT3 wild type |
40.0% vs 50.0% |
NPM1 mutation vs NPM1 wild type |
75.0% vs 44.8% |
In the subgroup analysis, 75% of patients with an NPM1 mutation responded, which supports the theory that selinexor reverses inhibition of nuclear export of NPM1.
In total, 15 patients (36%) moved on to SCT: 8 with CR/CRi, 5 with SD and 2 with PD.
Table 4: EFS and RFS by cohort and median values
|
Cohort 1 |
Cohort 2 |
Median |
---|---|---|---|
RFS (months) |
10.88 (2.83–not reached [NR]) |
NR (4.08–NR) |
17.69 (4.60–NR) |
EFS (months) |
5.62 (2.93–12.56) |
4.31 (0.89–10.36) |
4.93 (3.02–8.02) |
The rates of grade 3–5 adverse events (AEs) occurring in over 10% of patients are shown in Table 5. In total, 25 patients died during treatment; these were predominantly due to PD (n = 12) and sepsis (n = 4). Other causes of death included lung infection, graft-versus-host disease and multiple organ failure.
Table 5: Grade 3–5 AEs occurring in over 10% of patients
|
Cohort 1 |
Cohort 2 |
Total |
---|---|---|---|
Nausea |
11.1% |
13.3% |
11.9% |
Diarrhea |
55.6% |
40.0% |
50.0% |
Anorexia |
37.0% |
13.3% |
28.6% |
Febrile neutropenia |
85.2% |
33.3% |
66.7% |
Fatigue |
14.8% |
13.3% |
14.3% |
Leukopenia |
63.0% |
60.0% |
61.9% |
Thrombocytopenia |
70.4% |
46.7% |
61.9% |
Anemia |
70.4% |
33.3% |
57.1% |
Hypokalemia |
22.2% |
0.0% |
14.3% |
Decreased neutrophil count |
44.4% |
40.0% |
42.9% |
Mucositis oral |
18.5% |
13.3% |
16.7% |
Lung infection |
22.2% |
20.0% |
21.4% |
Sepsis |
25.9% |
20.0% |
23.8% |
The median duration of neutropenia (<1000μl) was 40 days in cohort 1 and 30 days in cohort 2, whilst for thrombocytopenia (<100,000μl) this was 42 days in cohort 1 and 35 in cohort 2.
Prof. Fielder concluded that the ORR of 50% reported in this study is high, relative to other published studies. There was a median OS of 8.2 months (4.7–26.3), with eight of 20 responding patients (40%) receiving a first or second allogeneic SCT. Reducing the dose from 40mg/m2 twice weekly for 4 weeks in cohort 1 to a flat dose of 60mg twice weekly for three weeks appears to make the regimen more tolerable.
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