General AML

EHA 2019 | Phase II results of the SAIL study in relapsed/refectory acute myeloid leukemia (AML)

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), adarubicin and selinexor (KPT-330) in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML).1

Background
  • Patients with R/R AML represent a population with an high unmet need since there is currently no standard-of-care, and limited efficacious treatment options are available
  • Selinexor is a selective inhibitor of nuclear export (SINETM)
    • By blocking nuclear export, the nucleus retains topoisomerase (TOPO) IIα protein
    • Cancer cells become re-sensitized to TOPO inhibitors including anthracyclines
    • This prevents DNA damage repair and enhances cell death
    • Hypothesis: anthracycline and selinexor have a synergistic mechanism of action
Study design and patient characteristics
  • Patients with R/R AML (N = 42)
  • All patients received Ara-C (100mg/m2 on days 1–7 by continuous infusion) + idarubicin (100mg/m2 on days 1, 3 and 5) with either:
    • Cohort 1 (n = 27): oral selinexor: 40mg/m2 twice weekly for 4 weeks
    • Cohort 2 (n = 15): oral selinexor: 60mg twice weekly for 3 weeks of a 4 week cycle
    • Due to prolonged aplasia, high rates of febrile neutropenia and severe diarrhea in cohort 1, a subsequent cohort (cohort 2) was recruited and patients received a flat dose of 60mg
  • If patients achieved a complete remission (CR) or CR with incomplete blood count recovery (CRi) they received either:
    • Allogeneic stem cell transplant (SCT)
    • Consolidation and maintenance:
      • Consolidation with Ara-C + selinexor
        • Patients <60 and with good performance status:
          • Ara-C: 3000mg/m2 twice daily on days 1–3 as a 2 hour infusion
          • Selinexor: twice weekly as in cohort 1 and 2
        • Patients >60:
          • Ara-C: 1000mg/m2 twice daily on days 1–3 as a 2 hour infusion
          • Selinexor: twice weekly as in cohort 1 and 2
      • Maintenance with selinexor only, dosed as per cohort 1 and 2

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.

Efficacy

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

 

Cohort 1

(n = 27)

Cohort 2

(n = 15)

Total

(n = 42)

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%

* 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.

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)

Safety

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

(n = 27)

Cohort 2

(n = 15)

Total

(n = 42)

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.

Conclusion

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.

References
  1. Fielder W. et al. A phase II study of selinexor plus cytarabine and idarubicin in patients with relapsed/refractory acute myeloid leukemia (AML). Oral abstract #S880. 2019 Jun 15. European Hematology Association (EHA) 24th Annual Meeting, Amsterdam, NL
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