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Early results from the phase III AMLSG 09-09 trial

Feb 28, 2020

In December 2019, early results from the prospective, randomized, multicenter, phase III trial, AMLSG 09-09 ( NCT00893399), were published in the Journal of Clinical Oncology by Richard F. Schlenk, Ulm University Hospitaland Heidelberg University Hospital, DE, and colleagues. 1This study is evaluating gemtuzumab ozogamicin (GO) in combination with intensive induction and consolidation in patients with nucleophosmin-1- ( NPM1)-mutated acute myeloid leukemia (AML). This article provides a summary of the key take-home messages. 1


AML with NPM1gene mutation is recognized by the World Health Organization (WHO) classification as a distinct subtype associated with a favorable prognosis in older patients. Patients with this subtype of AML may benefit from an intensive induction chemotherapy. 2

Studies have found a strong association between NPM1mutations and CD33 expression. GO is an antibody–drug conjugate consisting of a humanized anti-CD33 antibody linked to a potent enediyne antitumor antibiotic. 3GO is already approved by the United States Food & Drug Administration(FDA) and European Medicines Agency(EMA) for the treatment of newly diagnosed CD33-positive AML, in combination with induction and consolidation therapy. 4,5

Adding all-trans retinoic acid (ATRA), an oncoprotein targeting agent, to chemotherapy has been reported to benefit patients with AML with NPM1mutations. A study by Maria Paola Martelliand colleagues described the proteasome-dependent degradation of NPM1 leukemic protein and apoptosis in NPM1-mutated AML cell lines and patients primary AML cells. 6Additionally, the AMLSG 07-04 ( NCT00151242) study investigated ATRA in combination with intensive chemotherapy in younger patients with AML and found that, in a pre-specified per-protocol analysis, the addition of ATRA led to an improved event-free survival (EFS) in NPM1-mutated AML. 7

The investigators therefore hypothesized that the addition of GO and ATRA to induction and consolidation therapy in patients with NPM1-mutated AML would improve EFS and overall survival (OS). 1

Study design 1

  • Adult patients with AML eligible for intensive therapy (N = 588) enrolled in the AMLSG BiO study were included
  • Randomly assigned induction (1:1):
    • Standard: idarubicin (I), cytarabine (C), etoposide (E), and ATRA (ATRA-ICE; n = 296)
    • GO: ATRA-ICE + GO (n = 292)
    • Three patients died prior to first induction therapy, meaning patient numbers treated were (standard vsGO): 295 vs290
  • Two cycles of induction therapy were dosed, as below:
    • I: two cycles of 12 mg/m 2intravenously (IV) on Days 1, 3, and 5
      • For Cycle 2, and for patients aged > 60: Days 1 and 3 only
    • C (continuous IV): 100 mg/m 2on Days 1–7
    • E (IV): 100 mg/m 2on Days 1–3
      • For Cycle 2, and for patients aged > 60 years: Days 1 and 3 only due to prolonged hematologic recovery in both arms
    • ATRA: 45 mg/m 2orally on Days 6–8 and 15 mg/m 2on Days 9–21
    • GO arm only: GO: 3 mg/m 2IV on Day 1
  • Three cycles of consolidation therapy were given to patients who achieved complete remission (CR) or CR with incomplete hematologic recovery (CRi):
    • C: dosed by age category:
      • Age 18–60: 3 g/m 2every 12 hours on Days 1–3
      • Age ≥ 60: 1 g/m 2every 12 hours on Days 1–3
    • ATRA: 15 mg/m 2/day orally on Days 4–21
    • Pegfilgrastim: 6 mg subcutaneously on Day 8
    • GO: 3 mg/m 2IV on Day 1 in first consolidation therapy (GO arm only)
  • The number of patients receiving induction and consolidation therapy is shown in Table 1
  • Early primary endpoint: EFS evaluated six months after patient enrollment had completed
  • Exploratory endpoints: cumulative incidence of relapse (CIR), cumulative incidence of death (CID), and toxicity
Table 1.Number of patients receiving induction and consolidation therapy

GO, gemtuzumab ozogamicin

*These numbers relate to those patients in GO+ATRA arm receiving GO at each stage





Cycle 1

Cycle 2

Cycle 1

Cycle 2

Cycle 3

Standard, n






GO*, n






Patient characteristics 1

Patient characteristics were well balanced between study arms in relation to age, sex, white blood cell (WBC) count, type of AML, cytogenetics, and European LeukemiaNet (ELN) 2010 risk category. The median patient age was 58.7 years (range, 18.4–82.3), most patients had de novoAML (89%), normal cytogenetics (87.1%), and were classified as favorable risk by ELN 2010 criteria (74.6%). The only significant difference was in hemoglobin level, which was significantly higher in the standard arm than the GO arm (p = 0.05).

Induction therapy 1

Given as standard vs GO

  • Responses to induction therapy are shown in Table 2
    • The CR/CRi rate was not different between arms (p = 0.27)
    • However, there was a higher death rate with GO (p = 0.05)
      • More patients aged > 70 died during induction in the GO arm: 4% vs 20.4%
Table 2 . Responses to induction therapy

CR, complete remission; CRi, complete remission with incomplete hematologic recovery; GO, gemtuzumab ozogamicin

*GO was not added to the first induction therapy in three patients assigned to the GO arm. GO was not added to the second cycle of induction therapy in 15 patients, mainly due to toxicity during the first cycle (n = 8)


Standard (n = 295)

GO (n = 290)*

Overall response to first induction therapy, n (%)

276 (93.2)

257 (88.0)

Second induction therapy started, n



Overall response to both cycles of induction therapy, n (%)


262 (88.5)

249 (85.3)

Refractory disease

16 (5.4)

12 (4.1)


17 (5.7)

30 (10.3)

WBC recovery was faster in the GO arm after first induction (p = 0.003), but not significantly different after second induction (p = 0.51). Platelet recovery was similar between arms after first induction (p = 0.18), but significantly prolonged in the GO arm after second induction (p < 0.001). Factors significantly associated with prolonged platelet recovery after second induction were:

  • GO treatment: hazard ratio (HR) 0.63; p < 0.001
  • Age > 60 years: HR 0.72; p = 0.002
  • Female sex: HR 0.62; p < 0.001
  • Prolonged platelet recovery after first induction cycle: HR 0.58; p = 0.03

Consolidation therapy 1

Given as standard vs GO

The number of patients in each arm subsequently receiving consolidation therapy is shown in Table 1. A higher number of consolidation cycles were completed in the standard arm (83% vs76%). Platelet recovery was again prolonged with GO after first consolidation (p < 0.001).

Survival analysis 1

  • Data cut-off: September 28, 2018
  • Median follow-up: 40 months (95% CI, 35.5–47.0)
  • EFS: age-stratified HR 0.83; 95% CI, 0.64–1.04; p = 0.10
  • In patients achieving a CR/CRi (n = 523):
    • Relapsed (n): 178
    • Died in CR/CRi (n): 48
    • There was a significantly higher CIR in the standard arm ( Table 3)
      • HR 0.66; 95% CI, 0.49–0.88; p = 0.005
    • There was no difference in CID (p = 0.80, Table 3)
  • Age-stratified univariable analysis found no significant differences in EFS by 2017 ELN criteria (p = 0.10) and according to protocol (p = 0.05)
Table 3.EFS, CIR, and CID analysis for total cohort and by treatment arm

CID, cumulative incidence of death; CIR, cumulative incidence of relapse; EFS, event-free survival; GO, gemtuzumab ozogamicin; NR, not reported

*Defined by ELN 2017 recommendations





Median EFS, months (95% CI)*

39.4 (27.1–59.2)



Two-year EFS, months (95% CI)*

55.3 (51.3–59.7)

52.6 (47.0–58.9)

58.1 (52.5–64.4)

Two-year CIR, %

(95% CI)


36.9 (30.8–43.0)

25.5 (19.7–31.2)

Two-year CID, %

(95% CI)


7.1 (3.9–10.3)

8.3 (1.8–11.8)

Subgroup analysis for EFS and CIR endpoints 1

  • GO was significantly more beneficial (in relation to EFS and CIR) in female patients, patients aged 70 and under, and patients without a FLT3-ITD:
    • Female patients had a significantly improved EFS with GO (HR 0.67; 95% CI, 0.49–0.92) that was not seen with male patients. This was also true for CIR.
    • Interaction between FLT3-ITD and treatment arm was significant (p = 0.002):
      • Patients with the FLT3-ITD mutation did not benefit from the addition of GO in relation to EFS (HR 1.53; 95% CI, 0.95–2.48), whilst patients without the FLT3mutation did (HR 0.72; 95% CI, 0.56–0.95)
    • Younger patients aged < 70 years had an improved EFS by ELN recommendations (p = 0.05) and by protocol with the addition of GO (p = 0.02)

Safety 1

The rates of adverse events (AEs) were within the expected range. No significant differences were observed in the rate of Grade 3–5 AEs, as shown in Table 4, or in AEs of any grade (data not shown) between treatment arms. The main cause of death rate in both arms was predominantly infection.

Table 4.Grade 3–5 AEs occurring in ≥ 8% of patients in either arm

AE, adverse event; GO, gemtuzumab ozogamicin

AE, %



p value

Blood/bone marrow












Constitutional symptoms
















Pulmonary/upper respiratory




Conclusion 1

In this randomized study, thought to be the first to focus on NPM1-mutated AML, GO did not improve response rate after induction therapy, and led to a higher death rate. Overall, GO failed to provide a significant EFS benefit when added to intensive induction therapy in patients with NPM1-mutated AML. Significant reductions in the CIR with GO, however, does provide evidence that GO has antileukemic activity. The authors of this study suggest GO should be restricted to first induction only.

  1. Schlenk R.F. et al.Gemtuzumab ozogamicin in NPM1-mutated acute myeloid leukemia: early results from the prospective randomized AMLSG 09-09 phase III study. J Clin Onc.2020 Feb 20; 38(6):623–632. DOI: 1 0.1200/JCO.19.01406
  2. Arber D.A. et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood.2016 May 19; 127(20):2391–2405. DOI: 1 0.1182/blood-2016-03-643544
  3. Giles F. et al.Gemtuzumab ozogamicin in the treatment of acute myeloid leukemia. C ancer.2003 Nov 15; 98(10):2095–2104. DOI: 10.1002/cncr.11791
  4. U.S. Food & Drug Administration. FDA approves gemtuzumab ozogamicin for CD33-positive AML. Available at: 2017 Jan 09. [Accessed 2020 Feb 02]
  5. European Medicines Agency (EMA).Mylotarg. Available at: Published 2018 May 04. [Accessed 2020 Feb 02]
  6. Martelli M.P. et al.Arsenic trioxide and all-trans retinoic acid target NPM1 mutant oncoprotein levels and induce apoptosis in NPM1-mutated AML cells. B lood.2015 May 28; 125(22):3455–3465. DOI: 10.1182/blood-2014-11-611459
  7. Schlenk R.F. et al.All-trans retinoic acid as adjunct to intensive treatment in younger adult patients with acute myeloid leukemia: Results of the randomized AMLSG 07-04 study. Ann Hematol.2016 Oct 3; 95:1931–1942. DOI: 10.1007/s00277-016-2810-z