General AML

What impact does time from diagnosis to treatment have on patient outcome in newly diagnosed AML?

Once a diagnosis of acute myeloid leukemia (AML) has been made, the recommendation and gold-standard is to begin therapy as soon as possible. In 2009, Sekeres et al. showed that delaying treatment for five or more days in young patients with AML leads to an inferior prognosis, while delayed treatment in older patients has no impact on outcome.1

Historically, a one-size-fits-all approach was applied to the treatment of AML, based on the limited therapeutic options available and the lack of more specific diagnostic tests. However, with the advent of new, novel, targeted therapies such as midostaurin, a more thorough diagnostic work-up can allow clinicians to assign patients to the most effective therapy for their AML subtype. Since these diagnostic tests can take several days to return results, and therefore would delay treatment, the question is; can we delay treatment whilst awaiting diagnostic work-up without compromising patient outcomes?

In order to address this question, Christoph Röllig, Universitätsklinikum Carl Gustav Carus, Dresden, DE, and colleagues conducted a retrospective analysis of newly diagnosed patients with AML, treated with intensive therapies in the first-line setting. Their aim was to analyze whether delaying therapy impacted patient outcome. These results were presented on behalf of the Study Alliance Leukemia (SAL) group during the 61st American Society of Hematology (ASH) meeting in Orlando, US.2

Study design and patient characteristics2

The study aimed to investigate whether time from diagnosis to treatment (TDT) had an impact on complete remission (CR) rates, early mortality, and overall survival (OS). Additionally, univariable and multivariable analyses were conducted to account for prognostic factors such as age, white blood cell count, and cytogenetics.

Of 4,700 patients with AML in the SAL AML registry, 2,263 patients were included in this retrospective analysis. These patients had received intensive treatment in the first-line setting, had a TDT of >0 but <50 days, and follow-up data available up to at least 12 months. Patients with a diagnosis of acute promyelocytic leukemia (APL) were not included.

The 2,263 patients identified were split into four groups based on TDT; 0–5 days, 6–10 days, 11–15 days and >15 days. Overall, the patient characteristics were similar between groups in relation to factors such as the Eastern Cooperative Oncology Group (ECOG) status (0–1), allogeneic stem cell transplant in first CR, and the use of a 7+3 induction regimen. Most patients had a TDT of 0–5 days, and these patients were more likely to have de novo AML, a higher median white blood cell (WBC) count, higher median lactate dehydrogenase (LDH) level, and more favorable cytogenetics (Table 1).

Table 1. Patient characteristics by TDT

TDT

05 days

6–10 days

11–15 days

>15 days

N

1,547

447

106

163

Median TDT (days)

2

8

13

22

De novo AML, %

79

68

68

58

WBC median (G/l)

14.12

3.80

3.15

3.16

Median LDH (U/L)

443

318

280

252

FLT3-ITD mutation, %

23

13

7

13

AML, acute myeloid leukemia; LDH, lactate dehydrogenase; TDT, time from diagnosis to treatment;  WBC, white blood cells

When looking at patient outcome by TDT (Table 2), there was a tendency for a higher CR rate and lower death rate in younger patients, but no statistically significant or clinically relevant differences were observed. TDT had no impact on OS (p= 0.21), including when analyzed by patient age (≤60 years, p= 0.47 and >60 years, p= 0.88). TDT also did not impact OS when using a 5-day delay cut-off as recommended by previous literature (≤60 years, p= 0.13 and >60 years, p= 0.6).

Table 2. Patient outcomes by TDT

TDT

0–5 days

6–10 days

11–15 days

>15 days

N

1,547

447

106

163

CR/CRi rate, %

All ages

79

76

72

77

Age ≤60 years

88

83

79

78

Age >60 years

68

70

66

75

Early death, %

All ages

4

4

5

4

Age ≤60 years

2

3

4

2

Age >60 years

7

4

5

6

2-year OS, %

All ages

51

48

44

50

Age ≤60 years

64

60

63

57

Age >60 years

35

37

31

44

Multivariable models2

To eliminate bias, multivariable models and propensity score matching were used. Table 3 shows that the odds ratio (OR) for CR or early death, and hazard ratio (HR) for OS were all very close to one, with no significant p values. Propensity score matching also did not identify TDT to be an influencer of patient outcome.

Table 3. Impact of TDT on CR, early death and OS by multivariable models

 

OR/HR

95% CI

P value

CR

0.99

0.974–1.007

0.253

Early death

1.005

0.971–1.040

0.777

OS

1.002

0.993–1.011

0.617

CI, confidence interval; CR, complete remission; HR, hazard ratio; OR, odds ratio, OS, overall survival

Conclusion2

This retrospective analysis in a large, real-world cohort of patients with AML receiving intensive induction chemotherapy (7+3) demonstrated that TDT did not impact CR rates, early mortality or OS, as there were no statistically or clinically significant differences between TDT groups. These results were validated with various modelling techniques and multivariable analyses.

Whilst there is no practical option to address the impact of TDT in a randomized study, the results of this retrospective analysis indicate that waiting for diagnostic results, to ensure clinically stable patients are assigned to the most promising treatment approach for their subtype of AML, is safe and justified.

Read the AML Global Portal Steering Committee's expert opinions on this abstract in our Practice-Changing Abstracts resource available here: https://amlglobalportal.com/medical-information/ash-2019-practice-changing-abstracts-in-acute-myeloid-leukemia

References
  1. Sekeres M. et al., Time from diagnosis to treatment initiation predicts survival in younger, but not older, acute myeloid leukemia patients. Blood (2009) 113 (1): 28–36. DOI: 10.1182/blood-2008-05-157065
  2. Röllig C. et al., Time from diagnosis to treatment does not affect outcome in intensively treated patients with newly diagnosed acute myeloid leukemia. Oral abstract #13. 61st American Society of Hematology (ASH) meeting, Orlando, US
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