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Nelarabine plus standard chemotherapy does not improve survival in adult patients with T-ALL: First analysis of UKALL 14 study

Jan 26, 2022
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T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive variant of ALL with very poor prognosis mainly affecting children, adolescents, and young adults (AYA). The treatment for AYA with T-ALL is based on pediatric protocol in the UK. Nelarabine is a DNA-terminating nucleoside used in the treatment of patients with T-ALL. Toxicity events related to the use of nelarabine as a single agent or in combination with chemotherapy have been previously reported in patients with T-ALL, particularly those with relapse/refractory T-ALL. However, a recent USA study, previously reported by the ALL Hub, has shown improved survival with the addition of nelarabine to standard chemotherapy for pediatric and young adult patients with T-ALL. 

Here we summarize the key findings from the first analysis of the UKALL14 study (NCT01085617) presented during the 63rd American Society of Hematology (ASH) Annual Meeting and Exposition. Rowntree, et al.1 presented findings from their analysis investigating the efficacy of nelarabine when added to standard chemotherapy in patients with T-ALL.     

Study design

This was a phase III randomized controlled trial conducted in the UK between 2012 and 2018, in adult patients aged 25–65 years with newly diagnosed T-ALL. Patients with central nervous system disease were included at the start of the study; however, patients developing neurotoxicity Grade ≥2 before they were due to receive nelarabine were excluded. Eligible patients were randomized to standard of care (SOC) induction phase I and II chemotherapy with or without nelarabine. Patients in the SOC + nelarabine group received 1.5 g/m2 of nelarabine on Day 1, 3, and 5 following second phase of induction (Figure 1).

  • The primary endpoint was 3-year event free survival (EFS), defined as relapse or death from any cause.
  • Secondary endpoints included overall survival (OS), time to relapse, remission, and MRD negativity rates at end of phase 1 and 2 induction and toxicity.

An exploratory analysis was also conducted based on the hypothesis that most immature cases of T-ALL are detected through absence of biallelic T-cell receptor deletion (ABD), which is an adverse prognostic marker of T-ALL. In addition, early T-cell progenitors express high levels of SAMHD1, a gene recently shown to mediate resistance to nelarabine. The exploratory endpoint included association between ABD status and outcomes, and any differential effects of nelarabine according to ABD status.

Figure 1. Treatment schema*

AraC, cytarabine; D, day; DEX, dexamethasone; DNR, daunorubicin; MRD, minimal residual disease; Peg ASP, pegaspargase; W, week; VCR, vincristine; 6-MP, 6-mercaptopurine.
*Adapted from Rowntree, et al.1 

Results

Baseline characteristics

A total of 144 patients were included, 75 in SOC group and 69 in the SOC + nelarabine group, respectively. Twenty-one patients were not given nelarabine in the SOC + nelarabine group mainly due to persistent treatment-related toxicity (Figure 2).

Figure 2. Consort diagram*

N, nelarabine; SOC, standard of care
*Adapted from Rowntree et al.1 

The median age was 38 years (range, 25–61 years) and baseline characteristics were balanced between the two groups, except for a higher proportion of patients having complex cytogenetics in the SOC group compared with the SOC + nelarabine group (18% vs 4%; Table 1).

Table 1. Baseline characteristics*

Characteristics, % (unless otherwise stated)

SOC
(n = 75)

SOC + N
(n = 69)

Median age (range), years

38 (25–61)

36 (25–64)

Male

71

70

ECOG Performance Status

 

 

              0–1

95

93

              ≥2

5

7

WBC >100 × 109/L

23

23

Complex karyotype

18

4

Any UKALL14 CGN risk factor

20

9

UKALL14 risk group

 

 

              Standard

25

29

              High

64

61

CGN, cytogenetics; ECOG, Eastern Cooperative Oncology Group; N, nelarabine; SOC, standard of care; WBC, white blood cell.
*Adapted from Rowntree, et al.1

Efficacy and safety

  • The 3-year and 5-year EFS was 57% vs 61.7% and 54.1 vs 55.5% in the SOC vs SOC + nelarabine group, respectively (hazard ratio [HR], 0.88; p = 0.61).
  • Similarly, 3-year and 5-year OS was 61.5% vs 65.7% and 59.1 vs 57.2% in the SOC and SOC vs SOC + nelarabine group, respectively (HR, 0.91; p = 0.73).
  • A total of 39% vs 37% of deaths occurred in the SOC vs SOC + nelarabine group, respectively.
    • Including 10.7% vs 7.3% of deaths occurring in first remission in the SOC and SOC + nelarabine group, respectively.  
    • Relapse was the most common cause of death in both the SOC and SOC + nelarabine group (28.0% vs 26.9%, respectively).

Exploratory analysis

A total of 108 patients were included in the exploratory analysis, of which 11, 54, and 55 had indeterminate, ABD, and non-ABD status, respectively (Table 2). 

Patients with ABD status were:

  • Older compared to patients with non-ABD status (median age 43.5 vs 34 years) (Table 2);
  • Less likely to be MRD negative post-induction (p < 0.001) compared to non-ABD patients (Table 2); and
  • Had significantly higher relapse rate at 3 years (42.7% vs 16.0%) compared to non-ABD patients.

ABD status retained prognostic value in multivariate analysis, however there was no interaction with the treatment arm (p = 0.46).

Table 2. Baseline characteristics, responses, and outcomes in patients with ABD*

Characteristics, %

(unless otherwise

stated)

Non-ABD
(n = 55)

ABD
(n = 54)

p value

Median age (range), years

34 (25–60)

43.5 (25–64)

0.056

Age ≥41 years

30.9

55.6

0.009

Male

81.8

66.7

0.070

UKALL14 cytogenetic
risk factor

14.6

16.2

0.85

Extramedullary
involvement

83.6

72.2

0.15

Any high-risk factor at
baseline

56.4

75.9

0.031

Responses

Phase I CR

92.7

81.5

0.081

Phase I MRD negative CR

41.8

9.3

<0.001

Phase II CR

94.6

90.7

0.45

Phase II MRD negative CR

58.2

24.1

<0.001

No MRD target identified

1.8

42.9

<0.001

Outcomes

No further first line of treatment

12.7

16.7

SCT

54.6

57.4

Chemotherapy alone

32.7

24.1

ABD, absence of biallelic T-cell receptor deletion; CR, complete response; MRD, minimal residual disease; SCT, stem cell transplantation.
*Adapted from Rowntree, et al.1
Values in bold are statistically significant.

Conclusion

This phase III study demonstrated that three doses of nelarabine added to standard chemotherapy were well tolerated in adult patients with T-ALL. However, this did not translate into improved EFS or OS benefit. In comparison to historical trials, survival outcomes were improved in the UKALL14 trial, despite the older age of patients. ABD was identified as an independent negative prognostic factor in patients with de novo T-ALL and patients with ABD status were at higher risk of relapse. The study could not demonstrate the efficacy of nelarabine based on ABD status; therefore, further prospective studies are warranted to investigate the correlation between ABD status and outcomes in patients with T-ALL treated with nelarabine.

  1. Rowntree C, Kirkwood A, Clifton-Hadley L, et al. First analysis of the UKALL14 randomized trial to determine whether the addition of nelarabine to standard chemotherapy improves event free survival in adults with T-cell acute lymphoblastic leukaemia (CRUK/09/006). Oral abstract #366. 63rd American Society of Hematology Annual Meeting and Exposition; Dec 12,2021; Virtual.

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