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Comparison of outcomes in adolescent and young adult patients versus younger patients with high-risk B-ALL

Dec 15, 2021
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Pediatric patients with B-cell acute lymphoblastic leukemia (B-ALL) currently have an overall survival (OS) rate of >90%; however, OS and event-free survival (EFS) rates in adolescent and young adult (AYA) patients remain inferior and variable, attributed in part to the underlying leukemia biology. Historically many AYA patients with B-ALL have been treated using protocols for adult patients which are less intensive than those for pediatric patients. However, AYA survival rates on pediatric-inspired regimens have been higher than for adult protocols and the CALGB 1043 trial1 has reported improved outcomes for AYA patients treated with the prednisone Capizzi (PC) pediatric regimen of the Children’s Oncology Group (COG) AALL0232 trial.

The ALL Hub has previously reported a comparison of toxicities from CALGB 104031 and COG AALL0232 trials2 and more recently an educational theme article outlining the gene expression profiles in AYA and adult patients. Here we present the key findings by Burke, et al.3 published in Leukemia, comparing the outcomes and treatment-related toxicities between AYA and younger patients with high-risk B-ALL treated on the COG AALL0232 trial.

Study design

This was a retrospective cohort study comprising of patients enrolled in the COG AALL0232 trial between 2004 and 2011, with newly diagnosed high risk B-ALL patients, aged 1–9 years with an initial white blood cell (WBC) count ≥50,000/microliter or 10–30 years old with any WBC count. Patients with Down’s Syndrome (DS) were excluded due to increased toxicity. For the purposes of this study, AYA cohort included patients aged 16–30 years.

Patients enrolled in AALL0232 were randomized to receive dexamethasone or prednisone during induction and high dose MTX with leucovorin rescue (HD-MTX) or Capizzi escalating dose MTX (without leucovorin rescue) plus pegaspargase (C-MTX) during interim maintenance (IM) (Figure 1). Early responses were used to stratify patients and included:

  • Rapid early responders if they had a morphologic remission marrow (<5% blasts) by induction Day 15 and <0.1% minimal residual disease (MRD) in the bone marrow (BM) at Day 29.
  • Slow early responders if they had morphologic remission by Day 29 but had either an M2 (5–25% blasts) or M3 (>25% blasts) BM on induction Day 15 or Day 29 BM MRD ≥0.1%.

Figure 1. Treatment schedule in AALL0232*

C-MTX, Capizzi escalating dose MTX; MTX, methotrexate.
*Adapted from Burke, et al.4

At post-induction eligible and evaluable patients were grouped into four treatment regimens (Figure 2):

  • Prednisone/C-MTX (PC)
  • Prednisone/HD-MTX (PH)
  • Dexamethasone/C-MTX (DC)
  • Dexamethasone/HD-MTX (DH)

Figure 1. Consort diagram* 

AYA, adolescent and young adults; DC, dexamethasone/C-MTX; DH, dexamethasone/high dose methotrexate with leucovorin rescue; PC, Prednisone/ Capizzi escalating dose MTX (without leucovorin rescue) plus pegaspargase; PH, Prednisone/ high dose methotrexate with leucovorin rescue; VHR, very high risk.
*Adapted from Burke, et al.4

Results

Baseline characteristics

A total of 2,443 patients aged <16 years and 597 aged 16–30 years, were eligible and evaluable for induction therapy. The median age for AYA patients was 17 years and they were more likely to have Philadelphia-like ALL gene expression profile compared to younger patients with National Cancer Institute (NCI) high-risk B-ALL (p = 0.015) and less likely to have ETV6-RUNX1 fusion (p < 0.001) (Table 1). 

Table 1. Baseline characteristics*

Characteristics, % (unless otherwise stated)

Younger

(<16 years)

n = 2443

AYA

(≥16 years)

n = 597

p value

Sex, Male

53.3

64.5

<0.0001

Race

              White

84.1

89.3

 

              Black or African American

8.4

5.6

0.010

WBC count, ≥50

49.5

19.6

<0.0001

RER

80.2

66.5

 

SER

19.8

33.5

<0.0001

MRD induction Day 29

              <0.01

73.9

55.9

 

              0.01% ≤ MRD<0.1%

10.0

14.7

 

              0.1% ≤ MRD<1.0%

8.7

14.5

<0.0001

              1.0% ≤ MRD<10.0%

5.1

10.3

 

              MRD ≥10%

2.3

4.6

 

BMI ≥30

4.8

19.5

<0.0001

Ph-like status

              Yes

11.5

17.7

 

              No

88.5

82.3

0.015

ETV6-RUNX1

              Yes

16.4

3.8

 

              No

83.6

96.2

<0.0001

Triple trisomy

              Yes

12.4

12.0

 

              No

87.6

88.0

0.828

Double trisomy

              Yes

16.1

16.2

 

              No

83.9

83.8

0.960

KM2TA (MLL-R) rearrangement

              Yes

3.9

4.0

 

              No

96.1

96.0

0.899

Hypodiploidy

              Yes

2.7

3.0

 

              No

97.3

97.0

0.711

BCR-ABL1 positive

              Yes

4.9

6.3

 

              No

95.1

93.7

0.189

Number of patients completing protocol therapy

65.8

50.3

<0.0001

AYA, adolescent and younger adults; BMI, body mass index; MRD, minimal residual disease; Ph, Philadelphia; RER, rapid early responders; SER, slow early responders; WBC, white blood cell.
*Adapted from Burke, et al.4
Values in bold are statistically significant.

Toxicity of therapy

Induction and post-induction toxicities are summarized in Table 2. Rates of Grade ≥3 hyperglycemia (p < 0.0001) and hyperbilirubinemia (p = 0.0007) were higher while those of Grade ≥3 febrile neutropenia (p < 0.0001) were lower during induction in AYA patients compared to the younger patients. Grade ≥3 febrile neutropenia remained lower (p < 0.0001) in AYA patients during the post-induction period, but there were significantly more deaths in AYA patients in remission compared to younger patients (5.4% vs 2.4%, respectively; p < 0.0001).

Table 2. Induction and post-induction toxicities*

Toxicities, % (unless otherwise stated)

Younger
 (<16 years)

AYA
(
≥16 years)

p value

Induction

Hyperglycemia

15.4

23.6

<0.0001

Hyperbilirubinemia

3.7

6.9

0.0007

Thrombosis

1.2

1.5

0.470

Pancreatitis

0.5

0.5

0.972

Febrile neutropenia

13.8

7.4

<0.0001

Post-induction

Mucositis
during IM #1

11.7

18.2

0.0002

Peripheral motor
Neuropathy
(overall)

7.8

12.1

0.001

Febrile neutropenia

56.8

45.2

<0.0001

Hyperbilirubinemia

9.5

17.3

<0.0001

Hepatic failure

0.3

1.3

0.009

AYA, adolescent and young adults; IM, interim maintenance.

*Adapted from Burke, et al.4
Values in bold are statistically significant.

Treatment response and outcome

  • AYA patients had a significantly higher rate of induction failure compared to younger patients (p < 0.001), including when more a stringent definition of M3 induction failure was applied (p = 0.038) (Table 3).
  • The 5-year EFS and OS rates were inferior for AYA patients (65.4% and 77.4%) compared to younger patients (78.1% and 87.3%; p < 0.0001) and were similar when patients with VHR cytogenic features were excluded.
  • Cumulative incidence rate of relapse was higher in AYA patients compared to younger patients (p = 0.0006), mainly due to higher cumulative incidence rates of BM relapse ± extramedullary disease (p < 0.0001) (Table 3).
  • Obesity was a significant risk factor for inferior EFS irrespective of age; however, obese AYA patients showed significantly lower EFS compared to younger patients (p = 0.006) (Table 3).
  • AYA patients showed a significantly higher cumulative incidence of remission deaths compared to younger patients (p < 0.0001) (Table 3).

Table 3. Induction events and cumulative incidence rates by event type*

Events

Younger (<16 years)
n = 2,443 (%)

AYA (≥16 years)
n = 597 (%)

p value

Induction death

1.6

2.2

0.366

Induction failure (per
protocol definition)

3.5

7.2

<0.001

Induction death or
failure (per protocol
definition)

5.2

9.4

<0.001

M3 induction failure

1.0

2.0

0.038

 

5-year rate ±
standard error (%)

5-year rate ±
standard error (%)

 

Relapse

13.5 ± 0.7

18.5 ± 1.7

0.0006

Marrow ± EMD

9.1 ± 0.6

14.0 ± 1.5

<0.0001

Isolated CNS relapse

3.6 ± 0.4

3.9 ± 0.8

0.830

Relapse, other

0.9 ± 0.2

0.6 ± 0.4

0.567

SMN

0.8 ± 0.2

1.0 ± 0.4

0.818

Remission death

2.4 ± 0.3

5.7 ± 1.0

<0.0001

AYA, adolescent and young adults; CNS, central nervous system; EMD, extramedullary disease; SMN, secondary malignant neoplasm.

*Adapted from Burke, et al.4
Values in bold are statistically significant.
>25% leukemia blasts present in the bone marrow.

Univariate and multivariable analyses of risk factors

Significant risk factors for inferior EFS identified in the univariate analysis included age, race, WBC count, end of induction MRD, cytogenetic features, and BMI. These factors retained their significance in the multivariate analysis (Table 4).

Table 4. Multivariate analyses for EFS*

Parameter

HR (95% CI)

p value

Age (<16 vs ≥16 years)

0.77 (0.63–0.96)

0.018

Age as continuous variable

1.04 (1.02–1.06)

<0.0001

Race (Black vs White)

1.46 (1.09–1.95)

0.011

WBC count (<50k vs ≥50k)

0.72 (0.60–0.86)

0.0003

EOI MRD (<0.01% vs ≥0.01%)

0.28 (0.24–0.34)

<0.0001

Cytogenetics

              Neutral vs favorable

2.39 (1.82–3.15)

<0.0001

BMI

              30–40 vs <30

1.67 (1.24–2.26)

0.0009

              >40 vs <30

1.78 (1.01–3.14)

0.046

BMI, body mass index; CI, confidence interval; EOI, end of induction; HR, hazard ratio; MRD, minimal residual disease; WBC, white blood cell.
*Adapted from Burke, et al.4
Values in bold are statistically significant.

Conclusion

This retrospective cohort study from COG AALL0232 demonstrated that AYA patients had significantly inferior EFS and OS rates, as well as having higher rates of treatment related toxicity when compared with younger patients. The findings were consistent with studies reported >15 years ago and although treatment intensification strategies have improved outcomes in younger patients, these have not translated into improved outcomes for AYA patients. Further trials with novel approaches to improve outcomes and reduce toxicity in AYA patients are therefore warranted.

  1. Stock W, Luger SM, Advani AS, et al. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood. 2019;133(14):1548-1559. DOI: 1182/blood-2018-10-881961
  2. Larsen EC, Devidas M, Chen S, et al. Dexamethasone and high-dose methotrexate improve outcome for children and young adults with high-risk B-acute lymphoblastic leukemia: A report from Children's Oncology Group Study AALL0232. J Clin Oncol. 2016;34(20):2380-2388. DOI: 1200/JCO.2015.62.4544
  3. Burke MJ, Devidas M, Chen Z, et al. Outcomes in adolescent and young adult patients (16 to 30 years) compared to younger patients treated for high-risk B-lymphoblastic leukemia: report from Children's Oncology Group Study AALL0232. Leukemia. 2021. Online ahead of print. DOI: 1038/s41375-021-01460-6

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