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CNS involvement at diagnosis and its association with CNS toxicities in childhood ALL

By Quintina Dawson

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Dec 2, 2022

Learning objective: After reading this article, learners will be able to recall a new clinical development in acute lymphoblastic leukemia.


Central nervous system (CNS) leukemia is clinically characterized by the presence of leukemic cells in cerebrospinal fluid (CSF). Routine diagnosis by cytomorphology (CM) has been linked to an increased risk of CNS toxicities and early posterior reversible encephalopathy syndrome (PRES) in recent studies. Flow cytometric immunophenotyping (FCI), which is a less commonly used diagnostic tool, can detect low levels of leukemic blasts in the CSF and has a higher sensitivity than CM.

CNS-directed chemotherapy is administered to all patients with acute lymphoblastic leukemia (ALL) at diagnosis as a preventative measure against CNS relapse, regardless of CNS involvement. On the other hand, enhanced intrathecal chemotherapy, which has been associated with CNS toxicities, is given to patients with ALL on diagnosis of CNS leukemia. There is still uncertainty as to whether CNS toxicities are due to directed CNS prophylactic measures, or a result of the presence of leukemic cells in the CNS.

Here, we summarize a recently published article by Anastasopoulou et al.1 in Blood, investigating the role of minimal CNS involvement at diagnosis on the risk of CNS toxicities by FCI in pediatric patients with ALL.

Methods

Patients included in the analysis were

  • children aged 1–17.9 years;
  • diagnosed with ALL between 2008 and 2015;
  • treated according to the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol; and
  • had diagnostic data on CNS involvement by both CSF by FCI and CM.

CNS involvement by CM categorized patients into three groups:

  • CNS1: no CNS involvement
  • CNS2: <5 /μl leukemic cells and blasts in the CSF
  • CNS3: 5 /μl leukemic cells and blasts in the CSF or clinical signs of CNS involvement

CNS involvement by FCI classified patients into two groups:

  • positive for CNS involvement (CNSflow+): ≥10 leukemic blasts in the CSF by FCI
  • negative for CNS involvement (CNSflow): <10 leukemic blasts in the CSF by FCI

The three groups of CNS toxicities in patients were:

  • all CNS toxicities (including any associated toxicity)
  • seizures (both isolated and secondary to CNS toxicities)
  • PRES

The study endpoints were the association between CNS leukemia by FCI at diagnosis and the risk of CNS toxicities; the association of CNSflow+ with CNS toxicity was also tested.

Results

Baseline clinical characteristics and toxicities

Overall, 370 patients were included in the study. Within the CNS1 group (n = 320), 256 were CNSflow and 64 were CNSflow+, as seen in Figure 1.

Figure 1. Patient classification of CNS involvement at diagnosis based on combined CM and CSF FCI data* 

ALL, acute lymphoblastic leukemia; CM, cytomorphology; CNS, central nervous system; FCI, flow cytometric immunophenotyping; NOPHO, Nordic Society of Paediatric Haematology and Oncology.
*Data from Anastasopoulou, et al.1

At baseline, 38 patients overall reported at least one type of CNS toxicity, with 22 of these cases occurring with seizures. Of these 22, 16 cases were associated with PRES. In CNS1 patients who were CNSflow+, there was a total of 33 CNS toxicity cases; 18 presented with seizures and 14 of these related to PRES.

Clinical characteristics that were significantly higher at diagnosis in CNS1 patients with CNSflow+ included white blood cell count and T-cell immunophenotypes (p < 0.001; Table 1).

Table 1. Clinical characteristics at diagnosis of CNS1 patients*

BCP, B-cell precursor; CNS, central nervous system; FCI, flow cytometric immunophenotyping; WBC, white blood cells.
*Data from Anastasopoulou, et al.1
Values missing for six patients.

Characteristic, % (unless
otherwise stated)

CNS1
(n = 320)

CNSflow−
(n = 256)

CNSflow+
(n = 64)

p value

Age median and range
(years)

4.0 (1.0–17.0)

4.0 (1.0–17.0)

4.0 (1.0–16.0)

Sex

 

 

 

               Male

54.1

56.6

43.8

 

               Female

45.9

43.4

56.3

0.064

WBC, × 109/L

 

 

 

 

               <100

90.9

95.3

73.4

 

               >100

9.1

4.7

26.6

<0.001

Immunophenotype

 

 

 

 

               BCP

89.4

93.0

75.0

 

               T cell

10.6

7.0

25.0

<0.001

Induction therapy

 

 

 

 

               Prednisolone

84.7

89.7

64.5

 

               Dexamethasone

15.3

10.3

35.5

<0.001

Stratification into block treatment at the end of induction

 

 

 

 

               Non-block treatment

85.0

85.9

81.3

 

               Block treatment

15.0

14.1

18.8

0.348

The univariate analysis in all CNSflow+ patients, which included both patients who received (CNS1) and did not receive enhanced intrathecal treatment (CNS2 and CNS3), revealed an increased risk for seizures (hazard ratio [HR], 2.72; 95% confidence interval [CI], 1.18–6.28; p = 0.019] and PRES (HR, 2.72; 95% CI, 1.18–6.28; p = 0.019) when compared with CNSflow patients. After adjusting for the type of induction therapy in the multivariate analysis, patients with CNSflow+ still had a significant risk for PRES (HR, 2.72; 95% CI, 1.18-6.28; p = 0.019).

Among CNS1 patients who did not receive enhanced intrathecal treatment, univariate analysis showed that CNSflow+ status alone was associated with an increased risk of all CNS toxicities, seizures, and PRES when compared with toxicities in CNSflow- patients . In the multivariate analyses, which adjusted for age and subsequently induction therapy, CNS1flow+ status was still a significant risk factor for all CNS toxicities (Table 2).

Table 2. Risk of CNS toxicity in CNS1 patients*

CI, confidence interval; CNS, central nervous system; HR, hazard ratio; PRES, posterior reversible encephalopathy syndrome.
*Data from Anastasopoulou, et al.1
Adjusted for age.
Adjusted for induction therapy.

Toxicity, % (unless
otherwise stated)

Controls

Cases

Univariate HR (95% CI; p value)

Multivariate HR(95% CI; p value)

Multivariate HR (95% CI; p value)

All CNS toxicities, n

287

33

 

 

 

               CNSflow-

81.5

66.7

Ref.

Ref.

Ref.

               CNSflow+

18.5

33.3

2.08 (1.01–4.28; 0.048)

2.35 (1.13–4.87; 0.022)

1.90 (0.88–4.10; 0.101)

 

 

 

 

 

 

Seizures, n

287

18

 

 

 

              CNSflow-

81.5

55.6

Ref.

Ref.

Ref.

               CNSflow+

18.5

44.4

3.34 (1.32–8.47; 0.011)

3.83 (1.50–9.76; 0.005)

3.33 (1.26–8.82; 0.016)

 

 

 

 

 

 

PRES, n

287

16

 

 

 

               CNSflow-

81.5

43.8

Ref.

Ref.

Ref.

               CNSflow+

18.5

56.3

5.30 (1.98–14.24; < 0.001)

6.13 (2.26–16.64; < 0.001)

4.85 (1.71–13.75; 0.003)

Conclusion

This study demonstrated that minimal CNS involvement without enhanced CNS chemotherapy, as determined by FCI, is significantly associated with an increased risk for CNS toxicities, with the highest risk seen for PRES. Despite the small cohort, both univariate and multivariate analyses reported a positive association between CNS leukemia and risk of CNS toxicities. These results can be a foundation for future studies on the allocation of CNS prophylactic measures.

References

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