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A minority (4–11%) of adult patients with acute lymphoblastic leukemia (ALL) have central nervous system (CNS) involvement at the time of diagnosis.1 CNS involvement has been associated with lower overall survival (OS) rates in the MRC UKALL XII/ECOG E2993 trial,2 and involvement of additional extramedullary sites, T-cell ALL, and a higher white blood cell (WBC) count at diagnosis are more common in this subset of patients.1 Since the introduction of pediatric-inspired regimens, the outlook for adult patients with Philadelphia chromosome-negative ALL has significantly improved; however, the effects of initial CNS involvement had not previously been reexamined.1 The ALL Hub previously reported on CNS involvement at diagnosis and its association with CNS toxicities in childhood ALL.
Here, we summarize an article recently published in Haematologica by Orvain et al.1, which investigated the impact of CNS involvement in adult patients with Philadelphia chromosome-negative ALL in the GRAALL-2005 study.
Patients included in the analysis were:
CNS involvement was categorized as:
Measurable residual disease (MRD) was monitored by standardized quantitative real-time polymerase chain reaction with a sensitivity of ≥10−4, which was performed after the first induction course.
The aim of the study was to evaluate the impact of CNS involvement on survival outcomes.
Figure 1. Flowchart of patients with CNS involvement at diagnosis*
allo-SCT, allogeneic stem cell transplantation; CNS, central nervous system; CR, complete remission.
*Adapted from Orvain, et al.1
Table 1. Characteristics of patients with or without CNS involvement*
Characteristic, % (unless otherwise stated) |
All |
CNS-negative |
CNS-positive |
p value |
---|---|---|---|---|
Median age, years |
36 |
37 |
30 |
0.15 |
Female |
40 |
40 |
33 |
0.27 |
Median BMI, kg/m2 |
23.6 |
23.7 |
23.5 |
0.75 |
Phenotype |
|
|
|
0.004 |
B-cell |
67 |
68 |
49 |
|
T-cell |
33 |
32 |
51 |
|
Median WBC count at diagnosis, G/L |
12 |
11 |
23 |
0.15 |
Median hemoglobin level at diagnosis, g/dL |
10.2 |
10.1 |
11.1 |
0.02 |
Median platelet count at diagnosis, G/L |
72 |
72 |
78 |
0.16 |
Poor early PB blast clearance |
24 |
24 |
27 |
0.50 |
Poor early BM blast clearance |
39 |
39 |
38 |
0.58 |
CR |
92 |
92 |
91 |
0.79 |
Induction death |
6 |
6 |
6 |
0.99 |
MRD1 negativity |
16 |
16 |
13 |
0.26 |
Allo-SCT in first CR |
35 |
34 |
55 |
0.002 |
allo-SCT, allogeneic stem cell transplantation; BM, bone marrow; BMI, body mass index; CNS, central nervous system; CR, complete remission; MRD1, measurable residual disease after induction; PB, peripheral blood; WBC, white blood cells. |
As shown in Table 2, univariable Cox regression analysis revealed a positive association between lower OS and age (p < 0.001), body mass index (p < 0.001), leukocytes ≥30 G/L (p = 0.1), CNS involvement (p = 0.001), and poor early BM blast clearance (p = 0.02).
In addition, the multivariable Cox regression model showed a significant association between CNS involvement at diagnosis and lower OS (p <0.001). The only other key variable factors associated with lower OS were age (p < 0.001) and leukocytes ≥30 G/L (p = 0.03; Table 3).
Table 2. Univariable analysis of factors associated with NRM, relapse, and overall survival by Cox regression*
Variable |
NRM |
Relapse |
Overall survival |
|||
---|---|---|---|---|---|---|
HR |
p value |
HR |
p value |
HR |
p value |
|
Age/10 |
1.6 |
<0.001 |
1.1 |
0.1 |
1.3 |
<0.001 |
Female |
1.4 |
0.06 |
1 |
0.7 |
1.1 |
0.4 |
BMI/10 |
1.8 |
<0.001 |
1.1 |
0.4 |
1.4 |
<0.001 |
T-cell phenotype |
0.7 |
0.04 |
1 |
0.8 |
0.8 |
0.2 |
WBC count at diagnosis >30 G/L |
0.9 |
0.7 |
1.7 |
<0.001 |
1.4 |
0.01 |
CNS involvement |
2.1 |
0.01 |
1.5 |
0.1 |
1.8 |
<0.001 |
Poor early PB blast clearance |
1.1 |
0.7 |
1.4 |
0.02 |
1.3 |
0.05 |
Poor early BM blast clearance |
1.2 |
0.3 |
1.5 |
0.01 |
1.3 |
0.02 |
BM, bone marrow; BMI, body mass index; CNS, central nervous system; HR, hazard ratio; NRM, non-relapse mortality; PB, peripheral blood; WBC, white blood cells. |
Table 3. Multivariable analysis of factors associated with NRM, relapse, and overall survival by Cox regression*
Variable |
NRM |
Relapse |
Overall survival |
|||
---|---|---|---|---|---|---|
HR |
p value |
HR |
p value |
HR |
p value |
|
Age/10 |
1.5 |
<0.001 |
1.1 |
0.1 |
1.3 |
<0.001 |
Female |
1.3 |
0.2 |
0.9 |
0.6 |
|
|
BMI/10 |
1.4 |
0.1 |
1.1 |
0.4 |
1.2 |
0.1 |
T-cell phenotype |
0.9 |
0.6 |
0.8 |
0.2 |
|
|
WBC count at diagnosis >30 G/L |
0.9 |
0.6 |
1.7 |
<0.001 |
1.3 |
0.07 |
CNS involvement |
2.8 |
<0.001 |
1.6 |
0.08 |
2.1 |
<0.001 |
Poor early PB blast clearance |
1.2 |
0.5 |
1.1 |
0.6 |
1.1 |
0.5 |
Poor early BM blast clearance |
1.2 |
0.3 |
1.4 |
0.03 |
1.3 |
0.04 |
BM, bone marrow; BMI, body mass index; CNS, central nervous system; HR, hazard ratio; NRM, non-relapse mortality; PB, peripheral blood; WBC, white blood cells. |
This study demonstrated that CNS involvement is significantly associated with poor outcomes in patients with newly diagnosed Philadelphia chromosome-negative ALL. This association was mainly due to excessive toxicity with no benefit from allo-SCT in this patient population. As this condition occurs in a minority of adult patients with ALL, it is unlikely that various treatment modalities will be tested in prospective controlled trials in patients with CNS involvement. Overall, these results can be a foundation for future studies on the allocation of CNS prophylactic measures in adult patients with newly diagnosed Philadelphia chromosome-negative ALL.
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