Patients’ characteristics
The characteristics of 7 patients with PDGFRB fusion were showed in Table 1, including 5 males and 2 females, with a median onset age of 21 (range, 17 to 39) years. There were 5 cases of initial diagnosis and other 2 cases of recurrence ALL. The median white blood cell (WBC) count at diagnosis was 7.85 (range, 2.3 to 111.25)×10^9/L, and median platelet count was 51 (range, 28 to 191)×10^9/L. The fusion partners were EBF1 (n=4), SMIM3 (n=1), TERF2 (n=1) and only 1 case with a unknown partner gene. For patients with EBF1-PDGFRB fusion, corresponding mutations were found with BCORL1 germline mutation, and somatic mutation of PAX5 and RUNX1, respectively. Case 3 was combined with SMIM3/PDGFRB fusion and TP53 somatic mutation. 4 of 7 cases showed anemia and most of patients (6/7) presented as normal karyotype at diagnosis. No eosinophils were found in bone marrow morphology, and there was no 5q31-33 rearrangement in karyotype in all patients (Table 1).
Table 1. Clinical data for PDGFRB fusion patients
|
Sex
|
onset age (y)
|
Diagnostic state
|
WBC×10^9
|
HB(g/L)
|
PLT×10^9
|
BM: blasts%
|
FCM: blasts%
|
Method
|
Fusion type
|
mutant gene
|
chromosome
|
1
|
F
|
17
|
preliminary
|
7.9
|
70
|
45
|
51.5
|
86.3
|
PCR
|
EBF1/PDGFRB
|
BCORL1 Germline mutation
|
normal
|
2
|
M
|
39
|
relapse
|
47.3
|
143
|
28
|
90.0
|
90.9
|
PCR、FISH
|
EBF1/PDGFRB
|
PAX5 mutation
|
normal
|
3
|
M
|
21
|
preliminary
|
2.3
|
76
|
45
|
87.5
|
87.8
|
RNA-seq
|
SMIM3/PDGFRB
|
TP53 mutation
|
normal
|
4
|
M
|
21
|
preliminary
|
11.3
|
120
|
185
|
52.0
|
71.8
|
RNA-seq
|
EBF1/PDGFRB
|
RUNX1 mutation
|
abnormal*
|
5
|
F
|
26
|
preliminary
|
111.3
|
56
|
51
|
90.0
|
76.2
|
RNA-seq
|
TERF2/PDGFRB
|
negative
|
no metaphase
|
6
|
M
|
20
|
preliminary
|
2.4
|
73
|
172
|
91.5
|
55.7
|
PCR
|
EBF1/PDGFRB
|
NK
|
normal
|
7
|
M
|
28
|
relapse
|
4.6
|
131
|
191
|
6.0
|
55.7
|
FISH
|
PDGFRB fusion
|
IKZF1-IK6
transcribed isomers
|
normal
|
F, female; M, male; NK, not known; WBC, white blood cell count; HB, hemoglobin; PLT, platelet; BM, bone marrow; FCM, flow cytometry.*48-49XY,?+19,+mar2,inc[cp2]/46,XY[8]
Response and Adverse Events of Induction Therapy
Of 7 patients, the overall rate of early response was 42.86% (3/7, Table 2). To 33 days after induction therapy, ORR was 71.43% (3 cases with CRMRD-; one case with CR and unknown MRD status), the CR rate at the end of induction therapy was only 57.14% (4/7). For case 1, 4 and 5 without CR after initial induction therapy, reached CR after plus chemotherapy, CAR-T, dasatinib plus chemotherapy, respectively. The common adverse events during induction chemotherapy were febrile neutropenia (2/7,28.57%), oral mucosal hemorrhage (1/7,14.29%), nausea (3/7,42.86%), and vomiting (1/7,14.29%). No patients died from induction chemotherapy. The median time of CR was 33 (range, 7 to 85) days, and the median time of MRD negative was 33 (range, 18 to 139) days.
Consolidation, Relapse and Survival
Three cases undertook a comprehensive therapy combined with TKI; TKI was administrated after CR for case 1, after MRD- for case 2, and in the middle of induction chemotherapy for case 3, respectively. Four cases received CAR-T therapy (2 for eliminating MRD, and 2 for re-induction therapy) and 6 cases underwent allo-HSCT from haploid-related donors. The recurrence rate was 28.57% (2/7). Case 2 and 7 experienced disease recurrence before allo-HSCT, with 2 and 7 months from CR to relapse, respectively. Both cases 3 and 6 were treated with Hyper CVAD A/B in consolidation therapy. The patients were followed up until January 30, 2021, and a median follow-up time was 29 (range, 7 to 72) months. Case 7 died of infection after allo-HSCT, with a persistent positivity of MRD. The estimated 36 months of Event-free survival (EFS) and Overall survival (OS) was 75.0% and 66.7%. (Table 2, Figure 1, Figure 2)
Table 2. therapy and survival data for PDGFRB fusion patients
|
Induction
|
14d
|
33d
|
Time of CR (d)
|
Time of MRD- (d)
|
targeted therapy
|
CAR-T
|
HSCT
|
Months to
Relapse(m)
|
Status(moths)
|
1
|
VILP
|
NR
|
NR
|
85
|
never
|
Imatinib
|
Yes
|
No
|
NA
|
loss to follow-up
|
2
|
VDCP
|
PR
|
CRMRD-
|
33
|
33
|
Dasatinib
|
Yes
|
Yes
|
2
|
Alive (16)
|
3
|
Hyper-CVAD A
|
CRMRD-
|
CRMRD-
|
7
|
18
|
No
|
No
|
Yes
|
NA
|
Alive (29)
|
4
|
VILP
|
NR
|
NR
|
77
|
110
|
No
|
Yes
|
Yes
|
NA
|
Alive (37)
|
5
|
CIVP+ Dasatinib
|
NR
|
PR
|
61
|
139
|
Dasatinib
|
Yes
|
Yes
|
NA
|
Alive (7)
|
6
|
VILP
|
PR
|
CRMRD-
|
29
|
29
|
No
|
No
|
Yes
|
NA
|
Alive (72)
|
7
|
VDLP
|
NK
|
CR
|
33
|
NK
|
No
|
No
|
Yes
|
7
|
Died of infection (32)
|
V, Vincristine; D, daunorubicin; L, L-asparaginase/pegaspargase/Pegaspargase; P, prednison; C, cyclophosphamide; I, Idarubicin; NR, non-remission; NK, not known
Treatment of CART
A total of 4 patients were infused with CAR-T cells for re-induction or eliminating MRD (Figure 1, Table 3). Case 2 was successfully infused with anti-CD19CD22 (5*10^6/kg), while other 3 patients (case 1,4,5) received the therapy of anti-CD19 (5*10^6/kg) CAR-T cells. Grade 2 of CRS appeared in 2 of 4 patients. Three cases (3/4, 75%) achieved MRD remission after CAR-T treatment. A persistent positivity of MRD was presented in case 1, with a 0.001 level of MRD. Bridging transplantation was performed in case 2, 4, 5 after CAR-T treatment. Allo-HSCT was not performed because there was no donor available for case 1 (Table 3).
Table 3. CAR-T data for PDGFRB fusion patients
|
Relapse before CART
|
Status before CART
|
Blasts before FC%
|
CART source
|
Target
|
cell quantity
×10^6/kg
|
CRS
|
therapeutic effect
|
Bridging transplantation
|
1
|
No
|
CRMRD+
|
0
|
Autologous
|
CD19
|
5
|
2
|
CRMRD+
|
0
|
2
|
Yes
|
NR
|
37
|
Autologous
|
CD19CD22
|
10
|
2
|
CRMRD-
|
1
|
4
|
No
|
PR
|
7
|
Autologous
|
CD19
|
5
|
0
|
CRMRD-
|
1
|
5
|
No
|
CRMRD+
|
0
|
Autologous
|
CD19
|
5
|
0
|
CRMRD-
|
1
|
Allo-HSCT
A total of 6 patients underwent Allo-HSCT from haploid-related donors (Haplo-HSCT). A total of 3 cases underwent CART bridging transplantation, and case 2 received CAR-T therapy as re-induction therapy before transplantation. Case 7 underwent Hyper-CVAD, VDCP, VTCP, AAG (cytarabinoside + acracycin + G-CSF) regimen and did not achieve CR, and then received Salvage transplantation. The median time was 5.5 (range, 4-16) months from diagnosis to transplant. Side effects were mainly for the mild skin GVHD (grade 1) and diarrhea. No cases have disease recurrence after transplantation.Table 4.
Table 4. Haplo-HSTC data for PDGFRB fusion patients
|
CAR-T
|
relapse
|
Status before HSCT
|
Diagnosis to HSCT time (m)
|
stem cell source
|
MNC (10^8/Kg)
|
CD34+ (10^6/Kg)
|
Neutrophil engraftment (d)
|
Platelet engraftment (d)
|
complication
|
Post-HSCT
MRD level
|
relapse of post-HSCT
|
2
|
Yes
|
Yes
|
CR2MRD-
|
6
|
CB+PB
|
7.05
|
2.97
|
11
|
12
|
GVHD skin
|
0*10E-4
|
No
|
3
|
No
|
No
|
CR1MRD+
|
6
|
CB+BM
|
3.3
|
1.518
|
11
|
13
|
GVHD skin
|
0*10E-4
|
No
|
4
|
Yes
|
No
|
CR1MRD-
|
4
|
CB+BM+PB
|
11.48
|
3.77
|
12
|
13
|
diarrhea
|
0.1*10E-4
|
No
|
5
|
Yes
|
No
|
CR1MRD-
|
5
|
CB+PB
|
5.44
|
5.02
|
12
|
12
|
No
|
0*10E-4
|
No
|
6
|
No
|
No
|
CR1MRD-
|
5
|
CB+BM+PB
|
10.2
|
2.04
|
10
|
11
|
No
|
0*10E-4
|
No
|
7
|
No
|
Yes
|
NR
|
16
|
CB+BM
|
9.48
|
2.75
|
12
|
12
|
GVHD skin
|
0*10E-4
|
No
|
CB, cord blood; BM, bone marrow; PB, peripheral blood