Improved Survival of Adolescents and Young Adults Patients with T-Cell Acute Lymphoblastic Leukemia

Figures & data

Figure 1 Overall survival of the whole population.

OS: Overall survival.

Figure 2 Disease-free survival of the whole population.

DFS: Disease-free survival.

Figure 3 Event-free survival of the whole population.

EFS: Event-free survival.

Figure 4 Event-free survival according to CNS status.

EFS: Event-free survival.

Figure 5 Overall survival according to post-consolidation minimal residual disease status.

BM: Bone marrow; MRD: Minimal residual disease; OS: Overall survival.

Table 1 Risk stratification of T-cell acute lymphoblastic leukemia.

	T-cell acute lymphoblastic leukemia
High risk	• White blood cell count <50000 • CNS negative
Very high risk	• White blood cell count >50000 • CNS positive • D14 bone marrow with >5% blasts

Table 2 Modifications of CCG 1900 protocol.

Modification	Comment
Addition of pre-phase	Use of pre-phase prednisone for 4 days prior to induction
Anticoagulation	Use of prophylactic anticoagulation with asparaginase
Minimal residual disease	Use of minimal residual disease with stem cell transplant decision if minimal residual disease is positive after consolidation phase
First intrathecal	Shifting first intrathecal to day 7, to reduce risk of contamination.

Table 3 Chemotherapy protocol AYA 15.

Treatment	Dose	Days
Pre-phase (4 days)
Prednisone	40 mg/m^2	For 4 days
Induction (28 days)
Daunorubicin	25 mg/m^2 iv.	0, 7, 14, 21
Vincristine	1.5 mg/m^2 iv. push	0, 7, 14, 21
Peg-asparaginase	2500 IU/m^2 iv. (with prophylactic enoxaparin)	3
Prednisone	20 mg/m^2 p.o. t.i.d.	0–28 then tapering
Intrathecal AraC	70 mg	7
Intrathecal MTX	12 mg	14, 28
Consolidation (53 days)
Cyclophosphamide	1000 mg/m^2 iv.	0 and 28
AraC	75 mg/m^2/day iv. or sc.	1–4, 7–10, 29–32 and 35–38
6-MP	60 mg/m^2/day p.o.	0–13 and 28–41
Vincristine	1.5 mg/m^2 iv. push	14, 21, 42, 49
Peg-asparaginase	2500 IU/m^2 iv. (with prophylactic enoxaparin)	14, 42
Intrathecal MTX	12 mg	0, 7, 14, 21
Interim maintenance (49 days)
MTX	5000 mg/m^2 continuous infusion over 24 hrs	7, 21, 35 and 49
6-MP	25 mg/m^2/day p.o. daily	0–56
Intrathecal MTX	12 mg	6, 20, 34 and 48
Delayed intensification (57 days)
Re-induction
Daunorubicin	25 mg/m^2 iv.	0, 7, 14
Vincristine	1.5 mg/m^2 iv. push	0, 7, 14
Peg-asparaginase	2500 IU/m^2 iv. (with prophylactic enoxaparin)	3
Dexamethasone	10 mg/m^2/day p.o.	0–6 and 14–20. No taper
Re-consolidation
Cyclophosphamide	1000 mg/m^2 iv.	28
AraC	75 mg/m^2/day iv. or sc.	29–32 and 35–38
Thioguanine	60 mg/m^2/day p.o.	28–41
Vincristine	1.5 mg/m^2 iv. push	42, 49
Peg-asparaginase	2500 IU/m^2 iv. (with prophylactic enoxaparin)	42
Intrathecal MTX	12 mg	28, 35
Maintenance (83 days per cycle) (2 years for females and 3 years for males)
Vincristine	1.5 mg/m^2 iv. push	0, 28, 56
Prednisone	40 mg/m^2/day	0–4, 28–32, 56–60
6-MP	75 mg/m^2/day p.o.	0–83
MTX	20 mg/m^2/dose p.o.	7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 77
Intrathecal MTX	12 mg	0 and 28 (cycles 1–4) 0 only (cycles 5 and after

Patients with very high-risk disease will receive double interim maintenance phases (high-dose MTX) during first interim maintenance and Capizzi MTX during second interim maintenance.

6-MP: 6-mercaptopurine; AraC: Cytarabine; iv.: Intravenous; MTX: Methotrexate; p.o. Oral; sc. Subcutaneous; t.i.d. Three-times daily.

Table 4 Patient characteristics.

Variable	Patients (n=35), n (%)
Age (years), median (range)	20 (14–41)
Presenting white blood cells, median (range)	14 (1–350) × 10^9/l
Male	25 (72%)
Risk stratification	High-risk T-ALL: 11 (31.4%) Very high-risk T-ALL: 24 (68.6%)
CD1a	Positive:13 (37.1%) Negative: 5 (14.3%) NA: 17 (48.6%)
CNS involvement	CNS negative: 32 (91.4%) CNS positive: 3 (8.6%)
Cytogenetic by karyotyping	Standard: 25 (71.4%) Complex or hypodiploid or MLL: 3 (8.6%) Missed: 7 (20%)
Cytogenetic by FISH	Standard: 23 (65.7%) Complex or hypodiploid or MLL: 5 (14.3%) Missed: 7 (20%)
Bone marrow/PET day 28 (induction)	Negative: 31 (88.6%) Positive: 4 (11.4%)
CR in day 28	Yes: 31 (88.6%) No: 4 (11.4%)
Day 28 MRD	Negative: 19 (54.2%) Positive: 6 (17.2%) NA: 10 (28.6%)
Bone marrow postconsolidation MRD	Negative: 25 (71.4%) Positive: 3 (8.6%) NA: 7 (20%)
Patient went for allogeneic stem cell transplant	Yes: 5 (14.3%) No: 30 (85.7%)
Relapse	Yes: 6 (17.1%) No: 29 (82.9%)
Death	Yes: 8 (22.9%) No: 27 (77.1%)

MLL: Mixed-lineage leukemia; MRD: Minimal residual disease; T-ALL: T-cell acute lymphoblastic leukemia.

Table 5 Toxicities.

Common adverse events	Induction phase, n (%)	Consolidation phase, n (%)
Fever	13 (40.6%)	23 (71%)
Infection	9 (28.1%)	15 (46.9%)
Thrombosis	9 (25.7%)	1 (3.2%)
Bleeding	2 (5.7%)	1 (3.2%)
Hyperglycemia	8 (22.9%)	1 (3.2%)
Allergic reaction	8 (22.9%)	7 (21.9%)

Table 6 Hepatotoxicity in induction and consolidation phase according to CTCAE grading.

Adverse event	Grade 0, n (%)	Grade 1, n (%)	Grade 2, n (%)	Grade 3, n (%)	Grade 4, n (%)	NA
Induction phase
Transaminases	4 (12.5%)	12 (37.5%)	4 (11.4%)	11 (31.4%)	1 (2.9%)	3
Bilirubin	9 (28%)	10 (31%)	9 (28%)	2 (6.3%)	2 (6.3%)	3
Consolidation phase
Transaminases	4 (12.9%)	15 (48.4%)	9 (29%)	3 (9.7%)	0	4
Bilirubin	13 (41.9%)	9 (29%)	7 (22.6%)	2 (6.5%)	0	4