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1. Pre-phase (maximum 7 days, -7 to -1) with Prednisone and triple intrathecal therapy (TIT)
2. Induction (day 1 to day 28 or up to hematological recovery) Vincristine (VCR): 1.5 mg/m2 IV days 1, 8, 15 and 22. Daunorubicin (DNR): 45 mg/m2 IV days 1, 8, 15 and 22. Prednisone (PDN): 60 mg/m2/day, IV or PO, days 1 to 27. Ponatinib 30 mg, PO from day 1 to consolidation. TIT, days 1 and 22.
3. Consolidation Mercaptopurine (MP): 50 mg/m2, PO days 1 to 7, 28 to 35 and 56 to 63. MTX: 1,5 g/m2, IV days 1, 28 and 56. VP-16: 100 mg/m2/12 h, IV, days 14 and 42. ARA-C: 1000 mg/m2/12 h, IV, days 14-15 and 42-43. TIT days 1, 28 and 56. Ponatinib 30 mg/d PO, from day 1 to day 7 before HSCT".
4. HSCT (performed ideally within 1 month from the end of consolidation).
5. Post HSCT therapy (MRD monitoring)

Prednisone 60 mg/m2/day IV over 7 days (-7 a -1) and triple intrathecal therapy (TIT)

Vincristine (VCR): 1.5 mg/m2 (maximum 2 mg) IV days 1, 8, 15 and 22.

Daunorubicin (DNR): 45 mg/m2 IV days 1, 8, 15 and 22.

Prednisone (PDN): 60 mg/m2/day, IV or PO, days 1 to 27.

Ponatinib 30 mg, PO from day 1 to consolidation

Mercaptopurine (MP): 50 mg/m2, PO days 1 to 7, 28 to 35 and 56 to 63.

MTX: 1,5 g/m2, IV (24 h continuous infusion) days 1, 28 and 56

VP-16: 100 mg/m2/12 h, IV, days 14 and 42

VP-16

ARA-C: 1000 mg/m2/12 h, IV, days 14-15 and 42-43.

ARA-C:

TIT (MTX: 12 mg, ARA-C: 30 mg, hydrocortisone: 20 mg), , days 1, 28 and 56.

Ponatinib 30 mg/d PO, from day 1 to 15 days before HSCT.

Myeloablative conditioning with cyclophosphamide and total body irradiation (TBI) whenever possible and autologous transplantation

Autologous transplantation

Myeloablative conditioning with cyclophosphamide and total body irradiation (TBI) whenever possible and allo transplantation

Allo transplantation

Evaluate the response (complete hematologic response \[CHR\], complete cytogenetic response \[CCyR\], major molecular response \[MMR\] and complete molecular response \[CMR\] of the combination of ponatinib with standard chemotherapy (according to PETHEMA ALL Ph08 trial) in young patients with Ph+ (BCR-ABL) ALL.

All patients are treated with:

Pre-phase (maximum 7 days, -7 to -1):

Prednisone 60 mg/m2/day IV over 7 days (-7 a -1) and triple intrathecal therapy (TIT) (Methotrexate \[MTX\]: 12 mg, ARA-C: 30 mg, hydrocortisone: 20 mg). 2. Induction (day 1 to day 28 or up to hematological recovery) Vincristine (VCR): 1.5 mg/m2 (maximum 2 mg) IV days 1, 8, 15 and 22. Daunorubicin (DNR): 45 mg/m2 IV days 1, 8, 15 and 22. Prednisone (PDN): 60 mg/m2/day, IV or PO, days 1 to 27. Ponatinib 30 mg, PO from day 1 to consolidation. TIT, days 1 and 22. 3. Consolidation (day 1 to day 63) Mercaptopurine (MP): 50 mg/m2, PO days 1 to 7, 28 to 35 and 56 to 63. MTX: 1,5 g/m2, IV (24 h continuous infusion) days 1, 28 and 56. VP-16: 100 mg/m2/12 h, IV, days 14 and 42. ARA-C: 1000 mg/m2/12 h, IV, days 14-15 and 42-43. TIT (MTX: 12 mg, ARA-C: 30 mg, hydrocortisone: 20 mg), , days 1, 28 and 56. Ponatinib 30 mg/d PO, from day 1 to 15 days before HSCT. 4. HSCT (performed ideally within 1 month from the end of consolidation). AlloHSCT preferred over autoHSCT (autoHSCT only indicated if alloHSCT not feasible). Myeloablative conditioning with cyclophosphamide and total body irradiation (TBI) whenever possible. 5. Post HSCT therapy After alloHSCT. Frequent monitoring of MRD (every month). I After autoHSCT: Frequent monitoring of MRD (every month).

Objectives Primary

1. To evaluate the response (complete hematologic response \[CHR\], complete cytogenetic response \[CCyR\], major molecular response \[MMR\] and complete molecular response \[CMR\] of the combination of ponatinib with standard chemotherapy (according to PETHEMA ALL Ph08 trial) in young patients with Ph+ (BCR-ABL) ALL.
2. To evaluate the event free survival (EFS) of the combination of ponatinib with standard chemotherapy (according to PETHEMA ALL Ph08 trial) in young patients with Ph+ (BCR-ABL) ALL. Secondary

   * To evaluate the rate of patients receiving an allogeneic hematopoietic stem cell transplant (alloHSCT) in first CR
   * To evaluate the frequency of MMR and CMR at the time of alloHSCT
   * To evaluate the transplant-related mortality (TRM)
   * To evaluate the CR duration and overall survival (OS) of the combination of ponatinib with standard chemotherapy (according to PETHEMA ALL Ph08 trial) in young patients with Ph+ (BCR-ABL) ALL.
   * To evaluate the outcome measures (CR duration, OS and EFS) in context of those observed in the PETHEMA ALL Ph08 trial.
   * To observe the type and number of BCR-ABL kinase domain mutations developing during and after the study.
   * To evaluate side effects, adverse events (AE) and serious AE (SAE).

Interventions:

1. Pre-phase (maximum 7 days, -7 to -1):

   Prednisone 60 mg/m2/day IV over 7 days (-7 a -1) and triple intrathecal therapy (TIT) (Methotrexate \[MTX\]: 12 mg, ARA-C: 30 mg, hydrocortisone: 20 mg).
2. Induction (day 1 to day 28 or up to hematological recovery) Vincristine (VCR): 1.5 mg/m2 (maximum 2 mg) IV days 1, 8, 15 and 22. Daunorubicin (DNR): 45 mg/m2 IV days 1, 8, 15 and 22. Prednisone (PDN): 60 mg/m2/day, IV or PO, days 1 to 27. Ponatinib 30 mg, PO from day 1 to consolidation. TIT, days 1 and 22.
3. Consolidation (day 1 to day 63) Mercaptopurine (MP): 50 mg/m2, PO days 1 to 7, 28 to 35 and 56 to 63. MTX: 1,5 g/m2, IV (24 h continuous infusion) days 1, 28 and 56. VP-16: 100 mg/m2/12 h, IV, days 14 and 42. ARA-C: 1000 mg/m2/12 h, IV, days 14-15 and 42-43. TIT (MTX: 12 mg, ARA-C: 30 mg, hydrocortisone: 20 mg), , days 1, 28 and 56. Ponatinib 30 mg/d PO, from day 1 to 15 days before HSCT.
4. HSCT (performed ideally within 1 month from the end of consolidation). AlloHSCT preferred over autoHSCT (autoHSCT only indicated if alloHSCT not feasible). Myeloablative conditioning with cyclophosphamide and total body irradiation (TBI) whenever possible.
5. Post HSCT therapy After alloHSCT. Frequent monitoring of MRD (every month). If MRD negative: no therapy. If MRD positive, Ponatinib 30 mg/d, po, until 2 yr. after HSCT. The ponatinib dose will be reduced to 15 mg/d in the second year in patients with sustained molecular response. After autoHSCT: Frequent monitoring of MRD (every month). All patients will receive Ponatinib: 30 mg/d, PO, mercaptopurine, (40 mg/m2/d, PO) and methotrexate (15 mg/m2/week, IM), during the first year after HSCT. The ponatinib dose will be reduced to 15 mg/d in the second year in patients with sustained molecular response.

Ponatinib With Chemotherapy for Young Adults Ph Positive Acute Lymphoblastic Leukemia

Concurrent Ponatinib With Chemotherapy for Young Adults With Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

To evaluate the response (complete hematologic response \[CHR\], complete cytogenetic response \[CCyR\], major molecular response \[MMR\] and complete molecular response \[CMR\] of the combination of ponatinib with standard chemotherapy (according to PETHEMA ALL Ph08 trial) in young patients with Ph+ (BCR-ABL) ALL.

To evaluate the event free survival (EFS) of the combination of ponatinib with standard chemotherapy (according to PETHEMA ALL Ph08 trial) in young patients with Ph+ (BCR-ABL) ALL

PETHEMA Foundation

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Ponatinib With Chemotherapy for Young Adults Ph Positive Acute Lymphoblastic Leukemia	NCT02776605	ALL	Prednisone Vincristine Daunorubicin Prednisone Ponatinib Mercaptopurine Methotrexate VP-16 ARA-C: TIT Ponatinib Autologous tran... Allo transplant...	18 Years - 55 Years	PETHEMA Foundation
Ponatinib With Chemotherapy for Young Adults Ph Positive Acute Lymphoblastic Leukemia	NCT02776605	ALL	Prednisone Vincristine Daunorubicin Prednisone Ponatinib Mercaptopurine Methotrexate VP-16 ARA-C: TIT Ponatinib Autologous tran... Allo transplant...	18 Years - 55 Years	PETHEMA Foundation

Spots Global Cancer Trial Database for allo transplantation