Phase II study of dasatinib in combination with chemotherapy and allogeneic stem cell transplantation for newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia by Japan Acute Leukemia Study Group (JALSG Ph+ALL213) (JALSG Ph+ALL213 study)
1. Acute lymphoblastic leukemia.
2. BCR/ABL1 positive.
3. aged >= 15 years and < 64 years.
4. Patients must not be previously treated except PSL in the pre-phase PSL therapy.
5. ECOG performance status of 0, 1, 2 or 3.
6. Patients must have adequate cardiac, hepatic, renal, and pulmonary functions.
7. Voluntary written consent must be given before enrollment.
1. Heart insufficiency.
2. Pulmonary fibrosis, interstitial pneumonitis.
3. Uncontrollable diabetes mellitus.
4. Grade 4 infection.
5. HIV antibody positive.
6. HBs antigen positive.
7. Concurrent disease which may exaggerate adverse events by dasatinib.
1) Pleural effusion, ascites, or other fluid retention.
2) Congenital bleeding diathesis.
3) Diseases requiring anticoagulant or anti-platelet agents.
4) Acquired bleeding diathesis.
8. Psychiatric illness.
9. Active another malignancy.
10. Female patients who are breast feeding or pregnant.
11. Patients who, in the judgment of the investigator, would be inappropriate for entry into this study.
After the 7-day PSL therapy, during which positivity of BCR-ABL fusion transcript must be proved, 4-week dasatinib(DA) is given with 3-week PSL to achieve CHR. Then 4-week DA is given following 4 drugs (VCR, CPM, DNR, and PSL) combination to aim at CMR. C1 (HDMTX/AraC+DA) and C2 (VCR, DNR, CPM +DA) consolidation are repeated up to 4 cycles. Patient who has an adequate donor proceed to allogeneic SCT during the consolidation. Patient who has no adequate donor proceed to 12 courses of 4-week DA-based maintenance therapy.
1. The proportion of complete hematological remission (CHR) after induction.
2. CMR rate at the following points.
(1) after induction(IN), (2) after intensive consolidation(IC), (3) after C1-1
3. The proportion of complete molecular remission (CMR) at pre- and post-alloHSCT.
(1) pre-alloHSCT, (2) day30 post-alloHSCT, (3) day100 post-alloHSCT.
4. 3-year OS, EFS, RFS.
5. Prognostic significance of CMR at the following points.
(1) after intensive consolidation, (2) pre-SCT, (3) day30 of post-SCT, (4) day100 of post-SCT
6. The efficacy of hematopoietic SCT.
(1) day100, (2) 1-year OS, (3) relapse free survival, (4) relapse rate, (5) non-relapse mortality
7. Prognostic significance of additional cytogenetic abnormalities.
8. The proportion of therapy related mortality.
9. Analysis of early death in induction and intensive consolidation therapy.
10. The frequency of adverse events in each steps of treatment.
11. Safety of hematopoietic SCT.
(1) frequency of graft failure, (2) acute GVHD, (3) chronic GVHD.
12. Frequency of dose reduction of DA and median ration of actual dose to expected total dose in each regimen.
13. Mutation analysis of BCR-ABL transcript on patients who relapsed hematologically
14. Analysis of patients with major BCR-ABL.
(1) percentage of patients who had neutrophil-BCR/ABL1 FISH in PB,(2) CHR rate after IC, (3) CMR rate after IC, (4) 3Y-EFS, 3Y-OS, 3Y-RFS