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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)

JALSG Ph+ALL213 study (JALSG Ph+ALL213 study)

78

Baseline characteristics Median age years (range) 45 (16-64) Gender, male/ female n (%) 37 (47.4)/ 41 (52.6) ECOG PS, 0/1 44 (56.4)/ 29 (37.2) 2/3 4 (5.1)/ 1 (1.3) WBC x10^9 /L 32.5 (0.9-443.2) Hb g/dL 10.9 (3.3-11.9) PLT x10^10 /L 4.3 (0.3-28.1) BCR-ABL1 type major n (%) 17 (21.8) minor n (%) 56 (71.8) major + minor n(%) 5 ( 6.4) Copy no. of BCR-ABL1 (x10^5) all case med. (range) 3.9 (0.21-34.0) major med. (range) 2.7 (0.86- 4.9) minor med. (range) 4.2 (0.21-34.0) Cytogenetics t(9;21) only n (%) 18/ 77 (23.4) additional abnormality n (%) 50/ 77 (64.9) normal n (%) 6/ 77 ( 7.8) no mitosis n (%) 3/ 77 ( 3.9)

Eighty-one patients were enrolled from 46 hospitals between 1 November 2013 and 12 April 2016. Of them, 78 patients were eligible. One hundred percent of them achieved complete hematological remission after induction. Fifty-eight patients, whose complete molecular remission rate was 75.9%, underwent allogeneic hematopoietic stem cell transplantation (alloHSCT) and 6 patients completed the protocol chemotherapy. Fourteen patients withdrew the study because of relapse (5), toxicity (4), reasons other than toxicity (3), and physician^s decision (2). Follow up of the study was ended on 1 July 2019.

Chemotherapy-related mortality was not reported during chemotherapy. Major toxicities were neutropenia and related infectious complications, such as febrile neutropenia and sepsis. Grade 4 neutropenia were noted 51.3%, 93.5%, 98.6% and 34.9% in IND, IC, C1-1, and C2-1, which caused grade 3 febrile neutropenia 6.4%, 15.6%, 69.0%, and 7.0%, respectively. Grade4 FN were reported 2.8% in C1-1. Grade 4 sepsis was reported 1.3%, 6.5%, 8.5%, and 0.0%. Grade 4 other non-hematological were 1.3%-1.4%. As DA related toxicities, grade 3 liver dysfunction were reported 12.8%, 3.9%, and 12.7%, in IND, IC, and C1-1, respectively. One patient developed severe allergic reactions. Six (10.3%) patients died in remission due to transplant-related toxicity. Three (27.3%) of 11 patients who underwent alloHSCT after withdrawing the protocol died of transplant-related toxicity. Grade1/2 bleeding was reported 5 and 2 patients in IN and C1-1, respectively. Three of 5 bleeding in IN were complicated with grade3/4 DIC. Grade1/2 pleural effusion was reported 2, 1, and 1 patient in IN, IC, and C1-1.

Primary Endpoint: At the median follow-up of 4 years (2.5-5.4), the 3Y-EFS was 66.2% (90%CI, 56.4%-74.2%). The lower level of 90% CI was 56.4%, which exceeded the threshold of 45%. Thus, the treatment in this trial was determined to be effective. Secondary Endpoint: 1. The proportion of complete hematological remission (CHR) after induction: 100% 2. CMR rate after the following treatments. (1) after IN 21.8%. (2) after IC 52.6%. Not tested (5). (3) after C1-1 57.7%. Proceed to alloHSCT (2), withdrawing (5). 3. The proportion of complete molecular remission (CMR) at the following points. (1) pre-alloHSCT: 75.9% (44/58) (2) day30 after alloHSCT: 87.9% (51/58). NRM (2) (3) day100 after alloHSCT: 75.9% (44/58). NRM (2), RM (4) 4. 3Y-OS, 3Y-EFS, 3Y-RFS. With median FU duration of 4.0 year(range,2.5-5.4) (1) 3Y-OS: 80.5% (95%CI, 69.7-87.7%) (2) 3Y-EFS: 66.2% (95%CI, 54.4-75.5%) (3) 3Y-RFS Almost equal to 3Y-EFS because all patients achieved CR at the same point. 5. Prognostic significance of CMR at the following points. (1) after intensive consolidation, MRD (-) vs. MRD (+): 3Y-EFS: 66.1% vs 75.8%, p=0.392. NS. 3Y-OS: 90.9% vs 70.3%, p=0.0913. NS. (2) pre-SCT MRD (-) vs MRD (+): 3Y-EFS: 79.5%vs 57.1%, p=0.0577. NS. 3Y-OS: 90.9% vs 64.3%, p=0.0075. S. (3) day30 and day100 from alloHSCT Not analyzed because CMR rates of patients who could be analyzed at day30 and day100 were 92.7% and 93.6%, respectively. 6. The efficacy of alloHSCT; (1) Day100 survival rate: 93.1% (95%CI, 82.7-97.4%) (2) 1Y-OS: 87.9% (95%CI, 76.3-94.1%) (3) Relapse free survival: (4) Relapse rate (Cumulative Incidence of Relapse; CIR): 1Y-CIR 13.0% (95%CI, 3.5-21.5%), 3Y-CIR 18.8% (95%CI, 7.6-28.7%) (5) Non-relapse mortality (Cumulative Incidence of Non-relapse Mortality; CINRM): 1Y-CINRM 8.7%(95%CI,1.1-15.7%), 3Y-CINRM 10.9% (95%CI, 2.2-18.7%) 7. Prognostic significance of additional cytogenetic abnormalities -Additional CA (+) vs (-) for all patients 3Y-EFS 61.8% vs 77.8%, p=0.1792. NS. 3Y-OS 73.9% vs 100%, p=0.0346. S. -Additional CA with der(22)t(9;22) vs Ph+only for patients 3Y-EFS, 46.8% vs 77.8%, p=0.0842. NS. 3Y-OS 62.7% vs 100%, p=0.0175. S. -Additional CA with der(22)t(9;22) vs Ph+only for transplanted patients 3Y-EFS 49.0% vs 86.7%, p=0.0424. S. 3Y-OS 63.5% vs 100%, p=0.0443. S. 8. The proportion of therapy related mortality No patients died with chemotherapy. Six of 58 patients who underwent alloHSCT@1CR and 3 of 11 patients who underwent alloHSCT outside the protocol died of transplant related toxicity. 9. Analysis of early death in induction and intensive consolidation therapy. No patient died in the induction and intensive consolidation. 10. The frequency of adverse events in each step of treatment. Described in adverse events. 11. Safety of alloHSCT; frequency of graft failure, acute and chronic GVHD. (1) graft failure 6.9% (4/58) (2) acute GVHD 50.0% (29/58) (3) chronic GVHD 31.0% (18/58) 12.Frequency of dose reduction of DA and median ration of actual dose to expected total dose in each regimen. In the treatments of IN (n=78), IC (n=77), C1-1 (n=71), C2-1(n=45), (1) withdrawal and skip Withdrawals were 9.0%, 7.8%, 5.6%, and 4.4%, and skips were 2.6%, 3.9%, 2.9%, and 2.2%, respectively (2) median ratio of actual dose to expected dose (%, range) were 95.7% (39.3-100), 96.9% (7.5-100), 95.7% (39.3-100), and 95.7% (39.3-100), respectively. 13. Mutation analysis of BCR-ABL transcript on patients who relapse hematologic. All 4 patients who relapsed during chemotherapy had T315I mutation. Samples of patients who relapsed after completed chemotherapy (3 patients) and after alloHSCT (9) could not be collected. 14. Analysis of patients with major BCR-ABL (n=22) (1) Percentage of patients who had neutrophil-BCR/ABL1 FISH in PB: major vs minor 70.6% (12/17) vs 54.5% (6/11) (2) CHR rate after IC 100% (3) CMR rate after IC major vs minor 455% (10/22) vs 53.6% (30/56), p=06173. (4) 3Y-EFS, 3Y-OS, 3Y-RFS Major vs minor: 3Y-EFS: 75.9% (95%CI, 51.4-89.2%) vs 62.4% (95%CI, 48.4-73.7%), p=0.3485. NS. 3Y-OS: 90.5% (95%CI, 67.0-97.5%) vs 76.7% (95%CI, 63.3-85.8%), p=0.2512. NS. 3Y-RFS: almost same as 3Y-EFS because all patients achieved complete hematological remission.

DA-based two-step induction in which DA was introduced instead of IM to enhance efficacy and two-step induction to minimize toxicity showed improved survival significantly in terms of the primary endpoint of 3Y-EFS. Toxicity was minimized. Major toxicity was neutropenia and related infectious complications, such as febrile neutropenia and sepsis. No one died of chemotherapy-related toxicity. However, 16% of patients died of transplanted-related toxicity. 3Y-EFS and OS for the patients who underwent alloHSCT

Feb. 01, 2022

Jan. 25, 2022

https://doi.org/10.1182/bloodadvances.2021004607

No

none

https://jrct.mhlw.go.jp/latest-detail/jRCTs041180136

Sugiura Isamu

Toyohashi Munical Hospital

50 Hachikennishi,Aotake-cho, Toyohashi, Aichi, JAPAN

sugiura-isamu@toyohashi-mh.jp

Sugiura Isamu

Toyohashi Munical Hospital

50 Hachikennishi,Aotake-cho, Toyohashi, Aichi, JAPAN

+81-532-33-6111

sugiura-isamu@toyohashi-mh.jp

Complete

Nov. 01, 2013

Interventional

single arm study

open(masking not used)

uncontrolled control

single assignment

treatment purpose

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.

Both

Philadelphia chromosome positive acute lymphoblastic leukemia

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.

Philadelphia chromosome positive acute lymphoblastic leukemia

3-year event-free survival

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

+81-52-951-1111

Mar. 05, 2019

none