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Phase II study for a patient with Philadelphia-chromosome positive acute lymphoblastic leukemia to determine the role of Dasatinib combined chemotherapy and allogeneic stem cell transplantation
(PHII-PHD trial)

PHII-PHD trial (PHII-PHD)

15

Baseline Characteristics of the Patients. Characteristic Enrolled Patients(N=15) Age-years Median 49 Range 24-64 Sex-no.(%) Male 9(60%) Female 6(40%) White cell count-per micl Median 9680 Range 2200-172000 BCR-ABL mRNA-no (%) minor 11(73%) Major 2(13%) minor and Major 2(13%) Performans Status 0-1 14(93%) 2 1(7%)

enrollment and outcome 15 patients enrolled and evaluable, began to receive dasatinib plus PSL induction therapy, and all of 15 patients reached complete hematological remission at day50. no one withdrew from this trial and no death with complication or adverse event were observed during induction phase. 15 patients completed dasatinib plus CVAD1 consolidation and dasatinib plus MA1 consolidation. After that, 1 underwent protocol specified all-SCT in 1st CR, and alive in mCR. 1 discontinued clinical trial because of residual Ph chromosome. 13 patients completed dasatinib plus CVAD2. after that, 8 underwent protocol specified allo-SCT in 1st CR. 2 discontinued clinical trial because of hematological relapse, and protocol violation respectively. 3 patients completed dasatinib plus MA2 consolidation. After that, 2 underwent protocol specified all-SCT in 1st CR. 1 patients completed dasatinib plus CVAD3 consolidation, and underwent protocol specified also-SCT in 1st CR.

non hematological adverse event during induction %of patients with event Liver function test G1-2 47 G3 13 Pulmonary effusion G1-2 33 Fever G1-2 20 Headach G1-2 13 Rash maculopapuler G1-2 13 Weight gain G1-2 13 Hyper glycemia G1-2 13 non hematological AE during consolidation %of patients with event Febril Neutropenia G3 46.8 Liver function test G1-2 13 G3 6.4 Nausea G1-2 17 Mucositis oral G1-2 10.6 Constipation G1-2 8.5 Diarrhea G1-2 6.4

Survival analysis The median follow up of censored patients was 53months (range, 28-68). The estimated median overall survival was not reached (95% confident interval, 18.6-not available). The 2-year and 4-year OS were 73.3% (95% CI, 43.6-89.1), 57.0% (95% CI, 27.7-78.2) respectively. Disease free survival (DFS) was defined as hematological relapse or death from any cause whichever comes first, the estimated median disease free survival was 52.3months (95% CI, 13.1-not available). 2-year and 4-year DFS were 60%(95%CI, 31.8-79.7), 51.4%(95%CI, 23.8-83.5) respectively. Correlation between type of BCR/ABL transcript and prognosis We focused on type of BCR/ABL transcript (minor BCR/ABL vs. Major BCR/ABL) and survival outcomes. No significant difference with respect to 4-year OS was observed between patients with minor-BCR/ABL 61.4%(95%CI, 26.6-83.5), and Major-BCR/ABL 50.0% (95%CI, 5.8-84.5)(p=0.397). Similarly, no significant difference with respect to 4-year DFS was observed between patients with minor-BCR/ABL 53%(95%CI, 20.9-77.3), and Major-BCR/ABL 50.0% (95%CI, 5.8-84.5)(p=0.848). Correlation between Molecular response after induction therapy and prognosis Again, we focused on molecular response (RQ-PCR<50copies/micg RNA vs. RQ-PCR>50copies/micg RNA) after dasatinib induction therapy and long term survival. When OS was analyzed according to the molecular response after dasatinib induction therapy, 4-year OS was 71.4% (95%CI, 25.8-92.0) for patients with RQ-PCR<50, and 50.0%(95%CI, 11.1-80.4) for patients with RQ-PCR>50. Although there was a tendency for good prognosis for those who had molecular response, difference did not reach statistical significance (p=0.181). Similarly, when 4-year DFS was analyzed, no significant difference was observed, 60% (95%CI, 19.5-85.2) for patients with RQ-PCR<50, and 50% (95%CI, 11.1-80.4) for patients with RQ-PCR>50 (p=0.597). Complete molecular response before SCT predicts long term survival Of the 12 patients who received allograft within this trial, 8(66.6%) received allograft with CMR (nested PCR negative) before SCT, and 4(33.3%) received allograft with non-CMR (nested PCR positive). The median follow up surviving patients after transplantation was 30.9months (range, 23.9-64.2). The probability of 2-year OS after SCT among patients who had CMR before SCT was superior, as compared with among patients with non-CMR: 87.5% (95%CI, 38.7-98.1) vs. 25% (95% CI, 0.9-66.5), p=0.0053. One of 8 patients who had CMR died from bronchiolitis obliterans, whereas the remaining 7 patients still alive in molecular remission. Contrastively, all of 4 patients who had non-CMR died (2 relapse and progression of leukemia, 1 post-transplant lymphoproliferative disease, 1 idiopathic pulmonary syndrome). CMR before allo-SCT was associated with long term survival.

we conducted phase 2 clinical trial with dasatinib based regimen for Ph positive ALL. Although this is a small number trial, our study shows that dasatinib based induction and consolidation with dasatinib plus intensive chemotherapy resulted in significantly higher remission, no mortality before SCT, all patients could undergo allo-grafting in CR1, 2-year OS was 73.3%. Given that both third generation TKI and BiTE antibody are incorporated in first line therapy, treatment outcome will be further improved.

Mar. 31, 2023

Jan. 17, 2024

https://authors.elsevier.com/c/1iUXEX17otjGh

No

non

https://jrct.mhlw.go.jp/latest-detail/jRCTs031180284

Kanda Yoshinobu

Jichi Medical University Hospital

3311-1 Yakushiji, Shimotsuke-shi, Tochigi-ken, Japan 329-0498

ycanda-tky@umin.ac.jp

Hatano Kaoru

Jichi Medical University Hospital

3311-1 Yakushiji, Shimotsuke-shi, Tochigi-ken, Japan 329-0498

+81-285-58-7353

kaorunob@jichi.ac.jp

Complete

Aug. 17, 2015

Interventional

single arm study

open(masking not used)

no treatment control/standard of care control

single assignment

treatment purpose

1. Patient with Philadelphia chromosome-positive acute lymphoblastic leukemia, or blastic phase of chronic myelogenous leukemia who have not been diagnosed as chronic phase, or Philadelphia chromosome-positive mixed phenotype acute leukemia.
2. In case of Philadelphia chromosome negative, those who are BCR/ABL fusion gene positive.
3. over 18 years old and up to 65 years old
4. No prior treatment of anticancer drug, excluding pre-phase PSL.
5. ECOG performance status within 1 to 3
6. Appropriate organ function (heart, liver, kidney, lung) withstand dasatinib therapy.
7. Given after appropriate information, all participant provided written informed consent.

1. Patient with active double cancer
2. Patient with severe past illness, or uncontrollable complication
3. Prior TKI use or chemotherapy
4. HIV positive
5. HBs-Ag positive
6. Sever psychosis
7. Not to be eligible to study participation by attending physician

Both

Philadelphia chromosome positive acute lymphoblastic leukemia

Multi-drug chemotherapy combined with Dasatinib and hematopoietic stem cell transplantation

Philadelphia chromosome positive acute lymphoblastic leukemia

Philadelphia chromosome positive acute lymphoblastic leukemia,Dasatinib,allogeneic hematopoietic cell transplantation

overall response

2-year disease-free survival, event-free survival, overall survival

+81-285-58-7637

Mar. 04, 2019

none