Interim Results of a Phase II Study of Dasatinib and Prednisone As an Oral, Chemo-Free Induction and Consolidation Regimen for Adults with Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia
Authors: Xie Mixue , Lu Ying , Ouyang Guifang , Zhang Liming , Hu Huixian , Shi Ting , Li Xueying , Ye Xiujing , Jin Jie , Zhu Hong-Hu 
Published: November 2021

Abstract
Background
Tyrosine kinase inhibitors (TKIs) combined with intensive chemotherapy as a first-line treatment regimen significantly improved the prognosis of Philadelphia (Ph) chromosomal positive acute lymphoblastic leukemia (Ph+ALL). However, it has been reported that 74% of patients fail to complete 8 cycles of chemotherapy, and the early mortality rate during induction was as high as 13%. Our previous retrospective study determined an oral, chemo-free regimen (dasatinib plus prednisone) as induction and consolidation yields 100% of complete remission (CR) rates in Ph+ ALL with minimal induction death (Li XY, et al. Br J Haematol. 2020;189:e231-e234). To further verify the effectiveness of this completely oral and chemo-free regimen, we conducted a phase II, one-arm and multicenter trial (ChiCTR200038053).
Methods
Adults ≥16 years of age with new diagnosed Ph+ALL were eligible. Induction (Course I) used dasatinib 100 mg daily on days 1-28 and prednisone 1mg/kg/daily on days 1-21, 0.5 mg/kg/daily on days 22-28. Patients not in CR/CRi received Course I as second induction again. Two courses of consolidation (Course II and III) used dasatinib 100 mg daily on days 1-28 and prednisone 1mg/kg/daily on days 1-7. CNS prophylaxis used intrathecal cytarabine and dexamethasone. Patients 16-65 years old underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) if they had a HLA-matched donor; otherwise they received 6 cycles of hyper-CVAD chemotherapy alternating regimen-B (methotrexate, cytarabine) and regimen-A (cyclophosphamide, doxorubicin, vincristine, dexamethasone). The dose of chemotherapy was reduced by a third in patients 60-70 years old and by half in patients over 70 years. The primary objectives were to determine induced complete remission rate and major molecular response of the dasatinib/prednisone oral, chemo-free regimen.
Results
To date, 32 patients from 10 centers enrolled. Median age was 54 years (range: 15-84). The dominant BCR-ABL1 isoform was p190 in 72%, p210 in 18%, rare types in 6.3% and not reported in 3.1%. Patients received an average of 2.5 courses of dasatinib/prednisone regimen (Course I-III). Most patients were tolerable the dose of dasatinib, and two patients were reduced to 50mg daily due to severe pleural effusion. Allo-HSCT was performed in 10 patients, 50% after remission and 50% after marrow relapse.
As shown in Figure 1, the CR rate was 97% with one induction death due to sepsis. The major molecular response (MMR was defined as: 3-log reduction in BCR-ABL1 transcript) was 50% and the complete molecular response (CMR was defined as: the absence of a detectable BCR-ABL1 transcript with 0.01% sensitivity/4.5-log) was 40% either at 3 months after starting induction or before HSCT, respectively. From Course I to Course II, the CMR increased from 18.5% to 48%, but accompanied by an increase in marrow relapse rates, which were 16% and 18.75% at course II and course III, respectively. Marrow relapse occurred in 9 patients, all occurred within 6 months after starting induction. T315I mutation in ABL1 KD was detected in 5 of 7 marrow relapses (72%). With a median follow up of 232 days (range: 77-392 days), 1-year OS and 1-year event-free survival (events were defined as marrow relapse and death) was 97% and 54%, respectively (Figure 2). The cumulative molecular relapse rate (defined as BCR-ABL1:ABL1 ratio rises after reaching the CMR level) was 35% at 3 months, 48% at 6 months, and 54% at 1 year (Figure 2).
Conclusions
The chemotherapy-free, oral combination of dasatinib and prednisone appears promising induction efficacy in de novo Ph+ ALL; the high CR rates and acceptable molecular response rates were similar to results reported by GIMEMA LAL2116 study (Foà R, et al. N Engl J Med. 2020;383:1613-1623). However, two subsequent consolidation courses of the chemo-free regimen led to early molecular relapse with T315I mutations, which urged us to modify the study protocol such as strengthening consolidation therapy or incorporating promising drug blinatumomab.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.