Nilotinib Combined with Multi-Agents Chemotherapy for Adult Patients with Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Results of a Prospective Study from a Single Center
Authors: Liu Bingcheng , Wang Ying , Zhou Chunlin , Wei Hui , Lin Dong , Li Wei , Liu Kaiqi , Zhang Guangji , Wei Shuning , Li Yan , Gong Benfa , Liu Yuntao , Mi Yingchang , Wang Jianxiang 
Published: October 2019

Abstract
Background: Imatinib combined with conventional chemotherapy has significantly improved the prognosis of adults with Philadelphia-positive acute lymphoblastic leukemia ( Ph+ ALL ). Nilotinib, the second generation TKIs is approximately 30 fold more potent than imatinib and is active in vitro against multiple BCR/ABL mutations. Here, we report the efficacy and safety of nilotinib combined with multiple reagents chemotherapy in newly diagnosed patients with Ph+ ALL.
Methods: Newly diagnosed Ph+ ALL patients aged 15 to 59 and with adequate organ function were recruited. The 4weeks induction cycle consist of vincristine, daunorubicin, cyclophosphamide and prednisone. After achieving hematological complete remission (HCR), patients received 2 years of consolidation and maintenance therapy. Consolidation therapy was including 7 courses of multiple drug chemotherapy or allogeneic/autologous hematopoietic cell transplantation (allo/auto HCT). Nilotinib was the only drug for maintenance therapy. Nilotinib 400mg was given orally twice daily along with combination chemotherapy starting from day 15 of induction until the initiation of conditioning for transplantation, hematological relapse or continuing for 2 years since achievement of hematological complete remission (HCR).Central nervous system (CNS) prophylaxis was performed by intrathecally administering triple agents. The data cut-off day was June 1st 2015. HCR and molecular complete remission (MCR), overall survival(OS), hematologic relapse free survival (HRFS), toxicity, nilotinib concentration in serum and cerebrospinal fluid(CSF) were evaluated. MCR was defined as Bcr-Abl fusion gene becomes negative in bone marrow using quantitative RT-PCR.
Results: A total of 30 patients (19 males and 11 females) were enrolled from September 2011 to November 2013. The median age was 40 (range 21-57) years old. The type of BCR breakpoint was minor in 24 patients, major in 2 patients and both in 4 patients. All the 30 patients (100%) and 8 patients (26.7%) achieved HCR and MCR respectively after the induction cycle. Cumulative MCR rate was 80%. 17 patients underwent HCT, 14 patients with alloHCT and 2 patients with autoHCT in first HCR, 1 patient received alloHCT after relapse. 9 patients died from leukemia relapse and 4 patients died post-alloHCT without relapse. The median HRFS and OS were 20.7 and 34 months respectively. The 4 year HRFS rate was 41% and the 4 year OS rate was 48%. The molecular response after induction has no impact on HRFS and OS. Patients achieving MCR had better HRFS (32 vs 8.9 months, p=0.006) but not OS(33.3vs 17.2months, p=0.068) than those patient without MCR. During induction, 23 patients experienced infectious fever including 2 patients with septicemia and 6 patients with pneumonia needing antifungal therapy. Intestinal obstruction occurred in 7 patients during induction and relived by interrupting nilotinib treatment. The incidence of non-hematologic adverse events (AE) over grade 3 during the study was 23% jaundice, 10% rash, 6.7% arthralgia and bone pain, 6.7%headache, 3.3% ALT elevation. No QTc prolongation over 500ms happened. Grade 2 tachycardia and premature ventricular contraction occurred in 2 patients and 1 patient respectively. During the high-dose methotrexate treatment cycle, delaying of methotrexate metabolism happened in 20 patients (66.7%), increasing creatine occurred in 8 patients (26.7%, grade 3 in 3 patients), 1 patient received haemodialysis. Nilotinib serum level reached to stable concentration after 15 days of administration. Only traces of nilotinib was detected in CSF.
Conclusion: In this prospective study, combination of nilotinib and cytotoxic drug was shown to be effective and tolerable for adult Ph+ALL. Nilotinib could not penetrate the blood brain barrier. (ChiCTR-ONC-12002469)

Disclosures
Off Label Use: nilotinib,the 2nd generation TKI, was approved for CML. Wang:Novarits and Bristol-Mayers squibb. G.S.: Consultancy.