J Clin Oncol August Vol 28 R2. 석화영 / Pf. 윤휘중

Background  Imatinib, a powerful inhibitor of ABL1-type tyrosine kinase :tremendous impact on treatment concepts for Philadelphia chromosome (Ph)–positive leukemia  300 to 1,000 mg daily (median 600 mg) : median time to clear circulating blast cells of only 6 days → even a brief imatinib course could be therapeutically effective → use of imatinib combinations with other antileukemic drugs  In vitro studies highlighted pharmacologic synergy and imatinib- mediated drug-induced apoptosis which in theory could help overcome the drug resistance of Ph-positive lymphoblasts.

Background  In the clinical setting, a first study  14-day imatinib courses in combination with Hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone, alternating with highdose cytarabine and methotrexate) chemotherapy blocks, resulting in improved early survival compared with historical patients. -Blood 103: , 2004  Subsequent reports of imatinib and chemotherapy combinations improved outcome, which included an overall survival of 36% to 76% at 1 to 2 years, 23% to 78% at 3 years, and 30% to 52% at 4 years, often in relation to an increased applicability of allogeneic stem-cell transplantation (SCT)

Background  Northern Italy Leukemia Group (NILG) designed  chemotherapy-plus-imatinib trial: 7-day imatinib pulses starting 3 days before chemotherapy  hypothesis that imatinib would sensitize Ph-positive ALL cells to standard antileukemic drugs  Objective  To translate the concept of drug synergy into an improved outcome, first reducing the risk of early treatment failure and subsequently enabling more patients to receive hematopoietic SCT  Primary study end point  to improve the long-term outcome of adult patients with Ph-positive ALL compared with a prior patient cohort treated with the same chemotherapy program without imatinib.

Methods-Patients  Untreated Ph-positive ALL  t(9;22) detectable on cytogenetic analysis and/or  P190- or P210-type BCR-ABL1 rearrangements detected by real- time quantitative polymerase chain reaction (RT-PCR)  For minimal residual disease (MRD) assessment, three serial bone marrow (BM) samples were prospectively taken at weeks 10, 16, and 22

Methods-Treatment Protocol  NILG protocol 09/00  February 2003: Imatinib was added to each chemotherapy course at 600 mg/d administered orally for 7 consecutive days, starting 3 days before chemotherapy  From March 2005, L-Asparaginase (L-Asp) was omitted from the induction cycle in view of serious toxicity episodes reported in a first patient group

Methods-Definition  Complete remission (CR) :standard criteria  hemoglobin >10 g/dL  neutrophils >1x109/L  platelets > /L  bone marrow without ALL cells (blast cells < 5%)  no sign of extramedullary disease  Early death (ED) :Death before treatment response  Refractory ALL(NR, no reponse): the persistence of leukemia after cycle 2  Relapse: the reappearance of blast cells (>5%) in the bone marrow or extramedullary sites.  Overall survival (OS) : calculated from the date of diagnosis to death  disease-free survival (DFS) : calculated from the date of CR to relapse or death in CR  Cumulative incidence of relapse (CIR) and treatment related mortality (TRM) : calculated from the date of CR to recurrence or death in CR

Methods-End point and Statistics  The primary end point to significantly improve the 5-year survival over the historical control group.  Data analysis was closed in July 2009  Secondary end points concerned CR, DFS, CIR, SCT, TRM data analysis.  Prognostic and outcome parameters were compared by using χ 2 test  OS, DFS, CIR, and TRM curves were plotted by the Kaplan-Meier method and were compared by using the log-rank test  Multivariate analyses were carried out by means of a Cox linear regression model

Results  Beginning in April 2000  100 patients enrolled on protocol NILG 09/00 were diagnosed with Ph- positive ALL  Of these 100 patients, 35 received chemotherapy only, 59 were included in the imatinib program (IM-positive group), and six were treated with chemotherapy plus a subcontinuous imatinib schedule (7 weeks during induction and 2 weeks during subsequent consolidation courses)

Results

Remission Induction

Postremission Therapy

Long-Term Results 0.38 vs vs vs 0.72

SCT Results

Prognostic Analysis

Discussion  In this prospective NILG trial, brief imatinib pulses were administered together with standard chemotherapy to untreated patients with Ph positive ALL to increase the number of durable remissions and to allow more patients to undergo SCT → significant prolongation of survival compared with a previous cohort treated with the same program without imatinib  The rationale for adopting the brief, intermittent imatinib schedule  rapid inhibition of ALL cell growth by imatinib, together with the pharmacologic synergy documented by several in vitro studies  This feature was presumably amplified by sequential drug administration, which aimed to render Ph-positive blasts more susceptible to drug-induced apoptosis.

Discussion  Induction regimen resulted in a 100% CR rate once L-Asp was withdrawn in view of the toxic adverse effects observed in a first patient group →high response rate is reported without L-Asp  Severe metabolic and liver function impairment from a combination of idarubicin plus L-Asp, which could be aggravated by concurrent imatinib  Recent study showed the emergence of BCR-ABL1-specific cytotoxic T cells after long-term imatinib administration, which resulted in improved molecular response and survival.  Rationale for the use of imatinib after allogeneic SCT, and they prompt investigation of the role of autologous SCT plus imatinib-based maintenance, particularly in frail patients who have contraindications to allogeneic SCT

Discussion  This study demonstrated a 5-year survival close to 40% for 59 adult patients with Ph-positive ALL  imatinib given cyclically at 600 mg/d for 7 days and in association with chemotherapy  improved CR and SCT rates  Several points of interest  the shaping of an effective, moderately toxic induction regimen  the possible benefit from an autologous SCT (plus maintenance)  the need for long-term monitoring and re-treatment of residual molecular disease

Conclusion  Imatinib-based protocol improved long-term outcome of adult patients with Ph-positive ALL  With SCT, post-transplantation mortality and relapse remain the major hindrance to additional therapeutic improvement