Treatment of Adult Acute Lymphoblastic Leukemia (ALL) with a Modified DFCI Pediatric Regimen - The Princess Margaret Experience.
Authors: Storring John M. , Brandwein Joseph , Gupta Vikas , Schuh Andre C. , Schimmer Aaron , Yee Karen , Wells Richard A. , Lipton Jeffrey H. , Messner Hans A. , Xu Wei , Minden Mark D. 
Published: October 2019

Abstract
Between June 2000 and December 2004, 68 adult patients with newly diagnosed ALL were treated at Princess Margaret Hospital in Toronto, Canada using a modified Dana Farber Cancer Institute pediatric ALL protocol (DFCI 91-01). This protocol includes a remission induction phase, a CNS prophylaxis phase with intrathecal chemotherapy and 12 Gy cranial irradiation, a 30-week intensification phase, and a 72-week maintenance phase. Since 2002, bcr-abl+ patients received concurrent therapy with imatinib mesylate. Before 2002, all patients in CR1 were referred for allogeneic stem cell transplant (alloSCT) if a suitable matched sibling donor was identified (n=11); after 2002, only high-risk patients were referred for alloSCT (n=14). In addition bcr-abl+ and t(4:11) patients were considered for matched unrelated donor alloSCT. Median age was 34.5 years (range, 17–61 years). Sixteen (23.5%) patients were bcr-abl+ and 13 (19.1%) pre-B with WBC > 30. Ten of 16 (62.5%) of the bcr-abl+ patients received concurrent imatinib mesylate; 11 of 16 (69%) of these subsequently underwent alloSCT. The complete remission (CR) rate was 85.4% (58/68), with a 5.9% induction death rate. CNS prophylaxis was administered to 54 patients and was well tolerated. Fifty-seven patients proceeded to therapy in the intensification phase, which consisted of vincristine (VCR) 2 mg × 10 doses, L-asparaginase (l-asp) 12,500 IU/m2 weekly × 30 doses, doxorubicin 30 mg/m2 × 7 doses, 6-mercaptopurine, dexamethasone and methotrexate. Thirty-four patients completed this phase, while 18 patients had an abbreviated course of intensification before proceeding to alloSCT. Major side effects during the intensification phase included grade 3–4 neutropenia (63%), peripheral neuropathy (40%), thrombosis (17.5%) and central venous catheter infection (18.2%). Intensification was administered on an outpatient basis with 12/57 (21%) requiring hospitalization for any reason. Maintenance therapy was given to 32 patients and was well tolerated. At a median follow-up of 2.7 years (range, 0.05–5.8 years), both median overall survival (OS) and relapse free survival (RFS) were 4.9 years. Among non-transplanted patients (n=44), Kaplan-Meier 3-year OS and RFS were 65.5% and 77.3%, respectively with most deaths occurring in induction or from progressive leukemia in primary non-responders. For the entire group, younger age (< 25 years) was associated with improved OS and RFS (p= 0.03) whereas bcr-abl positivity was not. Due to neuropathy, vinblastine (VBL) was substituted for VCR in 13/33 (39.4%) patients during intensification without affecting RFS and OS (p=0.22). Of the 34 patients who completed intensification without relapse, those who received >80% of the targeted l-asp dose had a significantly longer OS (p=0.02) and RFS (p=0.04). These results demonstrate the feasibility of administering the pediatric DFCI protocol to adults up to the age of 61 years with acceptable toxicity. As with the DFCI pediatric experience (Blood2001; 97(5): 1211-8), the ability to deliver >80% of the targeted l-asparaginase dose during the intensification phase appears to produce improved efficacy. Longer follow-up will be needed to further characterize the anti-leukemic efficacy of this regimen in adults.