Pediatric-Based Versus Adult Treatment Protocols in Young Adults (18-40 years) with Standard Risk Acute Lymphoblastic Leukemia: The BC Cancer Agency Experience

Introduction

In recent decades, overall survival rates for children with acute lymphoblastic leukemia (ALL) have improved dramatically. Unfortunately, older patients have not experienced the same benefit. Recent years have seen investigation into the use of pediatric protocols for younger adults with ALL. Increased toxicity has often limited use to patients 40 years or younger.

The Leukemia/Bone Marrow Transplant Program of BC is the referral center for adults with ALL in British Columbia. Approximately 20 patients are newly diagnosed with ALL each year. Until 2008, an adult protocol (known as ALL 89-1) was used in patients over 18 years. Since 2008, pediatric-based chemotherapy has been offered to patients 40 years or younger.

We analyzed whether this change altered complete remission (CR), relapse and survival rates. We assessed whether the more intense protocol increased toxicity.

Methods

A retrospective analysis was performed on patients treated for ALL on a pediatric-based protocol. These protocols (ALL 08-01 and ALL 13-01) were modifications of the Donna Farber Cancer Institute 01-175 protocol. The format included induction with high dose methotrexate, followed by central nervous system (CNS) therapy including cranial irradiation. A single cycle of etoposide and high-dose cytarabine was given. Consolidation and continuation cycles included doxorubicin, asparaginase, vincristine and dexamethasone. Patients were included if they were aged 18-40 years and had standard risk, Philadelphia chromosome negative ALL.

Between February 2008 and November 2014, 25 eligible patients were identified. These were compared with the 23 consecutive standard risk patients most recently treated with ALL 89-1. They had been diagnosed between February 2003 and July 2008.

Exclusion criteria were age greater than 40 and non-standard risk ALL.

Demographic and clinical data were collected on all patients from the Leukemia Program databases.

Overall survival (OS) was calculated from time of diagnosis until death. Event free survival (EFS) was calculated from diagnosis until death, induction failure or relapse. Estimation of OS and EFS was performed using the Kaplan-Meier method. Patient characteristics were compared using Chi-squared test or Fisher's exact test.

Ethics approval was obtained from the University of British Columbia ethics board.

Results

The median age of the combined patient group was 24.5 years. There were no statistically significant differences pre-treatment between groups. Combined median follow up was 28.7 months

All 25 patients receiving a pediatric protocol achieved a CR, compared to 19 of 22 with the adult protocol. Despite the more intense chemotherapy dosing regimen in the pediatric protocol, there was no increase in hospitalizations, invasive fungal infections or deaths from treatment toxicity (Table 1). There was a trend towards increased thrombotic events in the pediatric-treated group, at 32% versus 9%. These included deep vein thrombosis in 4 patients, pulmonary emboli in 2, and cerebral sinus thrombosis in 2.

Relapse occurred in 24% of the pediatric-treated patients and 45% of the adult-treated ones (p=0.215). Allogeneic stem cell transplantation was performed in 4 patients in the former group and 7 in the latter. Nine of these were carried out in CR2 or later, with two patients going into transplant with active disease. Overall survival following transplant was 44%.

Two year event free survival was significantly improved in the group treated on the pediatric protocol (Figure 1), at 79% versus 36% (p=0.011). There was a trend towards improved overall survival in this small cohort, at 83% versus 49% (Figure 2).

Conclusions

A pediatric-based ALL treatment protocol was tolerated in patients up to the age of 40 years. In our centre, this is associated with an increase in EFS, and a trend towards increased OS, even considering the small cohort. We await with interest the results of larger studies investigating the ideal upfront therapy for young patients with ALL.

 

Table 1. Results
	All Patients N=47		Adult N=22		Pediatric N=25		P
	Number	%	Number	%	Number	%
CR after induction	44 of 47	94	19 of 22	86	25 of 25	100	.095
Severe infection	20 of 47	43	9 of 22	41	11 of 25	44	.831
Thrombosis	10 of 47	21	2 of 22	9	8 of 25	32	.079
Pancreatitis	2 of 47	4	0 of 22	0	2 of 25	8	.491
Toxicity deaths	3 of 47	6	2 of 22	9	1 of 25	4	.593
Relapse	16 of 47	34	10 of 22	45	6 of 25	24	.215
AlloHSCT	11 of 47	23	7 of 22	32	4 of 25	16	.303