Re-Induction Outcome for Pediatric Patients with Relapsed or Refractory B-Cell Precursor Acute Lymphoblastic Leukemia: A Retrospective Cohort Study of the Therapeutic Advances in Childhood Leukemia Consortium

Introduction

Remission induction rates after a second or greater relapse is a critical endpoint in phase II trials of childhood acute lymphoblastic leukemia (ALL). A robust benchmark is crucial for identification of novel multi-agent regimens worthy of further study. The Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) consortium previously reported the response rates of children with multiply relapsed and refractory (R/R) ALL treated between 1995 and 2004, which provided a benchmark for clinical trials. To define more recent treatment patterns and test the robustness of this benchmark, we performed a retrospective cohort review of children with R/R ALL who experienced second or greater treatment failure at TACL consortium sites between 2005 and 2013.

Patients and Methods

Eligible patients were identified at participating TACL institutions. This cohort was comprised of patients with medullary R/R B-cell precursor ALL who experienced at least 2 treatment failures or relapsed after hematopoietic stem cell transplant. Patient demographic data and details of the initial and R/R disease characteristics were abstracted from medical records and entered into a central database. This study was approved by the IRB of each participating institution.

Treatment failure was defined by the presence or re-emergence of circulating blasts, M2/M3 BM, or extramedullary (EM) disease despite therapy. Complete remission (CR) was defined as M1 marrow, no EM disease and evidence of peripheral count recovery. For the purpose of statistical analysis, patients who met these criteria without platelet recovery (CRp) or normal blood count recovery (CRi) were included as CR. Univariate and multivariate logistic regression were utilized to evaluate the risk of re-induction failure. Predictors included in this preliminary analysis were NCI risk criteria at diagnosis, duration of the prior remission, the treatment attempt number, and the EM and BM status at the start of each therapy attempt.

Results

This report includes 214 patients. Fifty-six percent were male. At initial diagnosis, 32% were at least 10 years old, 26% had initial white blood cell (WBC) counts over 50,000/µL, and 39% were classified as high risk by the NCI risk criteria (Table 1). Therapy involved various combinations of agents and ranged between 2 and 10 attempts. The CR rate was 42% for third treatment attempt and 24% for fourth and subsequent treatment attempts (Table 2). Treatment failures were significantly associated with increased number of treatment attempts (p < 0.001), shorter duration of previous CR (p < 0.001) and NCI risk category at diagnosis (p = 0.018).

Conclusion

This preliminary analysis found similar CR rates in patients with third treatment failure compared to the 1^st TACL retrospective study of the prior decade (42% vs. 44%, Ko et al, 2010) and an Austrian report with a small cohort of patients (Reismüller et al, 2013). Further analysis will be performed in comparison to the initial TACL retrospective study cohort once enrollment to this study has been completed (approximately 400 patients). A robust, contemporary historical control may serve as an alternative to a randomized control when outcome with past therapies in unacceptably poor.

Table 1. Patient Characteristics at Initial Diagnosis of Patients with ALL who received at least two treatment attempt (n = 214 patients)

Characteristic		No of patients	%
Age, years	< 1 (infants)	18	8
	1-9	126	59
	10 and over	70	33
WBC count/uL	< 50K	128	60
	50K and over	56	26
	Unknown	30	14
NCI risk criteria at diagnosis	Non-infants, standard risk	82	38
	Non-infants, high risk	84	39
	Non-infants, unknown	30	14
	Infants	18	8
Sex	Female	94	44
	Male	120	56
CNS disease	Yes	42	20
	No	148	69
	Unknown	24	11
Karyotype1	Normal	68	30
	11q23 (MLL gene) rearranged	19	8
	Hypodiploidy	7	3
	Hyperdiploidy	26	12
	iAMP21	2	1
	t(12;21)	6	3
	t(1;19)	7	3
	t(9;22)	15	7
	Other	46	21
	Unknown	28	12
1 Karyotype is available for 214 unique patients; 2 entries were reported for 7 patients, and 4 entries were reported for 1 patient.

Table 2 Achievement of CR/CRp/CRi After Treatment of R/R ALL by Preceding Remission Duration and Treatment Attempt

	Third treatment attempt			Fourth through tenth treatment attempt
Duration of preceding CR	Response	Total	%	Response	Total	%
Not achieved (refractory)	24	63	38	20	86	23
< 18 months duration	28	78	36	11	49	22
18 to 36 months duration	9	15	60	3	5	60
≥ 36 months duration	8	8	100	0	1	0
All patients combined	69	164	42	34	141	24