Current approach to relapsed acute lymphoblastic leukemia in children

Table 3 Clinical and biological data of early vs late relapses

	Clinical data	Biological explanation	Ref.	Biological evidence	Ref.
Early relapse	Patients failing to achieve CR2 with the same agents used at primary diagnosis usually do not respond to different drug combinations	Intrinsic drug resistance: the malignant cells responsible for relapse are present at diagnosis and are selected for during treatment	Yang et al[45], 2008	Genome-wide analysis of DNA CNAs and LOH on matched diagnostic and relapse BM samples revealed that the majority (94%) of relapse cases was related to the presenting diagnostic leukemic clone	Mullighan et al[46], 2008
	Equivalent post-relapse survival for patients undergoing different intensity regimens at primary diagnosis	The malignant cells responsible for relapse are present at diagnosis and mutate to a resistant phenotype through the acquisition of spontaneous mutations	Freyer et al[17], 2011	Primary diagnosis and relapse clones originates from a common ancestral clone and acquire distinct CNAs before emerging as the predominant clone at diagnosis or relapse
	Decrease in CR rates after subsequent relapses and treatment attempts	Acquisition of resistance-conferring mutations induced by initial treatment	Ko et al[19], 2010	Adquisition of new genetic alterations at relapse, often involving cell proliferation and B-cell development pathway	Bhojwani et al[48], 2006 Yang et al[45], 2008 Mullighan et al[46], 2008 Hogan et al[49], 2011
Late relapse	The distribution of patients experiencing early and late relapses were highly skewed towards NCI HR in the former group and NCI standard risk in the latter	Late relapse represents de novo development of a second leukaemia from a common premalignant clone	Nguyen et al[16], 2008	Distinct patterns of gene expression in pairs of relapsed samples from patients who relapse early from those relapsing later	Bhojwani et al[48], 2006
				Pattern of NOTCH1 mutations and genome-wide copy number showed a common clonal origin between diagnosis and early relapse but not for late relapses of T-cell ALL	Szczepanski et al[53], 2011
				Distinct pattern of deletions at the non-translocated TEL allele at primary diagnosis and relapse of TEL-AML1-positive ALL	Zuna et al[51], 2004

ALL: Acute lymphoblastic leukaemia; CAN: Copy number abnormalities; CR: Complete remission; CR2: Second complete remission; HR: High risk; LOH: Loss-of-heterozygosity; NCI: National Cancer Institute.