Current approach to relapsed acute lymphoblastic leukemia in children

Table 1 Features at primary diagnosis of acute lymphoblastic leukaemia associated with an increased risk of relapse[3]

Clinical features		High-risk group stratification1
Age	Infants < 1 yr old	Yes
	≥ 10 yr	Yes2
WBC	≥ 50 × 109/L	Yes2
Sex	Male	No
Ethnicity	Blacks	No
	Native American	No
	Alaskan Native	No
	Hispanic	No
CNS status	CNS3	No
Response to therapy
Morphological response	PPR	Yes
	Induction failure3	Yes
MRD ≥ 0.01%	After induction (day 33)	Yes
	After consolidation (day 78)
Biology
Immunophenotype	T-cell	No
	Early T-cell precursor	Accepted by some study groups
Genetic alterations	BCR-ABL1	Yes
	MLL translocation	Yes if age < 1 yr
	Hypodiploidy (< 44 chromosomes)	Yes
	TCF3-PBX1 (E2A-PBX1)	No
	TCF3-HLF	Accepted by some study groups
	iAMP21	Accepted by some study groups
	BCR-ABL1-like ALL4	No
	IKZF1 mutation or deletion	No

¹Some features have prognostic importance but are not commonly used in risk stratification;

²The National Cancer Institute (NCI)/Rome risk criteria categorize as high risk patients all those patients with WBC ≥ 50 × 10⁹/L and/or age ≥ 10 yr;

³Induction failure: failure to achieve morphological remission after 4 to 6 wk of induction therapy;

⁴The BCR-ABL1-like or Ph-like ALL with a gene expression profile similar to that of Ph + ALL. ALL: Acute lymphoblastic leukaemia; CNS: Central nervous system; CNS3: ≥ 5 WBC/μL in cerebrospinal fluid with blasts or cranial nerve palsy; MRD: Minimal residual disease; PPR: Poor prednisone response defined as ≥ 1 × 10⁹/L leukemic blasts in the peripheral blood after 1 wk prednisone prophase; WBC: White blood cell count.

Table 2 Basic concepts of acute lymphoblastic leukemia relapse

Site of relapse				Ref.
BM	> 25% blasts in the BM (M3 marrow) and/or blasts cell in the PB	Isolated BM	No evidence of ALL in the CNS or any other site	[21,24,26, 28,30,36,38]
		Concurrent or combined	≥ 5% blasts in the BM in combination with EM ALL	[22,24,26, 28,30,38,39]
Isolated CNS	≥ 5 cells/mm3 with leukemic blasts in a cytocentrifuge preparation of the cerebro-spinal fluid demonstrating leukemic blasts (cytomorphological) without major blood contamination ( ≤ 20 erythrocytes/mm3)1 OR clinical signs of CNS disease OR a leukaemic mass found on cranial computed tomography or magnetic resonance imaging		< 5% blasts in the BM, no blasts in the PB and absence of leukemic infiltrations elsewhere	[24,25,28,30,36,38,39]
Isolated testicular2	Leukemic infiltrations in the testis demonstrated by biopsy (both microscopically and immunologically)		< 5% blasts in the BM, no blasts in the PB and absence of leukemic infiltrations elsewhere	[24]
Other extramedullary	Leukemic infiltrations demonstrated by biopsy (both microscopically and immunologically)		< 5% blasts in the BM, no blasts in the peripheral blood and absence of leukemic infiltrations elsewhere	[24,38]
Length of first CR
COG classification				[16,26,28, 29,36]
Early	Within 36 mo from initial diagnoses	Very early	< 18 mo from initial diagnoses
		Intermediate	18-36 mo from initial diagnosis
Late	≥ 36 mo from initial diagnosis
BFM classification
Early	Occurring within 6 mo of the completion of frontline therapy	Very early	Within 18 mo from diagnosis	[42]
Late	More than 6 mo after the completion of frontline therapy
Response evaluation after relapse
CR3	M1 marrow	(< 5% blasts by bone marrow aspirate) in absence of clinical signs of disease with no evidence of circulating blasts or extramedullary disease and a recovered bone marrow4		[19,22,25, 28,30,38]
	M2 marrow	presence of 5% to 25% blasts in the BM aspirate by conventional morphology		[28]
	M3 marrow	presence of > 25% blasts in the BM aspirate by conventional morphology		[28]
CNS remission	< 5 WBC cells/mL regardless of cytologic evaluation			[36]
Remission of testicular relapse	Defined clinically by return to normal testicular size			[36]
Reinduction failure	Reinduction treatment not resulting in CR			[19]
Refractory patients	Surviving patients after reinduction failure			[19]
Relapse after a new remission	A pathologically confirmed M3 marrow (≥ 25% leukemic blasts) or the presence of leukemia in any other site (e.g., CNS, PB)			[19]
Treatment failure5	All cases of relapse and reinduction failure			[19]
MRD response	positive	Identification of ≥ 0.01% blasts (1/10000) in the BM using flow cytometry–based assays		[28]
	negative	< 0.01% blasts in the BM using flow cytometry–based assays		[28]

¹Some studies require the demonstration of the presence of leukemic cells in the CSF in two consecutive CSF samples taken with an interval of at least 24 h (van de Berg, PBC-2011; Barredo, JCO-2006);

²In some studies, testicular relapse was diagnosed in case of uni- or bilateral painless enlargement of the testicles (Reismüller, BJH-2009; Saarinen-Pihkala, JCO-2006). In case of unilateral testicular relapse, excluding a subclinical involvement of the contralateral testis is recommended (Einsiedel, JCO-2005);

³Second, third and subsequent remissions are designated as CR2, CR3 ... respectively;

⁴Recovery of the BM is assumed in case that white blood cell (WBC) count is > 2.0 × 10⁹/L and platelet count > 50 × 10⁹/L (van de Berg, PBC-2011). Other studies considered the recovery of peripheral counts if absolute neutrophil count is ≥ 750-1000/µL with platelet count ≥ 75000-100000/μL) (Ko, JCO-2010, Raetz, JCO-2008, Raetz, 2012). Some studies consider patients without platelet recovery but fulfilling the remaining criteria for CR as “CR without platelets” (Ko, JCO-2010, Raetz, JCO-2008, Kolb, Leukemia-2003);

⁵Treatment failures, development of a second malignant neoplasm, or death from any cause are generally considered events for disease-free survival (DFS) analysis (Ko, JCO-2010). ALL: Acute lymphoblastic leukaemia; BFM: Berlin-Frankfurt-Münster; BM: Bone marrow; CNS: Central nervous system; COG: Children Oncology Group; CR: Complete remission (complete response); EM: Extramedullary; MRD: Minimal residual disease; PB: Peripheral blood.

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.

Table 4 Relative incidence of site of relapse

Isolated BM	Combined BM	Isolated EM	Isolated testis	Other isolated EM	Year	Ref.
42.90%	19.60%	37.50%			1996-2000	Malempati et al[34], 2007
47%	23%	30%			1995-2002	Roy et al[20], 2005
63%	16%	13%	7%		1981-1999	Reissmüller et al[22], 2009
57%	12%	15%	10%	2%	1972-1998	Chessells et al[32], 2003

BM: Bone marrow; EM: Extramedullary.

Table 5 Risk stratification after relapse

	BCP			T-cell
	Isolated EM	Combined BM	Isolated BM	Isolated EM	Combined BM	Isolated BM
Risk stratification according to the BFM Group classification[42]
Very early1	Intermediate	High	High	Intermediate	High	High
Early1	Intermediate	Intermediate	High	Intermediate	High	High
Late1	Standard	Intermediate	Intermediate	Standard	High	High
Risk stratification according to the United Kingdom ALLR3 Study classification[30]
Very early1	High	High	High	High	High	High
Early1	Intermediate	Intermediate	High	Intermediate	High	High
Late1	Standard	Intermediate	Intermediate	Standard	High	High
Current approach to risk stratification according to I-BFM SG
Very early1	High	High	High	High	High	High
Early1	Standard	Standard	High	Standard	High	High
Late1	Standard	Standard	Standard	Standard	High	High

¹Very early, less than 18 mo from initial diagnosis; Early: More than 18 mo from initial diagnosis but < 6 mo from completion of primary treatment; Late: More than 6 mo after completion of primary treatment. BCP: B-cell precursor; BM: Bone marrow; EM: Extramedullary; I-BFM SG: International BFM Study Group.

Table 6 Children oncology group approach to relapsed acute lymphoblastic leukaemia[29]

Relapse	Site	Time		MRD
B-lineage	Marrow	Early	Chemotherapy vs chemotherapy plus novel agents	Negative	SCT
				Positive	Bridging study before HSCT
		Late	Chemotherapy vs chemotherapy plus novel agents	Negative	Continuation therapy
				Positive	SCT
	IEM	Early	Chemotherapy vs chemotherapy plus novel agents	Any	SCT
		Late	Chemotherapy vs chemotherapy plus novel agents	Negative	Continuation therapy
				Positive	SCT
T-lineage	Marrow	Early	Chemotherapy vs chemotherapy plus novel agents	Negative	SCT
		Late		Positive	Bridging study before HSCT
	IEM	Early	Chemotherapy vs chemotherapy plus novel agents
		Late		Any	SCT

IEM: Isolated extramedullary; SCT: Hematopoietic stem cell transplantation.