Current approach to relapsed acute lymphoblastic leukemia in children

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.