Childhood ALL: ContRoL it or not?

In this issue of Blood, Ensor et al describe the features associated with the deregulation of CRLF2 signaling in childhood B-cell precursor acute lymphoblastic leukemia. They conclude that CRLF2 deregulation is not an independent predictor of event-free survival.¹ 

Cytokine receptor-like factor 2 (CRLF2) or thymic stromal-derived lymphopoietin receptor is a protein encoded by the CRLF2 gene. This gene encodes for a cytokine receptor chain related to γc/IL2Rc. Deregulated expression of CRLF2 results from either a cryptic chromosomal translocation [t(X;14)(p22;q32)/t(Y;14)(p11;q32)] or interstitial deletion within the pseudoautosomal region [PAR1; del(X)(p22.33p22.33)/del(Y)(p11.32p11.32)]. Overexpression of CRLF2 is driven by its juxtaposition to either the IGH@ enhancer (IGH@-CRLF2) or the P2RY8 promoter (P2RY8-CRLF2). This phenomenon has recently been found in B-cell precursor acute lymphoblastic leukemia (BCP-ALL), including Down syndrome patients, lacking recurring chromosomal translocations. CRLF2 deregulation occurs in 5%-7% of childhood ALL but is more frequent among Down syndrome patients (50%-60% of the cases).^2-6  Overexpression of CRLF2 is associated with activation of the JAK-STAT pathway in cell lines and transduced primary B-cell progenitors, sustaining their proliferation and indicating a causal role of CRLF2 overexpression in lymphoid transformation. Increased CRLF2 expression is in most of the cases associated with a JAK2 mutation, suggesting that mutant JAK2 and CRLF2 may cooperate to contribute to BCP-ALL genesis.

To evaluate incidence and clinical and prognostic relevance of CRLF2 deregulation assessed by fluorescence in situ hybridization (FISH) in pediatric ALL, Ensor and colleagues screened 865 BCP-ALL patients treated in the MRC ALL97 trial for the presence of this abnormality and evaluated its effect on outcome within the context of other risk factors. In fact, 2 different UK protocols (ALL 97 and ALL 99) with similar randomized questions (dexamethasone vs prednisone and 6TG vs 6MP) were pooled. Eight hundred sixty-five samples were available from 1725 children included in these 2 consecutive protocols. In a comprehensive multivariate analysis, the CRLF2 deregulation did not remain an independent prognostic factor.

First, the study showed that no matter the criterion (relapse numbers, relapse-free survival [RFS], event-free survival [EFS], or overall survival [OS]) or the population (non-Down syndrome or Down syndrome), the patients with CRLF2 deregulated expression do worse. The impact on OS was significantly in the multivariate analysis. Second, despite the large size of this ALL series, still relatively few patients with CRLF2 rearrangement were analzyed (38 non-Down Syndrome patients and 14 Down syndrome patients). Moreover, these patients were treated in 2 consecutive randomized protocols (ALL97 and ALL99) thus resulting in 8 treatment subgroups. As noted in previous articles from the UK group, the leukemic events were reduced in the dex arms (bone marrow [BM] and [CNS] relapse) and the 6TG arms (CNS relapse). However, in the 6TG arm, deaths in complete remission were more frequent, giving comparable EFS curves for the 2 antimetabolites. Thus, despite biostatistical adjustments, the low numbers could render the conclusions weaker, especially in the context of these cofounding factors.

These results are also to be compared with those published by the BFM study group and the Children's Oncology Group.^7,8  In the ALL BFM 2000 study, a high level of CRLF2 expression was found in 9% of the patients (49 of 555 patients) and was associated with a poor EFS. In a multivariate analysis, the presence of P2RY8-CRLF2 (3.8% of the patients) but not a high level of CRLF2 expression—irrespective of the underlying aberration—provided independent prognostic information. This effect was mainly related to a greater cumulative relapse incidence in the so-called non–high-risk patients (classification mainly based on D33 and D78 minimal residual disease evaluation). In the COG P9906 study, CRLF2 rearrangement was documented in 29 of 207 NCI–high-risk patients (14%). This feature was associated with a poor outcome in univariate but not in multivariate analysis, where the deletion of IKZF1 was found to be the sole independent variable associated to the risk of relapse. A deletion of IKZF1 was indeed found in 21 of 29 CRLF2 rearranged cases (72%) and in only 19 of 49 evaluable cases (38%). Those 21 patients with CRLF2 rearrangement and IKZF1 alteration had the worst outcome of the COG-P9906 cohort (estimated RFS at 4 years: 26.4%).

For stratification purposes, it would be useful to know whether non-Down syndrome NCI standard-risk patients (age 1-9, white blood cells < 50 G/L, without initial CNS involvement, without poor-risk cytogenetics) with CRLF2 deregulation do worse than those without in independent cohorts and thus should be excluded from the standard-risk group of non-Down syndrome BCP-ALL.

More globally, many questions have now arisen from the identification of acquired genetic abnormalities in B-lineage ALL, mainly deletion of IKF1 and deregulation of CRLF2 and JAK mutations. Only prospective studies will answer the numerous issues of the technical aspects for reproducible and sensitive detection and their relative contribution to prognostic stratification. Finally, the rarity of these subsets will render international cooperative studies mandatory.