**4.2 Treatment**

*Advances in Hematologic Malignancies*

risk of relapse [60, 61].

*4.1.2 IKZF1 deletions*

mutations [69].

with ALL [73].

unclear [59].

*4.1.5 iAMP21*

remission [41, 42].

*overexpression*

*4.1.3 JAK-pathway mutations.*

lymphopoietin receptor *(TSLRP)/CRLF2*. Other pathways involving CRLF2 include *PI3K* and the *mTOR* pathways [58]. *CRLF2* gene rearrangements have been associated with 50% of the cases of Ph-like ALL, of which another 50% also show positivity for *JAK* mutations [33, 56]. Additionally, *IKZF1*deletions (28%), *EPOR, RAS* pathway (10%) are also seen in this group. Patients harboring the *CRLF2* alterations fare poorly with high risk of relapse [59]. Similarly, increased expression of *IKZF1* possibly translates into high post induction MRD as well as higher

The *IKZF1* deletion has recently emerged as a novel genomic marker in childhood ALL. This subtype is commonly seen in older children, those with higher WBC counts, Down syndrome (DS), BCR-ABL and Ph-like ALL [55, 59, 62, 63]. Increased association is also seen with *CRLF2* mutations [62]. *IKZF1* deletion is an independent poor prognostic genomic feature in multivariate analysis [64–68]. The AIEOP-BFM group showed *IKZF1* deletions confer a poor prognosis only in the high end-induction MRD group with co-existent *CDKN2A*, *CDKN2B*, *PAX5*, or *PAR1*

*JAK* mutations are commonly found in Ph-like ALL (20%) and are also associated with *CRLF2* mutations [33]. These are also seen in approximately 15% of children with DS ALL [34, 70, 71]. Identification of this mutation is essential as it has therapeutic implications with responses seen both *in vitro and in vivo* to TKIs [72]. The ongoing phase II trial AALL1521 is testing upfront addition of ruxolitinib to chemotherapy for *CRFL2* rearranged or *JAK*-pathway mutant children

*IGH*, a novel, adverse prognostic, cytogenetic driver is seen in less than 3% of pediatric and 10% of AYA ALL [74]. This rearrangement is characterized by the juxtaposition of a partner oncogene like *CRLF2* (25%) or *CEBP* (10%) with *IGH* that drives the overexpression. *CRLF2* overexpression is seen in a very high proportion (>50%) of children with DS, but the prognostic significance is still

This novel prognostic marker is seen in about 1.5–2% of pediatric ALL and is characterized by ≥3 extra copies of *RUNX1* gene on a single abnormal chromosome 21q22 [75, 76]. Increased predisposition to develop *iAMP21* ALL is seen in carriers of the Robertsonian translocation involving chromosomes 15 and 21 [77]. This subtype presents in older children (median 10 years), is more com-

of this mutation confers a poor prognosis with standard therapy as well as high post remission-induction MRD [41, 78, 79]. However, the outcomes are better with MRD-guided and intensive chemotherapy, as shown in the UKALL2003 and the ALL-BFM 2000 studies, hence precluding the need for SCT in first

/L. Presence

*4.1.4 Immunoglobulin heavy chain gene (IGH) rearrangement, CRLF2* 

mon in females, and presents with WBC count of less than 50 × 10<sup>9</sup>

**36**
