*4.2.4 Hypodiploid ALL*

*Advances in Hematologic Malignancies*

without transplant and 35–45% with transplant in CR1. However, survival has drastically improved with the advent of TKIs as seen in the UKALLXII/ECOG2993 study, 4-year OS with imatinib compared to historical cohort, 38% vs. 22% [91]. The AALL0031 reported excellent 5-year EFS of 70% ± 12% in patients treated with continuous imatinib and intensive chemotherapy compared with 31–39% for historical controls [92, 93]. Second generation TKIs are highly potent, demonstrate faster and deeper remissions, as well as increased CNS activity with an acceptable toxicity profile. The COG AALL0622 trial, did not show any survival advantage of dasatinib over imatinib when added to upfront chemotherapy backbone, 5-year OS 81% vs. 86% for AALL0031 and AALL0622 respectively. In the same study, IKZF1 deletions were identified in 57% of cases and were associated with inferior outcomes [94]. Ph + ALL is no longer considered a subgroup for allogeneic SCT in CR1, and is reserved for poor responders or for relapsed disease. The AALL0031 study showed improved 3-year EFS equal to or better than sibling-related SCT (88% vs. 57%) for patients treated with imatinib and intensive systemic chemotherapy. Long-term follow-up data from the same study showed 5-year DFS of 70% in the imatinib plus chemotherapy group compared to SCT (65%-sibling donor, 59%-unrelated donor) [93]. The Korean Society of Adult Hematology working party showed similar 2-year molecular relapse-free survival in those not transplanted versus those transplanted (65% vs. 53%) [95]. In a study by Ravandi et al., achievement of negative MRD status was a significant prognostic factor regulating long-term survival. The 4-year OS rates were 66, 43 and 32% in patients with 3-month CMR, major molecular remission (MMR) and less than MMR, respectively [96]. Hence, adequate molecu-

lar response is the deciding factor for no SCT versus SCT.

With regards to the use of TKIs in the post-transplantation period, the consensus statement of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation, recommends patients with undetectable MRD post allogenic SCT may be either treated prophylactically or, may be monitored and treated pre-emptively with TKI if they have detectable MRD post-transplant. TKIs may be continued for a period of 12 months of continuous MRD negativity for those undergoing SCT in CR1, and continued indefinitely for those undergoing SCT in ≥2nd CR status [97]. Currently AALL1631, an international collaborative trial between the COG and the EsPhALL groups, is testing combination chemotherapy with imatinib in Ph + ALL. This randomized trial will assess survival and toxicity outcomes with less intensive therapy for those who are MRD negative post induction compared to the current EsPhALL and COG AALL1122 protocols. The role of post-transplant imatinib in the high-risk group of Ph + ALL undergoing SCT is also

Ph-like ALL constitutes a high-risk subtype of pediatric B ALL. Most studies demonstrate a poorer prognosis despite augmented traditional chemotherapy [54, 57, 70]. Interestingly, the Total XV study showed MRD directed therapy negated its poor prognosis [99]. Research is currently ongoing for a better understanding of the genomics of this group and we now know that this group harbors certain targetable genetic alterations. Potential targets and agents tested in preclinical models include; *CRLF2* inhibition (Givinostat [100], Luminespib [101], Selumetinib [102], TSLPR CART cells [103]), *JAK-2* (CHZ868) [104], *mTOR* pathway (Rapamycin) [105], *PI3K* and *mTOR* pathways (Gedatolisib) [106], and *TNF-a* inhibition (Birinapant) [107]. These targets are now being prospectively studies in clinical trials across various centres. The MDACC trial in children older than 10 years is testing ruxolitinib or dasatinib with chemotherapy [108].

**38**

being evaluated [98].

*4.2.3 Philadelphia-like ALL (Ph-like ALL)*

Hypodiploidy (<45 chromosomes) is present in less than 5% of ALL. Survival across various studies ranges between 50 and 60% on currently available therapy [111–113]. Near haploid (24–30 chromosomes) and low-hypodiploidy (chromosome 31–39) fare poorly on current protocols with 5–8-year EFS of 25–40% for near-haploid and 30–50% for low-hypodiploid ALL [111, 112, 114]. Interestingly, MRD has emerged as an important prognostic marker; improved long-term survival is seen in those with MRD negativity post induction compared to MRD positive disease as shown by Mullighan et al. (85.1% vs. 44.4%) [115]. Recent studies show that children carrying pathogenic germline TP53 mutations have a significantly higher incidence of hypodiploidy (65% vs. 1%), inferior EFS, OS and a very high chance of developing second cancers [92]. Also, a significantly large proportion (91.2%) of low hypodiploidy ALL is associated with germline TP53 mutation suggesting a possible association of hypodiploid ALL with Li-Fraumeni syndrome. In a study by Holmfeldt et al., near-haploid ALL was found to be associated with *RAS*-signaling, *CREBBP*, *CDKN2A/B*, *PAG1* and *IKZF3*, and low hypodiploidy with *P53*, *IKZF2*, *RB1*, *histone modifiers* and *CDKN2A/B* [32, 116, 117]. The COG ALL03B1 showed no survival benefit from CR1 SCT. Interestingly, this was also true if children were MRD (>0.01%) positive pre-transplant [113]. Novel therapeutic approaches with emphasis on molecular targets could be the way forward in improving the outcomes of this high-risk subset of pediatric ALL.
