4.2. Low-Hypodiploid B-ALL

The genetic hallmark of low-hypodiploid B-ALL is TP53 mutations, which are observed in >90% of patients in both childhood and adult low-hypodiploid B-ALL ^{[19][21][30][33]}[30,38,51,55]. Most are missense mutations in exons 5–8, affecting the DNA-binding domain and the nuclear localization sequence ^[19][21][30,38]. Other characteristic and recurrent genetic alterations in the low-hypodiploid B-ALL subtype are RB1 mutations or deletions (41% of cases), deletions of IKZF2/Helios (53% of cases) and deletions of CDKN2A/B genes (22% of cases) ^[19][21][30,38]. Mutations of TP53 are found in homozygosity in virtually all low-hypodiploid B-ALL cases due to the very recurrent loss of chromosome 17. TP53 mutations are frequently found in non-tumor hematopoietic cells in 50% of the cases of childhood low-hypodiploid B-ALL ^[21][30][38,51], suggesting that these cases may be a manifestation of Li-Fraumeni syndrome or other germline TP53 cancer-predisposing mutations ^[19][33][34][30,55,56]. Accordingly, genetic counseling is recommended for children with low-hypodiploid B-ALL carrying TP53 mutations, and their relatives ^[35][36][57,58]. In contrast to childhood cases, TP53 mutations in low-hypodiploid adult B-ALL are somatic, are not found in healthy hematopoietic cells, and not detectable in remission samples ^[19][21][30,38].

5. Etiology of Hypodiploidy in B-ALL

Genomic analyses of these subtypes have been difficult given the limited number of cases; however, a study on a small cohort of 8 near-haploid and 4 low-hypodiploid B-ALL samples suggested that the massive loss of chromosomes is the primary oncogenic event, with other oncogenic insults occurring after hypodiploidy ^[20][37]. This is consistent with similar analyses in high-hyperdiploid B-ALL cases, the most frequent aneuploid entity in B-ALL, indicating that chromosome gains were the primary oncogenic event ^[37][38][60,61]. Thus, similar pathogenic mechanisms involving gross aneuploidies may be shared in these B-ALL subtypes. Furthermore, the genomic landscape of near-haploid and low-hypodiploid B-ALL subtypes, as well as that of high-hyperdiploid subtypes, is characterized by aneuploidy and subtype-specific mutations, with significant fewer microdeletions and structural chromosomal rearrangements in comparison with other cytogenetic subtypes containing structural chromosomal reorganizations ^[19][37][30,60]. Collectively, these data strongly suggest that hypodiploidy has a direct impact on cell transformation and leukemogenesis rather than being solely a passenger event. The fact that severe hypodiploidy is observed in a wide spectrum of neoplasms further indicates that it is indeed a major contributor of tumorigenesis ^[39][62].

6. Outcome and Treatment Strategies for B-ALL with Hypodiploidies <40 Chromosomes

6.1. Relationship of Genetic and Clinical Features with Patient Outcome

The EFS is not significantly different between patients with near-haploid or low-hypodiploid B-ALL, including those cases with “masked hypodiploidy” ^[13][14][35][23,24,57]. In some cases, hypodiploidy may accompany other primary genetic abnormalities, such as BCR-ABL1, TCF3-PBX1, ETV6-RUNX1 and KMT2A rearrangements, which modulate the prognosis of the disease. Accordingly, some authors have suggested that these patients should be treated based on the primary structural abnormalities rather than the hypodiploidy, and on their MRD values after induction ^[14][24]. The high presence of germline TP53 mutations among patients with low-hypodiploidy confer an increased risk of relapse in this group and is associated with the development of secondary neoplasms ^[14][24]. Therefore, it is highly recommended that all patients with low-hypodiploidy B-ALL are tested for germline TP53 mutations ^[14][40][24,69]. Strikingly, the germline TP53 mutations in these cases have been associated with increased mortality due to second neoplastic malignancies following hematopoietic stem cell transplantation (HSCT), highlighting the importance of the germline study in low-hypodiploid B-ALL to assess HSCT versus less toxic alternative therapies ^[16][41][42][26,67,70]. 

6.2. Current Treatment Protocols

Different study groups, such as the UKALL, NOPHO, AALL0031 and COG studies, consistently stratify near-haploid and low-hypodiploid B-ALL subtypes as high-risk based on the poor prognosis of the patients, which does not depend on treatment era or on the NCI risk group in which they are classified ^[14][16][43][24,26,71]. In view of the poor prognosis of patients with hypodiploid B-ALL, they have been classically treated with high-dose chemotherapy followed by allogeneic transplantation. However, different studies assessing the impact of HSCT on B-ALL with near-haploidy and low-hypodiploidy failed to demonstrate a clear benefit of HSCT in MRD positive or negative patients ^{[13][14][35][44]}[23,24,57,66]. Notwithstanding these findings, the outcome of hypodiploid B-ALL with <40 chromosomes has been substantially improved by MRD-guided therapy, which intensifies treatments based on the MRD EOI status ^[13][23]. 

6.3. Novel Therapeutic Targets and Approaches to Treat B-ALL with <40 Chromosomes

7.4. Novel Therapeutic Targets and Approaches to Treat B-ALL with <40 Chromosomes

New treatments aiming to target recently identified biological drivers of hypodiploidies as well as immunotherapy strategies are currently being explored to achieve better responses before HSCT or to be used as alternative approaches. The recent discovery of near-universal TP53 alterations in low-hypodiploid B-ALL has highlighted a key role for this gene in leukemogenesis. Investigation of this germinal mutation in this population is recommended when evaluating treatment with chemotherapy and HSCT. It remains to be demonstrated, however, whether therapies directed at this genetic lesion have an effect on low-hypodiploidy ^[36][58]. The anti-apoptotic protein BCL-2, has been identified as an effective therapeutic target for hypodiploid B-ALL with <40 chromosomes ^[45][75], and the efficacy of BCL-2 inhibitors (mainly venetoclax) has been demonstrated in ex vivo models of B-ALL with near-haploidy and low-hypodiploidy, especially in cases with elevated levels of the apoptosis-related factors BIM or BAD.