Hypodiploidy: A Poor Prognostic Cytogenetic Marker in B-CLL

Abstract

In B-cell chronic lymphocytic leukemia (B-CLL), hypodiploidy is a rare but aggressive subtype of the disease with a very bad prognosis. Hypodiploidy, in contrast to normal B-CLL chromosomal aberrations, is marked by widespread genomic instability, which promotes treatment resistance and quick illness development. Its persistence after treatment implies that chromosomal loss gives cancerous clones a selection edge, which is made worse by telomere malfunction and epigenetic changes. Since thorough genetic profiling has a major impact on patient outcomes, advanced diagnostic methods are crucial for early detection. Treatment approaches must advance beyond accepted practices because of its resistance to traditional medicines. Hematopoietic stem cell transplantation (HSCT) and chimeric antigen receptor (CAR) T-cell therapy are two potential new therapeutic modalities. Relapse and treatment-related morbidity continue to be limiting concerns, despite the noteworthy improvements in outcomes in high-risk CLL patients receiving HSCT. Although more research is required, CAR T-cell treatment is effective in treating recurrent B-ALL and may also be used to treat B-CLL with hypodiploidy. Novel approaches are essential for enhancing patient outcomes and redefining therapeutic success when hypodiploidy challenges established treatment paradigms. Hypodiploidy is an uncommon yet aggressive form of B-CLL that has a very bad prognosis. Hypodiploidy represents significant chromosomal loss and structural imbalance, which contributes to a disordered genomic environment, in contrast to more prevalent cytogenetic changes. This instability promotes resistance to certain new drugs as well as chemoimmunotherapy and speeds up clonal evolution. Its persistence after treatment implies that hypodiploid clones have benefits in survival, which are probably strengthened by chromosomal segregation issues and damaged DNA repair pathways. Malignant progression and treatment failure are further exacerbated by telomere erosion and epigenetic dysregulation. The need for more sensitive molecular diagnostics is highlighted by the fact that standard karyotyping frequently overlooks hypodiploid clones, particularly those concealed by endoreduplication, despite the fact that these complications make early and correct diagnosis crucial. Hypodiploidy requires a move toward individualized treatment because of their link to high-risk genetic traits and resistance to conventional regimens. Although treatments like hematopoietic stem cell transplantation and CAR T-cells show promise, long-term management is still elusive. To improve long-term results and avoid early relapse, addressing this cytogenetic population necessitates combining high-resolution genomic technologies with changing therapy approaches.

1. Introduction

In B-cell chronic lymphocytic leukemia (B-CLL), hypodiploidy—an uncommon but clinically relevant cytogenetic abnormality—is defined by chromosomal loss that results in less than the usual diploid number. Common chromosomal abnormalities in B-CLL, like deletions of 13q, 11q, and 17p, have long been linked to treatment stratification and prognosis; however, hypodiploidy is unique because of its significant effects on treatment resistance and disease aggression [1,2]. In addition to having more complex karyotypes, patients with hypodiploid clones are often discovered to have additional high-risk genetic characteristics, such as unmutated IGHV genes or TP53 mutations, which all impair the prognosis [3,4]. Mechanistically, centrosome or spindle assembly checkpoint dysfunctions are frequently the cause of chromosomal missegregation events such nondisjunction or anaphase lagging, which can result in hypodiploidy [5,6]. Additionally, chromosomal instability has been linked to telomere shortening and epigenetic changes, which allow hypodiploid leukemic cells to have clonal dominance [7,8,9]. In addition to highlighting hypodiploidy as a factor in leukemogenesis, these biological foundations imply that its persistence after therapy might provide a selection advantage in the leukemic population [10]. The low mitotic index of B-CLL cells makes it difficult to detect hypodiploidy clinically, requiring the use of sophisticated diagnostic techniques like array-based comparative genomic hybridization (aCGH), fluorescence in situ hybridization (FISH), and next-generation sequencing [11,12,13]. Since hypodiploid B-CLL is often linked to early treatment needs, refractoriness to current medicines, and an increased risk of disease transformation or progression, accurate identification is essential [14,15]. In light of these observations, understanding the clinical and biological impact of hypodiploidy in B-CLL is vital. Its identification at diagnosis should prompt clinicians to consider more aggressive or alternative therapeutic strategies, including targeted agents and hematopoietic stem cell transplantation, in order to improve outcomes for this high-risk patient subgroup [16,17]. About 3–5% of B-CLL cases exhibit hypodiploidy, and its correlation with complicated karyotypes is frequently linked to a shorter time to initial therapy and greater rates of therapeutic failure [4,18].

2. The Role of Hypodiploidy in B-CLL

When compared to patients with normal or less complex cytogenetic profiles, hypodiploidy in B-cell chronic lymphocytic leukemia (B-CLL) is linked to poor clinical outcomes and frequently indicates a more aggressive disease course and a worse prognosis [2]. Critical tumor suppressor genes, such as those that may be found on chromosomes that are frequently lost, may be deleted in hypodiploid B-CLL patients who have lost chromosomes or large chromosomal regions. This can result in treatment resistance and a shorter progression-free survival [1]. Clinical research has connected hypodiploidy to characteristics such as complex karyotypes and unmutated IGHV status, which are associated with advanced disease stages, an increased chance of Richter transformation, and a lower overall survival rate [3]. Hypodiploidy increases the risk of refractoriness to conventional treatments like fludarabine-based regimens when paired with other high-risk cytogenetic abnormalities, such as 17p deletion. This calls for the use of alternative strategies, such as targeted inhibitors or allogeneic transplantation [14]. Thus, the existence of hypodiploidy in B-CLL patients emphasizes how crucial a thorough cytogenetic evaluation is at diagnosis in order to direct risk assessment and maximize treatment choices [2]. According to clinical studies, patients with hypodiploid B-CLL may be more susceptible to Richter transformation, especially if they also have complicated karyotypes or TP53 mutations [13,15]. The cytogenetic and molecular factors that are known to raise the incidence of Richter transformation, such as del (17p), TP53 mutations, and genomic complexity, are strongly correlated with hypodiploidy, despite the fact that hypodiploidy itself has not yet been independently confirmed as a risk factor for RT [7,19]. Individuals with these characteristics are frequently categorized as high-risk, necessitating earlier PET-CT imaging to identify transformation and closer clinical monitoring. The cumulative incidence of Richter transformation in patients with complicated karyotypes or TP53 abnormalities may surpass 15–20% over time, according to retrospective investigations [15]. Although larger prospective studies are required to assess this, especially in the hypodiploid subgroup, it is plausible to anticipate a heightened risk because hypodiploidy frequently coexists with these changes. Given the urgent requirement for early risk stratification in hypodiploid B-CLL, the onset of RT in these patients usually calls for a switch to intense chemoimmunotherapy, experimental drugs, or CAR T-cell therapy in clinical practice [20,21]. Patients with B-cell chronic lymphocytic leukemia (B-CLL) who are hypodiploid are at a higher risk of developing the disease and responding less well to standard treatments, which has a substantial impact on clinical outcomes [4]. This anomaly frequently occurs during clonal evolution, when a higher tumor burden and a higher probability of needing early therapeutic intervention are associated with genetic material loss [7]. Cytogenetic data suggest that hypodiploidy individuals might have shorter time-to-treatment durations, indicating a faster clinical progression that defies conventional care approaches [15]. Moreover, hypodiploidy has been found to raise the risk of problems or secondary cancers in B-CLL, possibly as a result of the underlying genomic instability it causes [10]. In order to increase survival rates and the quality of life for impacted patients, our findings highlight the necessity of continuous monitoring and potentially more aggressive or innovative treatment methods [4].

3. Mechanism of Hypodiploidy in B-CLL

Complex cellular and molecular mechanisms that lead to the loss of chromosomes or large chromosomal segments are the mechanism behind hypodiploidy in B-cell chronic lymphocytic leukemia (B-CLL), changing the genetic makeup of the leukemic cells [5]. During mitosis, this anomaly frequently results from mistakes like nondisjunction or anaphase lagging, in which chromosomes do not segregate correctly, resulting in daughter cells with fewer chromosomes [5]. Defects in spindle assembly checkpoint mechanism or centrosome dysfunction may contribute to hypodiploidy in B-CLL. These factors compromise the integrity of chromosomal segregation and are made worse by the inherent genomic instability of the leukemic cells [6]. Furthermore, selective pressure favoring clones with beneficial deletions, including those removing DNA repair genes, may cause the loss of particular chromosomes, improving the survival of malignant B-cells under stressful circumstances like chemotherapy [7]. Telomere dysfunction, where shorter or unprotected telomeres cause chromosome missegregation and consequent hypodiploid situations, is another issue that is being implicated by emerging research [8]. Moreover, centromeric areas may become unstable due to epigenetic changes like changed histone acetylation, which increases the likelihood of chromosomal loss in B-CLL cells [9]. These mechanistic findings imply that hypodiploidy is a dynamic process that alters the genomic architecture of B-CLL, contributing to its pathogenesis rather than being a random occurrence. The hyperdiploid clone is an exact duplication of the near-haploid or low-hypodiploid clone, in rare instances, the structural chromosomal abnormalities are also shared in paired chromosomes, and hyperdiploid cell lines have been established in culture from near-haploid B-ALL patient samples, and there is evidence that chromosomal doubling occurs by endoreduplication [22]. Whole-genome doubling (WGD) is a frequent occurrence in nature that produces “polyploid” cells, which have multiple copies of every chromosome [23]. According to reports, polyploidy is essential for appropriate organ formation and development in a variety of organisms, including humans and fungi [23,24]. More recently, it has been linked to tissue homeostasis and wound healing [24]. Additionally, because polyploid cells have been shown to be more tolerant of aneuploidy due to their capacity to buffer harmful mutations that impair cellular fitness, polyploidization has been linked to early carcinogenesis and the development of neoplasms [25,26]. Given that WGD produces chromosomally doubled clones with presumably lower cell-fitness costs and higher adaptation capacity than their hypodiploid counterparts, it is tempting to hypothesize that WGD is even more relevant in near-haploid and low-hypodiploid cellular backgrounds [18,27]. Alternative cell cycle programs known as endoreduplication or endocycles, in which cells repeatedly replicate their genomic DNA without separating their chromosomes during mitosis, give rise to WGD [23]. Endoreduplication is a term that should only be used to describe the most extreme truncation of the mitotic phase. Known as “endomitosis”, cell cycles that involve some mitotic processes—such as spindle formation, nuclear envelope disintegration, and chromosome condensation—abort mitosis mostly during metaphase or anaphase and do not exhibit cytokinesis [23]. According to Molina et al. [18], these occurrences are linked to mitotic abnormalities that cause mitotic slippage. Either a cell with an enlarged single nucleus or a cell that maintains separate nuclei, producing multinucleate cells, are the outcomes of both situations. Many of the same mechanisms that control the G1–S phase transition in typical “mitotic cell cycles” are also used in endoreduplication cycles [18]. Two fundamental changes must be made to the cell cycle in order to transform the mitotic cell cycle into an endoreduplication cycle. On the one hand, without obstructing DNA replication, by avoiding the essential steps of mitosis, chromosomal segregation, and cytokinesis [18]. In plant and animal cells, this is achieved by downregulating the cyclin-dependent kinases (CDKs) responsible for the progression of the G2-to-M phase while permitting the CDKs responsible for the progression of the G1-to-S phase to remain active [18]. On the other hand, pre-replication complexes can be reassembled during a G1-like gap with low S-phase-specific CDK activity caused by the periodic inactivation of CDKs involved in the G1-to-S phase transition [23,24].

4. Diagnosis

Low mitotic activity in leukemic B-cells is overcome by using specialist cytogenetic and molecular approaches to detect chromosomal losses in order to diagnose hypodiploidy in B-CLL [11]. The low in vitro proliferation of B-CLL cells limits the efficacy of conventional karyotyping, which depends on mitogen stimulation to cause cell division, and frequently calls for alternative methods [4]. Conventional karyotyping can disclose a chromosome count below 46. A sensitive and trustworthy technique for verifying hypodiploidy is Fluorescence in Situ Hybridization (FISH), which uses targeted DNA probes to detect the loss of particular chromosomes or significant chromosomal regions in interphase cells [14]. Furthermore, by identifying both entire chromosome losses and submicroscopic deletions, array-based comparative genomic hybridization (aCGH) improves diagnostic accuracy and offers a thorough genomic profile that supplements FISH results [12]. When combined, these diagnostic techniques allow for the precise detection of hypodiploidy in B-CLL, making it easier to include it in clinical risk assessment and treatment plans [11]. With increased sensitivity and specificity, emerging diagnostic tools further improve the identification of hypodiploidy in B-CLL [13]. A comprehensive picture of the genome is offered by next-generation sequencing (NGS), which can detect hypodiploidy and related mutations that could affect the course of the disease [13]. Even in samples with little material, multiplex ligation-dependent probe amplification (MLPA) provides a quick and affordable way to evaluate several chromosomal areas at once, confirming hypodiploid situations [28]. These novel techniques are especially helpful for early identification in patients with little disease, guaranteeing that the role of hypodiploidy in B-CLL is acknowledged and dealt with [28].

The diagnosis of hypodiploidy in B-CLL has been much improved by recent developments in cytogenetic and molecular diagnostics, especially in light of the limits of traditional karyotyping because leukemic B-cells exhibit low mitotic activity. Next-generation sequencing (NGS), in addition to FISH and aCGH, is now a vital tool for detecting cryptic chromosomal deletions and related mutations, like TP53 or ATM, which commonly co-occur with hypodiploidy in high-risk B-CLL [7,13]. High-resolution identification of clonal and subclonal genomic abnormalities is made possible by NGS, which sheds light on the development of tumors and resistance mechanisms under treatment pressure [13]. NGS enables longitudinal tracking of mutational landscapes and reveals characteristics indicative of early relapse or transformation, as demonstrated by studies like Landau et al. [13]. A quick and accurate method for determining the DNA content of individual cells, flow cytometry-based ploidy analysis (FCPA) is especially useful for identifying hypodiploidy, even in tiny or mosaic populations [3]. FCPA has remarkable selectivity in separating hypodiploid from diploid and hyperdiploid cell fractions by measuring fluorescence intensity using DNA-binding fluorescent dyes [3]. By identifying samples for additional genomic testing, this method can supplement molecular diagnostics and is well-suited to low-resource environments [3]. Recently, optical genome mapping (OGM) has become a potent single-platform technique that can identify chromosomal rearrangements, aneuploidy, and structural changes without the need for cell culture or metaphase spreading [29]. OGM has demonstrated particular use in resolving complicated karyotypes and detecting hidden hypodiploidy due to endoreduplication in hematologic malignancies such as ALL and CLL [29]. In order to improve risk classification and treatment planning, Carroll et al. showed that OGM (in conjunction with mate-pair sequencing) can reveal hypodiploid clones that were previously mistakenly identified as hyperdiploid [29].

5. Clinical Implications

Hypodiploidy B-CLL is associated with a much worse prognosis [2]. Due to their increased risk of rapid illness progression and decreased overall survival, patients with hypodiploid B-CLL require more specialized treatment and close monitoring [21]. Additional high-risk genetic changes, such as TP53 mutations, are commonly linked to hypodiploidy, which restricts therapeutic options and complicates clinical management [19]. Since TP53 mutations disrupt the DNA damage response mechanism, hinder p53-mediated apoptosis, and enable the survival of genomically unstable clones even in the face of cytotoxic stress, they rank among the most clinically relevant genetic changes in hypodiploid B-CLL [7]. A significant percentage of hypodiploid cases have these mutations, which are frequently accompanied by deletions of 17p, the chromosomal location that codes for the TP53 gene itself. This results in a biallelic inactivation that significantly reduces the responsiveness of treatment [19]. Individuals with TP53-mutated hypodiploid CLL often have quick recurrence or primary treatment failure and show significant resistance to fludarabine-based chemoimmunotherapy [16]. International guidelines advise early intervention with novel targeted medicines, such as BTK inhibitors like ibrutinib and acalabrutinib or BCL2 inhibitors like venetoclax, in order to address this resistance and avoid standard regimens in such patients [16]. Long-term illness control is still difficult, and even though these medications have improved outcomes in TP53-aberrant disease, they do not completely remove the negative prognostic impact [17]. Early consideration of allogeneic hematopoietic stem cell transplantation is recommended for suitable patients, particularly those with double-hit traits (i.e., TP53 mutation with hypodiploidy or complicated karyotype) [17]. Next-generation sequencing is essential in these situations because it can detect co-occurring subclonal TP53 mutations that traditional tests could overlook yet have a big impact on prognosis and therapeutic approach [7]. In hypodiploid CLL, TP53 mutations affect the DNA damage response, which helps clones survive genotoxic stress and resist treatment. These mutations, which are frequently observed in hypodiploid CLL, affect eligibility for new drugs or transplantation techniques and are prognostic of poor outcomes [19]. Furthermore, cytogenetic analysis can be used to identify hypodiploidy, which might inform risk classification and lead physicians to think about other options, such as allogeneic stem cell transplantation, for qualified patients [17]. The rarity of hypodiploidy in B-CLL highlights the need for additional study to enhance treatment procedures and improve patient outcomes, even with advancements in understanding its significance [30].

Because hypodiploidy in B-cell chronic lymphocytic leukemia (B-CLL) frequently indicates a need for more aggressive or experimental methods because of poor responses to traditional chemoimmunotherapy, it also has consequences for therapeutic decision-making [31]. According to Byrd et al. [16], this chromosomal aberration is associated with a higher incidence of refractoriness to first-line treatments, such as fludarabine-based regimens, which leads clinicians to consider new medicines such as BTK inhibitors or BCL-2 inhibitors. Furthermore, the correlation between hypodiploidy and genomic instability may raise the possibility of clonal evolution, necessitating frequent evaluation of the genetic profile of the illness in order to modify treatment approaches [13]. It is important to consider the psychological toll that this high-risk characteristic takes on patients, as it may call for more supportive care in addition to medical intervention. All things considered, the identification of hypodiploidy as a sign of severe illness emphasizes how urgent it is to incorporate state-of-the-art diagnostics and focused treatments into standard clinical practice.

6. Treatment: Options, Complications, and Advancements

Although rare, B-cell chronic lymphocytic leukemia (B-CLL) with hypodiploidy can be treated by modifying standard CLL procedures to address its potentially aggressive characteristics. In hypodiploid B-CLL, the results of standard chemoimmunotherapy regimens, including fludarabine, cyclophosphamide, and rituximab (FCR), are especially poor, with treatment refractoriness and early recurrence frequently noted [16,30]. While symptomatic instances with B-CLL frequently receive targeted therapy like Bruton’s tyrosine kinase (BTK) inhibitors, such as ibrutinib, acalabrutinib, or zanubrutinib, careful waiting is still the norm for early-stage, asymptomatic patients [32]. These inhibitors provide efficient control with manageable side effects by interfering with B-cell signaling pathways that are essential for leukemia cell proliferation [16]. Furthermore, the BCL2 inhibitor venetoclax targets cell survival processes and produces high remission rates in CLL, maybe even extending to hypodiploid forms. It is commonly used in conjunction with anti-CD20 monoclonal antibodies such as obinutuzumab or rituximab [30]. Allogeneic hematopoietic stem cell transplantation (HSCT) presents a potential solution for conditions with poor prognostic traits, such as hypodiploidy; nevertheless, because of the high risks involved, its usage is restricted to relapsed or refractory disease [17].

Patient outcomes are impacted by these treatments’ varying degrees of complications. Although they might be revolutionary, BTK inhibitors can cause hypertension, atrial fibrillation, and bleeding tendencies, which makes long-term use problematic [31]. Particularly in individuals with a high tumor burden, venetoclax therapy increases the risk of tumor lysis syndrome (TLS), a potentially lethal consequence of rapid cell breakdown [31]. Due to the significant hazards associated with allogeneic HSCT, such as infections and graft-versus-host disease (GVHD), as well as treatment-related mortality rates reported in studies, its use in older CLL populations may be discouraged [33]. Due to treatment resistance and genomic instability, hypodiploidy, which is linked to poor survival in B-ALL (e.g., 5-year survival sub 50% in children), may make these issues worse [18]. Additionally, infections, anemia, and thrombocytopenia are frequently caused by marrow suppression in CLL, and these symptoms may exacerbate in hypodiploid patients [34].

Treatment developments for B-CLL offer hope for hypodiploid subtype management. With ibrutinib-rituximab outperforming conventional regimens in high-risk CLL, the switch from chemoimmunotherapy (such as fludarabine, cyclophosphamide, and rituximab) to targeted treatments has increased progression-free survival [35]. In clinical trials for high-risk CLL, novel combinations such as venetoclax and BTK inhibitors are showing promise and producing deeper molecular remissions [36].

One long-time problem that has been present in the diagnosis is the presence of “masked hypodiploid” [18]. The presence of a clone with an exact or nearly exact chromosome doubling of the hypodiploid clone, resulting in a clone with a modal chromosome number of 50–78, in the high-hyperdiploid or triploid range, is a characteristic shared by patients with near-haploid and low-hypodiploid B-CLL/B-ALL [22,37,38]. Notably, during chromosome doubling, some chromosomes—usually chromosomes 2, 5, 6, 10, 14, and 22—are lost [39]. Approximately 60–65% of patients with near-haploid and low-hypodiploid B-ALL have hypodiploid doubled clones [18]. These clones are typically seen as a mosaic, with both hypodiploid and hyperdiploid (doubled) clones discernible by standard cytogenetics, fluorescence in situ hybridization (FISH), or flow cytometry analysis of DNA content [40]. The manifestation known as “masked hypodiploidy” can also result from the doubled clone being the only one identified at diagnosis. This can be clinically problematic because patients may be mistakenly diagnosed and treated for high-hyperdiploid B-CLL when they are at a higher risk of treatment failure. According to reports, patients with “masked hypodiploidy”, those who are mosaic for both a doubled clone and a hypodiploid clone, and those who have solely a hypodiploid clone do not differ in their clinical outcomes [41]. Furthermore, compared to their hyperdiploid (doubled) counterparts, hypodiploid clones are quantitatively more likely to relapse, which may indicate that the hypodiploid clones themselves are more resistant to chemotherapy [42]. Advanced cytogenetic techniques, such as mate-pair sequencing, can differentiate between “masked hypodiploidy” and hyperdiploidy in hypodiploid leukemias, improving risk assessment and treatment strategy [29]. Chimeric antigen receptor (CAR) T-cell treatment is being researched for CLL and may be able to target resistant hypodiploid clones. It has been successful in treating relapsed or refractory B-ALL [20]. Studies on molecular factors, including TP53 mutations that are frequently seen in low-hypodiploid leukemias, could help tailor treatments and improve outcomes for this population [19].

Bruton’s tyrosine kinase (BTK) inhibitors, such as ibrutinib, acalabrutinib, and zanubrutinib, have transformed the treatment of chronic lymphocytic leukemia, particularly difficult cases including hypodiploidy, a rare chromosomal defect characterized by a decreased chromosome count. Due to its correlation with complicated karyotypes and high-risk genetic markers such as TP53 mutations or 17p deletions, hypodiploidy in CLL is frequently linked to a dismal prognosis [43]. The groundbreaking BTK inhibitor ibrutinib works by binding to BTK, a crucial component of the B-cell receptor signaling pathway that is necessary for the survival and growth of CLL cells, in an irreversible manner [43]. Even in high-risk groups, this blockage significantly reduces the development of cancer cells [43]. Though data specific to hypodiploidy is still limited due to its rarity, studies show that ibrutinib can produce long-lasting responses in CLL patients with hypodiploidy, particularly those with 17p deletions, outperforming traditional chemoimmunotherapy in progression-free survival (PFS) [43]. According to an additional study, it is a cornerstone medication that effectively overcomes resistance associated with genetic complexity [35].

By reducing off-target effects and increasing tolerability, acalabrutinib, a second-generation BTK inhibitor, improves the profile of ibrutinib with increased selectivity [44]. Acalabrutinib inhibits BTK similarly in hypodiploid CLL patients, but it also lessens bleeding and atrial fibrillation, which are important adverse effects for this vulnerable population [44]. In relapsed/refractory CLL with high-risk characteristics (such as 17p deletions frequently observed with hypodiploidy), the ELEVATE-RR study compared acalabrutinib and ibrutinib. The results showed that acalabrutinib had a better safety profile and a noninferior PFS (38.4 months for both) [44]. Hypodiploidy was not specifically mentioned, but its effectiveness in high-risk subgroups points to its potential as a dependable treatment that provides longer-lasting control with fewer disruptions from toxicity. According to Byrd et al. [45], supporting research supports its use in treating recurrent disease and improves patient quality of life by lowering adverse events.

Another cutting-edge BTK inhibitor, zanubrutinib, has excellent pharmacokinetics and specificity, guaranteeing ongoing reduction of CLL cells [46]. With a PFS hazard ratio of 0.65 and fewer cardiac problems—important for hypodiploid patients with possible comorbidities—the ALPINE study showed zanubrutinib’s superiority over ibrutinib in relapsed/refractory CLL [46]. With a hazard ratio of 0.53 for progression or death compared to ibrutinib, it performed exceptionally well in patients with TP53 mutations or 17p deletions, which are frequent in hypodiploidy [46]. Although there are not many studies specifically focused on hypodiploidy, this makes zanubrutinib a strong option for hypodiploid CLL, balancing safety and efficacy [46]. Its appeal for complicated patients is increased by additional research that emphasizes its long-term advantages and reduced discontinuation rates [47].

7. Discussion

Hypodiploidy in B-CLL is unmistakably associated with a dismal prognosis and aggressive disease activity [2]. It differs from normal B-CLL abnormalities, indicating that different treatment approaches are required. Given that this aberration is linked to rapid development and treatment resistance, it requires immediate care [1]. In the end, it pushes for specialized management by redefining risk in B-CLL [3]. Hypodiploidy’s involvement as a driver of malignancy is confirmed by the underlying reasons, which indicate a chaotic genomic landscape [5]. Its durability during treatment supports the notion that chromosomal loss represents a selective advantage for resistant clones [7]. This instability is reinforced by telomere problems and epigenetic changes, which enhances the effects of hypodiploidy [8]. It is not just a byproduct, but a crucial element in the development of B-CLL [9]. The diagnosis of hypodiploidy depends on sophisticated instruments, demonstrating their importance for efficient risk assessment. Despite the difficulties in diagnosing B-CLL, these techniques verify its existence, guaranteeing prompt response [11]. Since comprehensive genetic profiling influences patient outcomes, it cannot be compromised [13]. High-resolution genomic profiling, such as next-generation sequencing and mate-pair sequencing, has been shown in a number of studies, including those by Carroll et al. [29] and Landau et al. [13], to not only identify masked or subclonal hypodiploidy, but also to inform the selection of targeted therapies and transplant eligibility, indicating a shift toward precision medicine in high-risk B-CLL. Given the aggressive course of hypodiploidy, early identification is essential [4]. Hypodiploidy requires tailored choices because it resists conventional medicines, therefore treatment must change from typical procedures [16]. Despite their hazards, newer agents indicate a change in care and offer hope [31]. To meet the needs of this subtype, HSCT and new treatments such as CAR T-cells offer promising avenues for advancement [17]. Since hypodiploidy redefines therapeutic success, innovation is crucial.

Hypodiploidy in B-CLL may be a genetic marker of clonal persistence and evolutionary adaptability under treatment pressure, in addition to its well-established link to a poor prognosis. Questions concerning the intrinsic survival mechanisms of hypodiploid clones are raised by their persistence in the face of treatment, especially when therapy-induced selection bottlenecks are present. Subclonal investigations, for instance, have shown that genomic complexity, which is frequently enriched in hypodiploid instances, favors escape pathways through mutations in apoptotic regulators and DNA damage response genes [7,13]. In addition to reflecting treatment resistance, this evolutionary landscape emphasizes the necessity of ongoing genomic surveillance, especially when employing medicines with well-defined molecular targets. Furthermore, the combination of co-occurring cytogenetic abnormalities and hypodiploidy may increase clinical risk. Multiple genomic hits may work in concert to disrupt cell cycle checkpoints and restore fidelity, as evidenced by the frequent co-occurrence of 17p deletions or TP53 mutations in hypodiploid B-CLL [11,19]. Even in the age of BTK and BCL2 inhibitors, the propensity for early recurrence and refractoriness may be explained by this combined impairment of chromosomal integrity and tumor suppressor activity [16,30]. Additionally, regardless of the depth of the initial remission, these anomalies may predispose patients to severe disease trajectories, according to findings from similar leukemias such as low-hypodiploid B-ALL [18]. Another level of difficulty is introduced by masked hypodiploidy, especially when incorrect risk categorization results from diagnostic misclassification. When endoreduplication occurs, hypodiploid clones may exhibit hyperdiploid karyotypes, masking their actual high-risk status [29,40]. These incorrect diagnoses may unintentionally lead patients to pursue less intensive treatment plans, hence raising the chance of relapse. In order to uncover these mysterious clones and properly customize treatment, it is essential to incorporate high-resolution methods, such as mate-pair sequencing or sophisticated FISH panels [12,13]. Pathobiologically speaking, continued research on the centromere stability and telomere length in hypodiploid CLL may help explain how these cells survive despite extensive chromosomal loss. According to Lin et al. [8] and Parker et al. [9], telomere dysfunction may encourage continuous chromothripsis-like events in addition to contributing to missegregation, which would enhance karyotypic evolution. Similarly to this, hypodiploid clones with aggressive phenotypes may be more easily selected due to altered epigenetic landscapes caused by disrupted histone modifications [6]. New biomarkers for early identification and therapeutic response may result from an understanding of these molecular characteristics. Although new drugs like acalabrutinib and zanubrutinib have increased tolerability and given high-risk B-CLL patients more alternatives, there is still a lack of information about hypodiploidy [44,46]. To determine if these agents actually change the natural history of this aggressive variation, longitudinal research concentrating on hypodiploid subsets is required. Additionally, hopes are raised by the development of CAR T-cell therapy for relapsed or refractory CLL, including those with complicated karyotypes; nevertheless, specific research into its effectiveness in hypodiploid patients is necessary [20]. Incorporating these techniques could eventually change the way physicians approach treatment planning for this difficult-to-reach and dangerous minority.