The e13a3 (b2a3) BCR-ABL1 transcript is generated through direct linkage of e13 of the BCR gene to e3 (a3) of the ABL1 gene, resulting in deletion of ABL1 e2 (a2). This fusion produces a truncated protein that retains constitutively activated TK activity (27). The lack of the Src homology 3 (SH3) domain in this variant is linked to its unique structural properties, contributing to the formation of an SH3-deficient isoform. SH3 deficiency can impact downstream signaling, enhancing kinase activity and potentially promoting leukemogenesis (28). SH3-deficient variants such as e13a3 are associated with altered protein interactions and subcellular localization, potentially affecting cell signaling pathways and contributing to disease progression. In murine models, e13a3, as an SH3-deficient variant, shows slower disease progression compared with canonical isoforms, though it retains leukemogenic potential, capable of inducing CML (29). This slower progression may be influenced by changes in cell adhesion, which alter the interaction between leukemic cells and the microenvironment, affecting disease dynamics. The SH3 domain normally serves as a negative regulator of ABL1 TK activity, and its deletion in the e13a3 variant enhances kinase activity (7). The e13a3 fusion breakpoint resides within the major breakpoint cluster region, resulting in the production of a 210 kDa (p210) fusion protein. Notably, the absence of the SH3 domain in the truncated ABL1 moiety induces structural alterations in the chimeric protein. This aberrant protein retains constitutively activated TK activity, which drives leukemic cell proliferation and inhibits differentiation (27). Compared with canonical fusion subtypes such as e14a2 or e13a2, this variant exhibits a unique genomic architecture (30). The e13a3 transcript is predominantly observed in patients with chronic phase CML, with rare case reports in Ph chromosome-positive ALL (31–33). Notably, a Chinese study initially failed to detect the e13a3 fusion using RT-qPCR, underscoring the risk of missing rare fusion subtypes when employing primer sets targeting conventional breakpoints, even in cases with confirmed t(9;22) translocation (17). Conversely, another study (34) documented a CML case with a normal karyotype and negative RT-PCR findings, where subsequent FISH analysis revealed BCR-ABL1 fusion. This highlights the importance of multimodal diagnostic approaches, particularly when conventional methods yield equivocal results.

Imatinib, a first-generation TKI is widely utilized in e13a3 variant CML. Most Ph-positive CML patients receiving 400 mg/day imatinib achieve complete cytogenetic remission (CCyR) within 6–12 months and maintain durable responses (35,36). McCarron et al (37) reported a 66-year-old male patient with Ph-positive CML who attained progressively deepening cytogenetic responses and declining BCR-ABL1/ABL1 ratios following sustained 400 mg/day imatinib therapy. In Ph-negative CML cohorts (representing 5–10% of cases, characterized by CR-ABL1 rearrangements undetectable by conventional cytogenetics) (38,39), studies (34,40) have evaluated second-generation TKIs including nilotinib. These agents demonstrate efficacy in achieving CCyR and major molecular response (MMR) in Ph-positive populations (17,27), which is consistent with the report by Zhou et al (41). Dasatinib, another second-generation TKI, has also been employed in this context. Mechanistic and in vitro studies indicate that the e13a3 variant may exhibit resistance to asciminib, with clinical evidence remaining limited (7). Resistance observed in e13a3 variant CML is largely based on laboratory-based research (7,42), and there is insufficient clinical data to support these findings.

Combination strategies integrating TKIs with chemotherapy have been explored. One notable example is the use of the ponatinib-fludarabine + Low-dose Cytarabine (Ara-C) + Granulocyte Colony-Stimulating Factor(G-CSF) + idarubicin regimen followed by allogeneic stem cell transplantation (ASCT), which resulted in molecular negativity and full donor chimerism at 19 months post-transplant in one case (43). Massimino et al (44) implemented a tailored approach in an 89-year-old male patient with mild renal impairment, including initial hydroxyurea (2,000 mg/day) for leukocytosis management, transitioning to dasatinib 100 mg/day, which achieved a deep molecular response (MR), characterized by a further reduction in transcript levels to undetectable. This strategy has also been used in other studies (17,30).

Most studies suggest that e13a3-positive patients exhibit a lower risk of progression to accelerated phase or blast crisis, with superior long-term event-free survival compared with rare variants such as e1a2 or e19a2 (12,45). Most patients attain deep, sustained responses following TKI monotherapy or combination regimens. A patient achieved complete hematological remission (CHR) at 2 months and MMR with RT-PCR negativity by 8 months, maintaining remission for 2 years (44). Another case demonstrated FISH-confirmed CCyR (0% BCR-ABL1 fusion) at 6 months, sustained beyond 24 months (34). While certain TKI-treated cases exhibit persistent low-level e13a3 transcripts despite CCyR (37), combination therapies have shown favorable results. In addition to treatment efficacy, it is key to evaluate how the treatment regimen affects quality of life. Long-term use of TKIs can lead to side effects such as chronic fatigue, nausea and musculoskeletal pain, which may limit the ability to perform daily tasks and participate in social activities (46,47). Balancing treatment effectiveness with the impact on physical and emotional wellbeing is essential for optimal clinical decision-making. Resistance to treatment can develop due to ABL kinase mutations such as T315I or activation of compensatory signaling pathways such as PI3K/AKT and SRC, which allow the leukemic cells to survive despite the presence of TKIs (48). These mechanisms of resistance contribute to treatment failure and disease progression. In these cases, next-generation TKIs such as ponatinib and asciminib, which target resistant mutations, can be effective, although they may be associated with more severe side effects (49–51). Combining TKIs with other therapeutic modalities, including chemotherapy or stem cell transplantation, may be necessary for patients with resistant disease to achieve long-term disease control (52). Evidence on e13a3 variant outcomes is summarized in Table II. Further multi-center studies are needed to validate these prognostic outcomes in CML.

In this fusion transcript, the ABL1 breakpoint resides within intron 2, generating a chimeric mRNA linking BCR e14 to ABL1 e3. This rearrangement induces structural and functional alterations in the fusion protein, dysregulating intracellular signaling pathways to promote leukemic cell proliferation, survival and immune evasion. A previous study employed customized RT-PCR coupled with Sanger sequencing to confirm this fusion mRNA (53), concurrently identifying non-synonymous mutations in TP53, FMS-like tyrosine kinase 3, KIT Proto-Oncogene, Receptor Tyrosine Kinase(KIT) and paired box 5, underscoring the molecular heterogeneity. Another case report documented methylenetetrahydrofolate reductase mutation in a patient with CML harboring this BCR-ABL1 fusion, providing insights for future investigations (54). A study identified a BCR-ABL1 fusion in a rare CML case, where the breakpoints occurred at BCR intron 14 and ABL1 intron 2, using NGS (53). This unique fusion led to a compromised SH3 domain, which was associated with altered drug response and distinct clinical manifestations (53). These findings emphasize the critical role of SH3 domain loss in modulating therapeutic outcomes and the molecular heterogeneity underlying CML.

TKI monotherapy with imatinib or nilotinib has been used in e14a3-positive cases. A Chinese study (11) reported a 67-year-old Ph-positive female with coexisting e13a3 and e14a3 variants, the first documented instance of dual rare BCR-ABL1 fusions in China, who achieved therapeutic response with imatinib. Vaniawala et al (55) reported e14a3 BCR-ABL1 fusion in a 30-year-old male managed solely with imatinib. Nilotinib was similarly employed to treat a 52-year-old male by Massimino et al (56), with both cases achieving a treatment response.

Personalized combination regimens have also been explored. In a study by Lyu et al (53), hydroxyurea was initially administered for rapid leukocytosis control prior to TKI initiation, with subsequent imatinib dose reduction (from 400 to 300 mg/day) due to intolerance, emphasizing individualized dosing. A previous study (57) reported sequential intolerance to imatinib and dasatinib, ultimately transitioning to hydroxyurea monotherapy.

Most patients with e14a3 variant CML exhibit favorable prognoses, achieving sustained hematological, cytogenetic and molecular remissions. In a Chinese cohort (11), imatinib monotherapy induced rapid MR, with CCyR attainment within 3 months and notable BCR-ABL1-e14a3 transcript reduction. Nilotinib-treated cases similarly demonstrated favorable outcomes (56). Combination regimens have shown variable efficacy: One study reported TKI monotherapy achieving CHR at 2 months, MMR at 3 months and sustained transcript negativity for 9 years without kinase domain mutations (21). Adjuvant agents such as interferon, hydroxyurea, and aspirin were incorporated, though immunomodulatory effects of interferon yielded inconsistent results compared with prior reports (57,58). Conversely, a patient requiring hydroxyurea-nilotinib combination therapy achieved hematological and molecular remission after dose adjustment (54). Key e14a3 variant case reports and outcomes are summarized in Table III.

The e1a3 transcript arises from direct fusion of e1 of the BCR gene to e3 (a3) of the ABL1 gene, skipping ABL1 e2 (a2). This structural alteration results in a truncated fusion protein lacking approximately two-thirds of the sequence encoding the SH3 domain within the ABL1 moiety (8). Distinct from common variants, its unique fusion junction may perturb subcellular localization, substrate specificity and signaling pathways, thereby disrupting cellular homeostasis. This transcript is relatively rare, with a single case (4.8%) identified among patients with CML in a Syrian study (59). Additionally, its occurrence has been documented in Ph⁺ ALL and AML (31). Some researchers have posited that a subset of e1a3 BCR-ABL1-positive ALL cases may represent undiagnosed CML in lymphoid blast crisis, requiring exclusion through comprehensive clinical history review (60). A previous study (61) identified multiple atypical BCR-ABL1 transcripts in CML, challenging prior assumptions of singular fusion dominance. Conventional RT-PCR frequently fails to detect these transcripts, often yielding false-negative results (62), while RNA sequencing (RNA-seq) uncovers their presence, highlighting the necessity for advanced molecular diagnostics in clinical practice. The e1a3 and e6a2 BCR-ABL1 transcripts are characterized by unique fusion breakpoints within the ABL1 gene (63,64). These isoforms are less common and associated with more aggressive disease progression, including early blast crisis and resistance to standard TKIs (65,66). These isoforms demonstrate TKI resistance and often require multimodal therapy, including the use of third-generation TKIs or stem cell transplantation (67,68).

Unlike e13a3 and e14a3 variants, dasatinib serves as the primary TKI for e1a3-positive CML. The majority of reported cases demonstrate an indolent clinical course (62,69). A previous study (64) reported a patient achieving CCyR following immediate dasatinib initiation (140 mg/day). An 80-year-old Ph-positive male treated with 400 mg/day imatinib attained rapid CCyR and hematological normalization but subsequently developed lymphoblastic crisis at 5 months, suggesting a risk of ALL transformation (8). Combination therapies, including dasatinib with nilotinib or ponatinib, have shown variable efficacy (68,70); the T315I mutation frequently serves as the primary resistance mechanism, necessitating the switch to third-generation TKIs (71).

Innovative approaches, such as third-generation TKIs combined with ASCT, have been employed in a previous study (72). A 56-year-old female patient maintained disease-free status post-ASCT with continued olverembatinib therapy, underscoring the potential of next-generation TKIs and ASCT in managing this rare subtype (72).

Prognoses for e1a3 variant CML patients exhibit marked heterogeneity. A Japanese male (64) achieved CCyR by 6 months with dasatinib, despite presenting with extramedullary leukemia lacking leukocytosis, which is rare in CML. A previous case (72) demonstrated sustained remission post-ASCT and olverembatinib maintenance, yet developed isolated central nervous system (CNS) infiltration without hematological/cytogenetic relapse, implicating the CNS as a potential sanctuary site. Due to the blood-brain barrier and relatively immune-privileged status, conventional systemically administered chemotherapeutic and targeted therapeutic agents often fail to achieve effective concentrations within the CNS. This allows cancer cells to evade treatment, survive, and cause a relapse in this sanctuary site, while the rest of the body may still be in a state of remission. A patient harboring the e1a3 fusion, typically associated with aggressive disease, maintained stable, untreated CML, challenging the association between BCR-ABL1 variants and clinical severity (64). Key e1a3 variant case reports and outcomes are summarized in Table IV.

The e1a2 variant arises from fusion between e1 of the BCR gene and e2 of the ABL1 gene, generating a chimeric protein with distinct structural and functional properties. By contrast with the canonical p210 isoform, the p190 variant lacks central e13 and 14 of the BCR gene. Despite this truncation, the p190 fusion protein retains notably enhanced TK activity, which remains sufficient to drive leukemogenesis (73,74). The e1a2 transcript is rare in CML, accounting for ~1.8% of cases in a cohort of 2,322 patients treated with TKIs, including 1,326 male and 996 female patients, with a median age of 48 years (range 18–88) (14,75), In the aforementioned study, 41 patients (1.8%) exhibited the e1a2 fusion, confirmed by RT-PCR. This variant is associated with a distinct phenotype marked by monocytosis, absence of basophilia and blast crisis presentation at initial diagnosis in 61% of cases, significantly higher than in patients with canonical transcripts (76). In a study by Gong et al (52), 16 of 41 patients with the e1a2 transcript presented with blast crisis at initial diagnosis, two had accelerated phase and 23 were in chronic phase (76) The frequency of monocytosis at initial diagnosis was confirmed in 10 patients with available blood counts, showing a median of 11.5% (range, 5–36%), with seven patients exhibiting monocytosis >10% (76). In Ph-positive adult ALL, the e1a2 variant accounts for 61.2% of cases, as reported in a national cohort of 67 patients with Ph⁺ ALL, and is typically associated with elevated leukocyte count and lymphoid lineage differentiation (77). RT-PCR for BCR-ABL1 detection, and Sanger sequencing are employed to confirm atypical fusion transcripts.

Imatinib remains the primary therapeutic agent for e1a2-positive leukemia. A standard initial dose of 400 mg/day is administered in patients with ALL and CML, with dose escalation or TKI switching considered for suboptimal responders. However, it is important to consider the impact of side effects on daily life (78). Common adverse reactions such as fatigue, gastrointestinal disturbance and skin rashes can significantly disrupt daily activities and affect the overall quality of life (79). These side effects should be weighed when selecting the most appropriate treatment regimen, and supportive care may be necessary to improve patient comfort during therapy (80). A previous study (81) documented a patient with Ph-negative CML achieving molecular remission (undetectable e1a2 BCR-ABL1 by RT-PCR) after 2 months of imatinib monotherapy, alongside rare cyclical leukocyte fluctuations and spontaneous normalization without intervention. However, resistance to TKIs is a major challenge, particularly in patients with mutations in the ABL kinase domain, such as the T315I mutation, which notably impairs the binding of TKIs to the BCR-ABL1 fusion protein (82,83). These mutations lead to decreased efficacy of first- and second-generation TKIs. Additionally, compensatory signaling pathways, including the PI3K/AKT and SRC kinase pathways, may be activated, allowing leukemic cells to bypass the inhibition of BCR-ABL1, contributing to treatment resistance (84). To overcome these mechanisms of resistance, third-generation TKIs such as ponatinib and asciminib, which are designed to target BCR-ABL1 with T315I mutations and other resistant forms, show promising results (50,51,85). However, these agents also cause more severe side effects, including cardiovascular complications, which should be managed. Combining TKIs with other therapeutic strategies, such as chemotherapy or immunotherapy, may provide an alternative approach to overcome resistance, but this requires consideration of the risk-to-benefit ratio for each patient (86–89).

Combination approaches are frequently employed, often incorporating consolidation chemotherapy post-remission (68,90). Japanese protocols (91) combine hydroxyurea with TKIs. For relapsed/refractory cases, TKI substitution or chemotherapy intensification may be pursued. A previous study (92) reported initial imatinib-induced symptom resolution and 2.5-log BCR-ABL1 reduction, followed by leukemic transformation at 6 months necessitating high-dose chemotherapy and nilotinib. Transcript isoform switching may be a potential molecular mechanism underlying disease recurrence (93).

Prognostic heterogeneity characterizes e1a2 variant CML. While some patients achieve durable remission with imatinib-based regimens (81,92,94,95), clonal dynamics complicate outcomes. Multivariable analyses have confirmed that e1a2 BCR-ABL1 serves as an independent adverse prognostic factor, with a median OS of 69.5 months. Given its clinical behavior resembling Ph-positive ALL, certain researchers advocate classifying e1a2 as a distinct high-risk subtype of CML (76). One case (96) harbored dual e13a3 and e1a2 clones, developing imatinib resistance linked to e1a2 persistence despite achieving CHR, ultimately progressing to blast crisis and death. Notably, resistance occurred without ABL1 kinase domain mutations, suggesting alternative mechanisms. A separate study (97) described extramedullary blast crisis at TKI initiation, mirroring e1a3 cases, yet subsequent multimodal therapy (TKIs, ASCT) achieved sustained complete molecular remission (CMR) for >48 months. These findings underscore the necessity for comprehensive molecular monitoring and adaptive therapeutic strategies. Key e1a2 variant case reports and outcomes are summarized in Table V.

e6a2 variant results from fusion between e6 of the BCR gene and e2 of the ABL1 gene. This rearrangement alters the fusion protein structure, conferring distinct TK activity and protein interaction profiles compared with common variants, thereby dysregulating multiple intracellular signaling pathways to drive leukemogenesis (98). This transcript accounts for 0.02–2.30% of all BCR-ABL1-positive CML cases. Although most patients present in chronic phase, up to 40% of cases are diagnosed in accelerated phase or blast crisis, with this variant frequently demonstrating an aggressive clinical course (9,65). This transcript was also detected in a case of ABL (99). Notably, conventional RT-qPCR may fail to detect the e6a2 BCR-ABL1 transcript, necessitating specialized RT-PCR strategies for rare fusion detection (66). Zagaria et al (100) employed ddPCR for e6a2 transcript quantification, leveraging its high sensitivity, absolute quantification without standard curves and multiplexing capabilities. Concurrent additional sex combs-like 1(ASXL1) mutations, identified via NGS in e6a2-positive cases, may synergize with the fusion to promote acute transformation (65). Domains retained or missing in each subtype fusion protein are presented in Table VI.

TKIs including imatinib (101), nilotinib (63) and dasatinib (102) are used for e6a2 variant management, with imatinib remaining the cornerstone. However, certain scholars advocate upfront use of second-generation TKIs or ASCT to circumvent suboptimal responses to imatinib (103). In one CML case (102), initial hydroxyurea therapy for thrombocytosis was discontinued due to neutropenia, followed by successful imatinib 400 mg/day administration. In vitro sensitivity assay measuring Crk-like protein and phosphorylated-Src family kinase (Tyr416) inhibition confirmed imatinib responsiveness, guiding therapeutic decisions (103).

Combination regimens integrating chemotherapy and TKIs are employed in refractory cases. Crampe et al (65) reported a patient achieving hematological and morphological remission (BCR-ABL1/ABL1: 0.06%) with imatinib dose escalation (from 400 to 600 mg/day), though subsequent sepsis necessitated allogeneic ASCT. Furthermore, targeted therapies may confer prognostic benefits in patients harboring co-occurring ASXL1 mutations.

Prognoses for e6a2 variant CML exhibit marked variability, with frequent fatal outcomes. While some achieve sustained remission post-TKI monotherapy (63,102) or ASCT (65), others experience rapid progression. Prognostic indices indicate that despite a subset of patients exhibiting low-risk Sokal scores (63), OS rates remain inferior to those observed in patients with common transcript subtypes. A patient with Ph-positive CML maintained CCyR for 6 months on dasatinib despite notable eosinophilic hyperplasia with atypical precursors (a morphology potentially linked to the e6a2 transcript) (100). Conversely, Beel et al (66) documented rapid blast crisis within 3 months of TKI initiation, culminating in fatal multidrug-resistant bacteremia post-ASCT. Rohon et al (103) advocated early ASCT or clinical trial enrollment for e6a2-positive cases following short-term TKI or dual Src/ABL inhibitor therapy.

Aggressive presentations include iliac sarcoma at diagnosis (104) and novel BCR-ABL1 kinase domain mutations (K245E, L284S) emerging during imatinib therapy, culminating in blast crisis CML and death (105). These findings underscore the need for personalized strategies addressing variant-specific biology. Key e6a2 variant case reports and outcomes are summarized in Table VII.

The e8a2 variant is rare in CML cases. It is characterized by fusion between e8 of the BCR gene and exon a2 of ABL1, with insertion of a 127-bp sequence from e8 of Ral GEF with PH domain and SH3 binding motif 1 (106). Studies demonstrate that the generation of this transcript requires at least three chromosomal breaks (106,107): The first occurs within ABL1 intron 1b, causing inversion and insertion of this region downstream of BCR e8; the second occurs at BCR intron 8, facilitating fusion of BCR e8 with ABL1 a2; the third may involve additional chromosomes, forming a four-way translocation (107). While the BCR-ABL1 e8a2 transcript is predominantly observed in CML, its occurrence in ALL remains rare (106,108). A Uruguayan study (109) documented a rare four-way translocation t(1;17;9;22)(p35;q24;q44;q11) in a 51-year-old female patient with e8a2-positive CML, highlighting the complexity of chromosomal rearrangements in leukemogenesis. Researchers (110) have identified somatic mutations in tumor protein p53 binding protein 2 and cadherin-10 via whole-exome sequencing, absent in typical CML or healthy controls, suggesting potential BCR-ABL1-driven mutagenesis. Burmeister et al (107) proposed a mechanistic model for cryptic exon activation, generating transcripts containing 55-bp ABL1 intron 1b sequences. While the 55-bp insertion has been suggested as a potential prerequisite for sustaining kinase activity (111), documented cases demonstrate that insertion-free e8a2 retains oncoprotein-coding capacity, suggesting molecular heterogeneity (112,113). The e8a2 and e19a2 variants are rare and associated with complex chromosomal rearrangements. These variants can be considered distinct from typical BCR-ABL transcripts. due to their distinct structural features, including the involvement of additional chromosomal breaks that contribute to unique functional properties of the fusion proteins. These isoforms are less commonly associated with early TKI resistance but are often found in patients with advanced disease or when conventional diagnostic techniques fail.

TKI regimens (imatinib, dasatinib, nilotinib) constitute the primary therapeutic approach for e8a2-positive CML, often supplemented by individualized protocols. Dasatinib is prioritized as frontline therapy (110), with adjunctive measures such as thromboprophylaxis and allopurinol administration tailored to patient-specific factors, including age, comorbidity and disease phase. Close clinical monitoring ensures timely regimen optimization.

Most patients with e8a2 variant CML show a tendency towards favorable outcomes under TKI therapy (114); while initial studies associated the e8a2 transcript with thrombocytosis and suggested a poorer prognosis, more recent findings indicate that prognosis may vary, and the evidence remains inconclusive (107,115). Imatinib-treated cases typically demonstrate robust responses, while interferon-intolerant patients achieve CHR and CMR (BCR-ABL1 <0.001%) within 6 weeks, sustained beyond 6 months (110). Tchirkov et al (116) validated real-time RT-PCR for precise molecular monitoring, enabling therapeutic efficacy assessment and relapse prediction. Key e8a2 variant case reports and outcomes are summarized in Table VIII.

The e19a2 (µ-BCR-ABL1) transcript arises from aberrant fusion of BCR intron 19 to ABL1 exon a2, encoding a 230-kDa fusion protein (117). Its formation involves submicroscopic insertion events, resulting in FISH-negative/RT-PCR-positive detection. While p230 retains BCR oligomerization domains and ABL1 TK activity, structural divergence from p210 may compromise kinase-dependent signaling efficiency. Sequencing of cDNA microproducts (118) has identified mutations in ABL1 e4-9, while WGS uncovered a 122-kb ABL1 insertion into the BCR locus (117).

Management of e19a2-positive leukemia involves sequential or combinatorial TKI regimens. Patients frequently achieve MMR through sequential use of nilotinib, dasatinib or ponatinib. Imatinib, though initially employed, is often substituted due to resistance, thrombocytopenia, fluid retention or drug interactions (119,120). Dose escalation may partially restore hematological/cytogenetic responses in resistant cases. For imatinib-resistant patients harboring the E355G mutation, second-generation TKIs such as nilotinib induce major cytogenetic responses, offering alternative therapeutic avenues (121). Allogeneic ASCT is utilized in select cases (122), primarily because it remains the only potentially curative treatment for CML. It becomes a critical salvage treatment option when patients develop resistance to or intolerable severe side effects from multiple TKIs, or when the disease progresses from the chronic phase to the prognostically unfavorable accelerated or blast phase.

The prognosis of patients with e19a2 variant CML is influenced by genetic architecture, therapeutic regimen and individual comorbidities. Evidence indicates a trend towards favorable outcomes, but individual responses differ (119,122). While studies have linked the e19a2 transcript to an indolent phenotype (115,123), accumulating cases demonstrate clinical courses indistinguishable from classic CML (117), with potential heightened aggressiveness (124). Second-generation TKIs such as nilotinib and dasatinib demonstrate robust efficacy, exemplified by a 72-year-old patient with chronic-phase CML who achieved CCyR at 6 months and MMR at 12 months with dasatinib combined with hydroxyurea and interferon adjuncts, underscoring its utility as frontline therapy (120). Disease progression may occur in certain cases, manifesting as leukocytosis or marrow dysplasia. Notably, a patient managed with nilotinib required dose interruptions due to grade 2 hepatotoxicity yet maintained sustained CCyR and deep MR during long-term follow-up, aligning with findings by Crampe et al (121) and Ernst et al (122), which confirmed nilotinib durable efficacy following treatment interruptions (125). Hydroxyurea monotherapy has also stabilized leukocyte counts without complications in select cases (126–128).

Resistance mechanisms pose challenges. An Italian study (118) reported a dasatinib-resistant T315I mutation, typically associated with TKI refractoriness, where dose escalation partially restored hematological and cytogenetic responses, suggesting salvage potential in mutation-positive patients. Clonal evolution, including double Ph chromosomes and tetraploidy detected via FISH and cytogenetics in an imatinib-treated patient (129), culminated in fatal blast crisis within 2 years, emphasizing the need for personalized strategies in e19a2 BCR-ABL1-positive CML. e19a2 variant case reports and outcomes are summarized in Table IX.