The initiating event for chronic myeloid leukemia (CML) is acquisition of the Philadelphia (Ph) chromosome. The resultant BCR::ABL1 fusion oncoprotein has aberrant tyrosine kinase activity that drives the relatively benign chronic phase (CP). Additional genomic abnormalities may play a central role in transformation to a rapidly fatal acute leukemia, termed blast phase (BP), which inevitably occurs in the absence of treatment. Tyrosine kinase inhibitor (TKI) therapy controls the disease and prevents transformation in most patients. Rapid initial reduction of BCR::ABL1 transcripts has prognostic significance, and successful outcome is contingent on vigilant molecular and clinical monitoring and careful management of side effects and drug resistance.1,2 Resistance occurs in 10% to 20% of patients and has driven the ongoing development of BCR::ABL1 inhibitors. Missense mutation within the BCR::ABL1 kinase domain that interferes with drug binding is the best known resistance mechanism, and these mutations emerge during therapy in 30% to 60% of resistant patients and signal treatment failure.1,2 Individual BCR::ABL1 mutations have different sensitivity profiles to the various TKIs, which is a factor when considering a switch of TKI. Emergent additional chromosomal abnormalities in Ph-positive cells also indicate treatment failure. Therefore, BCR::ABL1 mutation analysis and karyotyping are the main procedures for investigating TKI resistance.
Role of Additional Genomic Abnormalities in TKI Resistance
The expanded use of next-generation sequencing has recently revealed genomic abnormalities in blood cancer–related genes that potentially drive drug resistance in CML.3–17 These genomic abnormalities comprise missense, frameshift, nonsense, and RNA splice–altering variants; known and novel gene fusions; and specific submicroscopic gene deletions. In some cases, gene fusions involving common fusion partners KMT2A and RUNX1 were cytogenetically cryptic or submicroscopic.6 Certain variants are associated with transformation, whereas others are more frequently observed at diagnosis in CP. At diagnosis, approximately 15% to 25% of patients had clinically relevant additional genomic abnormalities, which were associated with poor treatment outcome.5,6,8,10,12,14,16 The gene most often mutated at diagnosis is ASXL1, with a frequency of approximately 9% of patients.6–8,10,14–16,18 At BP, an integrative genomic analysis using whole exome sequencing, copy number variation, and RNA sequencing detected clinically relevant genomic abnormalities in blood cancer–related genes in all 39 patients tested.6,9 RUNX1, IKZF1, and ASXL1 are among the most frequently mutated genes at BP.6,7,12–14 Gene fusions and deletions are more frequently detected at BP than at diagnosis. Notably, when BCR::ABL1 mutations were detected at BP, they mostly co-occurred with blood cancer–related gene variants.4,6 A recent study of patients with CP-CML in whom treatment with at least 2 prior TKIs failed confirmed that BCR::ABL1 mutations and cancer gene variants frequently co-occur.19 Therefore, the predicted TKI sensitivity profile of individual BCR::ABL1 mutations could be modified when coupled with other variants. Furthermore, the number of additional genomic abnormalities impacted treatment failure. The higher the number of variants detected in individual patients, the higher the risk of treatment failure.19 We propose that the detection of additional genomic abnormalities may influence treatment decisions, and genomic analysis could be more broadly used to investigate TKI resistance. Further clinical evaluation will provide answers to outstanding questions that will enhance patient management (Table 1).
Questions to Be Answered to Enable Evidenced-Based Genomic Clinical Management Guidelines
Current Recommendations for Genomic Testing in CML
NCCN recognizes the potential for expanded genomic testing for patients with CML.1 The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for CML indicate that myeloid mutation panel testing could be considered for patients who present in accelerated phase or BP.1 At resistance, myeloid mutation panel testing could be considered to identify BCR::ABL1-independent resistance mutations in patients with no BCR::ABL1 kinase domain mutations. Testing for BCR::ABL1-independent mutations may be useful for patients who do not achieve optimal response milestones, which is consistent with the recommendation for BCR::ABL1 mutation testing for such patients. However, the incorporation of these suggestions into clinical practice guidelines is problematic at this stage for the following reasons: (1) there is currently no guidance for the management of patients when a mutated myeloid gene is detected; (2) restricting testing to myeloid genes will miss clinically relevant genomic events for patients with a lymphoid phenotype where submicroscopic deletions of specific genes predominate, such as IKZF1, CDKN2A/B, and RB13,9,13,20; (3) blood cancer gene variants frequently co-occur with BCR::ABL1 kinase domain mutations,4,6,13,19 and restricting myeloid gene panel testing to patients without BCR::ABL1 mutations could mask factors that modify TKI sensitivity; and (4) a DNA-based myeloid mutation panel will not detect gene fusion transcripts involving transformation-associated genes, such as KMT2A and RUNX1.6,10,11,13,17
Sequencing Strategies to Detect Various Types of Genomic Abnormalities
Data support molecular analysis tailored for the detection of multiple types of genomic abnormalities, including gene deletions and fusions, rather than restricting to a myeloid-focused approach for the detection of single nucleotide variants (SNVs) and small insertions and deletions (indels).3–17 An RNA-based sequencing methodology may provide the most comprehensive assessment of specific genomic abnormalities.21 A relatively short list could comprise the bulk of genes in which clinically relevant somatic variants occur for patients with CML (Table 2). High sensitivity of variant detection will be relevant for samples with lower BCR::ABL1 levels to detect genomic abnormalities.
Genes for a Myeloid/Lymphoid Focused CML Panel and the Most Frequent Clinically Relevant Types of Varianta
Only Variants of Potential or Known Clinical Relevance Should Be Reported
Each genomic abnormality must be critically assessed for pathogenicity to exclude benign germline or other benign variants that have no role in treatment outcome, as outlined in joint consensus guidelines from expert groups.22–24 Furthermore, interpreting the impact of variants is complicated because some could reside in nonleukemic cells rather than, or in addition to, Ph-positive cells. The increasing depth of sequencing following advances in technology makes this an important consideration as clones previously below the level of detection become measurable. An age-related form of clonal hematopoiesis with indeterminate potential (CHIP) gives rise to clonal stem cells in individuals without disease.25,26 Although rarely found in younger people, CHIP is prevalent in people aged >60 years. CHIP variants occur in several blood cancer–related genes, including DNMT3A, TET2, and ASXL1, and if they arise in the leukemic clone, may influence its survival fitness.
The conventional variant allele frequency (VAF) threshold for the classification of CHIP is ≥2%, but CHIP mutants can be detected at lower levels in the preleukemic, leukemic, and/or nonleukemic stem cell populations. Thus, a variant detected in a CHIP gene should be carefully evaluated because it could reside in a nonleukemic clone with no relevance for TKI response. The VAF of a potential CHIP variant when compared with the BCR::ABL1 transcript level can provide some insight into the cell compartment where the variant resides. For example, a CHIP-related variant at 50% VAF that arises during therapy in a patient with low BCR::ABL1 likely resides in the non–BCR::ABL1-expressing clone. Tracking VAFs over time will also provide insight (Figure 1).27
Resolving clonal relationships by tracking variant allele frequencies over time relative to the BCR::ABL1 IS ratio. The VAF of potentially pathogenic variants should be considered in the context of the BCR::ABL1 ratio to aid the interpretation of clinical relevance. An increasing VAF of a cancer-related gene mutant in a sample with a declining BCR::ABL1 ratio could indicate that the variant resides within nonleukemic cells. Shown are representative fishplots modeled on genomic data that denote inferred clonal relationships between BCR::ABL1 expressing cells and other variants.6,16,21 Each color represents an individual variant and BCR::ABL1 is represented in dark blue in each plot. Variants within other variants represent a clone with more than one variant. The width of the clone at each timepoint represents the relative VAF of each variant. (A) Example of a typical TKI responsive patient with high BCR::ABL1 and no additional variants at diagnosis. The BCR::ABL1 ratio rapidly declined upon commencing therapy. The width of the clone at the time of diagnosis indicates that most cells expressed BCR::ABL1, whereas by 12 months the BCR::ABL1 ratio was very low. (B) Two low-level hotspot variants in ASXL1 and U2AF1 were detected at diagnosis. The relevance of low-level variants at diagnosis is uncertain and both genes are CHIP-associated. The change in VAF over time relative to BCR::ABL1 infers that both variants resided within separate subclones of BCR::ABL1 expressing cells. The ASXL1 variant became undetectable and the low-level U2AF1 variant expanded and evolved with gain of a RUNX1 variant during disease progression. (C) Low-level ASXL1 and TET2 variants were detected at diagnosis. Both genes are CHIP-associated. Massive expansion of the TET2 variant with the decline of BCR::ABL1 indicated that the TET2 variant resided within BCR::ABL1 negative cells. ASXL1 became undetectable and was potentially a BCR::ABL1 subclone. (D) A case of a preexisting ASXL1 variant where a subclone evolved and gained BCR::ABL1. The variant was present in the BCR::ABL1 negative (2a) and positive (2b) cells and expanded in the nonleukemic cells during TKI therapy. A second CHIP-associated DNMT3A variant expanded during TKI therapy in the nonleukemic cells. Fishplots were generated in R using the fishplot package.27
Abbreviations: CHIP, clonal hematopoiesis with indeterminate potential; IS, International Scale; TKI, tyrosine kinase inhibitor; VAF, variant allele frequency.
Citation: Journal of the National Comprehensive Cancer Network 22, 1; 10.6004/jnccn.2023.7335
Distinguishing nonleukemic CHIP clones from leukemic clones is important and could have health-related issues for patients with CML. CHIP is associated with increased risk of cardiovascular disease and the development of hematologic neoplasms.25,26,28–32 This could influence the choice of TKI, because higher rates of cardiovascular events are reported with second-generation TKIs.33–35
Clinical Relevance of Mutated ASXL1
ASXL1 variants are the most frequently detected at CML diagnosis and could most frequently influence initial therapeutic decisions. ASXL1 variants are heterozygous frameshift and nonsense variants that almost exclusively occur in the last exon and escape nonsense-mediated decay to generate truncated proteins.36–38 Mutated ASXL1 is associated with poor prognosis across a range of myeloid blood cancers39,40 and was more frequently detected at diagnosis of CP-CML in patients who subsequently had a poorer outcome.6,14,18 Mutated ASXL1 at CP diagnosis was associated with inferior failure-free survival among 200 first-line imatinib-treated patients, despite active treatment intervention for suboptimal response,16 and inferior molecular response among 222 patients treated with first-line nilotinib.15 Mutated ASXL1 at CP diagnosis was also associated with inferior failure-free survival in a cohort of 41 patients.14 Furthermore, there may be a link between mutated ASXL1 and BCR::ABL1 kinase domain mutation acquisition. These were acquired more frequently in patients with mutated ASXL1 at diagnosis.16 Mutated ASXL1 co-occurred more frequently with BCR::ABL1 mutations in patients with TKI-resistant CP.14,19,41 Data suggest that mutated ASXL1 is an early event in CML and associated with inferior outcome.14–16 However, these variants do not always remain detectable at disease progression when more transforming mutants evolve.6,18 Mutated ASXL1 may be a marker of a genetically unstable disease with a propensity to acquire more variants, including BCR::ABL1 mutations. Nevertheless, some patients with mutated ASXL1 achieved a major molecular response.6,15,16,18 An ASXL1 mutant at CML diagnosis in a patient with high-risk factors or additional mutated cancer genes may confer a less favorable prognosis.15,16 Clinical management guidelines for patients with CP-CML with mutated ASXL1 will evolve. Based on the currently available data, mutated ASXL1 at diagnosis is associated with a less-than-optimal response to TKIs and could be considered a warning. Close attention to early molecular milestone responses is warranted, and treatment intervention following standard recommendations could be considered for patients with early signs of TKI resistance or less-than-optimal response.1,2
Clinical Relevance of Genomic Abnormalities Beyond CML Diagnosis
The transition from CP-CML to BP-CML is accompanied by changes in the frequency of specific mutated genes,7 such as RUNX1, IKZF1, and KMT2A gene fusions, which supports their role in transformation. More transforming mutants were acquired in almost all patients with mutated ASXL1 during disease progression to BP.13 Certain mutated genes appear to be enriched in myeloid BP, such as ASXL1 and gene fusions,4,6,13 whereas deletions involving IKZF1, CDKN2A/B, and RB1 predominate lymphoid BP.3,4,6,9,13
Mutated RUNX1 is the most frequently reported at BP and is mutated in both lymphoid and myeloid BP.4,6,7,11–14 RUNX1 is mutated by multiple mechanisms. Variant types include missense variants enriched in the RUNT domain; frameshift, nonsense, RNA splice–altering variants; partial gene deletions; amplification; and gene fusion.6,13 All of these variant types were detected in 39 patients in BP, in whom the frequency of mutated RUNX1 was 31%.6 SNVs and indels of RUNX1 were reported in 18% of 161 patients tested in accelerated phase or BP.7 RUNX1 is a transcription factor with multiple roles in regulating normal hematopoiesis, including the maintenance of lineage-committed cells in adult hematopoiesis.42,43 Mutated RUNX1 is rare at CP diagnosis and its clinical relevance at diagnosis is unknown. However, the acquisition of mutated RUNX1 during therapy could signal pending treatment failure requiring rapid intervention.1,2 The temporal relationship between the acquisition of mutated RUNX1 and the time to disease progression has not been established; however, the timeframe could be short.6
Mutated IKZF1 is among the most frequent at BP-CML and most abnormalities are intragenic or whole gene deletions. These mainly occur in lymphoid BP and are generated by aberrant RAG-mediated recombination.3,9 They have also been reported in myeloid BP and acute myeloid leukemia (AML).3,4,6,9,44 IKZF1 codes for the key transcription factor IKAROS that has regulatory functions in lymphopoiesis.45 In B-cell acute lymphoblastic leukemia (B-ALL), deletion of IKZF1 is a predictor of poor outcome.46 IKZF1 alterations conferred stem cell–like properties and decreased responsiveness to dasatinib therapy in BCR::ABL1 mouse models.47 IKZF1 deletions are rarely reported at CP-CML diagnosis, but are likely to be highly predictive of disease progression. In a small cohort of 27 patients with CP-CML tested at diagnosis, rapid progression to lymphoid BP by 3 to 6 months occurred for all 3 patients with IKZF1 deletions.6 If acquired during TKI therapy, IKZF1 deletions are also likely to predict rapid disease progression, and prompt treatment intervention is warranted, including evaluation for allogeneic stem cell transplant. Gene deletions involving RB1, PAX5, CDKN2A/B, and RUNX1 have also been reported.6,9,11,13,20 RAG-mediated gene deletions were detected in 31% of 39 patients in BP.6,9
Other mutated genes recurrently detected at BP include BCORL1, BCOR, TP53, and SETD1B.6,9,11,13 Furthermore, gene fusions are enriched in BP. In a study of 39 patients in BP, gene fusions involving RUNX1, KMT2A, CBFB, and MECOM were detected in 26% of patients.6 Whether gene fusions are detectable in the early stages of TKI resistance to allow sufficient time for treatment intervention is currently unknown and awaits retrospective longitudinal analysis. However, the emergence of any pathogenic genomic abnormality during TKI therapy in a patient with a suboptimal molecular response or loss of response would support treatment failure.
Potential Targeted Therapy for Specific Genomic Abnormalities
Specific therapeutic intervention strategies are limited for patients with CML with additional genomic abnormalities. Many of these abnormalities also occur in patients with AML or acute lymphoid leukemia and research is ongoing for the development of targeted therapy approaches for leukemia. Some of these promising tools are discussed here for the most frequent genomic abnormalities in CML.
Mutated ASXL1 occurs at a relatively high frequency in both CP and advanced phase CML. Mutated ASXL1 expression may confer an increased hematopoietic stem cell self-renewal and biased myeloid differentiation.48 This is consistent with the observation that mutated ASXL1 is enriched in myeloid BP.4,6,13 Specific intervention strategies are currently lacking. However, small molecule inhibitors of mutated ASXL1 are under investigation. The stable gain-of function proteins generated by ASXL1 nonsense and frameshift variants lead to increased BAP1 levels.38 BAP1 has an important role in cancer cell growth, and the catalytic activity of BAP1 is involved in mutant ASXL1–induced malignancy. A small molecule inhibitor of BAP1 activity was identified through an unbiased biochemical screen that inhibited ASXL1-driven leukemic gene expression and impaired tumor progression in vivo.38 The CML cell line K562 harbors an ASXL1 nonsense variant and was significantly more sensitive to BAP1 inhibitor treatment than wild-type ASXL1 cells in vitro. An interaction of mutant ASXL1 with BRD4 and hypersensitivity to BET bromodomain inhibitors has also been reported.37 Novel therapeutic possibilities for high-risk patients with CML with mutated ASXL1 are on the horizon. Because mutant ASXL1 predominates the CP, treatment before clonal evolution and the acquisition of more transforming mutants could potentially delay or prevent transformation.
Effective treatment of BP-CML is difficult.49 A better understanding of the molecular factors driving transformation may reveal therapeutic vulnerabilities. Targeting specific molecular abnormalities, however, will likely be complicated by the co-occurrence of other variants.4,6,13 Patients in BP with RUNX1, IKZF1, or BCR::ABL1 mutations had multiple co-occurring variants.6 Nevertheless, a recent study found that RUNX1-mutated CML blasts were sensitive to CD19 CAR-T cells in ex vivo assays.12 Furthermore, high-throughput drug sensitivity revealed mutated RUNX1 cells to be highly responsive to mTOR, BCL2, and VEGFR inhibitors, and glucocorticoids.12 AML cells with mutated RUNX1 were found to be more sensitive to the protein synthesis inhibitor omacetaxine,50 a drug that has been used to treat patients with CML that failed to respond to TKIs.51,52 Cotreatment with omacetaxine and the BCL2 inhibitor venetoclax or a BET inhibitor improved efficacy of RUNX1-mutated AML cells in vivo.50
IKZF1 alterations are a hallmark of high-risk Ph-positive B-ALL3 and confer poor responsiveness to TKI therapy.47 Retinoids are a potential therapeutic approach because they were shown to reverse the mutant IKZF1 phenotype and increased the responsiveness to dasatinib.47
Gene fusions involving KMT2A were the most frequently detected at BP and had few co-occurring variants.6 Menin is a critical oncogenic cofactor for KMT2A-rearranged leukemogenisis.53 A selective small molecule inhibitor of the menin–KMT2A binding interaction, revumenib, has recently received FDA breakthrough therapy designation for the treatment of patients with relapsed/refractory acute leukemia with KMT2A rearrangement.54 Complete remission was achieved in 30% of patients treated with revumenib in a phase I trial.55 Menin inhibition is a potential future therapeutic strategy for KMT2A-rearranged CML.
Conclusions and Clinical Implication of Genomic Abnormalities
Expanded genomic analysis for patients with CML has revealed variants of clinical relevance that could be actionable in terms of prognostication and for directing therapeutic intervention. Whether more-potent inhibition of BCR::ABL1 at diagnosis will be beneficial for patients with relevant additional genomic abnormalities ultimately requires randomized clinical trials. Nevertheless, we suggest that the detection of a somatic variant that meets the criteria for potential or known clinical relevance in a blood cancer–related gene at diagnosis is a warning that close molecular monitoring is required in the early months of TKI therapy. Patients with high-risk clinical or cytogenetic features or multiple genomic abnormalities at diagnosis could be at greater risk. Nonoptimal milestone molecular responses could be a trigger for early intervention following current recommendations.1,2 The detection of an IKZF1 deletion at diagnosis is likely a very high-risk abnormality due to its association with rapid progression to lymphoid BP. In this case, evaluation for an allogeneic stem cell transplant would be advised. Mutated RUNX1 at diagnosis is rare but may not have the same negative impact as IKZF1 deletions. In our genomic studies, mutated RUNX1 at diagnosis was not associated with impending disease progression and could be considered a warning.16
The acquisition of genomic abnormalities during therapy in a patient with CP-CML with suboptimal response or loss of response likely indicates treatment failure that warrants a change of therapy. At this stage, the most appropriate treatment intervention for individual variants is not known, and future therapy targeted at specific variants may become available. Importantly, BCR::ABL1 kinase domain mutations frequently co-occur with other cancer-related variants that could cooperate to drive drug resistance. Therefore, treating patients with a BCR::ABL1 mutation–sensitive TKI may not yield the predicted response. Suboptimal BCR::ABL1 inhibition could provide an environment for the stepwise acquisition of variants. On the contrary, potent BCR::ABL1 inhibition could enhance the evolution of specific mutant subclones by removing sensitive BCR::ABL1-expressing cells, thus eliminating competitors. The acquisition of certain abnormalities during therapy that are associated with disease progression, such as IKZF1 deletions, mutated RUNX1, and gene fusions, may confer a greater risk, and evaluation for an allogeneic stem cell transplant would be advised.
We suggest that patient management will benefit from expanded genomic analysis at specific timepoints, including at diagnosis and at suboptimal or loss of response. However, reliable data interpretation relies on testing samples with adequate levels of BCR::ABL1 to assess the genomic composition of the leukemic clone (>2%–5% International Scale [IS]). The exclusion of nonleukemic clonal hematopoiesis variants will not always be straightforward and will be aided by evaluation of the mutant VAF, while taking into account the BCR::ABL1 ratio. Analysis should not be restricted to patients without BCR::ABL1 kinase domain mutations, and a myeloid gene panel will be inadequate to detect certain prognostic abnormalities. We propose that the acronym AGA be used to denote additional genomic abnormalities and further clinical evaluation will enhance evidence-based clinical management guidelines.
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