A critical review of management of allogeneic transplant-eligible adults with Ph+ acute lymphoblastic leukaemia.

Acute lymphoblastic leukaemia (ALL) in 20%-30% of adult patients contains the Philadelphia (Ph+) chromosome. Historically, Ph+ ALL denoted a markedly inferior outcome and long-term survival in the absence of an allograft was uncommon. However, the advent of targeted therapy directed against the BCR::ABL1 fusion protein with various tyrosine kinase inhibitors (TKIs) has markedly improved the prognosis, resulting in a number of treatment controversies in allograft-eligible patients. Which is the best TKI to use in induction? What is the clinical relevance of the subdivision of Ph+ ALL into multilineage vs lymphoid types? Do all patients in first morphological complete remission (CR1) after induction and consolidation with chemotherapy/TKI require an allograft? If not, what risk factors predict a poor outcome without an allograft? Can chemotherapy-free approaches, such as blinatumomab in conjunction with more potent TKIs, obviate the need for an allograft in high-risk patients? What is the best strategy to deal with persistent or emerging minimal residual disease both pre- and post-transplant? Is maintenance TKI indicated in all patients post allograft? Can salvage therapy and a subsequent allograft cure patients who relapse after not being transplanted in CR1? This manuscript reviews the latest data influencing contemporary management and discusses these controversies.

Asciminib Monotherapy as Frontline Treatment of Chronic-Phase Chronic Myeloid Leukemia: Results from the ASCEND Study.

Asciminib is a myristoyl site BCR::ABL1 inhibitor approved for chronic phase chronic myeloid leukaemia (CP-CML) patients failing ≥2 prior lines of therapy. The Australasian Leukaemia & Lymphoma Group (ALLG) conducted the ASCEND study to assess efficacy of asciminib for newly-diagnosed CP-CML. Patients commenced asciminib 40 mg twice daily (BID) and thereafter were managed according to molecular milestones. Patients with treatment failure, defined as BCR::ABL1 >10% (IS) at 3 or 6 months, or >1% at 12 or 18 months, received either imatinib, nilotinib or dasatinib in addition to asciminib. In patients with suboptimal response, defined as levels of 1-10% at 6 months, >0.1-1% at 12 months, or >0.01%-1% at 18 months, the asciminib dose was increased to 80 mg BID. With a median follow-up of 21 months (range 0-36), 82/101 patients continue asciminib. The most frequent reasons for treatment discontinuation were adverse events (6%), loss of response (4%) and withdrawn consent (5%). There were no deaths; one patient developed lymphoid blast crisis at 6 months. The co-primary endpoints were early molecular response (BCR::ABL1 ≤10% at 3 months), achieved in 93% (96% CI 86-97%), and major molecular response by 12 months achieved in 79%; (95% CI 69.7-86.8%), respectively. The cumulative incidence of MR4.5 was 53% by 24 months. One patient had 2 cerebrovascular events; no other arterial occlusive events were reported. Asciminib as frontline therapy in CP-CML produces high rates of molecular response with excellent tolerance and a low rate of discontinuation for toxicity. (ANZ Clinical Trials Registry ACTRN12620000851965).

Clinical outcomes of chronic myeloid leukaemia patients taking asciminib through a Managed Access Programme (MAP) in Australia.

Asciminib is a novel allosteric STAMP (specifically targets the ABL myristoyl pocket) inhibitor of the BCR::ABL1 oncogene. Real-world clinical outcomes of patients with tyrosine kinase inhibitor (TKI)-resistant/intolerant chronic myeloid leukaemia (CML) in Australia on the Managed Access Programme for asciminib showed higher molecular responses for those with intolerance versus resistance ± intolerance to their last TKI. There remains a clinical need to improve outcomes in patients with CML who have resistance to multiple TKIs, especially in the ponatinib-pretreated cohort.

Beyond BCR::ABL1-The Role of Genomic Analyses in the Management of CML.

Chronic myeloid leukemia (CML) is a model of genomically based diagnosis and management where BCR::ABL1 is successfully targeted by tyrosine kinase inhibitor (TKI) therapy in most patients. The dynamics of BCR::ABL1 transcript decline during therapy is a dependable biomarker of response, relapse, and drug resistance. Missense mutations acquired within the BCR::ABL1 kinase domain that disrupt TKI binding can evolve during therapy and are frequently detected in patients for whom TKI treatment fails. Importantly, specific BCR::ABL1 missense mutations are targetable alterations and direct therapeutic decisions based on the individual mutant TKI sensitivity profile. Nevertheless, BCR::ABL1 mutations are only implicated in approximately half of the cases of acquired resistance. Furthermore, not all patients with a single BCR::ABL1 mutation that is predicted to be sensitive to a specific TKI will experience a response when switched to that TKI. Progression to blast phase heralds independence from BCR::ABL1, and this phase of the disease is notoriously difficult to treat. The independent drivers of resistance and disease progression have long been investigated to both predict progression and to find targets for therapeutic intervention. Recent data reaffirm that drug resistance and disease progression is a mutation-driven process in CML, and somatic variants in genes that are known to drive acute myeloid and lymphoid leukemia have been detected in patients in the advanced phases of CML. Genomic testing over the last few decades for patients with blood cancer has revealed of variety of genomic aberrations that drive disease. Consequently, incorporation of genomic factors into patient management for a range of blood cancers has led to the implementation of high-throughput gene testing to detect clinically actionable variants. Is it time to integrate broader genomic screening into clinical management strategies for patients with CML?

Accelerated-phase CML: de novo and transformed.

Despite the dramatic improvements in outcomes for the majority of chronic myeloid leukemia (CML) patients over the past 2 decades, a similar improvement has not been observed in the more advanced stages of the disease. Blast phase CML (BP-CML), although infrequent, remains poorly understood and inadequately treated. Consequently, the key initial goal of therapy in a newly diagnosed patient with chronic phase CML continues to be prevention of disease progression. Advances in genomic investigation in CML, specifically related to BP-CML, clearly demonstrate we have only scratched the surface in our understanding of the disease biology, a prerequisite to devising more targeted and effective therapeutic approaches to prevention and treatment. Importantly, the introduction of the concept of "CML-like" acute lymphoblastic leukemia (ALL) has the potential to simplify the differentiation between BCR::ABL1-positive ALL from de novo lymphoid BP-CML, optimizing monitoring and therapeutics. The development of novel treatment strategies such as the MATCHPOINT approach for BP-CML, utilizing combination chemotherapy with fludarabine, cytarabine, and idarubicin in addition to dose-modified ponatinib, may also be an important step in improving treatment outcomes. However, identifying patients who are high risk of transformation remains a challenge, and the recent 2022 updates to the international guidelines may add further confusion to this area. Further work is required to clarify the identification and treatment strategy for the patients who require a more aggressive approach than standard chronic phase CML management.

Adverse outcomes for chronic myeloid leukemia patients with splenomegaly and low in vivo kinase inhibition on imatinib.

Variability in the molecular response to frontline tyrosine kinase inhibitor (TKI) therapy in chronic myeloid leukemia may be partially driven by differences in the level of kinase inhibition induced. We measured in vivo BCR::ABL1 kinase inhibition (IVKI) in circulating mononuclear cells after 7 days of therapy. In 173 patients on imatinib 600 mg/day, 23% had low IVKI (<11% reduction in kinase activity from baseline); this was associated with higher rates of early molecular response (EMR) failure; lower rates of major molecular response (MMR), and MR4.5 by 36 months, compared to high IVKI patients. Low IVKI was more common (39%) in patients with large spleens (≥10 cm by palpation). Notably 55% of patients with large spleens and low IVKI experienced EMR failure whereas the EMR failure rate in patients with large spleens and high IVKI was only 12% (p = 0.014). Furthermore, patients with large spleen and low IVKI had a higher incidence of blast crisis, inferior MMR, MR4.5, and event-free survival compared to patients with large spleen and high IVKI and remaining patients. In nilotinib-treated patients (n = 73), only 4% had low IVKI. The combination of low IVKI and large spleen is associated with markedly inferior outcomes and interventions in this setting warrant further studies.

Lineage-specific detection of residual disease predicts relapse in patients with chronic myeloid leukemia stopping therapy.

ABSTRACT: Patients with chronic myeloid leukemia who are eligible for treatment-free remission (TFR) may still relapse after tyrosine kinase inhibitor (TKI) cessation. There is a need for accurate predictors of outcome to enable patients with a favorable profile to proceed while avoiding futile attempts. Sensitive detection of residual disease in total leukocytes at treatment cessation is associated with relapse but is not highly discriminatory, likely because it is a composite measure of residual leukemia derived from different cell lineages, whereas only some lineages are relevant for relapse. We prospectively measured BCR::ABL1 DNA as a predictive yes/no binary test in 5 cellular fractions from 48 patients meeting conventional criteria for TKI discontinuation. The median BCR::ABL1 DNA level was higher in granulocytes and T cells, but not in other lineages, in patients who relapsed. Among the 40 patients undergoing their first TFR attempt, we defined 3 groups with differing relapse risk: granulocyte-positive group (100%), granulocyte-negative/T-cell-positive group (67%), and granulocyte-negative /T-cell-negative group (25%). These data show the critical importance of lineage-specific assessment of residual disease in the selection of patients who can attempt to achieve TFR with a high expectation of success and, concurrently, defer patients who have a high probability of relapse.

Asciminib monotherapy in patients with CML-CP without BCR::ABL1 T315I mutations treated with at least two prior TKIs: 4-year phase 1 safety and efficacy results.

Asciminib is approved for patients with Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia (CML-CP) who received ≥2 prior tyrosine kinase inhibitors or have the T315I mutation. We report updated results of a phase 1, open-label, nonrandomized trial (NCT02081378) assessing the safety, tolerability, and antileukemic activity of asciminib monotherapy 10-200 mg once or twice daily in 115 patients with CML-CP without T315I (data cutoff: January 6, 2021). After ≈4-year median exposure, 69.6% of patients remained on asciminib. The most common grade ≥3 adverse events (AEs) included increased pancreatic enzymes (22.6%), thrombocytopenia (13.9%), hypertension (13.0%), and neutropenia (12.2%); all-grade AEs (mostly grade 1/2) included musculoskeletal pain (59.1%), upper respiratory tract infection (41.7%), and fatigue (40.9%). Clinical pancreatitis and arterial occlusive events (AOEs) occurred in 7.0% and 8.7%, respectively. Most AEs occurred during year 1; the subsequent likelihood of new events, including AOEs, was low. By data cutoff, among patients without the indicated response at baseline, 61.3% achieved BCR::ABL1 ≤ 1%, 61.6% achieved ≤0.1% (major molecular response [MMR]), and 33.7% achieved ≤0.01% on the International Scale. MMR was maintained in 48/53 patients who achieved it and 19/20 who were in MMR at screening, supporting the long-term safety and efficacy of asciminib in this population.

Impact of additional genetic abnormalities at diagnosis of chronic myeloid leukemia for first-line imatinib-treated patients receiving proactive treatment intervention.

The BCR::ABL1 gene fusion initiates chronic myeloid leukemia (CML); however, evidence has accumulated from studies of highly selected cohorts that variants in other cancer-related genes are associated with treatment failure. Nevertheless, the true incidence and impact of additional genetic abnormalities (AGA) at diagnosis of chronic phase (CP)-CML is unknown. We sought to determine whether AGA at diagnosis in a consecutive imatinib-treated cohort of 210 patients enrolled in the TIDEL-II trial influenced outcome despite a highly proactive treatment intervention strategy. Survival outcomes including overall survival, progression-free survival, failure-free survival, and BCR::ABL1 kinase domain mutation acquisition were evaluated. Molecular outcomes were measured at a central laboratory and included major molecular response (MMR, BCR::ABL1 ≤0.1%IS), MR4 (BCR::ABL1 ≤0.01%IS), and MR4.5 (BCR::ABL1 ≤0.0032%IS). AGA included variants in known cancer genes and novel rearrangements involving the formation of the Philadelphia chromosome. Clinical outcomes and molecular response were assessed based on the patient's genetic profile and other baseline factors. AGA were identified in 31% of patients. Potentially pathogenic variants in cancer-related genes were detected in 16% of patients at diagnosis (including gene fusions and deletions) and structural rearrangements involving the Philadelphia chromosome (Ph-associated rearrangements) were detected in 18%. Multivariable analysis demonstrated that the combined genetic abnormalities plus the EUTOS long-term survival clinical risk score were independent predictors of lower molecular response rates and higher treatment failure. Despite a highly proactive treatment intervention strategy, first-line imatinib-treated patients with AGA had poorer response rates. These data provide evidence for the incorporation of genomically-based risk assessment for CML.

Association of TIM-3 checkpoint receptor expression on T cells with treatment-free remission in chronic myeloid leukemia.

Dysregulation of immune-checkpoint receptors has been reported at diagnosis of chronic myeloid leukemia (CML), however, their role in the maintenance of remission after tyrosine kinase inhibitor (TKI) cessation is unclear. We assessed programmed cell death-1 (PD-1), T-cell immunoglobulin, and mucin-domain containing protein-3 (TIM-3), cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), lymphocyte-activation gene-3 (LAG-3), and T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domains (TIGIT) expression on T-cell subsets, regulatory T cells (T-regs), and natural killer (NK) cells at the time of TKI cessation in 44 patients (22 patients sustained treatment-free remission [TFR] and 22 experienced molecular relapse [MolR]). We confirmed our previous finding that absolute numbers of T-regs are increased in patients who experienced MolR compared with those who sustained TFR. The immune-checkpoint receptors PD-1, CTLA-4, LAG-3, and TIGIT on T or NK cells were not differentially expressed between the MolR and TFR groups. However, TIM-3 was consistently upregulated on bulk T cells (CD3+) and T-cell subsets including, CD4+ T cells, CD8+ T cells, and T-regs, in patients who relapsed in comparison with those who maintained TFR after discontinuation. Furthermore, gene expression analysis from publicly available data sets showed increased TIM-3 expression on CML stem cells compared with normal hematopoietic stem cells. These findings suggest that among the targetable immune-checkpoint molecules, TIM-3 blockade may potentially improve effector immune response in patients with CML stopping TKI, while concomitantly targeting leukemic stem cells and could be a promising therapeutic strategy for preventing relapse after cessation of TKI in patients with CML.

Management of TKI-resistant chronic phase CML.

Chronic phase CML (CP-CML) patients who are resistant to 2 or more tyrosine kinase inhibitors (TKIs) have limited therapeutic options and are at significant risk for progression to the blast phase. Ponatinib has been the drug of choice in this setting for the past decade, but when given at full dose (45 mg/d), the risk of serious vascular occlusive events is substantial. Lower doses mitigate this risk but also reduce the efficacy. Emerging data suggest that a high dose of ponatinib is important to achieve response, but a lower dose is usually sufficient to maintain response, introducing a safer therapeutic pathway for many patients. The recent development and approval of the novel allosteric ABL1 inhibitor, asciminib, for CP-CML patients with resistant disease provides another potentially safe and effective option in this setting. These recent therapeutic advances mean that for most resistant CP-CML patients who have failed 2 or more TKIs, 2 excellent options are available for consideration-dose modified ponatinib and asciminib. Patients harboring the T315I mutation are also candidates for either ponatinib or asciminib, but in this setting, higher doses are critical to success. Lacking randomized comparisons of ponatinib and asciminib, the best choice for each clinical circumstance is often difficult to determine. Here we review emerging evidence from recent trials and make some tentative suggestions about which drug is preferable and at what dose in different clinical settings using case studies to illustrate the key issues to consider.

Asciminib for chronic myeloid leukaemia: Next questions.

Recent approval of asciminib, a novel "specifically targeting the ABL myristoyl pocket" (STAMP) BCR-ABL1 inhibitor, for the treatment of chronic myeloid leukaemia (CML) patients who have either failed ≥2 lines of therapy or have the T315I mutation, has provided clinicians with a wider selection of potentially effective treatment options. Asciminib has the attractive twin attributes of high potency directed against BCR-ABL1 and good tolerability based on its limited off-target effects. However, it is unclear exactly where asciminib will be positioned amongst the other available tyrosine kinase inhibitors (TKIs), especially ponatinib which is also available for the same indications. There are many questions yet to be answered with regard to the optimal use of asciminib which include its role in the first- and second-line settings, combination therapy with other TKIs, and effectiveness in advanced phase CML. In this review, we discuss the available data on asciminib while exploring a number of clinical trials in progress. Finally, we provide our opinion based on the current data about where asciminib is most likely to be the optimal choice, which will hopefully assist clinicians with therapy selection.

RNA-Based Targeted Gene Sequencing Improves the Diagnostic Yield of Mutant Detection in Chronic Myeloid Leukemia.

Mutation detection is increasingly used for the management of hematological malignancies. Prior whole transcriptome and whole exome sequencing studies using total RNA and DNA identified diverse mutation types in cancer-related genes associated with treatment failure in patients with chronic myeloid leukemia. Variants included single-nucleotide variants and small insertions/deletions, plus fusion transcripts and partial or whole gene deletions. The hypothesis that all of these mutation types could be detected by a single cost-effective hybridization capture next-generation sequencing method using total RNA was assessed. A method was developed that targeted 130 genes relevant for myeloid and lymphoid leukemia. Retrospective samples with 121 precharacterized variants were tested using total RNA and/or DNA. Concordance of detection of precharacterized variants using RNA or DNA was 96%, whereas the enhanced sensitivity identified additional variants. Comparison between 24 matched DNA and RNA samples demonstrated 95.3% of 170 variants detectable using DNA were detected using RNA, including all but one variant predicted to activate nonsense-mediated decay. RNA identified an additional 10 variants, including fusion transcripts. Furthermore, the true effect of splice variants on RNA splicing was only evident using RNA. In conclusion, capture sequencing using total RNA alone is suitable for detecting a range of variants relevant in chronic myeloid leukemia and may be more broadly applied to other hematological malignancies where diverse variant types define risk groups.

Asciminib: a new therapeutic option in chronic-phase CML with treatment failure.

Asciminib, a first-in-class allosteric inhibitor of BCR::ABL1 kinase activity, is now approved for the treatment of patients with chronic-phase chronic myeloid leukemia who failed 2 lines of therapy or in patients with the T315I mutation. Promising attributes include high specificity and potency against BCR::ABL1, activity against most kinase domain mutations, and potential for combination therapy with ATP-competitive tyrosine kinase inhibitors. Clinicians now have expanded third-line options, which in most cases will involve a choice between asciminib and ponatinib.

Genomic Mechanisms Influencing Outcome in Chronic Myeloid Leukemia.

Chronic myeloid leukemia (CML) represents the disease prototype of genetically based diagnosis and management. Tyrosine kinase inhibitors (TKIs), that target the causal BCR::ABL1 fusion protein, exemplify the success of molecularly based therapy. Most patients now have long-term survival; however, TKI resistance is a persistent clinical problem. TKIs are effective in the BCR::ABL1-driven chronic phase of CML but are relatively ineffective for clinically defined advanced phases. Genomic investigation of drug resistance using next-generation sequencing for CML has lagged behind other hematological malignancies. However, emerging data show that genomic abnormalities are likely associated with suboptimal response and drug resistance. This has already been supported by the presence of BCR::ABL1 kinase domain mutations in drug resistance, which led to the development of more potent TKIs. Next-generation sequencing studies are revealing additional mutations associated with resistance. In this review, we discuss the initiating chromosomal translocation that may not always be a straightforward reciprocal event between chromosomes 9 and 22 but can sometimes be accompanied by sequence deletion, inversion, and rearrangement. These events may biologically reflect a more genomically unstable disease prone to acquire mutations. We also discuss the future role of cancer-related gene mutation analysis for risk stratification in CML.

Multiplex technologies for the assessment of minimal residual disease and low-level mutation detection in leukaemia: mass spectrometry versus next-generation sequencing.

With the focus of leukaemia management shifting to the implications of low-level disease burden, increasing attention is being paid on the development of highly sensitive methodologies required for detection. There are various techniques capable of identification of measurable residual disease (MRD) either evidencing as relevant mutation detection [e.g. nucleophosmin 1 (NPM1) mutation] or trace levels of leukaemic clonal populations. The vast majority of these methods only permit detection of a single clone or mutation. However, mass spectrometry and next-generation sequencing enable the interrogation of multiple genes simultaneously, facilitating a more complete genomic profile. In the present review, we explore the methodologies of both techniques in conjunction with the important advantages and limitations associated with each assay. We also highlight the evidence and the various instances where either technique has been used and propose future strategies for MRD detection.

Clonal evolution and clinical implications of genetic abnormalities in blastic transformation of chronic myeloid leukaemia.

Blast crisis (BC) predicts dismal outcomes in patients with chronic myeloid leukaemia (CML). Although additional genetic alterations play a central role in BC, the landscape and prognostic impact of these alterations remain elusive. Here, we comprehensively investigate genetic abnormalities in 136 BC and 148 chronic phase (CP) samples obtained from 216 CML patients using exome and targeted sequencing. One or more genetic abnormalities are found in 126 (92.6%) out of the 136 BC patients, including the RUNX1-ETS2 fusion and NBEAL2 mutations. The number of genetic alterations increase during the transition from CP to BC, which is markedly suppressed by tyrosine kinase inhibitors (TKIs). The lineage of the BC and prior use of TKIs correlate with distinct molecular profiles. Notably, genetic alterations, rather than clinical variables, contribute to a better prediction of BC prognosis. In conclusion, genetic abnormalities can help predict clinical outcomes and can guide clinical decisions in CML.