Cytogenetic analysis encompasses a suite of standard-of-care diagnostic testing methods that is applied routinely in cases of acute myeloid leukemia (AML) to assess chromosomal changes that are clinically relevant for risk classification and treatment decisions. In this study, we assess the use of Genomic Proximity Mapping® (GPM) for cytogenomic analysis of AML diagnostic specimens for detection of cytogenetic risk variants included in the European Leukemia Network (ELN) risk stratification guidelines. Archival patient samples (n = 48) from the Fred Hutchinson Cancer Center (FH) leukemia bank with historical clinical cytogenetic data were processed for GPM and analyzed with the CytoTerra cloud-based analysis platform. Genomic proximity mapping showed 100% concordance for all specific variants that have associated impacts on risk stratification as defined by ELN 2022 criteria and 78% concordance when considering all variants reported by the FH Cytogenetics Lab. Notably, the percentage of blasts (ranging from 5– 96%) did not have a clear effect on the ability to detect these variants. In two cases, GPM identified a recurrent inv(9)(p13.3p13.1). These findings demonstrate GPM’s effectiveness for the evaluation of known AML-associated risk variants and a source for biomarker discovery.

Chronic myeloid leukemia (CML) is a leading example of how targeted therapy can transform cancer outcomes. Since the introduction of tyrosine kinase inhibitors (TKIs), survival in high-income countries has approached that of the general population. Large-scale access initiatives have demonstrated that sustained delivery of TKIs is also feasible in low- and middle-income countries (LMICs), with comparable outcomes, challenging assumptions about the limits of cancer care in resource-constrained settings.As treatment access has expanded in LMICs, the central challenge in CML care has shifted to delivery of optimized, sustainable care. Achieving optimal outcomes requires timely diagnosis, sustained adherence, regular molecular monitoring, and the ability to adjust treatment based on individual patients’ tolerance and response to therapy. However, gaps in diagnostic capacity, lack of coordination in care delivery, and persistent socioeconomic barriers continue to limit continuity of care and constrain the full benefits of therapy.Here we review the evidence on the evolving landscape of CML care in LMICs, including treatment access, molecular monitoring, adherence, and treatment-free remission (TFR). Molecular monitoring represents the critical bottleneck linking treatment access to optimized care and long-term outcomes, requiring innovative tools and approaches to scale up access to molecular diagnostics in resource-limited settings.Advancing equitable outcomes in CML will require multiple partners, including industry, government, academia, and non-profit entities. Access barriers for CML are a global concern, and lessons learned in addressing these challenges in LMICs may inform program strategies in other contexts, including marginalized communities in high-income countries.

1600 Background: Acute lymphoblastic leukemia (ALL) is a hematological malignancy affecting 300,000 people worldwide, with an estimated incidence of 100,000 new cases annually. An important cytogenetic abnormality, the Philadelphia chromosome, causes an aggressive form of disease that affects 3-4% of pediatric and 20-30% of adult patients. Since the early 2000s, tyrosine kinase inhibitors (TKIs) have dramatically transformed the treatment of Philadelphia chromosome positive ALL (Ph+ALL). In high-income countries, different TKI regimens in combination with chemotherapy achieve remission rates >90%, but survival rates in low- and middle-income countries (LMICs) are persistently worse, largely due to access barriers, including high costs of innovative therapies. Methods: The Max Foundation provides TKIs at no cost to eligible patients with Ph+ALL and other diseases in resource-limited settings worldwide. We conducted a retrospective review of all patients with a diagnosis of PH+ALL initiating treatment with TKIs between January 1, 2007 and July 31, 2025 through the Glivec International Patient Assistance Program (2007-2017) or Max Access Solutions (since 2017). Data on age at diagnosis, treatments, sex, country of origin, program status, and reason for closure were analyzed using descriptive statistics, with correlations between available variables and length of treatment explored. Results: Of 1,671 patients enrolled, 342 (20.5%) remained active at the time of analysis. Males accounted for 967 patients (57.9%). Patients enrolled from 47 LMICs in the Americas (542, 32.4%), Asia excluding India (414, 24.8%), Eastern Europe (365, 21.8%), Africa (219, 13.1%), and India (131, 7.8%). Median age at diagnosis was 29, with 485 (29.0%) 18 years old or younger. Most patients (1594, 95.4%) initiated treatment with imatinib as first-line treatment; of these, 110 (6.9%) moved to a second-line treatment and 18 (1.1%) to a third-line. Among 1,329 closed cases, reasons for closure included death (526, 39.8%), lost to follow-up (291, 21.9%), and clinical reasons (260, 19.6%). Median treatment length was 17 months (range 0-197 months). Patients who died were older at diagnosis (median 34 vs 28 years old) and had a shorter median treatment duration (13 vs 19 months) compared with other patients. Treatment duration tended to decrease with age; with a significant negative correlation between age at diagnosis and total months of treatment ( r =-0.171, p<0.001). Since 2024, 25 patients received additional supportive services through The Max Foundation, including transportation assistance. Conclusions: This program demonstrates the feasibility of providing TKIs for the treatment of PH+ALL in diverse resource-limited geographies. Increasing access to TKIs is a critical step in eliminating global disparities in the burden of Ph+ALL.

Background: Disparities in adherence to guideline-recommended cancer monitoring persist, with historically disadvantaged populations receiving less frequent testing. Although primary care physicians (PCPs) play a central role in long-term cancer care, and oncologists directly oversee treatment, the influence of shared identity with either clinician type on biomarker testing adherence remains underexplored. This study examines whether patient-physician concordance in race/ethnicity and gender-specifically with PCPs and oncologists-is associated with adherence to BCR::ABL1 testing in chronic myeloid leukemia (CML). Patients and Methods: We analyzed electronic health record data of 425 patients with CML diagnosed between 2007 and 2019, 385 PCPs, and 113 oncologists from an integrated health care system. We defined concordance by shared race/ethnicity, gender, and their combination between patients and each physician type. Biomarker testing adherence was measured as the proportion of guideline-recommended BCR::ABL1 tests completed annually. Linear mixed-effects models assessed associations, adjusting for demographic, clinical, socioeconomic, and care-seeking factors. Random intercepts for patients and physicians were included to account for individual baseline adherence levels and variability in practice patterns across both PCPs and oncologists. Results: Over a 7-year follow-up, patient-PCP race/ethnicity and gender concordance was associated with a 4.8 percentage point (pp) increase in biomarker testing adherence in a given year (95% CI, 1.1-8.5; P=.012), with stronger effects among historically disadvantaged patients (6.6 pp; P=.03). Gender concordance alone showed a modest association (3.5 pp; P=.04). In contrast, no statistically significant associations were found for patient-oncologist concordance across any dimension (race/ethnicity: -1.4 pp; 95% CI, -5.8 to 2.9; P=.53; gender: 0.5 pp; 95% CI, -2.5 to 3.6; P=.73; combined race/ethnicity and gender: -1.1 pp; 95% CI, -6.2 to 3.9; P=.68). Conclusions: Shared identity with PCPs-but not oncologists-was associated with improved adherence to molecular monitoring guidelines in CML. In chronic cancer care within integrated health care systems, PCPs are well positioned to reinforce oncology-driven testing plans. These findings highlight the importance of fostering patient-centered relationships and promoting workforce diversity in primary care, particularly given that historically disadvantaged patients experienced the greatest gains in adherence.

Irregular monitoring and missing data limit the utility of longitudinal biomarkers in real-world practice. We developed a generalizable framework that combines interval-aligned preprocessing, localized multiple imputation, and machine-learning forecasting to generate complete trajectories and predict future biomarker values under routine clinical conditions. Using BCR::ABL1 monitoring in chronic myeloid leukemia as a case study, we aligned measurements to 90-day intervals, applied a windowed, uncertainty-propagating imputation strategy, and trained recurrent neural network (RNN) and XGBoost models to forecast values three and six months ahead. Full Information models achieved RMSEs of 1.22-1.24 for 3-month predictions-well below the biomarker's observed variability-and maintained accuracy even when the most recent visit was intentionally omitted, simulating extended follow-up. This framework preserves local temporal structure, supports individualized monitoring decisions, and is directly adaptable to other continuous biomarkers measured under irregular real-world schedules.

Donor-derived cytogenetic abnormalities are a rare finding following allogeneic hematopoietic cell transplantation. Deletion of the long arm of chromosome 20 [del(20q)] is one of the more frequently observed structural abnormalities, but its significance in the post-transplant setting remains unclear. We describe a unique case of donor-derived del(20q) with 26 years of post-transplant follow-up, the longest reported to date. The recipient remains well with normal blood counts despite persistent del(20q) in both myeloid and lymphoid lineages and the presence of coexisting somatic mutations in DNMT3A and TP53. Retrospective analysis of the donor’s marrow confirmed del(20q) and low-level DNMT3A and TP53 mutations at the time of transplant; the donor later developed therapy-related MDS after radiation therapy for thyroid cancer. To contextualize this case, we reviewed 20 published reports of donor-derived del(20q) post-transplant. The median time to detection was 16 months post-transplant, and 35% of cases progressed to donor-derived malignancy. Among those who progressed, the median time to malignancy diagnosis was 22 months post-transplant. Clinical outcomes across cases ranged from asymptomatic persistence and cytopenias to donor-derived myeloid malignancies, highlighting the need for long-term follow-up and potential use of molecular profiling to better define the neoplastic potential of donor-derived del(20q) after transplantation.

Background: In a proportion of patients with chronic phase CML who achieve a sustained deep molecular remission (DMR), treatment discontinuation may be attempted; successful treatment free remission (TFR) is approximately 50%. Remaining patients restart TKI with expectation of indefinite tyrosine kinase inhibitor therapy. Asciminib is a potent BCR::ABL1 inhibitor with a novel, allosteric mode of action. In vitro data demonstrated that the combination of asciminib and TKIs led to synergistic activity, and asciminib monotherapy proved effective in later line therapy and offers response and safety advantages as initial therapy. By using asciminib based therapy in patients with molecular relapse after prior TFR attempt, further and potential synergistic inhibition of residual leukemia causative of relapse after initial treatment discontinuation may induce a different quality of DMR and allow for successful subsequent TFR. Study Design: This is a single arm phase II study that will enroll a minimum of 47 subjects with a maximum of 51. All patients will have a confirmed diagnosis of CP-CML and must have previously attempted to discontinue TKI. All patients must have restarted the same TKI they were on prior to discontinuation at the time of relapse in order to be eligible for this trial. This trial will use any of the following (based on patient/physician preference) during the consolidation treatment phase: asciminib 40 mg PO daily plus imatinib (maximum dose of 400 mg PO once daily), asciminib 40 mg PO bid plus nilotinib (maximum dose of 300 mg bid), asciminib 80 mg PO daily plus dasatinib (maximum dose of 100 mg daily), asciminib 80 mg PO daily. All eligible patients will begin asciminib ±TKI on cycle 1 day 1 of the consolidation phase. They will continue therapy for a total of 12 cycles (minimum of 12 months). At the end of 12 cycles, asciminib ± TKI will be discontinued in patients who continue to satisfy the requirements for TFR attempt. The primary endpoint of this study is the 12-month ‘second’ TFR rate after completion of 12 cycles of asciminib based therapy. Patients will remain in the TFR phase of the study for up to three years and will have central PCR testing during the first two years. PCR testing will continue locally thereafter. Results: From Feb 2023 to June 2025, 9 patients were enrolled. The median age was 67 (45-72) and 56% were male. Prior to first TFR the median time on TKI was 5.6 years and 8/1 were on imatinib/dasatinib, respectively. The median time to restarting TKI in first TFR attempt was 100 days (range 59-315 days). After the restart, median duration to start of combination treatment was 4.1 years (range 1.2-6.8 years). Of 9 patients enrolled, 2 are still in combination phase, and 7 have completed the combination phase and attempted TFR. Among patients who reached TFR (N = 7), the median duration of TKI was 5.5 years (range 2.2-7.7 years) prior to second discontinuation and 7 were on Imatinib. Of the 7 patients who reached second TFR, 5 patients remain in TFR with a median duration of 384 days (range 154-502 days). Two patients restarted TKI at TFR days 63 and 236. The median time from second TFR to restarting TKI has not been reached (95% CI [236, –] days). The most common AEs were diarrhea (N = 4) and fatigue (N = 4). The only grade 3/4 AE was pain in extremity (N = 1, grade 3) and rectal fissure (N = 1, Grade 3). Conclusion: This is the first report of asciminib use to attempt 2nd TFR. The combination was well tolerated, and patients were able to complete the combination phase. Preliminary results suggest feasibility and potential to increase cure for CML. The study is ongoing and updated results will be presented at the meeting.

To evaluate single dose pharmacokinetics (PK) of novel reduced-dose film coated Danziten™ (nilotinib tablets) using a population PK approach, establish bioequivalence vs. Tasigna® (nilotinib capsules) and investigate food effects on PK of both formulations. A population PK model evaluating nilotinib capsules (300 or 400 mg) or tablets (142 or 190 mg) was developed using data from 14 single dose studies and > 30,000 plasma samples from healthy men and women. Steady-state nilotinib concentration–time profiles following twice daily dosing with various treatment and food conditions were simulated using a randomly sampled dataset of 50 subjects. PK was characterized by a 2-compartment model with linear elimination and zero-order absorption with lag time. Bioequivalence was met for all steady state exposure metrics for both doses under fasted conditions. A milligram strength for nilotinib tablets 50

As a key screening test for the NCI myeloMATCH clinical trial, karyotyping detects aberrations at single-cell resolution and uniquely delineates clonal evolution in hematologic malignancies. Its success starts with robust cell culturing methodologies that reveal chromosomal aberrations in dividing cells. While planning for 72-hour turn-around time (TAT) without compromising quality, we evaluated culturing conditions for 139 diagnostic acute myeloid leukemia (AML) and high-grade myelodysplasia (MDS) patient samples from Fred Hutchinson Cancer Center (McClung et al, 2023 JAM). We concluded that 48-hour culture with MarrowMax (48MM) was better than 24-hour cultures, especially for peripheral blood (PB). A similar trend was observed for bone marrow (BM) samples although 48MM appeared less critical. This study aims to evaluate prospectively collected AML/MDS patient samples undergoing karyotype analysis for myeloMATCH as the evidence base to confirm the best culturing condition allowing for rapid TAT. Methods We investigated 249 myeloMATCH specimens from 215 patients [median age 65.6 (Range 18.4 to 95.8); 45% female]. These were sent for diagnostic screening (191 BM and 24 PB) and reassessment (30 BM and 1 PB), together with 3 samples that canceled testing. Culturing conditions tested included media type [RPMI (n=244 ) vs MarrowMax (n=85)] and duration [24-hour only (n=64) vs 24- and 48-hour (n=180)]. To compare the effectiveness of various culturing conditions, we investigated the number of metaphase images captured per slide, the cytogenetic findings from 24- vs 48-hour cultures, and the clinical significance of the additional results contributed by 48MM. Results The 48MM culture improved mitotic index of the sample. The number of metaphase images captured per slide was measured as an indication for the mitotic index. The number of metaphase cells per slide from the 24-hour RPMI culture was set as the reference, where the performance of other cultures was presented as the log 2 value of the ratio of the metaphase cells per slide divided by that of the reference. The 48MM showed improved mitotic index, consistently observed from BM (n=160) with a median log2 ratio of 2.10 (95% CI 1.73-2.33) and PB (n=25, median 2.31, 95% CI 1.28-3.47). Further delineation showed consistent observation from different flask sizes (2.5, 5, 7.5, and 10 F). In 24-hour cultures, MarrowMax is not significantly better than the RPMI for BM (n=222, median=0.95, 95% CI 0.86-1.22) or PB (n=25, median=1.37, 95% CI 0.80-2.32). The 48MM improved success of the study. Karyotype results were compared for samples where analysis for both 24- and 48-hour cultures were attempted (n=184). One sample failed the the 24h cultures but yielded a full study with 20 cells from 48MM. A high number of samples had less than 20 analyzable cells (n=81; 33%) from 24-hour cultures and showed a normal result, including two samples with less than 5 cells for analysis, six with 6-10 cells, 72 with 11-15 cells, and one with 17 cells. Per SWOG cytogenetics guideline, when less than 20 cells are analyzed and the result is normal, the study is considered failure or limited. The 48MM culture yielded more metaphases to analyze and made 79 of the 81 (98%) workups into a full 20-cell study and the remaining two completed with 10 and 17 cells. Furthermore, qualitative assessment indicates 48MM cultures tend to have better chromosomal morphology compared to that of the 24-hour cultures. The 48MM revealed more abnormalities that improved diagnostic yield and produced prognostically significant findings and more thoroughly identified markers for disease follow-up. Two samples changed from normal results at 24h to abnormal from 48MM, representing 0.8% of the specimens. One of these is a reassessment sample that showed inv(3) and -7, key markers of the patient's disease, in one cell from 48MM. Fourteen samples showed additional abnormalities in 48MM compared with the 24-hour cultures, including 12 samples with clonal evolution and two with new independent clones in 48MM. Conclusions Our systematic assessment using the 249 NCI myeloMatch samples demonstrated that the inclusion of 48MM culture produces better quality karyotyping studies for AML/MDS than 24-hour cultures only. We therefore strategize that the 48MM to be incorporated routinely, especially when the 24-hour cultures yield a normal result or an abnormal result with intermediate risk.

Clinical next generation sequencing (NGS) typically relies on limited gene panels run on bulk marrow or blood. Current computational tools for inferring clonal relationships is generally limited by the use of a small panel of pathogenic mutations to define clones. We developed an online software (CloneTracker) that uses ‘incidentally-sequenced’ single nucleotide polymorphisms (SNPs) in the regions of recurrent somatic mutations in addition to conventional mutation data from bulk NGS gene panels to provide detailed visualizations of clonal evolution during cancer treatment, alongside clinical data. Tested on 29 patients who underwent non-myeloablative transplantation for AML, CloneTracker successfully reconstructed the evolutionary dynamics of donor engraftment from bulk NGS and rendered intuitive visualizations of residual patient-derived hematopoiesis and relapsing malignant clones. The software does not require sequencing donor samples, as donor-derived clones are identifiable from post-HCT SNP data. This manuscript aims to introduce CloneTracker to the BMT community and make it available for those who would ascertain its clinical utility, e.g, in BMT trials leveraging molecular minimal residual disease (MRD) monitoring and targeted interventions to pre-empt relapse.

Introduction: MyeloMATCH (mM), is an National Cancer Institute (NCI)-sponsored precision medicine initiative for newly diagnosed AML/MDS. It consists of an initial screening study (Master Screening and Reassessment Protocol, or MSRP) that involves centralized testing of bone marrow/whole blood, leading to assignment into several genetically driven treatment subprotocols within the mM portfolio. MSRP employs karyotype, 8-15 probe fluorescence in situ hybridization (FISH) and NCI-myeloid (NMAv2) assays to determine ploidy, translocations and mutational status needed for accurate disease subclassification, risk stratification as well as for theragnostic determination. NMAv2, a rapid next generation sequencing assay (TAT<48 hrs), interrogates 45 DNA and 35 RNA fusion driver genes to report 1661 hotspot DNA mutations and 779 targeted RNA fusions, including all relevant fusions in AML except Inv3/t(3;3)/MECOM rearrangement (Yeung et al, 2025). The initial mM MSRP workflow relied on karyotype and FISH assay results to identify fusion positive AML/MDS as per the current testing guidelines/ recommendations as well as to abide by the FDA's requirements under the investigational device exemption (IDE). Here we present concordance analysis between karyotype, FISH and NMAv2 assay to identify relevant fusions in AML/MDS. Methods: First 400 participants enrolled in the mM MSRP were included in this analysis. We examined the results from karyotype analysis analyzing 20 metaphase cells, 8-15 probe FISH analyzing 500 nuclei per probe, and NMAv2 curating fusion read counts greater than 100, performed at the mM labs to determine the prevalence of fusions in this cohort. Concordance analysis was performed to determine clinical utility of the NMAv2 assay to report relevant fusions at the time of initial diagnosis. The concordance analysis excluded biomarkers including Inv3/t(3;3)/MECOM rearrangement, KMT2A-PTD and other rare fusions that are beyond the scope of detection by NMAv2 and/or FISH assay. Results: Of the 400 patients analyzed in this cohort (median age 64, [range 20-95]; 43% female; 15.5% non-white; 9.5% Hispanic), translocations/fusions were reported in 67, 73 and 95 patients by karyotype, 8-15 probe FISH and NMAv2, respectively. The karyotypic analysis reported inv(16)/t(16;16) [15], t(11q23) [13], t(9;22) [10], inv3/t(3;3) [9], t(8;21) [6], t(15;17) [5], t(6;9) [4], t(21q22) [3], t(9q34) [1] and t(10;11) [1]. The FISH reported inv(16)/t(16;16) CBFB::MYH11 [15], t(11q23) KMT2A rearrangement [14], t(9;22) BCR::ABL1[10], inv3/t(3;3) MECOM rearrangement [10], t(8;21) RUNX1::RUNX1T1 [7], t(15;17) PML::RARA [5], t(6;9) DEK::NUP214 [5], t(21q22) RUNX1 rearrangement [3], t(11p15.4) NUP98 rearrangement [3], and t(9q34) ABL1 rearrangement [1]. The NMAv2 reported KMT2A-PTD [26], CBFB::MYH11 [15], KMT2A fusion [14], BCR::ABL1[12], RUNX1::RUNX1T1 [8], PML::RARA [5], DEK::NUP214 [5], RUNX1 fusion [4], NUP98 fusion[3], t(9q34) ABL1 fusion [1], PICALM::MLLT10 [1] and ETV6::MECOM [1]. The concordance analysis between NMAv2 and karyotype assay demonstrated positive percent agreement(PPA) of 100%, negative percent agreement(NPA) of 96.81% and overall agreement (OA) of 97.25% when using karyotype as reference. The concordance analysis between NMAv2 and FISH assay demonstrated PPA of 100%, NPA of 98.81% and OA of 99% when using FISH as reference. Of the 12 cases with discrepant results, 7 were due to presence of cryptic translocations missed by karyotype assay, 3 had suboptimal specimen submitted for karyotype/FISH analysis, 1 had false positive BCR::ABL1 fusion reported by NMAv2 due to low level contamination and 1 had minor subclonal population of leukemic blast with BCR::ABL1 fusion detected only by NMAv2. Conclusion: NMAv2 shows high concordance with karyotype and FISH assays which are the most commonly utilized assays to identify fusions/translocations in AML/MDS. NMAv2 is a faster, relatively cheaper and sample conserving method to identify fusions and is less prone to false negative results than karyotype/FISH assay from suboptimal specimen acquisition and testing. Based on the results above, mM MSRP workflow has been amended with FDA concurrence such that a combination of NMAv2, karyotype and MECOM breakapart FISH assay will be used to identify relevant fusion variants in all patients enrolled in mM, whereas additional specific FISH assay will be limited to cases where discrepant results between karyotype and NMAv2 are reported.

Introduction: With the success of tyrosine kinase inhibitors (TKIs) in the treatment of chronic myeloid leukemia (CML), since 2005 far fewer patients routinely undergo allogeneic hematopoietic stem cell transplantation (HCT). Those that do undergo HCT are typically referred in chronic phase (CP) after resistance or intolerance of multiple TKIs, after progression to accelerated phase (AP) or blast phase (BP), or, rarely, after de novo BP presentation. We retrospectively analyzed the outcomes of a single-center cohort of CML patients who underwent HCT to evaluate risk factors affecting overall survival (OS) and relapse-free survival (RFS). Methods: We retrospectively evaluated patients who received HCT for CML in all phases at Fred Hutchinson Cancer Center between 2005 and 2023, following IRB approval. Relapse was defined per 2025 NCCN guidelines. RFS was defined as time from transplant to relapse or death; OS was defined as time from transplant to death. Hazard ratios (HR) were estimated using Cox regression. Results: Over a 19-year period, we identified 135 patients with a median age of 45 years (range 18-74). Fifty-one were in first CP; 26 and 58 had AP or BP prior to HCT, respectively. Fifty-five of the 58 patients with prior BP were in CP on pre-transplant evaluation. Forty-one patients received only imatinib prior to HCT, while 94 had exposure to at least one second-generation TKI prior to HCT. The plurality had a matched-unrelated donor (58; 43%); other donor sources were: matched-related (41), mismatched-unrelated (21), cord blood (10), haploidentical (4), and mismatched-related (1). One hundred twenty-four patients received myeloablative conditioning and 11 had either reduced-intensity or nonmyeloablative preparative regimens. Sixty-four patients received a maintenance TKI after HCT. Thirty-one patients (23%) relapsed after HCT; median time to relapse was not reached. The hazard ratios (HR) for relapse among patients transplanted after AP and those transplanted after BP relative to first CP were 2.34 (95% CI 0.75-7.28) and 3.80 (95% CI 1.51-9.56), respectively. Median RFS was 100 months (95% CI 30-179 months). In univariate analyses of RFS, the HR for failure for recipient positive versus negative CMV serostatus was 1.93 (95% CI 1.14-3.26); BP prior to transplant vs CP HR=1.95 (95% CI 1.14-3.35); and reduced-intensity/non-myeloablative versus ablative conditioning HR=2.28 (95% CI 1.08-4.78). Estimated 10-year OS for all patients was 58% (95% CI 49 – 67%). Median OS was 179 months (CI 100 months – not reached). Estimated 10-year OS for first CP, AP, and BP was 64, 61, and 52%, respectively. In univariate analysis, recipient positive CMV serostatus HR=1.82 (95% CI 1.01-3.29) and reduced intensity or non-myelablative conditioning HR=2.38 (95% CI 1.12-5.05) were associated with higher mortality. Discussion: Long-term outcomes for patients receiving HCT for CML were excellent, with a median RFS of 100 months and median OS of 179 months. Notable risk factors associated with worse RFS or OS were recipient positive CMV serostatus, BP prior to HCT, and reduced-intensity conditioning. Patients who underwent reduced-intensity conditioning were either older or had underlying comorbidities that precluded myeloablative conditioning, which may partially explain poorer outcomes. With the advancement of TKI therapy for CML, patients that do undergo HCT have received multiple TKIs and likely have more aggressive disease biology. It is reassuring that HCT remains an effective potentially curative option for this patient population.

Background: Asciminib, an allosteric inhibitor of BCR::ABL1, has the potential to promote deeper molecular response (DMR) with reduced toxicity in patients with newly diagnosed chronic phase chronic myeloid leukemia (CP-CML). Additionally, asciminib may be combined with low dose ATP-competitive TKIs (lowTKI) to further enhance the depth of molecular response in patients who fail to achieve DMR or do not meet optimal response criteria as defined by the European LeukemiaNet. Methods: This is an ongoing, multicenter phase 2, investigator-initiated, single-arm, open-label study (NCT05143840) within the H Jean Khoury Cure CML Consortium (HJKC3). Patients received either asciminib 40 mg orally twice daily or 80 mg once daily. The primary study endpoint is the rate of MR4 or better at 12 months. Patients who did not achieve MR4.5 after 24 months on asciminib, experienced treatment failure at any time or had a warning response at 12 months were offered the addition of lowTKI (imatinib 300 mg, dasatinib 50 mg or nilotinib 300 mg daily). Patient reported outcomes were collected at multiple timepoints using NIH PROMIS and PRO-CTCAE measures with high rates of completion. With a planned enrollment of 100 subjects, the study is powered at 86% to detect a 13% absolute improvement in the rate of MR4 or better at 12 months from 25% to 38% estimated by the Wald test. Results: Between April 2022 to July 1st 2025, 61 patients were enrolled. The median age was 52 years (range 25-79) and 37.7% were female. Sokal score was low, intermediate, high, and unknown in 20, 18, 5 and 10 patients respectively. With a median follow up of 59 weeks (0-143), 55 (90.2%) patients remained on asciminib treatment. As of this analysis, 12 patients have met the criteria for adding lowTKI: 9 for a warning response, 2 for not achieving a DMR and 1 for failure. Of those 12 patients 7 have started lowTKI. The primary endpoint, MR4 or better at 12 months, was achieved in 41.9%% of patients (3 months 8%, and 29.2% at 6 months). MR3 was achieved in 36%, 60.4% and 74.4% at 3, 6 and 12 months respectively. MR4.5 was achieved in 6%, 12.5% and 25.6% at 3, 6 and 12 months respectively. Grade 1-2 hematologic adverse events (AEs) include anemia (28%), thrombocytopenia (31%), and neutropenia (13%). One patient developed grade 3 neutropenia. Non-hematologic AEs occurring in more than 10% of patients were fatigue (26%), nausea (20%), arthralgia (16%), headache (15%), hypertension (15%), increased CPK (11%), increased lipase (15%), increased ALT (16%), increased AST (13%) and myalgia (15%). Grade 3-4 AEs considered related to asciminib were increased ALT/AST (2%), headache (2%), abdominal pain (2%), flank pain (2%), hyperhidrosis (2%), insomnia (2%), rhabdomyolysis (2%), arthralgia (4%), myalgia (3%), increased CPK (5%), diarrhea (2%), insomnia (2%) pancreatitis (2%) and increased lipase (7%). A total of 6 (10%) patients discontinued treatment. Reasons for treatment discontinuation included grade 3 CPK increase (n=1), grade 3 arthralgia (n=1), grade 3 diarrhea (1), grade 2 nausea (n=1), grade 2 dizziness (n=1), and treatment failure (1). Conclusion: Asciminib monotherapy demonstrated rapid early and deep molecular responses in patients with CP-CML, with a favorable safety profile. Further data will be presented for patients who added lowTKI.

PURPOSE: Patients with acute myeloid leukemia with high-risk cytogenetics in first complete remission (CR1) achieve better outcomes if they undergo allogeneic hematopoietic cell transplantation (HCT) compared with consolidation chemotherapy alone. However, only approximately 40% of such patients typically proceed to HCT. METHODS: We used a prospective organized approach to rapidly identify donors to improve the allogeneic HCT rate in adults with high-risk acute myeloid leukemia in CR1. Newly diagnosed patients had cytogenetics obtained at enrollment, and those with high-risk cytogenetics underwent expedited HLA typing and were encouraged to be referred for consultation with a transplantation team with the goal of conducting an allogeneic HCT in CR1. RESULTS: Of 738 eligible patients (median age, 49 years; range, 18-60 years of age), 159 (22%) had high-risk cytogenetics and 107 of these patients (67%) achieved CR1. Seventy (65%) of the high-risk patients underwent transplantation in CR1 ( P < .001 compared with the historical rate of 40%). Median time to HCT from CR1 was 77 days (range, 20-356 days). In landmark analysis, overall survival (OS) among patients who underwent transplantation was significantly better compared with that of patients who did not undergo transplantation (2-year OS, 48% v 35%, respectively [ P = .031]). Median relapse-free survival after transplantation in the high-risk cohort who underwent transplantation in CR1 (n = 70) was 11.5 months (range, 4-47 months), and median OS after transplantation was 14 months (range, 4-44 months). CONCLUSION: Early cytogenetic testing with an organized effort to identify a suitable allogeneic HCT donor led to a CR1 transplantation rate of 65% in the high-risk group, which, in turn, led to an improvement in OS when compared with the OS of patients who did not undergo transplantation.

Objectives. Most chronic myeloid leukemia (CML) cases occur in low- and middle- income countries (LMICs) with limited or no access to essential tools for CML management and published studies demonstrate a higher CML disease-related morbidity and mortality, especially in younger patients, as compared to patients with higher socioeconomic status. Access to diagnostic testing and medication can radically improve the outcomes of CML patients in LMICs. The Max Foundation has provided tyrosine kinase inhibitors (TKIs) through the Glivec International Patient Assistance Program and Max Access Solutions programs at no cost to eligible patients. Dried blood spots (DBS) are a practical solution that can be carried out with minimal training and readily implemented in settings with fragile health infrastructure. DBS mitigate potential biohazard issues and costs of shipping fresh blood samples to distant laboratories. Cold storage is not required. Previously, we have shown the feasibility of BCR::ABL1 transcript monitoring using DBS including the use of point-of-care assays. We have now developed methods for next-generation sequencing (NGS) from DBS of targets implicated in treatment resistance (e.g., ABL1 tyrosine kinase domain (TKD) mutations), and associated with treatment response (e.g., ASXL1 variants) and disease progression (e.g., ASXL1, RUNX1, GATA2, IKZF1, andBCORL1). Methods. Blood was spotted locally on WhatmanTM 903 Proteinsaver Snap-Apart Cards (Thermo Fisher Scientific Inc., Waltham, MA) with 200 µL blood per card (4 spots, each 50 µL) and then dried. DBS samples from 177 patients from 9 countries were received between November 2019 and June 2024. The QIAamp® DNA Blood Mini Kit (QIAGEN, Hilden, Germany) was used to extract DNA. Two sequencing platforms were used during the study: the Archer VariantPlex® Myeloid panel (75 genes, N=50) and the Genexus OncomineTM Myeloid Assay GX V2 (40 genes, N=133). OEFC rules were set up to filter for any non-synonymous somatic mutations with < 106 population minor allele frequency across three genome population databases (dbSNP, 5000Exome global, and ExAC), as well as variants annotated as pathogenic (Tier I) or likely pathogenic (Tier II) by the VarSome database. The call threshold for pathogenic ABL1 mutations was set at 2%. Otherwise, the call threshold for hotspot variants was set at 5% except for ASXL1 G646Wfs*12 which was set at 10%. Results. The median age was 42 years (range, 18–70 years); 67 patients (38%) were from Africa, 97 (55%) from Southeast Asia, and 13 (7.3%) from Central and South America. ABL1 TKD mutations were identified in 34% of patients (74 ABL1 TKD mutations in 61 patients). The T315I mutation was the most common ABL1 TKD mutation identified (N= 28, 37.8% of mutations). The next most common mutations were E255K/V (N=8), F317L (N=5), and Q252H (N=5). Among 11 patients with multiple mutations, 5 had combinations with T315I (Y253H, M244V, E255K, F317L, and M351T). We identified 89 tier I and tier II gene variants (i.e., strong or potential clinical significance) by NGS in 69 patients including 14 patients with multiple variants. The most frequent gene variants detected were ASXL1 variants (52 variants in 49 (29%) patients). Among 61 patients with ABL1 mutations 27 (44%) had variants in ASXL1 in contrast to 116 patients without ABL1 mutations where 22 (19%) had gene variants in ASXL1. The next most common variants were DNMT3A (6), NF1 (6), RUNX1 (4), and BCOR (3). In univariate analysis the detection of ABL1 mutations, ASXL1 variants, or other gene variants did not correlate with sequencing method, patient age, or region of origin. The presence of pathogenic ASXL1 variants correlated strongly with the presence of any ABL1 TKD mutation and with T315I (P < 0.001). Patients with ASXL1 variants were twice as likely to harbor ABL1 TKD mutations. Conclusions. We have now demonstrated the value of DBS combined with sequencing technologies to detect ABL1 TKD mutations and other leukemia-associated gene variants. These new investigations expand our prior work and demonstrate the use of DBS across the CML clinical care spectrum including diagnostics, monitoring and resistance mutation detection. These methods offer hope of a cost-effective, practical, and sustainable approach for CML care globally. These approaches are also amenable to delineating molecular targets in other hematological malignancies with the goal of improving healthcare accessibility.